December, 2005
(31 Dec) Biotechnology bucks the market trend [the "Big Picture" of 2005]
(30 Dec) 2005 ends with a flurry of deals, positioning for the emerging disruptive PostGenetics business
(29 Dec) Perlegen, Pfizer Pen Four-Year PGx Partnership; Deal Covers IP Rights, Research Payments ["Bidding war" in the offing?]
(28 Dec) Pfizer Buys $ 50 M Stake in Perlegen; 12-Percent Ownership Could Grow If IPO Launched
(27 Dec) Banned in biology [Welcoming Bill Gates]
(24 Dec) Role of MicroRNA Identified In Thyroid Cancer ["PostGenes, PostGene Diseases, PostGenetic Medicine"]
(23 Dec) Cedars-Sinai researchers demonstrate a new way to switch therapeutic genes 'on' and 'off [PostGenetic Medicine is just a turn-on?]
(25 Dec) Breakthrough of the Year [of 1859]: Evolution in Action [What is news? Dog Bites Man, or "Man Bites Dog"?]
(23 Dec) Evolution in Action Highlighted in Science’s "Breakthrough of the Year" [of 1859]
(19 Dec) Civilisation has left its mark on our genes [correction, on human Genome]
(17 Dec) Probing Connection Between Regulatory DNA And Disease [ NEW TOOLS ARE NEEDED]
(19 Dec) GTG/GENE stock holds steady - what's next?
(16 Dec) Plan matures for partner to genome quest. Forget mutations: geneticists are hunting for subtler changes to DNA [Methylation].
(16 Dec) Genetic wins little fight over DNA work ["Junk" DNA is cheap or it is still an incredible bargain?]
(15 Dec) GTG Provides Further Details of the Settlement with Applera
(14 Dec) New Effort Aims to Unlock Secrets of Cancer Genes ["Don't blame me, I joined 'PostGenetics', focusing on 'Junk DNA' diseases"]
(13 Dec) [Hold it! - there is more to 'Junk DNA Industry'. Further announcement regarding GTG / APPLERA settlement]
(12 Dec) [Now it is official - The "Junk DNA Intellectual Property value proposition is forever validated"]
(10 Dec) [Half a Billion Dollars from Bill Gates for] Anti-Malaria Donation [Maybe software would help more directly?]
(09 Dec) Barking up new trees in search for cures [ALERT! The secret of your illness may well be in the 'junk' DNA"]
(09 Dec) Veil of secrecy "costs" GTG/GENE a 10% drop in stock price on a single day
(08 Dec) Man's best friend shares most genes with humans: [Triple whammy - time sobering up!]
(06 Dec) 'Junk DNA' Stock of GTG [NYSE symbol "GENE"] jumps 8.47% on a single day anticipating settlement tomorrow
(05 Dec) Further Update regarding Applera Dispute - [Court allows one more workday to settle with "GENE"]
(01 Dec) Startup Haplomics to Muscle In on Gene-Testing Market
(01 Dec) MicroRNA may have fail-safe role in limb development
(01 Dec) SETI and Intelligent Design
(01 Dec) Treasures in the Trash [Forbes Magazine]

November, 2005
(28 Nov) The elusive fountain of youth
(27 Nov) Rosetta Genomics' Isaac Bentwich: "Dark DNA" may be even more important than active genes in causing disease
(25 Nov) The earliest animals had human-like genes
(24 Nov) GTG and APPLERA ask Court time till 5th of December to finalize Junk DNA patent settlement
(19 Nov) Oops - the price of junkDNA just took off ... "junk DNA" is the word ...
(11 Nov) Further update regarding 'Junk DNA on Wall Street' (GTG settles with Applera) - an analysis
(09 Nov) JunkDNA made it to Wall Street - GTG earmarked to escalate to a $ 2 Billion business alone
(07 Nov) "Stipulated Revised Case Schedule and Order" on GTG website GTG, Applera Look to Be Nearing Settlement
(02 Nov) The American Heart Association donated about $1.23 M to fund University projects

October, 2005
(27 Oct) NHGRI's Collins Says US Must Launch Its Own Biobanking Project
(27 Oct) The Role of Junk DNA in Social Behavior
(20 Oct) Study: Junk DNA is critically important
(17 Oct) METHYLATION HYPOTHESIS OF FRACTOGENE;Predictive Scientific Theories on the Function of 'junk DNA'
(17 Oct) "Taxpayer Alert": Large-scale Sequencing Research Network Sets Its Sights On Disease Targets
(12 Oct) Smoking chimps show similarities to humans
(05 Oct) The greatest discovery of all time ("ET joins ED")
(04 Oct) Harmful Mutations Selectively Eliminated

September, 2005
(28 Sep) Experimental support of the FIRST PREDICTION OF "FRACTOGENE accepted for publication (in Press)
(26 Sep) New Analyses Bolster Central Tenets of Evolution Theory
"You only believe theories when they make predictions confirmed by scientific evidence"
(26 Sep) NIH Launches Program to Study Genetics and Genomics of Xenopus
(26 Sep) Search for genetic origins of disease
(23 Sep) There is more to non-coding DNA than meets the eye
(13 Sep) Rosetta Genomics raises $ 6 M in fourth round
(05 Sep) Importance of 'junk' DNA found
(05 Sep) Junk RNA Begins To Yield Its Secrets

August, 2005
(31 Aug) Scientists find chimps, people are 96 percent identical; San Jose Mercury News
(31 Aug) 'Life code' of chimps laid bare: BBC
(31 Aug) What does the fact that we share 95 percent of our genes with the chimpanzee mean? Sci. Am.
(31 Aug) Sisters under the skin; The Economist
(31 Aug) Study_compares_human_and_chimpanzee_DNA; Nature News
(31 Aug) Reading the chimp book of life; BBC
(31 Aug) Scientists find missing links in chimp genome; Guardian
(19 Aug) Genetic Efficiency and the Carbon Cycle; New Scientist

July, 2005
(30 Jul) Newsweek on JunkDNA
(14 Jul) Genomics study highlights the importance of junk DNA in higher eukaryotes
(04 Jul) The most successful business model of California Gold Rush - *toolmaking*

June, 2005
(29 Jun) Venter launches Synthic Genomics; Bacterium to generate hydrogen
(23 Jun) Junk DNA on National Television - "Extra DNA Makes Voles Faithful"
(21 Jun) Rosetta Genomics identifies hundreds of novel human microRNAs
(20 Jun) Founders of "The Human Genome Project" are ready to "re-thinking it all"... The Uncertain Future for Central Dogma
(16 Jun) The Economist: Helpful junk
(16 Jun) Rodent Social Behavior Encoded in Junk DNA

May, 2005
(31 May) Affy to Buy ParAllele for $ 120 M in Stock; Deal Expected to Close in Q3
(31 May) Agilent, Rosetta Biosoftware to Integrate Gene Expression Analysis Software
(27 May) Biochemistry Graduate Student Receives UCR Award for Outstanding Research
(30 May) Israel’s Rosetta Genomics - Cracking the RNA Code
(25 May) Agilent to Acquire Informatics Company Scientific Software for Undisclosed Amount
(22 May) Israel's Rosetta Genomics - cracking the RNA code
18 May) Debating the Merits of Intelligent Design
(18 May) Gene researchers find variations by ancestry

February, 2005
(14 Feb) New Theory of Life's Digital Complexity
(07 Feb) Power tools for the gene age - Affymetrix chips digging deeper into the genome

January, 2005
(27 Jan) Scientists Find Genome Structure Responsible for Gene Activation
(20 Jan) Highly Conserved Non-Coding Sequences [Submitted by IPGS Founder M. Achiriloaie]
(19 Jan) Scientists Decipher Genome Of Bacterium That Helps Clean Up Major Groundwater Pollutants
(14 Jan) Study finds more than one-third of human genome regulated by RNA [Affymetrix]
(14 Jan) Fujitsu BioSciences Licencses BioMedCAChe to GPC Biotech; New Version Due This Quarter
(07 Jan) Pharmacogenomics to Benefit from Steven Burrill's New $ 300 M - $ 500 M Life Sciences Venture Capital Fund
(05 Jan) Agilent Acquires Computational Biology in Bid to Expand Microarray Platform
(07 Jan)
Pufferfish genome clue to human and animal development
Affy Says Sales Surpassed $100 M in Q4 '04, a 17-Percent Increase
(05 Jan) Shares in Affymetrix Jump 6.95 % on News of Record Sales Growth

Biotechnology bucks the market trend [the "Big Picture" of 2005]

By Justin Gillis / The Washington Post /

Saturday, December 31, 2005

WASHINGTON — Shares of the nation’s largest biotechnology companies are trading at or near record levels as the year comes to a close, a payoff for investors in companies that have been putting intensive focus on cancer and other hard-to-treat diseases over the last few years.

The American Stock Exchange biotechnology index, which tracks some of the largest companies in the industry, hit a five-year high during the trading day Tuesday, powered by optimism over recent or impending treatment approvals at the Food and Drug Administration. Shares of the industry’s bellwether company, Genentech Inc., hit their highest point ever earlier this month, though they’ve pulled back a bit since then.

Analysts said the large biotech companies, which include Genentech and a handful of other big names, such as Amgen Inc. and Gilead Sciences Inc., are beginning to replace traditional pharmaceutical stocks in the holdings of many investment funds that want a piece of the growing health care market.

The strong performance is largely confined to the high end of the biotech industry — the companies that have put blockbuster drugs on the market and have grown into vast enterprises with thousands of employees and drug factories humming night and day.

The Amex index, which tracks the performance of these companies, is up 110 percent since bottoming out in mid-2002, compared with an increase of 30 percent over the same period in the Standard & Poor’s 500-stock index. For 2005, the biotech index is up 25 percent, while the broader market, as reflected by the S&P 500, rose a mere 4 percent.

By contrast, a separate index that reflects the share prices of smaller biotech companies, the Nasdaq Biotech Index, has essentially mirrored the broader market, up about 3 percent for the year.

The traditional drug industry hit a rocky patch this year: Merck & Co., once the world’s most respected drug company, is defending itself against a slew of lawsuits claiming it hid safety problems with its Vioxx painkiller. And the next couple of years don’t look much brighter for the big pharmaceutical companies, with numerous drug patents due to expire, potentially costing the industry billions of dollars in revenue.

“The Mercks and Pfizers are no longer unlimited growth machines,” said John McCamant, editor of the Medical Technology Stock Letter in Berkeley, Calif. “Interestingly enough, it looks like Amgen and Genentech are. We’ve had a changing of the guard.”

The century-old drug industry has historically used chemical techniques to discover its products, whereas the 30-year-old biotechnology industry has used genetic techniques. The latter approach is paying off for the leading companies, with a string of spectacular drugs for cancer and other tough diseases coming to market recently. And the companies have managed to sell them at extraordinary prices, sometimes exceeding $50,000 a year for each patient.

The split between big companies, with their rising stock prices, and smaller fry, with nearly flat prices, was reflected not only on the national scene but also in the Washington region.

MedImmune Inc., of Gaithersburg, Md., with an important preventive drug for respiratory disease in babies, was up 29 percent for the year, closing Thursday at $35.04. By contrast, Human Genome Sciences Inc., a Rockville, Md., company that gets plenty of publicity but has yet to put a drug on the market, was down 31 percent for the year, closing Thursday at $8.32.

Genentech, of South San Francisco, Calif., was the first biotech company, founded in 1976. It struggled for years, but recently has been on a roll. Genentech now sells the world’s top-selling cancer drug, Rituxan, and a recently-approved Genentech cancer product, Avastin, looks set to surpass it.

Genentech revenues are approaching $7 billion a year. An old-line pharmaceutical company, Pfizer Inc., takes in more than that from Lipitor, the world’s best-selling medicine. But Genentech is growing faster, and long-term growth potential seems to be what health care investors are looking for.

“Genentech had an incredible year as the company nailed one positive clinical trial after another in what is the best string of positive trial news we have ever seen in the biotech industry,” McCamant wrote in a recent edition of his newsletter.

The company’s stock is riding so high, in fact, that some investment professionals are worried. Morningstar Inc., the independent research firm, pegs “fair value” for Genentech shares at $70, compared with Thursday’s close of $92.06, and Morningstar rates the stock as a sell at current prices. “Genentech has had a long and impressive streak of good fortune, but drug development is probability-based, and odds are that the company will witness a setback at some point,” Morningstar analyst Jill Kiersky wrote recently.

Some analysts have a similar concern about the broad market in biotech shares. Merrill Lynch, Pierce, Fenner & Smith Inc. warned investors in a recent report that with many new cancer drugs coming to market, competition is stiffening. “The increasing availability of new cancer drugs to treat a variety of cancers is great for patients, but the market is becoming more crowded and it is becoming more difficult” to design convincing studies that can supplant previous treatment regimens, the brokerage house said.

McCamant has been urging his readers to focus their investments on smaller, undiscovered biotech companies with potentially valuable products under development. He figures that small companies will have more room to run in 2006. “You’re looking at an industry that can’t be judged with a rearview mirror, because it’s moving forward so fast,” he said.

[The "Big Picture" for 2005 was definitely the more than six-fold catapult of "Biotech" over "S&P 500". Within that, the shift to "PostGenetics - PostGene Diseases (Cancers) - PostGenetic Medicine (PostGenetic Oncology)" as the prevailing new Business Model for Big Pharma is clear. 2006 will be a tumultuous year - comment by A. Pellionisz, 31st of December, 2005]

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Affy Shares Climb 7.8 Percent on S&P 400 Listing
By a GenomeWeb staff reporter

NEW YORK, Dec. 28 (GenomeWeb News) - Shares in Affymetrix were up 7.8 percent, or $3.41, at $47.12 in mid-afternoon trading today after Standard & Poor's said it will add the company to its S&P 400 Index.

ABI Licenses Affy Microarray Patents for Gene Expression Analysis

By a GenomeWeb staff reporter

NEW YORK, Dec. 22 (GenomeWeb News) - Applied Biosystems has licensed "a number" of Affymetrix patents "related to the manufacture, sale, and use of microarrays for gene expression analysis," the companies said today.

Applera, the parent company of Applied Biosystems, has taken a non-exclusive, worldwide license to the patents.

ABI said that it will use the licenses to expand its Expression Array system and to enable customers "to use that system for gene expression, research and development purposes."

The companies did not disclose further details of the licensing agreement.

ABI's Decision to License Affy's Array IP Tops Most-Read GenomeWeb News Stories Last Week

By a GenomeWeb News editor

NEW YORK, Dec. 27 (GenomeWeb News) - What are GenomeWeb News subscribers reading? Below are the five most-read articles for the five-day period ended Friday, Dec. 23.

ABI, Continuing Pledge to Grow Consumables, Plans to Acquire Ambion’s RNA Business for $273M in Cash

By a GenomeWeb News staff reporter

NEW YORK, Dec. 27 (GenomeWeb News) - Applied Biosystems plans to acquire Ambion's research products division for around $273 million in cash, the companies said today.

With the acquisition, ABI gains entry into the consumables market for sample prep, RNAi, microRNA, and gene expression and array products.

"This acquisition is an important component of Applied Biosystems' strategy to drive growth by expanding our consumables product offering," Cathy Burzik, president of ABI, said in a statement today.

The deal, which is subject to regulatory and other condition, is expected to close in the first quarter of 2006.

The business ABI hopes to acquire develops and supplies consumables for stabilizing, synthesizing, handling, isolating, storing, detecting, and quantifying RNA. New products include microRNA and siRNA reagents used to study mechanisms of gene expression.

The market in which this business plays is believed to be around $500 million market and grows more than 10 percent annually, according to ABI. Independent figures could not immediately be obtained.

Ambion's diagnostics and service businesses will become a separate standalone company, Ambion said.

According to ABI, Ambion stands to generate more than $52 million in revenue in 2005, which would be a 22-percent improvement over last year's receipts.

Founded in 1989, Ambion's research division has approximately 300 employees. Ambion's research and development, manufacturing, and other operations will continue to be based in Austin, Texas, and report to ABI's molecular biology division.

[Business analysis on PostGenetics is available by appointment - A. Pellionisz, 30th of December, 2005]

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Perlegen, Pfizer Pen Four-Year PGx Partnership; Deal Covers IP Rights, Research Payments

By a GenomeWeb News staff reporter

NEW YORK, Dec. 28 (GenomeWeb News) - Perlegen Sciences and Pfizer have penned a four-year alliance to study whole genomes in an attempt to identity genes linked to undisclosed diseases and drug response, the companies said today.

The announcement, which comes one day after Perlegen disclosed Pfizer bought a 12-percent stake in it for $50 million, calls for researchers from both companies to conduct whole genome studies involving DNA samples from clinical trials. Perlegen will genotype the samples using Affy arrays.

Additional terms of the agreement between Perlegen and Pfizer call for the firms to share "certain" intellectual property rights that could result from the collaboration. Pfizer will provide research payments to Perlegen.

["Whole genomes" is a code-word to include "junk" DNA. In this seemingly "small news" (amounting to half the market cap of GTG) there are several "tell-tale signs". First, it is most unusual to "rush" such a deal in the last days of the year. Second, and more important, if Applera set its eyes on M/A with GTG (even to the limited extent of 25% that GTG Jacobson publicly announced) - Applera is not "the only game in town, anymore". It has become evident that the formerly "controversal, academic" issue of "junkDNA" is now a linchpin in the entirely new business model, replacing the dead "One Gene - One Disease - One Billlion Dollar Pill" paradigm by the "PostGenetics - PostGene Diseases - PostGenetic Medicine" paradigm of the 21st Century. Thus (leapfrogging expectations that "Junk" DNA will be picked up by "Big Information Technology" - although given Bill Gates' comment of yesterday it is not excluded at all), the "Gold Rush" may happen (or have happened already) by "Big Pharma" rushing to "cut their fundamental deals". Since "Big Pharma" was slowed on their track by the old business model becoming obsolete at least since 2003 and "PostGenetic Medicine" carries a price tag as big or even bigger than "Information Technology" (in which both Apple and Microsoft are sort of becoming "entertainment companies" with iPod/Pixar and X-box). With a looming "bidding war" by Applera/Pfizer (with Merck not far behind...) and possibly "Big IT" cutting in (since neither Genome of Big Pharma companies are geared to develop "the Microsoft of PostGenetics"), no wonder that GTG ("GENE" in NYSE) oscillates widely, with ten times of the volume of 3-month average trading. While for shortness of time and Holiday Season it is unlikely that GTG is already pondering over written offers in a "bidding war", the jittery Wall Street may know something that most people don't. - Business analysis is available by appointment. - Comment by A. Pellionisz, 29th of December, 2005]

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Pfizer Buys $50M Stake in Perlegen; 12-Percent Ownership Could Grow If IPO Launched

By a GenomeWeb staff reporter

NEW YORK, Dec. 27 (GenomeWeb News) - Pharmaceutical giant Pfizer invested $50 million in Perlegen Sciences, the private biotechnology company disclosed today.

The equity investment, in the form of preferred stock, gives Pfizer 12-percent ownership in the company.

If Perlegen executes an initial public offering in 2006, Pfizer has agreed to purchase up to an additional $25 million worth of stock in the company, Perlegen said.

The investment follows their first research collaboration, begun in December 2002, when Pfizer used Perlegen's DNA sample preparation, high-resolution SNP genotyping, and data-analysis capabilities.

Affymetrix, Maverick Capital, CSK Ventures, and Eli Lilly have stakes in Perlegen.

[The new paradigm of "PostGenetics - PostGene Diseases - PostGenetic Medicine" (replacing the "One Gene - One Disease - One Billion dollar pill" old paradigm) is working. Perlegen was the first significant US Genome company that took out a "non-coding DNA" licence from GTG (they were #4 from the now 24). Pfizer and Eli Lilly are obviously positioning for "PostGenetic Medicine" by buying deeper and deeper into Perlegen. No wonder that the GTG ("GENE" on NYSE) jumped on the news by 4.29% today in Wall Street. This is just the beginning - keep watching... - Comment by A. Pellionisz on 28th of December, 2005]

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Banned in biology

By Tom Bethell
December 26, 2005

Evolutionists are ecstatic about U.S. District Judge John E. Jones's ruling in the Dover, Pa., school board case, claiming it is a major setback for the intelligent design movement. The judge declared intelligent design cannot be so much as discussed in biology classrooms in area public schools -- a prohibition giving rise to free-speech concerns. Intelligent design is a "mere relabeling of creationism," he said.

But it is doubtful this ruling is even remotely a setback for intelligent design. For decades, the judiciary has dealt these "setbacks" to any and all critics of evolution. In that time, the intelligent design movement, which began perhaps 20 years ago, has gone from strength to strength.

If it had been advanced courtesy of the public schools, the judge's ruling would indeed have been a setback. But the schools had nothing to do with it. Intelligent design has gained adherents because a sizable number of Americans are capable of reading and thinking for themselves.

The best-known advocates of intelligent design have not attempted to advance their cause through state coercion in the schools. They understand how counterproductive such a strategy can be. Liberalism got a bad name to the extent that legislatures and courts tried to make it compulsory and its rivals illegal. The leading institutional supporter of intelligent design, the Discovery Institute in Seattle, issued a public statement after the judge's ruling, saying it "continues to oppose efforts to mandate teaching about the theory of intelligent design in public schools."

Discovery had opposed the original school board's mandating a brief statement in favor of intelligent design to be read to ninth-grade biology students. It is that school board action that was declared unconstitutional by the judge.

Attempts in the 1980s to legislate "balanced treatment" of life's origins were Bible-based and could legitimately be called "creationist." All were struck down, eventually by the Supreme Court. But contrary to Judge Jones's ruling, arguments that incline people to accept intelligent design are scientific, and to that extent, appropriate to the science class. They deal with such matters as the complexity of organisms at the cellular and microcellular level, the paucity of the fossil record, which has not revealed the transitional forms Darwinians anticipated, and the feebleness of the Darwinian mechanism of evolution ("the survival of the fittest.")

Still, this doesn't explain why design-based theories have gained so much traction in recent years. Perhaps the most important reason has been overlooked. The rise of computer science and information technology has caused many intelligent people not just to think about issues of design and the difficulties involved.

Software designers understand how precisely such information must be specified. There is no room for error. Yet each cell of the body contains a DNA chain of 3 billion nucleotides, encoded in such a way it specifies construction of all the proteins.

No one knows the source of this code or how it arose. It cannot have been by accident, but accident is the only method available to the evolutionists, who believe as a matter of dogma that early life arose from the random collision of atoms and molecules and nothing else.

It used to be said most of the DNA is "junk," because it didn't seem to do anything useful. But leading genome scientists such as Francis Collins of the National Human Genome Research Institute no longer believe that. And Microsoft's Bill Gates has said DNA "is like a computer program, but far, far more advanced than any software we have created."

The British philosopher Antony Flew said a year ago he was emboldened to turn away from atheism because he saw the implications of the structure of DNA. The cell itself, thought in Darwin's day to be a "simple little lump of protoplasm," is now understood to have the complexity of a high-tech factory. There are 300 trillion cells in the human body, and each "knows" its function. Cell biologists do not know how these things happen, or how they arose.

In recent weeks, I have been on many talk-radio programs, discussing my book "The Politically Incorrect Guide to Science," which includes chapters on evolution and intelligent design. What I can attest from this experience is that intelligent design arouses passionate reactions -- on both sides of the issue. The phone-banks light up, as talk show hosts tell me. People are intensely interested, and (to the dismay of some professionals in the field) they feel entitled to have an opinion and express it.

I dare say not one of these people developed their interest in public school. This interest will surely only increase in the years ahead. If the Pennsylvania case acts as a precedent, students in public schools will not be allowed to learn about these things in biology. But when did such prohibitions ever work?

Some students are already sure to be thinking: "What is it in biology that we are not allowed to be taught?" Books banned in Boston notoriously became best-sellers, and design banned from biology will resurface in computer studies. Or is Bill Gates to be relabeled a closet creationist?

[Ladies and Gentlemen, Please welcome Bill Gates to the league of "Big IT" "movers and shakers" to play a difference in "decoding 'junk' DNA in PostGenetics...

Dear Bill Gates, since no software was ever produced without an algorithmic basis, one imagines that you'd surely like to get some "news" of algorithmic, scientific (predictive and thus refutable, but already experimentally supported) mathematical theory of DNA - including "junk" (Genome now called Genes and PostGenes). Yes, FractoGene can lead to the "Microsoft of PostGenetics". Forget the pseudo-debate if such algorithms, e.g. e=mc^2 or z=z^2 + C are "intelligent designs" or "wonders of nature" - let's just get on with the business we know. - Comment by A. Pellionisz, 27th of December, 2005]

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Role Of MicroRNA Identified In Thyroid Cancer

The presence of only five tiny strands of RNA is enough to clearly distinguish cancerous thyroid tissue from otherwise normal tissue, scientists say.

The findings provide more evidence that an emerging set of RNA genes called microRNA (miRNA) is a powerful regulatory force in the development of cancer and other diseases. The study is published online in the Dec. 19 Proceedings of the National Academy of Sciences.

Scientists already know that some people inherit a predisposition to developing papillary thyroid cancer (PTC), the most common form of thyroid cancer, representing about 80 percent of all cases. Although changes in key cell-signaling systems and gene translocations are sometimes present in thyroid tumors, no specific gene mutations have yet been identified that are directly linked to the predisposition of this type of cancer.

That led researchers in The Ohio State University Comprehensive Cancer Center to conclude that while genetic mutations may indeed cause some people to be more likely to develop PTC than others, the mutations may not occur often enough to be readily detectable. They hypothesized that any predisposition to PTC might be more reasonably linked to a more subtle, complex interaction among several genes – suggesting a possible role for miRNAs.

MiRNAs are smidgens of genetic material no longer than 22 or so nucleotides in length. A gene, in comparison, can be tens of thousands of nucleotides long. Scientists used to think miRNAs were parts of long stretches of functionless, “junk” DNA in the genome. But Dr. Huiling He, a research scientist in the Human Cancer Genetics Program at Ohio State and the lead author of the study, says researchers are now beginning to understand how important they may be.

The identification of miRNA ‘signatures’ in cancer and other diseases has really changed the way we think about the process of malignant growth,” says He.

Old dogma held that a gene carries a recipe for a molecule of messenger RNA which, in turn, carries a blueprint for the creation of a particular protein. Any mutation in the gene could affect the production of the protein. But recent studies have shown that protein production can also be manipulated indirectly through miRNAs.

“MiRNAs can latch on to part of the messenger RNA and scramble its ability to properly carry out its original coding instructions,” says He.

Under the direction of Dr. Albert de la Chapelle, a professor in the department of molecular virology, immunology and medical genetics at Ohio State, He and other researchers examined samples of malignant tissue from 15 patients diagnosed with PTC and compared them with normal appearing tissue adjacent to the tumors.

They found 23 miRNAs that were significantly altered in the cancerous tissue when compared with the normal samples, with three of the miRs – miR-146, miR-221 and miR-222 – dramatically overexpressed, or “turned on,” registering 11-to-19-fold higher levels of expression in the tumors than in the unaffected tissue nearby.

Further investigation revealed that two additional miRs – miR-21 and miR-181a – when coupled with the three that showed dramatic overexpression, formed a “signature” that clearly predicted the presence of malignant tissue.

“We also discovered miR-221 expression in all of the apparently normal tissue of the patients with PTC, but it was significantly overexpressed in a subset of three of the samples, suggesting that increased activity of miR-221 may be one of the earliest signs of carcinogenesis,” says de la Chapelle.

Some scientists believe miRNAs act like oncogenes, molecules that promote cell growth, and they also feel they may be tumor and tissue specific. For example, in many other forms of cancer, miRNA activity is suppressed, but in PTC, researchers found just the opposite: 17 of the 23 miRNAs they discovered were overexpressed.

According to the American Cancer Society, the incidence of thyroid cancer has been increasing slightly over the past several years. It estimates that about 25,000 new cases will be diagnosed in the United States this year.

“This is just the beginning of our work identifying the role of miRNAs in thyroid cancer,” says He. “But we are encouraged by these findings. We feel that they help point the way toward new options in diagnosis and treatment for this disease.”

A grant from the National Institutes of Health supported the research team, which included Drs. Krystian Jazdzewski, Wei Li, Stefano Volinia, George Calin, Carlo Croce and Chang-gong Liu, all of the Ohio State Human Cancer Genetics Program; Dr. Saul Suster, from OSU’s department of pathology; Dr. Richard Kloos from OSU’s departments of internal medicine and radiology; Rebecca Nagy, a genetic counselor in the Human Cancer Genetics Program; Sandra Liyanarachchi, a biostatistician in the Ohio State Human Cancer Genetics Program; and Dr. Kaarle Franssila, from the department of pathology at Helsinki University Central Hospital, Finland.

[2005 the year in which the "One Gene - One Disease - One Billion dollar pill" dogma was replaced by the "PostGenes - PostGene Diseases - PostGenetic Medicine" paradigm - comment by A. Pellionisz, 24th of December, 2005]

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Cedars-Sinai researchers demonstrate a new way to switch therapeutic genes 'on' and 'off'

Novel signaling system may eventually help make gene therapies more effective

A gene therapy research team at Cedars-Sinai Medical Center has developed a new method of signaling therapeutic genes to turn "off" or "on," a mechanism that could enable scientists to fine-tune genetic- and stem cell-based therapies so that they are safer, more controllable and more effective.

Although other similar signaling systems have been developed, the Cedars-Sinai research is the first to give physicians the flexibility to arbitrarily turn the gene expression on or off even in the presence of an immune response to adenovirus, as would be present in most patients undergoing clinical trials. This has been a major obstacle in bringing the testing of genetic therapies to humans in a clinical setting.

As reported in a study published in the January issue of the Journal of Virology, the development of a new delivery system that can more effectively regulate therapeutic gene expression has important implications for efforts to advance gene and stem cell therapy strategies that may ultimately be used to treat life-threatening neurodegenerative diseases in the clinical setting. The study, which involved laboratory rats, focused on the area of the brain that has already been the target for research into genetic therapies for Parkinson's disease.

"Since some diseases treated with gene therapy will require constant therapeutic expression while others may have periods of remission and therefore only require treatment during 'active' disease states, a system that can more closely monitor the 'how much' and 'when' the therapeutic gene is produced is a critically important tool in the development of gene therapy treatments that could help people suffering from Parkinson's and other diseases," said Maria Castro, Ph.D., co-director of the Board of Governors' Gene Therapeutic Research Institute at Cedars-Sinai and lead author of the study.

"Until now, researchers working to develop successful gene therapy for diseases such as Parkinson's have hit roadblocks such as toxic side-effects from over-expression of the therapeutic gene, and adverse events caused by immune system reactions to the viral delivery systems currently used to deliver the therapeutic genes," said Pedro Lowenstein, M.D., Ph.D., co-director of the Institute and co-author of the study. "Now, we've engineered a genetic switch in a novel gene transfer vector that will overcome those barriers and set the stage to allow the next phase of research to occur."

Gene therapy is an experimental treatment that uses genetically engineered viruses (vectors) to transfer therapeutic genes and/or proteins into cells. As in a viral infection, the viruses work by tricking cells into accepting them as part of their own genetic machinery. To make them safe, scientists remove the viral genes that cause infection and engineer them so that they stop reproducing after they have delivered the therapeutic gene.

In this study, researchers created a genetic switch system that is turned on in the presence of the antibiotic tetracycline. Therefore, if this method is tested eventually in humans, patients would need to be given this antibiotic before they begin gene therapy treatment. The switch system also produces a protein called silencer, which completely shuts down gene expression in the "off" state, thereby preventing leakage of the therapeutic gene when it is no longer needed. According to Castro, this novel vector system is much less likely to create an undesirable immune response in the host and would still be functional in the presence of an infection to wild type adenovirus (a non-engineered virus that causes conjunctivitis and upper respiratory tract infections) as is present in a high percentage of patients undergoing clinical trails. These are the main hurdles that needed to be overcome before gene therapy can be considered a safe and efficacious clinical strategy.

According to Drs. Castro and Lowenstein, the next step in the development of this new signaling system is to activate the newly developed genetic switch to actively express compounds that are known to be effective at reversing the symptoms and rescuing the damaged neurons in Parkinson's disease patients. Researchers hope to begin a Phase 1 clinical trial in humans in the near future.

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Breakthrough of the Year [of 1859]: Evolution in Action [What is news? Dog Bites Man, or "Man Bites Dog"?]

Friday, December 23 2005
Elizabeth Culotta and Elizabeth Pennisi


Equipped with genome data and field observations of organisms from microbes to mammals, biologists made huge strides toward understanding the mechanisms by which living creatures evolve.

The big breakthrough, of course, was the one Charles Darwin made a century and a half ago.

By recognizing how natural selection shapes the diversity of life, he transformed how biologists view the world. But like all pivotal discoveries, Darwin's was a beginning. In the years since the 1859 publication of The Origin of Species, thousands of researchers have sketched life's transitions and explored aspects of evolution Darwin never knew.


Evolution in Action


Biologists have often focused on coding genes and protein changes, but more evidence of the importance of DNA outside genes came in 2005. A study of two species of fruit flies found that 40% to 70% of noncoding DNA evolves more slowly than the genes themselves. That implies that these regions are so important for the organism that their DNA sequences are maintained by positive selection. These noncoding bases, which include regulatory regions, were static within a species but varied between the two species, suggesting that noncoding regions can be key to speciation.

That conclusion was bolstered by several other studies this year. One experimental paper examined a gene called yellow, which causes a dark, likely sexually attractive, spot in one fruit fly species. A separate species has the same yellow gene but no spot. Researchers swapped the noncoding, regulatory region of the spotted species' yellow gene into the other species and produced dark spots, perhaps retracing the evolutionary events that separated the two. Such a genetic experiment might have astonished and delighted Darwin, who lamented in The Origin that "The laws governing inheritance are quite unknown." Not any longer.

[With 2005 coming to an end, one might wonder what was really "news" for this year. Claiming Evolution as a "breakthrough" for 2005, when it actually - admittedly! - happened 147 years ago is perhaps not the biggest masterpiece of Science journalism. While "Science" hid the actual news (non-coding DNA) so well, wrapped into "politics of Evolution", this article above by Culotta and Pennisi at least "calls a spade a spade": The real news in 2005 was "junk" DNA stepping forward to PostGenetics. It would have been nice to show some actual "breakthrough laws governing inheritance" emerging in 2005, assuming that their status is not unknown "any longer". What exact (new) "laws" do the authors refer to for the functioning of "noncoding" DNA?  Did some scientific (predictive and thus refutable) theory on "junk" DNA become experimentally supported in its first prediction - and its second prediction was formulated for refutation/support? It looks like the experimentally found fact that the "colors" were not determined by the "genes", but rather, by "PostGenes" (formerly, "Junk" DNA) was not predicted at all by Darwin(ists), since Darwin himself would have been "astonished"! In general, most Darwinists were outright wrong about "predicting" that "junk" DNA was just that (doing nothing). Thus, the true news for Evolution is not when it "beats" non-scientific (experimentally not refutable) theories, but when it comes up with any scientific theory with specific prediction(s) - already supported by experimentation. Comment by A. Pellionisz, 26th of December, 2005]

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HHMI Research on Evolution in Action Highlighted in Science’s "Breakthrough of the Year"

December 23, 2005

The journal Science has announced that the scientific “Breakthrough of the Year” is evolution in action. Recent experiments by four HHMI investigators were among those mentioned by Science as having provided evidence of evolution in action during the past year.

“It's been a great year for understanding how evolution works, through both experiment and theory. No single discovery makes the case by itself; after all, the challenge of understanding evolution makes multiple demands,” stated Science editor-in-chief Donald Kennedy in an accompanying editorial.

The research on evolution and nine other research advances make up Science's list of the top 10 scientific developments in 2005, chosen for their profound implications for society and the advancement of science. The Top Ten list appears in the December 23, 2005, issue of the journal Science.

In citing recent studies on evolution, Science highlighted recently published research from HHMI investigators Sean Carroll at the University of Wisconsin, Madison, David Kingsley at Stanford University, Bruce Lahn at the University of Chicago and Christopher Walsh at Harvard Medical School.


Christopher A. Walsh

Humans evolved in the most recent few moments of evolution's grand pageant. The evolutionary lineage leading to humans split off from the lineage leading to chimpanzees some 6 to 8 million years ago. But anatomically modern humans—people who looked as we do today—appeared only about 150,000 years ago (less than one three-thousandth of the time between us and the Cambrian period).

The lineage leading to humans obviously underwent profound changes since the time of our common ancestor with chimps. HHMI investigator Christopher A. Walsh at Harvard Medical School has been studying those changes in the brain.

Walsh points out that three genetic mechanisms could have caused the human brain to diverge from the chimpanzee brain. New genes may have been added to the human genome that are not present in the chimpanzee genome. Some of the genes that the two organisms share could encode subtly different proteins. Or the regulation of genes could vary—shared genes might be more or less active in the two organisms during different periods of development and in different tissues.

"We have some evidence for the action of all three of those mechanisms, and we're sorting out which of them is likely to be most important," said Walsh. Publication of the chimp genome revealed that a number of genes in humans have been duplicated and then altered since the days of our common ancestor, and some of those genes may influence the development of human brains. Similarly, many of our genes are slightly different from the corresponding genes of the chimp, although that animal's genome reveals a striking similarity in coding sequences across the two species.

But Walsh thinks that regulatory changes eventually will prove to be the most important distinguishing factor. Small changes in the expression of a gene can have dramatic effects on an organism. Researchers also have shown that levels of gene expression have changed more over time in the human lineage than in the chimpanzee lineage. Unfortunately, said Walsh, "Our tools for studying changes in noncoding DNA are very poor."

[Interesting politics, but not very good "Science". Evolution as a winner is not news at all. ET/ID never challenged the validity of Evolution as a theory - thus evolution did not need to "win". For evolution to prevail was enough that ET/ID failed to show that they have predictive theory. "PostGenetics is here - but there are no tools" - this is the "news to use" of 2005 - comment by A. Pellionisz, 23rd of December, 2005]

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Civilisation has left its mark on our genes [correction, on human Genome]

22:00 19 December 2005
From New Scientist Print Edition
Bob Holmes

Darwin’s fingerprints can be found all over the human genome. [So why restrict the analysis before PostGenetics on "genes only"?? - AJP]. A detailed look at human DNA has shown that a significant percentage of our genes have been shaped by natural selection in the past 50,000 years, probably in response to aspects of modern human culture such as the emergence of agriculture and the shift towards living in densely populated settlements.

One way to look for genes that have recently been changed by natural selection is to study mutations called single-nucleotide polymorphisms (SNPs) – single-letter differences in the genetic code. [The problem is, that this analysis, like almost all before PostGenetics, restricts investigation to "genes only" - though it is basic knowledge that "the majority of variations are found outside of genes, in the "extra" or "junk" DNA" - AJP]. The trick is to look for pairs of SNPs that occur together more often than would be expected from the chance genetic reshuffling that inevitably happens down the generations.

Such correlations are known as linkage disequilibrium, and can occur when natural selection favours a particular variant of a gene, causing the SNPs nearby to be selected as well.

Robert Moyzis and his colleagues at the University of California, Irvine, US, searched for instances of linkage disequilibrium in a collection of 1.6 million SNPs scattered across all the human chromosomes. They then looked carefully at the instances they found to distinguish the consequences of natural selection from other phenomena, such as random inversions of chunks of DNA, which can disrupt normal genetic reshuffling.

This analysis suggested that around 1800 genes, or roughly 7% of the total in the human genome, have changed under the influence of natural selection within the past 50,000 years. [What percentage of the 98.7% of DNA [before PostGenetics, 'junk' DNA shows and shows what kinds of SNPs? - AJP]. A second analysis using a second SNP database gave similar results. That is roughly the same proportion of genes that were altered in maize when humans domesticated it from its wild ancestors.

“Domesticated” humans

Moyzis speculates that we may have similarly “domesticated” ourselves with the emergence of modern civilisation.

“One of the major things that has happened in the last 50,000 years is the development of culture,” he says. “By so radically and rapidly changing our environment through our culture, we’ve put new kinds of selection [pressures] on ourselves.” [This profound question, of course, is highly debatable. In one view it is the "domestication" that causes changes in the DNA - not only, in fact mostly *not*, in "genes". In another view it is the polymorphism - in rare forms, called mutation of DNA- caused an altered behavior, "domestication". At the general mathematical level of DNA Information Theory, the upcoming book "FractoGene ... decoding 'Junk' DNA in PostGenetics" will provide some astonishing concept - AJP]

Genes that aid protein metabolism – perhaps related to a change in diet with the dawn of agriculture – turn up unusually often in Moyzis’s list of recently selected genes. So do genes involved in resisting infections, which would be important in a species settling into more densely populated villages where diseases would spread more easily. Other selected genes include those involved in brain function, which could be important in the development of culture.

But the details of any such sweeping survey of the genome should be treated with caution, geneticists warn. . Now that Moyzis has made a start on studying how the influence of modern human culture is written in our genes, other teams can see if similar results are produced by other analytical techniques, such as comparing human and chimp genomes.

Journal reference: Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.0509691102)

[Short of an encompassing analysis of the entire genome - including PostGenes (formerly 'junk') - analysis of SNPs, though it is already used for diagnostic purposes, presently is fractional, and awaits a spectacular blossoming - comment by A. Pellionisz, 22nd of December, 2005]

Probing Connection Between Regulatory DNA And Disease

Category: Genetics News

Article Date: 17 Dec 2005

Through the Human Genome Project, the HapMap Project and other efforts, we are beginning to identify genes that are modified in some diseases. More difficult to measure and identify are the regulatory regions in DNA - the 'managers' of genes - that control gene activity and might be important in causing disease.

Today, a team led by the Wellcome Trust Sanger Institute, together with colleagues in the USA and Switzerland, provide a measure of just how important regulatory region variation might be in a pilot study based on some 2% of the human genome. As many as 40 of 374 genes showed alteration in genetic activity that could be related to changes in DNA sequence called SNPs.

"We were amazed at the power of this study to detect associations between SNP variations and gene activity," commented Dr Manolis Dermitzakis, Investigator, Division of Informatics at the Wellcome Trust Sanger Institute. "We were even more amazed at the number of genes affected: more than 10% of our sample - or perhaps 3000 genes across the genome - could be subject to modification of activity in human populations due to common genetic variations."

The study combined the map of genetic variation developed through the HapMap with estimates of gene activity obtained from cell cultures from 60 individuals who provided samples for the HapMap. More than 630 genes were studied, of which 374 were active in the cell cultures. If gene activity in a cell culture was skewed from the average, it was investigated further.

These genes were correlated with more than 750,000 SNPs - sequence differences between individuals in the sample collection. A series of statistical tests were carried out to provide increased confidence in the association between gene activity and sequence variation.

"Our sample size of 60 individuals is relatively small," continued Dr Dermitzakis, "and we might expect not to detect rare variations. However, our pilot project gives us greater confidence to take on a genome-wide survey of gene activity."

A global map of sequence variation and gene activity will be an important tool in the interpretation of variation and disease. Such genome-wide association studies will be able to identify some regions of the genome with strong disease effects.

"The HapMap is proving to be useful in a wide range of applications," commented Dr Panos Deloukas, Senior Investigator, Division of Medical Genetics, Wellcome Trust Sanger Institute. "The journey for our biomedical research is from DNA sequence to individual people and individual disease. The HapMap is a bridge from sequence data to the differences in individuals."

The project focused on three regions of the human genome. The first, called the ENCODE regions, and about 30 million base-pairs of DNA, are being intensively studied around the world as a group of 'typical' human genome regions. The second was 35million base-pairs of chromosome 21 sequence: three copies of chromosome 21 lead to Down Syndrome. The third was a region of chromosome 20 - 10 million base-pairs - that is known to be associated with diabetes and obesity.

In comparison with gene sequences that contain the instructions to make proteins, regulatory regions that control genes are relatively poorly understood. Their structure is variable and their distance from the genes they control also varies among genes.

New tools are needed in the search of our genome for the sequences that contribute to disease, tools that will harness the massive amounts of DNA information and transform them into information of real biomedical utility. The methods described here, with the power of the HapMap data and the cell cultures available, will speed that transformation.

Publication details

Stranger et al. (2005) Genome-wide associations of gene expression variation in humans. PLoS Genetics 1: pp. nos to come.

DOI: 10.1371/journal.pgen.0010078

Dec 16, 2005

[Yes, "movers and shakers" of those who develop a new industry from a disruption, a major paradigm-shift.  It is widely known, that the majority of SNPs are *not* in the genes, but in the "non-coding DNA" ("junk"). This is the "new gold rush". Some lucky ones will make a fortune by finding the nuggets - but the smart, modest and *sure* way to make a fortune is to develop those "new tools". (In the California Gold Rush, the quickest fortune was made by buying up all the metals, and manufacturing & selling shovels... - comment by A. Pellionisz, 20th of December, 2005]

GTG/GENE stock holds steady - what's next?

After weeks of turbulence and uncertainty over GTG/APPLERA settlement, for several days now the NYSE price held steady (in fact, today, 19th of December, it closed 5.51% up).

[Thus, Wall Street evidently "knows more" than what meets the eye about the undercurrents of the "settlement". "JunkDNA Intellectual Property" value proposition is forever validated, and the only way to go is "up". How high up and when? Watch for "unexplained" spikes - likely signals of business propositions. Traffic is unprecedented - when the "business season" is supposed to be winding down for the year of 2005, the Centenary of Genetics and the year of "Happy Birthday for PostGenetics" - Comment by A. Pellionisz, on 19th of December - business analysis is available by appointment only]

Plan matures for partner to genome quest
Forget mutations: geneticists are hunting for subtler changes to DNA

[Submitted by Jules Ruis, a Founder of International PostGenetics Society]

c changes are just as important to our understanding of disease as straight mutations.

As many as half of the genetic alterations that cause cancer, for example, may be 'epigenetic' changes rather than mutations, says Stephen Baylin, a tumour biologist at Johns Hopkins University in Baltimore, Maryland, who is involved with the proposal.

In mutations, letters of the genetic code can be changed or stretches of DNA deleted. But in a common epigenetic change, for example, a small molecule simply latches on to DNA in a process called methylation. This does not change the genetic sequence, but it can still shut a gene down.

The plan for a Human Epigenome Project, backed by dozens of scientists, is published on 15 December in the journal Cancer Research1. Supporters say that have not encountered much resistance. But they add that this is probably because their proposal does not yet come with a price tag.

Organizations looking into the project, including the US National Cancer Institute and the American Association of Cancer Research, have not yet committed any funds.

"Nobody is denying that the epigenome project would be useful," says Michael Stratton, who heads a cancer genome project at the Wellcome Trust Sanger Institute in Hinxton, UK. "The constraint is always the cost."

Dark side of the genome

Researchers have only realized the importance of epigenetic changes in the past five years, says Baylin. In addition to cancer, the changes are known to underlie other diseases, including neurological disorders. And stem cells have been found to rely heavily on epigenetic processes, turning genes on and off as they divide and mature.

Each type of human cell comes with its own set of epigenetic settings. Understanding those, say proponents, would set the stage for understanding what goes wrong during disease, and would help select genes to target with drugs.

"You can go into the dark parts of the genome that you would never have imagined would yield drug targets and find things," says Stratton.

The technology for detecting methylation has advanced rapidly in the past few years. Several epigenetic projects are under way, and the Sanger Institute and others are running a pilot project looking at individual chromosomes. The Human Epigenome Project would coordinate these efforts and set research priorities.

Cancer atlas

The proposal comes on the heels of an announcement earlier this week that the US National Institutes of Health will allocate US$100 million in pilot funds for The Cancer Genome Atlas, a project that aims to catalogue the genetic changes associated with cancer (see 'Big money for cancer genomics').

This project will include an epigenetics component. But experts say there is much more scope for work in epigenetics than could be encompassed by the cancer atlas.

"If you went at it full scale, it would be as big or bigger" than the cancer project, says Baylin. "It could get huge."


Jones P. A.& Martienssen R. . Cancer Research, 24. 11241 - 11246 (2005).

[The Human Epigenome Project (with zero budget as yet) and the The Cancer Genome Atlas (with the paltry 0.1% NIH budget) should be comparatively analysed, as it is done in this article, and for the TCGA, done by this commentator 2 news items down in this digest. Evidently, the research and government communities are fiercely debating these projects - and for very serious reasons. The HEP Project addresses the "Methylation" issue that is well-known to cut across "coding" and "non-coding" DNA, and thus opens up the "pandorra box" of "Junk" DNA issue for sizable government projects. (No wonder it has a zero budget, as we speak...). At the same time, The TCGA Project, in spite of its "cute name", leaves ample ground for criticisms from all corners. (Paltry size, addressing "genes only", planning to work with models that needlessly call for re-sequencing "thousands of cells" - when e.g. the "Methylation Prediction of FractoGene" - see also in forthcoming book - can narrow it down from sequencing "thousands of cells" to as few as 4 (!)). Fortunately, such competition between colossal government projects (that sometimes miss the Mars for not converting British distance measures to metric, TWICE in a short time-span...) and private sector that watches the business "bottom line" with rigor and inventiveness, happened before. Since "regulatory diseases" such as many cancers are not at all purely "academic research activities" this commentator predicts that while the government projects are "debated", private industry will plunge into commercially exploiting the "FractoGene Methylation PostGene Discovery" - especially since in the era of PostGenetics, Foundations on Diseases whose origin is not limited to "Genes" but may (also) lie in "Junk DNA" exert formidable pressure and mobilize new resources. - Comment by Dr. Pellionisz on the 16th of December, 2005]

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Genetic wins little fight over DNA work ["Junk" DNA is cheap or it is still an incredible bargain?]

[Submitted by the Honorary Chairman of the International PostGenetics Society, Dr. Malcolm J. Simons]

By Helen Westerman and Rebecca Urban
December 16, 2005

SELF-STYLED giant slayer Mervyn Jacobson was reportedly elated earlier this week when his company, Genetic Technologies, finally settled its long-running legal case with the much larger US group, Applera Corporation.

Too bad the company's shareholders didn't share that feeling when they finally learned yesterday that the landmark settlement was worth — drum roll please — a measly $15 million.

And only part of that was in cash. The rest would come in equipment and intellectual property rights.

After three years' legwork and an estimated $6 million spent lining the hip pockets of lawyers, the market was obviously expecting something bigger. It swiped more than 20 per cent off the market value of the company, its shares falling 10.5¢ to 40¢. [In perhaps more savvy New York, it actually gained 9 cents - AJP]

Earlier this week, Genetic Technologies claimed that it had been prevented from releasing the financial details of the settlement because of a confidentiality agreement.

That soon changed after the Australian Stock Exchange raised concerns that the original announcement lacked sufficient detail for the market to judge the materiality of the settlement.

Genetic Technologies was suing Applera in the US District Court after Applera refused to obtain a licence for work it was carrying out on non-coding DNA, for which the local group controls the patent.

As part of this settlement, Applera now has a licence. [Sure (some of) the upfront settlement had to be disclosed, but the Annual Royalties are still a closely guarded secret .. AJP]

Jacobson, the company's chief executive and largest shareholder, was reported as saying the decision would act as a catalyst to force other company's infringing on the patents to take out licences. [Not a "catalyst" but the US Law - AJP]

Apparently he's identified hundreds of companies that he believes already owe substantial amounts of cash for past and present infringements. [Let's just multiply $15 M by a couple of hundred - it adds up to a small change - AJP]

And Jacobson's decision to paint the settlement as a "win" for Genetic Technologies has somewhat irked its former adversary. [A US Court ruling is by all definitions is a "win" - from the other side may look like "sour grapes" - AJP]

"Subsequent statements from GTG's representatives are misleading," Applera spokesman Peter Dworkin told Full Disclosure. "The facts are that Applera has never conceded the validity or infringement of GTG's patents, and settled the case on very favourable terms for Applera in order to spare it and its customers further distraction by the litigation." [Maybe in Australia some believe such transparent PR of "putting down the price" of what you intend to buy - but we may recall that it was not Applera that decided to settle - the Court ordered them to do it (leaving the "terms and conditions" to the Parties, as usual) - AJP]

Jacobson did not return calls yesterday.

[This is *not* the call Jacobson will take.  As long as Applera would be the only buyer, they try to "low ball the price". The readership of this column multiplied over the coverage of the "settlement" - there are plenty of interested parties from whom Jacobson *will* take a call ...

Business analysis is not available publicly. - Comment by Dr. Pellionisz on the 16th of December, 2005]

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GTG Provides Further Details of the Settlement with Applera
15 December, 2005

Company Announcements

On December 12th, 2005, Genetic Technologies Limited (ASX: GTG; NASDAQ: GENE) reported it had reached a final settlement of its patent dispute with Applera Corporation.

The announcement released to ASX was also released to NASDAQ and the wire services in USA. The form and content of that document was part of the agreed settlement process, which remains under the control of the US District Court, Northern District of California.

However, the Settlement Agreement does permit the release of further details, if requested by the ASX. On December 12th, 2005, the ASX contacted GTG seeking additional details regarding the material terms of the agreement. A trading halt was then sought by the Company to enable it to seek legal advice.

GTG can now report that the total value of the consideration receivable by GTG is approximately A$15 million, [USA $11.3 M] payable partly in cash and partly in kind - including agreements supplying GTG with certain Applera equipment, reagents and intellectual property rights.

In relation to the financial impact of the settlement, GTG expects to record approximately half the benefits from these contracts as revenue in the current financial year.

We trust these further details now clarify the relevance of this settlement to GTG.

With the release of this announcement, the trading halt will be lifted.


Dr. Mervyn Jacobson

Chief Executive Officer

[Why did the "settlement" take so much longer than the Court anticipated? Now we officially know that the issue was/is not singular! The "entitlement for suing hundreds of companies for royalties" was not on the table at all - it was already decided by the Court. Did $6 Billion Applera "arm-wrestle" with $200 M GTG for weeks and about $11.3 M (partly in cash...)? "Very Unlikely".

Business analysis is not available publicly. - Comment by Dr. Pellionisz on the 15th of December, 2005]

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New Effort Aims to Unlock Secrets of Cancer Genes
["Don't blame me, I was among the first to join 'PostGenetics', focusing on 'JunkDNA' diseases"]

New York Times

December 13, 2005

The government is beginning a project that aims to unlock all the genetic abnormalities that contribute to cancer, an effort that would exceed the Human Genome Project in complexity but could eventually lead to new diagnostic tests and treatments for the disease.

Government officials said today that they would spend $100 million [it sounds like a lot of money, but is actually 01.% of NIH' 3-year budget - comment by Dr. Pellionisz] over three years on a pilot phase of the project, which will be called The Cancer Genome Atlas. "This is a revolutionary project," Anna D. Barker, deputy director of the National Cancer Institute, said at a news briefing in Washington. "It's going to empower all cancer researchers with an entire new set of data to work with." [One may wonder what is the "new set" - read on! - comment by Dr. Pellionisz]

Her agency will contribute half the money with the other half provided by the National Human Genome Research Institute. Both are part of the National Institutes of Health.

Scientists have long known that genetic mutations that accumulate in normal cells over a person's lifetime can turn those cells cancerous. About 300 genes involved in cancer are known already and there are a handful of drugs that work by interfering with specific genetic abnormalities.

The drug Gleevec, which blocks a particular genetic change that causes a type of leukemia, produces remissions in most patients with that form of the disease. Some studies have shown that the lung cancer drug Iressa is likely to work very well for about 10 percent of patients with a particular mutation but barely at all for others.

But federal officials and many cancer researchers say that a more systematic search could find many more genes and gene variations that play an important role in determining how aggressive a cancer will be and what drugs might work best. The first fruits, such as new diagnostic tests, might be seen in several years.

"We are still working with an incomplete compass," said Francis S. Collins, director of the National Human Genome Research Institute. "The time is right to bring the full power of genomics to bear on the problem of cancer." [Sounds governmentese.  Would it be better to admit what has been missed with the "incomplete compass" and what has been absent from the "full power"? - comment by Dr. Pellionisz]

The project would involve determining the sequence of letters in the DNA of cancer cells taken from tumor samples taken from biopsies or surgery. The initials of the project's name, T.C.G.A., represent the four letters of the genetic code.

Scientists will also look for other changes, like duplications or deletions of genes, or differences between cells in which genes are turned on or turned off. [Here we go! An almost clear admission that finding "turned off" - methylated - genic AND NON-CODING (before PostGenetics, "Junk") DNA is a "silver bullet" approach to find out what may go haywire with "aberrant regulation". Two problems with the proposed approach are: a) Methylation occurs in some cases not in the "genes" but mostly in the "non-coding" sequeces, thus the program may still miss perhaps the most important part of the regulation by looking (as almost always, in Genetics) only in the "genes". b) Finding "turned off" sequences, if it is done by full sequencing the entire DNA (for cancerous cells in subsequent stages of cancer), is obviously a horrendously expensive plan. However, looking for methylation can be done by much more inexpensive methods, as well. Further, the "Methylation Proposition of FractoGene" pinpoints when to look, and with Neural Net methods even the likely sites are pinpointed - thus "resequencing to pin down PostGenes" is a highly streamlined and much more cost-effective methodology. (Interested parties may contact Dr. Pellionisz). However,as we saw it in the "human genome program sequencing horserace between government and private sector", this may be the "modus operandi"; The government proposes plans with built-in waste to feed an establishment, while the private sector "goes to the core of the problem" by cutting out all the middlemen and reduces the problem by highly innovative (proprietary) means. - comment by Dr. Pellionisz]

Today's announcement was not unexpected. In February a committee advising the National Cancer Institute had proposed such a project, which it estimated would cost $1.35 billion over nine years. [It has been obvious since the sequencing of the mouse, Dec. 5, 2002, that the 40% difference in "Junk" DNA is responsible for the "difference" between human and mouse. Why is it , still that 3 years after (and with the chimp and dog DNA sequencing at very significant expense) that some government programs are still slow in allocating resources; e.g. slashing to 22% of even that money that *their* experts recommended? The 0.1% speaks for itself! An available "cover" is: "Don't blame me, I was among the first to join International PostGenetics Society". - comment by Dr. Pellionisz]

But government officials said today that they would first assess the results of the three-year pilot project before deciding whether a full program would be worthwhile. They said it was too early to estimate how much a full project would cost.

The pilot phase would involve studying hundreds of tumor samples from two or three different types of cancer. The types of cancer have yet to be chosen. The decision will depend on such factors as the availability of tumor samples. A full project might involve studying 50 types of cancer.

Some scientists have expressed concern about the project, saying it might divert grant money from individual investigators at a time when the N.I.H. budget is no longer growing rapidly, as it was a few years ago. [Yes, this is the problem not only with "interesting politics", but also with the naturally declining strength of "Gene Discovery". If the number of genes is shrinking from projected 140,000 to about 15% (to about 19,000) no wonder that "Gene Discovery" has to painfully re-distribute a "downscaled pie of money". PostGenetics turns this negative spiral of dynamics around; creates enormous new momentum. With "non-coding DNA diseases" that hundreds of millions of taxpayers are suffering from, a quantum-jump of *new monies* should (and can) be appropriated by Congress, especially when non-coding DNA R&D is now vital not only to Health Care (Biotech), but also to remove the "Nanotechnology bottleneck" (no proteins are known to be synthesized without non-coding DNA information). - comment by Dr. Pellionisz]

Some have also said that cancer cells are so genetically heterogeneous - two cells in the same tumor can differ in their mutations - that it will be hard to find meaningful patterns. To minimize the risk of failure, the pilot project will choose types of cancer that have relatively little variability, officials said. [The logic here is questionable. While it does apply to cancers caused by spontaneous or environment-inflicted mutations, for a long list of cancers with hereditary origin of regulatory disorders, like in case of a weakened tumor suppressor mechanism, "finding meaningful patterns" (e.g. in the methylation-deficit according to FractoGene's "Methylation Prediction") is highly likely. See/discuss the very sharply focused Methylation Prediction of FractoGene, an axiomatic and algorithmic mathematical theory on non-coding and coding DNA, since the First (Fugu) Prediction of FractoGene has already received experimental verification). - comment by Dr. Pellionisz]

The amount of DNA sequencing involved could easily exceed what was done in the Human Genome Project, which determined the sequence of the 3 billion DNA units in human chromosomes. Since each cancer cell contains a complete genome, determining the full sequence of thousands of cells would be like doing thousands of genome projects. [The statement is correct, but the assumption is false - since models needing "thousands of cells" may already be superseded. For instance, the "Methylation Prediction of FractoGene" (when applied for the Purkinje neuron) could identify PostGenes by just 4 "entire DNA sequencing" (why should anyone think of "thousands of cells necessary") - and with much less expensive methylation detection applied, plus Neural Net methods pinpointing the likely sites, sequencing of tiny fragments of a single DNA might yield "hits" on PostGenes. - comment by Dr. Pellionisz]

"This is an audacious undertaking," Dr. Collins said at the news conference. In an interview, however, he said that since doing thousands of complete genomes is now impractical, the pilot project would involve sequencing only 1,000 or 2,000 specific genes. [Government programs have been beaten before - e.g. when Craig Venter's private sector program won "hands down" the "Human Genome Sequencing". This paltry 0.1% program, if it is true that it is aimed at sequencing "genes", simply "still does not get it". Investigating cancers that are often "regulatory diseases" one should perhaps look into the "regulatory mechanism" - i.e. the "non-coding DNA" - that are *not* the 1.3% of "genes", but the 98.7% of "non-genes". Not only experts but even laypeople (ordinary taxpayers, let alone "junk DNA disease patients" or "junkDNA disease" Foundation Leaders) may be shaking their heads in disbelief - comment by Dr. Pellionisz]

The findings will be put in one or more databanks and be available without cost to researchers, officials said. They said they anticipate that medical foundations, companies and academic researchers would take part in the project.

[So there is hope- since it is time for Medical Foundations of "Junk DNA Diseases", Companies and Academic researchers not only to do a better job than that of the government, but also it is time to take a stand for rapid re-plenishing of resources - Comment by Dr. Pellionisz on the 13th of December, 2005]

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[Hold it - there is more to 'JunkDNA Industry'. Further announcement regarding GTG / APPLERA settlement]

Company Announcements

Request For Trading Halt

13 December 2005

Mr. A. Walsh,
Assistant Manager Companies,
Australian Stock Exchange Limited,
Level 8, Exchange Plaza,
2 The Esplanade,
Perth W.A. 6000

Dear Mr. Walsh,


We refer to your letter dated 12 December 2005 regarding our announcement to the Market of the same date and the request by ASX that GTG provide the Market with further information regarding the settlement reached between the Company and Applera Corporation.

We advise that we are currently seeking advice on how to satisfy ASX’s request whilst at the same time meeting our obligations under the settlement agreement and to Northern California District Court.

In order to provide us with sufficient time to do this, we now request that the ASX impose a trading halt on the Company’s shares for a period of two Business Days, with the shares to recommence trading no later than Thursday, 15 December 2005, during which time we expect to make a further announcement regarding the settlement.

We trust that the above is satisfactory. However, should you have any further questions, please do not hesitate to contact us.

Yours sincerely,

Company Secretary

[Why did the "settlement" take much longer than the Court anticipated? We have an entirely new business at its germinal "seed stage"... Business analysis is not available publicly. - Comment by Dr. Pellionisz on the 13th of December, 2005]

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[Now it is official - The "Junk DNA Intellectual Property value proposition is forever validated"]

[GTG] Company Announcements

12 December, 2005


Genetic Technologies Limited (ASX: GTG; NASDAQ: GENE) reports that it has now reached a final settlement of its patent dispute with Applera Corporation, further to a Settlement Conference held last week in San Francisco, USA.

The parties have executed a number of binding agreements, including a final Settlement Agreement plus license agreements and a supply agreement, and the parties will now move to dismiss all claims and counterclaims in the legal action before Judge Phyllis Hamilton, of the US District Court, Northern District of California, San Francisco.

The commercial terms of the settlement reached between GTG and Applera are subject to confidentiality requirements, but it can be disclosed that the settlement also includes a license to the GTG non-coding patents.

GTG originally filed its law suit against Applera in March 2003. A Markman Hearing was held by the Court in September 2004. Subsequently, the Court arranged Mediation Settlement Conferences before Magistrate Judge Joseph C. Spero in San Francisco. These took place in December 2004, February 2005 and August 2005.

On October 13th, 2005, the parties executed a Confidential Term Sheet, and after further negotiations, have now reached a final settlement of all disputes between them.

Dr. Mervyn Jacobson
Chief Executive Officer
Genetic Technologies Limited


GTG celebrates win over Applera in patent battle 12/12/2005 14:29:12

Graeme O'Neill
Australian Biotechnology News

[also: Bio-ITworld]

13 December, 2005

An elated Dr Mervyn Jacobson, CEO of Genetic Technologies (ASX:GTG, NASDAQ:GENE) flew back to Melbourne from San Francisco this morning after slaying his company’s most reluctant dragon, giant US rival Applera.

After an exhausting mediation session lasting from 9am on December 8, to 3am on December 9, Applera’s lawyers agreed to pay an undisclosed fee to license GTG’s patented ‘junk DNA’ gene-testing technology, one of the broadest patents ever issued in the recombinant DNA technology field, and the only US patent on the use of non-coding DNA markers for gene testing.

The commercial terms of the settlement remain confidential, but according to GTG’s ASX announcement today, GTG and Applera have executed several binding agreements, including a final settlement agreement, a licence agreement, and a supply agreement, before Judge Joseph Spero, of the US District Court of Northern California.

The two parties will also move to dismiss all claims and counterclaims in their legal action before Judge Phillis Hamilton, in the same jurisdiction.

GTG originally sued Applera, and two other US gene testing companies, Novelo and Covance, in March 2003, for refusing to take licences and pay royalties on its patented technologies. Novelo and Covance both submitted and took licences in November 2004, leaving Applera – the largest gene-testing company in the US – as the lone holdout.

The first sign of a negotiated settlement came on October 13 this year, when the parties executed a confidential term sheet and agreed to further negotiations before Judge Spero

Applera and GTG were originally to have reached a negotiated settlement on November 9, but after three extensions, finally settled on December 9.

Jacobson today described the mediation process as “quite strenuous”.

But standing back and looking at it from 38,000ft, it’s a very significant result,” he said.

Since GTG launched its licensing program three years ago, we’ve had people challenging our right to charge licence fees, or telling us to go to hell and sue us.

It’s been constant – even when we were pursuing licences, there has always been some company or group challenging us, so we’ve been continually distracted with ongoing legal battles. But this is the end of the seventh and final battle.

Today, with the Applera matter settled, nobody in the world is challenging our patents. For a little Australian company to file a lawsuit against Applera, and have the resources to see it through, and bear the associated legal costs for three years, is obviously very significant.”

Jacobson said the research community and commercial gene-testing companies around the world had been watching the case, and would see it as a turning point – “Lots of people have hidden behind Applera, believe that time was on their side, if Applera could continue to obstruct us, and invalidate our patents – or simply wait us out.

Now that Applera has come to an agreement with us, they have nowhere to hide.

Jacobson warned that companied that had delayed taking a licence from GTG were now exposed. “The nature of the settlement may justify us repricing. Our own view on what the patents are worth may need to be reexamined.

I am now setting my sights on hundreds of targets who, in our view, already owe substantial amounts for past activities, and will owe us more for future activities.

Jacobson characterized the win as “a great victory for Australia’s biotechnology industry too.”

In human terms, this is a case of the little guy taking on a giant and prevailing. So we have to assume that the little guy had something of great value – that’s now clearly established.

So much has been written about Australian companies’ [lack of success] on the world scene, now here is an Australian company that has gone onto the world stage seven times and won – and we’ve not sued anybody within Australia.”


“Everyone has been waiting for an Australian biotechnology company to make a profit, and we now see ourselves powering ahead, and moving into something of a leadership position in the Australian industry.

With the prospect of a large backlog of unpaid licence fees and royalties, and more to come, Jacobson said GTG plans to pursue more licensing agreements, build its genetic testing business, and establish a greater presence in the US, the world’s major biotechnology market.

There’s so much business out there – we have do sign them up, one by one, because it’s not common that a company volunteers to come forward and pay us full value. Everyone has a story, and each needs to be a separate, intense negotiation.

In some ways, it’s comparable what happened with PCR in the 1980s. For those wanting to apply the method, ours is the only other patent to my knowledge where the patents apply to all genes in all species.”

Jacobson said he was astonished that, only now, 16 years after the filing of the original patents invented by his former partner and GTG co-founder Dr Malcolm Simons, was the world waking up to the significance of non-coding DNA in the human, animal and plant genomes.

I bought a copy of Forbes the other day, and there was an article titled ‘Treasures in the Trash’.

In it, they claim that the earliest recognition of the significance of non-coding DNA was in 1994. They still haven’t woken up to it – even though they had previously run an article on GTG and Malcolm Simons.”

Asked whether his company’s success, and rise to prominence, made it a takeover target, Jacobson said he expected it would certainly come to the attention of multi-national biotechnology companies. “One or more of them may see us as a significant opportunity, rather than an opponent.

They entitled to do so, because under the rules of the public market, shares are available to the highest bidder.

“But anyone attempting a hostile takeover would have a difficult time, because of the significant holdings of GTG shares in the hands of its founders, including myself and Fred Bart, and the original GeneType stockholders.”

[GeneType was the precursor company for GTG].

“They might acquire 25 per cent, but then we’d need to talk.”

[This is history - the entire "junk DNA story" is rewritten for PostGenetics. Old dogma, old news (speculations, rather) and what may be important from a business viewpoint, ridiculously depressed price offers no longer need to apply. Business analysis is not available publicly. - Comment by Dr. Pellionisz on the 12th of December, 2005]

[Half a Billion Dollars from Bill Gates for] Anti-Malaria Donation [Maybe software would help more directly?]

Originally Published: October 31, 2005

The Bill and Melinda Gates Foundation will donate $258 million to research on malaria, which kills 2,000 African children each day, Mr. Gates announced yesterday.

About $108 million will be put toward a vaccine, $100 million for new drugs, and $50 million to develop insecticides and other forms of mosquito control.

Since 1999, the foundation has donated about $230 million to malaria research. Six new drugs for the disease are now in clinical trials, compared with none five years ago, and an experimental vaccine that protects about 30 percent of inoculated children has been developed.

[Medicine is thrown into a revolution. For several "junk DNA diseases" even the exact locus and the exact glitch in the "junk DNA" is an established fact (Friedreich ataxia, Fragile X Syndrome, etc). Although for Malaria we are not yet there, Malaria is a "non-coding DNA disease" (before PostGenetics, "junk" DNA disease). This makes this commentator wonder if half a billion dollars, spent on just one of the "most of hereditary diseases" that are likely to be caused by "junk" DNA causes (Dave Haussler, UCSC, quoted by Forbes), could be directly used to address, inevitably by Information Technology methods, the very core of "junk" DNA function. - Comment by Dr. Pellionisz on the 10th of December, 2005]

Barking up new trees in search for cures

Scripps Howard News Service
December 07, 2005

- A kennel's worth of genetic information about dogs released Wednesday has researchers of both canine and human diseases drooling at the prospect of a new chapter in the 100,000-year-old relationship between man and dog.

With hundreds of breeds representing the greatest biological diversity of any mammal, dogs not only offer an incredible array of physical and behavioral traits, they also carry genetic codes linked to diseases that match many human ills.

So a set of publications that include a detailed gene map for a boxer named Tasha, a comparison of her genes with those of a poodle named Shadow, and then with snippets of genes from another nine breeds, plus four wolves and a coyote, along with other analyses of genes and specific traits, all could add up to healthier dogs - and their humans.

"Of the more than 5,500 (species of) mammals living today, dogs are arguably the most remarkable," said Eric Lander, a professor of biology and director of the Broad Institute of MIT and Harvard University who is senior author of the gene map published Thursday in the journal Nature.

"The incredible physical and behavioral diversity of dogs, from chihuahuas to Great Danes, is encoded in their genomes. It can uniquely help us understand embryonic development, neurobiology, human disease and the basis of evolution."

Humans domesticated dogs from wolves as far back as 100,000 years ago, but most of the roughly 400 distinct modern dog breeds can be traced to selective breeding going back several hundred years.

While breeders seek to preserve certain physical or behavioral traits, such as long coats or herding instinct, breeding also predisposes many dogs to genetic disorders that include heart disease, cancer, blindness, cataracts, epilepsy, hip dysplasia and deafness.

"The leading causes of death in dogs are a variety of cancers, and many of them are very similar biologically to human cancers," said Elaine Ostrander, chief of the Cancer Genetics Branch of the National Human Genome Research Institute and a co-author of the Nature study.

"Using the dog-genome sequence in combination with the human-genome sequence will help researchers to narrow their search for many more of the genetic contributors underlying cancer and other major diseases."

In the December issue of the journal Genome Research, scientists reported that there were 10,562 differences between the boxer and the poodle in short stretches of DNA that separate and regulate genes. [These "short stretches" that "regulate" genes used to be called, before PostGenetics, 'junk' DNA. With the "gene sets" of mouse, dog, chimp and human virtually identical, but huge, up to 40% difference in their PostGenes, many "disease hunters" are now barking up on the "new tree of 'junk' DNA". This is a nice way to put that zillions of dollars have been spent on "barking up on the wrong tree" - hunting non-existent "genes" of 'junk' DNA diseases. - comment, AJP]

The researchers from the nonprofit Institute for Genomic Research in Rockville, Md., say that, based on the comparisons with similar DNA stretches in the other dog and wolf breeds, there are about 20,000 such differences in the entire dog population. "This may have a profound impact on gene expression differences and disease determination in dogs," said Ewen Kirkness, lead investigator for the project.

Gene maps have already started to yield specifics about dog diseases for some breeds, such as a muscle-wasting disease in Labrador retrievers. The American Kennel Club's Canine Health Foundation, which has contributed $2 million, blood samples and other technical support to dog-DNA efforts, hopes to eventually be able to screen dogs for genes known to cause disease and disability before they're bred.

The dog research also helps reveal the evolutionary pedigree of human genes.

Humans and hounds branched off about 95 million years ago, yet nearly all of the estimated 19,300 dog genes correspond to similar genes in humans. But dog cells break their DNA into 78 chromosomes, compared with 46 in human cells.

As scientists compare the gene maps of the two species, they're beginning to wonder if humans really have 23,000 or more genes, as once thought, or if some genes really are just "junk DNA" that don't actually have any function.

Moreover, in comparing human, dog and mouse gene maps, researchers found that about 5 percent of the genes in all three species have gone virtually unchanged over the past 100 million years, and that preserved DNA is clustered in genes that regulate proteins involved in development.

[A wake-up call for hundreds of millions of patients - how do you spend your tax dollars on "gene discovery" of the non-existing "genes" causing your ill-health or demise. Call your Congressional Representative immediately! - Comment by Dr. Pellionisz on the 9th of December, 2005]

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Veil of secrecy "costs" GTG/GENE a 10% drop in stock price in a day

The public record shows that Australian GTG (traded on NYSE under stock symbol "GENE") "lost" over 10% of its value in a single day (9th of December, 2005). Further facts are beyond this "paper loss" that Applera/GTG were ordered by the Court for 9:30 A.M. on the 7th if settlement was not done till that time, and the stock shot up over 8% at that time, signalling that something did happen. Long and widely known fact is that the market does not like uncertainty. Since a "veil of secrecy" surrounds the outcome, and "insider trading records" are not available for this period, the cause of this jittery "paper loss" is anybody's speculation.

[Business analysis is not available publicly. - Comment by Dr. Pellionisz on the 9th of December, 2005]

Man's best friend shares most genes with humans

Full genome sequence of dog to be published today
Carl T. Hall, Chronicle Science Writer
Thursday, December 8, 2005

Scientists are publishing today the complete DNA sequence that makes a dog a dog, and it turns out to be uncannily close to what makes a person a person. [This dogma is obsolete in the age of PostGenetics. The very fact that human, mouse, chimp and now the dog "gene sets" are practically identical, it is no longer scientifically tenable to look for "what makes a person a person" in the "genes" - comment, AJP]

Genome sequencers at Harvard University, MIT and their affiliated Whitehead Institute for Biomedical Research in Cambridge, Mass., led an international team of scientists through a unique landscape of doggie DNA.

About 2.4 billion chemical units of DNA define a species uniquely shaped by people ever since dogs left the wolf pack and joined our human ancestors at least 15,000 years ago. Accurately mapping the dog genome took about two years and $30 million. [How much do the US taxpayers spend on 'junk' DNA R&D? - comment, AJP] Canis familiaris is the latest species to have its genetic code mapped, following that of the rat, mouse, fruit fly and, most famously, the human.

A report on the work appears today in Nature, the British science journal.

Simultaneously, Cold Spring Harbor Laboratory on Long Island devoted the December issue of its journal "Genome Research," exclusively to canine studies, and produced a book, "The Dog and Its Genome," co-edited by the Whitehead Institute's Kerstin Lindblad-Toh, lead author of the genome study.

Researchers note that dogs share many of the same gene-related health conditions as humans, including cancer and obesity. They have about 19,300 genes, scientists estimate, all but a handful close copies of human genes. [If this is not sobering, it is difficult to think what is - comment, AJP]Although humans have half a billion more DNA units ["Eureka!" - comment, AJP], or "base pairs," that's mostly because humans are thought to have more silent stretches of so-called junk DNA.

"It's basically the same gene set in dogs and humans," Lindblad-Toh said during a telephone interview this week.

Dogs attract keen research interest in part because of their astounding variety of sizes, physical forms, coat colors and, of course, behavioral traits. If some of these variations can be traced to genes, results may shed light on more subtle variability in other species, including humans. [A logical mistake - if the gene sets are "basically the same" even from dog to human, the variability must be in the 'junk' DNA that varies from individual to individual within each species, and there is more than half a billion basepair difference between dog and human 'junk' DNA - comment, AJP]

The task is made more manageable because the same breeding programs that generated the 350 or so modern dog breeds also left precise records of lineages going back many generations. These are tied in some cases to detailed medical records and observations by trainers and owners -- a treasure trove in the era of comparative genomics. [Before we throw money at that, we'd better spend it on human medical records from a comparative genomics viewpoint - see several articles in this digest - comment, AJP]

After hundreds of years of selective inbreeding, many of the most prized purebreds have a high risk of genetic maladies. Discovery of a narcolepsy gene in Dobermans, for instance, helped scientists understand what caused the human form of the sleep disorder.[True, but even more importantly, Society could start focusing on diseases that are already known, or strongly suspected to originate from -hitherto thrown away- 'junk' DNA; see 'junkDNA diseases' such as Tay-Sachs, Multiple Myeloma, Malaria, Epilepsy, Fragile X, Autism, and the list grows by the day. No "gene discovery" will help patients from suffering from hereditary diseases that are demonstrably caused by 'junk' DNA - comment, AJP]

"The dog is a good model for human disease," Lindblad-Toh said. "They are highly intelligent, social animals, and we interact with them in the same environment." [Wow - are we looking for the "intelligence gene" or "social gene"??? As we already know that for certain social behaviors 'junk' DNA may be the clue - comment, AJP]

[The dog DNA sequencing amounts to a "triple whammy" after sequencing the mouse in 2002 and the chimp this September. This is a true  "wake up call" to finally face reality and assign top preference to 'Junk' DNA in PostGenetics ! - Comment by Dr. Pellionisz on the 8th of December, 2005]

Australian GTG (holding the presently only US-issued 'junkDNA' patents), traded on NYSE under "GENE"

jumped today by 8.47%, anticipating [or leaking...] settlement by tomorrow's 9:30 A.M. (PST) Court-deadline.

[Speculation is rampant (and it is just "speculation") since Genomics already procuded "shotgun sequencing"... PostGenetics might also produce "shotgun wedding" - Business analysis is not available publicly. - Comment by Dr. Pellionisz on the 6th of December, 2005]

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Further Update regarding Applera Dispute - [Court allows one more workday to settle with "GENE"]

On November 24th, 2005, Genetic Technologies Limited (ASX: GTG; NASDAQ: GENE) advised the Market that the United States District Court, Northern District of California had posted on its website a joint Stipulation granting additional time, until Monday, December 5th, 2005 (US time), to complete a binding Settlement Agreement, as well as attendant licenses and a supply agreement.

GTG now advises that the Court has posted Civil Minutes from a recent telephone conference held between Judge Joseph Spero and the Parties requiring that, if the settlement documents have not been finalised by December 7th, 2005, the Parties must attend a further settlement conference in San Francisco, California at 9.30am that day. A complete copy of the Minutes is attached.

GTG sees this as a positive development in the progress of this matter.

Dr. Mervyn Jacobson
Chief Executive Officer

Genetic Technologies Limited

[What the GTG/Applera settlement will bring about (a personal appearance of GTG/Applera is set by the Court for Wednesday, 7th of December) is proprietary information. Business analysis is not available publicly. - Comment by Dr. Pellionisz on the 5th of December, 2005]

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Startup Haplomics to Muscle In on Gene-Testing Market

By Graeme O’Neill, Australian Biotechnology News
December 01, 2005

Melbourne gene-testing company Genetic Technologies Ltd. (GTG), currently engaged in a protracted court case with giant U.S. rival Applera over licensing and royalties for GTG’s controversial non-coding DNA patents, has a potential rival in its own backyard.

Fledgling Melbourne biotech Haplomics Technologies, established in 2003, has lodged provisional patents on two powerful new technologies for diagnosing genetic disorders, and identifying genes involved in inherited genetic diseases. [See outline of new IP of Haplomic Technologies Pty. Ltd., Melbourne, Victoria, AUSTRALIA - comment by A. Pellionisz, 9th of March, 2006]

The new techniques are the invention of GTG’s co-founder, and inventor of its controversial ‘junk’ DNA patents, New Zealand-born immunogeneticist Dr. Malcolm Simons. Simons quit GTG in 2000 after a rift with co-founder and current CEO Dr. Mervyn Jacobson. [Although it is on public record that Simons has zero financial or other interest in GTG, some still seem to be unaware of this fact - comment by A. Pellionisz, 9th of March, 2006]

Simons believes Haplomics’ new technologies represent a new paradigm in gene discovery, and will be a powerful tool for disentangling the contributions of genetic variation, variation in the cell’s RNA-based operating system, and environmental factors, to genetic diseases, genomic disorders like cancer and autoimmune diseases, as well as individual susceptibility to infection.

Crucially, Simons’ new techniques would allow geneticists to conduct gene discovery research, and diagnose genetic diseases, without being dependent on GTG’s marker technology.

Hunting Haploids

Today’s genetic tests, and gene-hunting research, are performed on mixed, diploid DNA—it has been almost impossible to distinguish the separate, haploid contributions of the male and female parents to individual’s genetic makeup, or to discern how they interact.

At this week’s 14th International HLA and Immunogenetics Workshop and Conference at the University of Melbourne, Simons described how he has implemented his ideas on a ‘haplotyping’ chip—a DNA microarray that will allow researchers to identify all sequence variation in corresponding, multi-gene segments of an individual’s paired chromosomes.

Haplomics’ HiSNP-typing chip will identify single nucleotide polymorphisms (SNPs) in gene exons that result in amino-acid substitutions in the encoded protein, and SNPs that result in so-called synonymous substitutions without altering the amino acid sequence of the eventual protein.

The haploid segments, spanning multiple genes on corresponding segments of paired chromosomes, will garner complete information about DNA sequence variation across multiple, linked genes.

It will enable identification of the separate contributions of the two haplotypes.

Tip of the Iceberg

Simons said DNA microarray technology had advanced to the stage where a single chip can carry hundreds of thousands of DNA probes. But until now, microarrays have been used to detect SNPs scattered across chromosomes, and separated by some thousands of nucleotides.

These represent SNPs identified by previous research. Simons said researchers have now realised that these widely spaced SNPs represent just the tip of the iceberg, and do not fully account for haplotype differences.

This technique, which Simons terms ‘interval SNPing’, fails to recognise the wealth of variation in the long intervals between selected SNPs. Interval SNPing, more commonly known as ‘resequencing’, was the preferred technology for the multi-million dollar international HapMap Project.

In a number of multi-gene complexes, such as the HLA (human leucocyte antigen) complex, which spans 4 million nucleotides on chromosome 6, as many as six or eight SNPs may occur within an interval of only 25 nucleotides,” Simons said.

The interval SNPing approach is tantamount to striding across a chromosome in seven-league boots—it misses an enormous number of SNPs and other forms of DNA-sequence variation in the intervening tracts of chromosome.

These unrecognised SNPs may contribute to genetic disorders, or disease susceptibility. Simons said his ‘overlapping SNP’ technique would blanket chromosome segments with huge numbers of overlapping probes to capture all sequence variation.

Focus on Immunity

Initially, Haplomics is focusing on the HLA complex, headquarters of the human immune system, and the 150,000 nucleotide killer-cell immunoglobulin-like receptor (KIR) complex on chromosome 19, which is at the core of innate immunity, and also modulates the adaptive immune response.

The KIR gene complex is involved in the outcome of tissue and organ transplants—immunogeneticists have recently identified the KIR complex as the source of a mysterious mechanism that allows some transplant patients to accept bone marrow or organ grafts from non-matching donors.

KIR genes have also been implicated in susceptibility to autoimmune disorders like insulin-dependent diabetes, multiple sclerosis and rheumatoid arthritis.

Simons used proprietary Oligo-Select software to identify 34,000-odd probes required to detect all variation in the major genes involved in tissue-matching.

Haplomics’ first chip, which is being delivered this week, detects variation at only nine of the more than 220 genes in the HLA complex

While the number of probes theoretically required to detect all variation in just nine HLA genes is potentially enormous, over the millennia, natural selection has winnowed the number of HLA gene combinations to a number that can be easily accommodated on a single chip.

Test of Time

Simons said certain combinations of HLA alleles have stood the test of time, and been welded by natural selection into integrated, functional units that tend to escape recombination, and are inherited en bloc as haplotypes extending up to tens of kilobases.

He expects the patterns of SNP combinations within these extended haplotype ‘blocks’ to be more revealing than those obtained with interval SNPing. He also expects synonymous substitutions in the DNA code, that do not alter amino acid sequence of the encoded protein, will be informative in assigning haplotypes.

Linked genes in the same block of chromosome are described as being in cis phase, but Simons’ technique opens up the possibility of detecting trans interactions—’cross-talk’ between alleles at the same locus on the paired chromosomes, and epistatic interactions between different loci on complementary chromosomes.

Being able to distinguish the two separate haplotypes is the Holy Grail of gene discovery,” Simons said. “It is recognised as being a far more powerful tool for identifying genes involved in disease, drug response and other traits than techniques based on single SNPs alone.”

IP Protection

Given that Haplomics’ new techniques have the potential to revolutionise research and genetic testing, GTG and its rivals—including Applera—may be keenly interested in the infant biotech’s new IP. [All inquiries regarding said IP must be directed exclusively to Dr. Simons. This commentator is not affiliated financially or obligated in any way to Haplomic Technologies or its inventors. Drs. Simons and A. Pellionisz share at this point zero Intellectual or other Property. They share the academic accomplishment of a peer-reviewed publication in support of the "Fugu prediction of FractoGene" and share with many others the common and fully public goals of the International PostGenetics Society, in order to attribute "number one priority to formerly 'junkDNA'". Specifically, both "FractoGene" and the "Methylation Prediction of FractoGene" are solely by A. Pellionisz - comment by A. Pellionisz, 9th of March, 2006]

GTG would have an interest in protecting its IP position against any rival gene testing technology that does not rely on Simons’ original invention, which detects disease-causing alleles of known genes by their association with markers in non-coding DNA—both in introns and inter-genic ‘junk’ DNA. The DNA marker and the disease-causing allele are ‘linked’ as extended haplotypes.

The GTG gene-search, another Simons invention, allows geneticists to identify anonymous genes through linkage disequilibrium. Linkage disequilibrium describes a tendency of a DNA marker and an anonymous gene to be co-inherited at a frequency much greater than would be predicted from the distance between them on the chromosome.

Simons can lay claim to being the first researcher in the world to realise that long-distance associations between markers in ‘junk DNA’ and particular diseases could be used to locate and identify genes involved in relatively rare inherited disorders, where no multi-generation, extended pedigrees are available. [Note that Malcolm J. Simons' above claims are intellectual, deserving credit as such; he does not claim financial (patent) royalties himself for his past pioneering. IPGS recognizes him for his intellectual conribution - comment by A. Pellionisz, 9th of March, 2006]

The GTG patent for this discovery describes how the technique can be applied to map disease genes, by identifying highly conserved haplotypes shared by affected, unrelated individuals—even individuals from different cultural or ethnic groups.

[December 1-5, 2005 are days that mark history. After over 25 years of pioneering, Malcolm J. Simons' patents have validated the concept of "Intellectual Property value" for the age of PostGenetics. His early patents, recognizing the diagnostic utility of the fact that the pattern in 'junk' DNA wasn't random, are now valued over $209 M and after the Australian GTG (traded on NYSE NASDAQ under stock symbol GENE), to which the patent were assigned, will settle with $6 B USA Genome-giant Applera, the value is bound to catapult. This is a time of historical singularity. The value proposition is proven beyond the slightest of doubt. However, the combined price tag as of today of all the outstanding Intellectual Property on 'junk' DNA (including Dr. Simons' new patents on diagnostic utility), and further IP (including algorithmic, thus software- and nanoengineering-ready, experimentally supported IP) is, at this very early stage of perhaps the most important disruptive R&D event in history - presently hovers around one tenth of the cash that eBay paid for Skype a few weeks ago. - What the GTG/Applera settlement will bring about (set by the Court for Monday, 5th of December) is proprietary information. Business analysis is not available publicly. - Comment by Dr. Pellionisz on the 2nd of December, 2005]

[FURTHER CLARIFYING NOTES were inserted in the above communique on the 9th of March, 2006 by A. Pellionisz]

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MicroRNA may have fail-safe role in limb development

University of Florida, Harvard researchers link microRNA to growth

Contact: John Pastor

GAINESVILLE, Fla. - A tiny strand of molecules plays a role in how our arms and legs develop and grow - a finding that sheds light on perplexing bits of material once dismissed as genetic "junk," say scientists at the University of Florida and Harvard University.

The research, available today in the online edition of Nature, may help scientists understand whether bits of RNA called microRNAs act as protective mechanisms in healthy development not just by strategically turning off gene activity, but by making sure it stays turned off.

More specifically, researchers report linking a specific microRNA - miR 196 - to limb development, a finding that may be useful in understanding birth defects.

Until about five years ago, genetic researchers focused on DNA, which contains all the genetic instructions for the human body, and RNA, which translates DNA's message into proteins - the building blocks of cells, organs and all of the various systems of the body.

Unnoticed next to the main ingredients, microRNAs were considered to be "junk" DNA, leftovers from millions of years of evolution. More recently, this genetic material is suspected to be part of an intricate mechanism that helps repress about one-third of our 25,000 genes. It has been linked to diabetes, hepatitis C, leukemia, lymphoma and breast cancer.

But only now have microRNAs been connected to actual growth processes.

"We found miR 196 expressed only in the hindlimbs of mice, not the forelimbs - in other words, the feet but not the hands," said Brian Harfe, Ph.D., an assistant professor of molecular genetics and microbiology in the College of Medicine and a member of the UF Genetics Institute. "In developmental biology, there has always been debate about why forelimbs are different from hindlimbs. We now think this microRNA is regulating something important in the hindlimbs but not in the forelimbs."

Scientists do not know exactly what is happening, but they think miR 196 acts as a protective mechanism in the hindlimbs in the event normal gene transcription goes awry.

"A large body of evidence indicates this new class of regulators is not something to turn things off in the first place, but a fail-safe," said Clifford Tabin, Ph.D., a professor of genetics at Harvard Medical School and senior author of the research. "You don't want cells in a hindlimb seeing cells that should only be in a forelimb - it would create a defective limb. So you not only want to shut the faucet tight on the wrong cells, you want to shove a towel into it, too, to really make sure the wrong thing doesn't leak out. One way of doing that is with microRNA."

Researchers looked at gene activity in chicken embryos and in mice, finding miR-196 silences a chemical important for transferring information from DNA to RNA within a cell - a transcription factor.

"It's turning off a transcription factor in the hindlimb that is important for forelimb development," Harfe said. "But it still doesn't explain why a hindlimb is a hindlimb and a forelimb is a forelimb."

The next step in the research is to observe limb development in mice engineered to not express miR 196.

"The authors have shown a role for miR 196 in limb development," said John Fallon, the University of Wisconsin's Harland Winfield Mossman professor of anatomy. "People talked about ways microRNA may have a role in embryonic development, and this work is a solid contribution that supports that idea. Researchers have also been looking for differences between gene expression in forelimbs and hindlimbs, with little success. This paper suggests there is a new mechanism to control the fidelity of protein expression in the limbs through microRNA expression. That is a hypothesis that people in the field will have to test, but it is strongly supported by their research."

[A major accomplishment and a conceptual development. Clearly, the "not very sophisticated" idea of simply "turning genes on and off" is conceptually superseded. It is replaced by the concept of "growth" (physiological, or in case of a number of "regulatory" diseases pathological growth). The "Methylation Hypothesis of FractoGene" is eminently suitable here - part of the "experimental tests" that are needed in a solid mathematical framework - comment by Pellionisz on 1st of December, 2005]

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SETI and Intelligent Design

By Seth Shostak
SETI Institute
01 December 2005

If you’re an inveterate tube-o-phile, you may remember the episode of "Cheers" in which Cliff, the postman who’s stayed by neither snow, nor rain, nor gloom of night from his appointed rounds of beer, exclaims to Norm that he’s found a potato that looks like Richard Nixon’s head.

This could be an astonishing attempt by taters to express their political views, but Norm is unimpressed. Finding evidence of complexity (the Nixon physiognomy) in a natural setting (the spud), and inferring some deliberate, magical mechanism behind it all, would be a leap from the doubtful to the divine, and in this case, Norm feels, unwarranted.

Cliff, however, would have some sympathizers among the proponents of Intelligent Design (ID), whose efforts to influence school science curricula continue to swill large quantities of newspaper ink. As just about everyone is aware, these folks use similar logic to infer a "designer" behind such biological constructions as DNA or the human eye. The apparent complexity of the product is offered as proof of deliberate blueprinting by an unknown creator—conscious action, presumably from outside the universe itself.

What many readers will not know is that SETI research has been offered up in support of Intelligent Design.

The way this happens is as follows. When ID advocates posit that DNA—which is a complicated, molecular blueprint—is solid evidence for a designer, most scientists are unconvinced. They counter that the structure of this biological building block is the result of self-organization via evolution, and not a proof of deliberate engineering. DNA, the researchers will protest, is no more a consciously constructed system than Jupiter’s Great Red Spot. Organized complexity, in other words, is not enough to infer design.

But the adherents of Intelligent Design protest the protest. They point to SETI and say, "upon receiving a complex radio signal from space, SETI researchers will claim it as proof that intelligent life resides in the neighborhood of a distant star. Thus, isn’t their search completely analogous to our own line of reasoning—a clear case of complexity implying intelligence and deliberate design?" And SETI, they would note, enjoys widespread scientific acceptance.

If we as SETI researchers admit this is so, it sounds as if we’re guilty of promoting a logical double standard. If the ID folks aren’t allowed to claim intelligent design when pointing to DNA, how can we hope to claim intelligent design on the basis of a complex radio signal? It’s true that SETI is well regarded by the scientific community, but is that simply because we don’t suggest that the voice behind the microphone could be God?

Simple Signals

In fact, the signals actually sought by today’s SETI searches are not complex, as the ID advocates assume. We’re not looking for intricately coded messages, mathematical series, or even the aliens’ version of "I Love Lucy." Our instruments are largely insensitive to the modulation—or message—that might be conveyed by an extraterrestrial broadcast. A SETI radio signal of the type we could actually find would be a persistent, narrow-band whistle. Such a simple phenomenon appears to lack just about any degree of structure, although if it originates on a planet, we should see periodic Doppler effects as the world bearing the transmitter rotates and orbits.

And yet we still advertise that, were we to find such a signal, we could reasonably conclude that there was intelligence behind it. It sounds as if this strengthens the argument made by the ID proponents. Our sought-after signal is hardly complex, and yet we’re still going to say that we’ve found extraterrestrials. If we can get away with that, why can’t they?

Well, it’s because the credibility of the evidence is not predicated on its complexity. If SETI were to announce that we’re not alone because it had detected a signal, it would be on the basis of artificiality. An endless, sinusoidal signal – a dead simple tone – is not complex; it’s artificial. Such a tone just doesn’t seem to be generated by natural astrophysical processes. In addition, and unlike other radio emissions produced by the cosmos, such a signal is devoid of the appendages and inefficiencies nature always seems to add – for example, DNA’s junk and redundancy.

Consider pulsars – stellar objects that flash light and radio waves into space with impressive regularity. Pulsars were briefly tagged with the moniker LGM (Little Green Men) upon their discovery in 1967. Of course, these little men didn’t have much to say. Regular pulses don’t convey any information—no more than the ticking of a clock. But the real kicker is something else: inefficiency. Pulsars flash over the entire spectrum. No matter where you tune your radio telescope, the pulsar can be heard. That’s bad design, because if the pulses were intended to convey some sort of message, it would be enormously more efficient (in terms of energy costs) to confine the signal to a very narrow band. Even the most efficient natural radio emitters, interstellar clouds of gas known as masers, are profligate. Their steady signals splash over hundreds of times more radio band than the type of transmissions sought by SETI.

Imagine bright reflections of the Sun flashing off Lake Victoria, and seen from great distance. These would be similar to pulsar signals: highly regular (once ever 24 hours), and visible in preferred directions, but occupying a wide chunk of the optical spectrum. It’s not a very good hailing-signal or communications device. Lightning bolts are another example. They produce pulses of both light and radio, but the broadcast extends over just about the whole electromagnetic spectrum. That sort of bad engineering is easily recognized and laid at nature’s door. Nature, for its part, seems unoffended.

Junk, redundancy, and inefficiency characterize astrophysical signals. It seems they characterize cells and sea lions, too. These biological constructions have lots of superfluous and redundant parts, and are a long way from being optimally built or operated. They also resemble lots of other things that may be either contemporaries or historical precedents.

So that’s one point: the signals SETI seeks are really not like other examples drawn from the bestiary of complex astrophysical phenomena. That speaks to their artificiality.

The Importance of Setting

There’s another hallmark of artificiality we consider in SETI, and it’s context. Where is the signal found? Our searches often concentrate on nearby Sun-like star systems – the very type of astronomical locale we believe most likely to harbor Earth-size planets awash in liquid water. That’s where we hope to find a signal. The physics of solar systems is that of hot plasmas (stars), cool hydrocarbon gasses (big planets), and cold rock (small planets). These do not produce, so far as we can either theorize or observe, monochromatic radio signals belched into space with powers of ten billion watts or more—the type of signal we look for in SETI experiments. It’s hard to imagine how they would do this, and observations confirm that it just doesn’t seem to be their thing.

Context is important, crucially important. Imagine that we should espy a giant, green square in one of these neighboring solar systems. That would surely meet our criteria for artificiality. But a square is not overly complex. Only in the context of finding it in someone’s solar system does its minimum complexity become indicative of intelligence.

In archaeology, context is the basis of many discoveries that are imputed to the deliberate workings of intelligence. If I find a rock chipped in such a way as to give it a sharp edge, and the discovery is made in a cave, I am seduced into ascribing this to tool use by distant, fetid and furry ancestors. It is the context of the cave that makes this assumption far more likely then an alternative scenario in which I assume that the random grinding and splitting of rock has resulted in this useful geometry.

In short, the champions of Intelligent Design make two mistakes when they claim that the SETI enterprise is logically similar to their own: First, they assume that we are looking for messages, and judging our discovery on the basis of message content, whether understood or not. In fact, we’re on the lookout for very simple signals. That’s mostly a technical misunderstanding. But their second assumption, derived from the first, that complexity would imply intelligence, is also wrong. We seek artificiality, which is an organized and optimized signal coming from an astronomical environment from which neither it nor anything like it is either expected or observed: Very modest complexity, found out of context. This is clearly nothing like looking at DNA’s chemical makeup and deducing the work of a supernatural biochemist.

[No other comment but "what a vaste of time and resources"! The "mystery" of "junk" DNA is being resolved by scientific (experimentally precitive and thus refutable) manner. What Darwinists might wish to concentrate on instead of "debating the undebatable" is to admit that most of them were wrong "predicting" that "junk" DNA was good for nothing - while ID/ET was/is actually right on this issue (it is NOT junk). Darwinism vastes every minute and penny when not going directly to the core of the issue- scientifically explaining the role of "junk" DNA. - comment by Pellionisz on 1st of December, 2005]

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Treasures in the Trash - [Now, we talk about Business; a fortcoming article from Forbes.. AJP]

Matthew Herper and Robert Langreth, 12.12.05

[As we have seen lately, even basic journalistic information is no longer "free" on "junkDNA". Since Forbes projects enormous "business treasure" - mostly in Big Phama for Drug Discovery, but other leading journals will cover the entire gamut from Biotech-to-Nanotech-to-Infotech - the article is not available "just for the clicking" - it has got to generate some business for Forbes, first. We'll see some telltale numbers from business from the second breaking news below to show how an entirely new business is taking off - comment on 24th of November by Dr. Andras J. Pellionisz]

What genetic researchers used to call junk DNA may conceal the most important medical secrets of all. [Wow - rather strong words... AJP]

When researchers began mapping the genome, aiming to decode the entire human gene sequence, they expected to eventually locate 100,000 or more active genes. After completing the genome map in 2001, they were startled to find that humans have only 25,000 active genes. The lowly roundworm has almost as many (19,000). [From this website, being re-organized for much easier navigation, it is easy to find that one year ago the human number was already down to about 20,000 ... start gettting used to the idea, that the "genes" are essentially the same for all living organism ... as is in chemistry, every existing or imagined chemical compound is made of "only" from the elements of the periodic table of Mendeleiev, established in physics. Genetics provided a pretty good knowledge of the rather constant set of sturdy "genes" - now it is up to Postgenetics, to provide the "chemistry" of how living organisms are "cooked" from the same ingredients - AJP]

That means the active genes contain a mere 1.5% of the 3 billion units of DNAthat make up our genetic structure. The rest is "dark" or "junk" DNA, long presumed to be present for no particular reason. [Until the International PostGenetics Society formally abandoned this misnomer - AJP]

But researchers are now finding this junk DNA, overlooked for decades by geneticists, may actually not be junk at all. They are finding hints of an enormous and previously unimagined command-and-control apparatus that regulates what our 25,000 genes do and how the body is assembled. Junk DNA, when it goes wrong, may be a culprit in major killers ranging from cancer to diabetes to infectious disease. [See a compilation of "junkDNA diseases" by AJP]

That insight could unearth hundreds of new targets for experimental drugs that had been aimed only at working genes. "It's sort of like Antiques Roadshow," says Harvard genome scientist John Quackenbush, who has long argued that the junk DNA could be vital. "You look in the closet full of junk and find out you have a Picasso." [With all due respect for Picasso, the analogy is wrong. It is more like that a door in the attic leads directly to the "Museum of PostModern Art" - AJP]

"This will revolutionize human genetics over the next few decades," says David Haussler, a Howard Hughes investigator at UC, Santa Cruz who was on the government team that decoded the human genome. He predicts that most disease-causing genetic flaws will be found lurking in our junk DNA.

[Wow! If this is true - and there is an increasing consensus that it is - society will gear up to a major re-allocation of resources, most likely starting with the $30 Billion-budget NIH, and estabishing "Non-coding DNA Programs" at Founding Agencies faster than light, to nip criticism in the bud that they have been ignoring a colossal vaste of money. "Gene Discovery" will make room to "PostGene Discovery" - at the least desperately searching for some suitable PostGene Discovery methods of how "genes" are working with "non-genes". Most obviously, the outcry will be loud and clear by Societies aimed at fostering faster progress in particularly nasty diseases, Fragile X Syndrome, Cancers (such as Multiple Myeloma), Ataxias (such as Friedreich), Tay-Sachs diseases (and a lot more), that "medicine has been barking up the wrong tree for too long - AJP]

The dark DNA "may be even more important" than active genes in causing disease, says Isaac Bentwich, chairman of Israel's Rosetta Genomics. Founded in 2000, Rosetta has applied for patents on 200 dark genes. He hopes for new treatments and diagnostic tools for lung cancer, prostate cancer and other diseases. [Very interesting; "Dark Genes". Does this mean that we are going to be held in the "dark" about the theoretical explanation of what "junkDNA" is doing? Patenting may not be the entire solution. Remember that 100,000+ "genes" were patented - when it turned out that at the least 80,000 of them don't exist. On the other hand - see next "news"- patents as few that can be counted on a badly injured one hand are generating an avalanche of cash-flow, since the applications are based on (non-random) principles of "junkDNA" found - AJP]

Bentwich's team is focusing on something called microRNA, a promising target discovered in the sea of junk DNA only five years ago. MicroRNAs essentially quell a gene's workings, and they already have been linked to diabetes, hepatitis C, leukemia, lymphoma and breast cancer.

"It's a revolution in how we understand the genome and how the cell functions," says MIT Nobel laureate Phillip Sharp. "There's a whole new frontier there." [Yepp, an the "revolution" already broke through some "frontiers". There are mathematicall stated theories, intellectual property, methods designed for finding "PostGenes" linked to "Genes", and an entire Society is emerging for "collective bargaining"- AJP]. Sharp and a few microRNA researchers have founded Alnylam Pharmaceuticals to invent RNA-based drugs to treat Parkinson's, cystic fibrosis and spinal injury. The firm has development deals with Merck and Novartis, and such rivals as San Francisco's Sirna Therapeutics are in pursuit.

The new view of junk DNA [Where is the "new view"? for one, see FractoGene - AJP] overturns 50 years of dogma in molecular biology. James Watson and Francis Crick discovered DNA's structure in 1953. The double-helix, twisted ladder of chemical base pairs is carried on the 23 pairs of chromosomes that inhabit every cell in the body. The human genome contains 3 billion base pairs (or "letters") of DNA, and one active gene can span thousands of base pairs.

For decades scientists have zoomed in on the active genes that carry instructions for making hundreds of thousands of proteins; this protein production is carried out by DNA's doppelgänger, RNA. The dark genes were dismissed as debris left over from millions of years of evolution

Now that junk-DNA theory looks to be junk. Huge expanses of dark DNA are nearly identical in numerous species, from flies to rats to humans. That nature has conserved the dark stuff for millions of years is a clear indication that it must do something crucial, biologists say.

Some say that the dark DNA that plays a crucial role in the body could occupy at least 4% of the genome--almost three times the portion taken up by active genes. A better guess is that a huge 40% to 70% of the whole DNAsequence is dark DNA with secret powers, posits Peter Andolfatto, a fruit-fly geneticist at UC, San Diego. [The numbers are slightly astray here - no wonder in the confusion. It would be more correct to say that no "free standing" living organism, not even bacteria, have been shown without "junkDNA" - the smallest percentage in the DNA is about 4% in some bacteria, although other bacteria may contain up to 50% "junk" in their DNA. The "almost three times" is probably a confusion of the fact that "genes" in *human* amount to 1.3% only (roughly one third of "4%", which is the "junkDNA" contents of some of the most primitive bacteria). In homo sapiens the "junkDNA" content is *not* "almost three times the portion taken up by active genes" , but an astounding "almost *seventy six* times the portion taken up by active genes". This is good news for business. It hardly ever happens, that a market suddenly explodes by 7,600%. Venture Capitalists typically expect a tenfold expansion in the short run - and sometimes have to settle for a threefold return. How about a 7,600% return? - AJP]

An early hint that junk DNA might hold treasures came in 1993, when Victor Ambros of Dartmouth Medical School studied a mysterious genetic mutation in worms that prevented them from maturing from the larva stage to adult. To his astonishment, he found that the mutation existed not in active genes but in dark DNAthat controlled a tiny strand of RNA, the first microRNA whose main function was to turn off another gene. [The "turning genes on and off" analogy probably irritates the hell out of concert pianists. While technically it is "true" that all they do is to either hit on some keys or not at any given time - and their 10 fingers is only a small fraction of all the available keys :-) - they might proudly believe that there is slightly more to be a concert pianist than "turning keys on and off" ... AJP]

The result remained an isolated curiosity until 2000, when Harvard Medical School geneticist Gary Ruvkun found a second microRNA in worms and showed it also was present in people. That suggested there might be a whole realm of mysterious and undetected RNA master controllers inside cells. Soon several supercomputers tried tracking them down-- and quickly found them, in abundance. Now researchers figure 300 to 1,000 human microRNAs form a hidden layer of control, helping determine which genes are turned off when. They may help regulate 30% or more of all proteins. ["Hidden layer" is a technical term "borrowed" from "neural net theory" - one of the earliest "success stories" of geometrization of biology. While "neural nets" are clearly one of the useful tools of "geometrization of Genomics", some of those who "wrote the book on Neural Nets" might not be particularly happy by the use of its sloppy, ill-defined or outright mistaken - usage - AJP]

One, called microRNA 375, can block insulin secretion and may be involved in diabetes. Another, microRNA 122, is found in the liver and is used by the hepatitis C virus to help it replicate; it could be a target for future drugs for the disease. "MicroRNAs are almost ideal drug targets. The field is exploding," says Rockefeller University's Markus Stoffel. He and colleagues at Alnylam recently created new RNAdrugs that bind to and break down specific microRNAs. When they tested one such RNA drug in mice, cholesterol levels fell 44%. [ALNY stock holders are happy to see that the price went up almost 80% since "Newsweek" published their article on "junkDNA" in the summer. Lipitor patent expires in 4 years - time to invest in "super-Lipitor"? - AJP]

MIT and Harvard researchers showed in June that 217 microRNAs were altered in a wide array of tumors. Ohio State University researchers, writing in the New England Journal of Medicine in October, found that levels of just 13 microRNAs predicted how quickly a common type of leukemia would progress. Moreover, of 75 patients studied, 11 patients with this leukemia had mutations in their microRNA that may have caused the disease. This was the first time such mutations had been found. "When I was giving talks about microRNAs three years ago, people thought I was from Mars," says cancer geneticist Carlo Croce, who led the research. [Yes, there are times when it is "too early" to invest. But there is also a time when "it is too late"... AJP]

But even microRNA, one of myriad types of RNA, accounts for only a tiny fraction of junk DNA. What the rest does is still mostly a mystery, but almost certainly it is doing something. Many areas of the genome previously thought to be barren actually are churning out huge quantities of RNA, chipmaker Affymetrix has found. There may be hundreds of thousands of RNA molecules of various kinds that boss around our genes, says Affymetrix research director Thomas Gingeras. ["To boss around our genes" is a great colloquial term. Affy, however, if far too serious to be content wish less than an algorithmic approach to "junkDNA" - at least, if it doesn't want to see a disruption in the microarray-field it invented ... AJP]

Even dark DNA that doesn't ever transform into microRNA or a protein-coding active gene may have crucial functions. A recent study examined a three-year-old Japanese girl with a DNA mutation that caused her to have two thumbs on each hand and seven toes on each foot. The mutation turned out to be in the junk DNA. Astoundingly, the junk DNA mutation somehow had disrupted the function of a distant development gene that lies a million DNA letters away. [So why don't we fact the issue that "junkDNA" is part of the set of the algorithmic expression of growth? We can count on the fingers of any limb what mathematical theories are around to generate growths.. . Hint: Fractals is one, an iterative process of self-similarity ... Fractals produce "beautiful" and "complex" growth, where "beauty is in the eye of the beholder", while "complexity is in the eye of the bewildered" - AJP].

[With so many comments in the excellent write-up above, one only wonders which leading Journal will draw some inevitable conclusions after Newsweek in the Summer and Forbes in the Fall. We may also wonder about the timing, since "timing is everything". Business conclusions are extremely unlikely to wait until the breakthrough in journalism... Comment by AJP on 24th of November, 2005]

The elusive fountain of youth

Kathleen Fackelmann
USA Today
Nov. 28, 2005 12:00 AM

Frank Murray gets up before dawn every morning and exercises to keep limber.

No big deal for a man in his 50s or 60s. But Murray's 101.

Murray drives to church on Sundays. He reads the newspaper every day. He cooks, mostly stews that he loads up with vegetables.

Murray, of Hayward, Calif., belongs to an elite fraternity, the 71,000 Americans who are 100 years old or older. Their ranks are growing. The U.S. Census Bureau projects that 114,000 Americans will be centenarians in 2010, a number expected to swell to 241,000 by 2020.

Why are so many living so long? Legions of scientists are probing the secrets of longevity, taking a hard look at everything from gray hair to damage deep within cells. They are trying to understand today's centenarians and to find ways to extend the human life span.

Medical advances of the 20th century, such as antibiotics and statin drugs for heart disease, have allowed the average person to live decades longer than someone born in 1900. If those advances continue, will scientists push the envelope of human life far past 100? Can people routinely live to 150 or even 200?

Right now, most Americans say they don't want to live that long. A just-released USA Today/ABC News poll of 1,000 adults shows that Americans, on average, would like to live to be 87, up from the current life span of nearly 78. Just a quarter of the people who responded to the poll said they want to live to be 100 or older.

Most worry that they'll become disabled by health problems and end up being a burden to family members.

But old age, as Murray illustrates, doesn't always translate into disability or even disease. Scientists have made some progress toward therapies that would slow the aging process.

Research by Richard Weindruch at the University of Wisconsin-Madison and others suggests that an extremely low-calorie diet, on the edge of starvation, pushes the life span of mice and other animals to an extreme.

If people got the same benefit, some might live beyond 120, about the longest the human body is thought to be able to last today.

Other advances on the horizon include research to identify those genes that might one day protect people from heart disease and other age-related killers.

The National Human Genome Research Institute last week announced plans to use its gene-sequencing capabilities to search for the genetic roots of diseases that have eluded scientists.

Scientists at the University of Utah and other research institutions believe that telomeres - long segments of repeated "junk" DNA on the ends of chromosomes - may hold the same key to human longevity that they do to the life of an individual cell. The Utah team linked shortened telomeres to higher death rates from heart and infectious diseases and speculated that telomere-lengthening drugs could add years to a human life.

"Nothing discovered yet has been shown to stop or slow down aging," says Robert Butler, president of the International Longevity Center-USA. Still, Butler and other experts say discoveries being made today can help people live longer and healthier lives.

"A baby born today has a 50 percent chance of living to about 79 or 80," says Leonard Hayflick, a researcher on aging at the University of California-San Francisco. Public health advances such as clean water and antibiotics have added decades to the average life expectancy.

But experts say there's a limit to the rise in life expectancy. Humans, he says, simply aren't built to live for 150 or 200 years.

"Our body parts, like the parts in an automobile engine, can't work forever," Hayflick says.

The oldest human on record, Jeanne Calment of Arles, France, died in 1997 at 122, probably of heart disease.

Experts say such super-agers are rare: "Only a small number of people have the potential to live that long," says Jay Olshansky, a demographer at the University of Illinois at Chicago.

People who live 100 years or longer probably inherited genes that slow the aging process or protect them from diseases such as cancer or heart disease, says Thomas Perls, director of the New England Centenarian Study at Boston University. Eventually, however, the wear and tear catches up, he says.

Perls and his colleagues are searching for genes that may offer a longevity edge. Researchers also are probing the biochemical basis of old age, looking for substances to slow the wear and tear.

But figuring out the aging process will take decades, says David Finkelstein at the National Institute on Aging. Even then, researchers may never find a pill to hold the line on old age.

"Some people really do want to live forever," says Christine Himes Fordyce, a geriatrics expert at the Group Health Cooperative in Seattle and co-author of a book on aging. "But most people just want to live as healthy and as full a life as they can."

[It looks these days that "junk DNA" is responsible for everything from cold feet to eternal life... Of course, the idea that telomeres - just like the hardened ends of your shoelace - will make it more difficult for your shoelace "to chip away" if they are longer, is not new. Silicon Valley start-up Geron introduced it as the cornerstone of its business and already holds an astounding number of patents on telomerese . It may be noted that both the "telemeres" and "methylation" are closely related not only to the lifespan, but also to life "as a sustainable growth process" - and either goes haywire the result may be cancer. The "Methylation Prediction of FractoGene" (see in Press Release on the 17th of October, 2005) proposes an experimentally testable prediction pertaining to a cell's life- Comment by A. Pellionisz on 28th of November, 2005]

Rosetta Genomics chairman Isaac Bentwich: "Dark DNA" may be even more important than active genes in causing disease

Gali Weinreb 27 November 2005

“Forbes” has cited Israeli start-up Rosetta Genomics Ltd. in an article on junk DNA “Forbes” writes that Rosetta Genomics is focusing on microRNA, a promising target discovered in junk DNA only five years ago.

Rosetta Genomics is one of the few commercial companies conducting research on microRNA. Founded in 2000, the company has registered patents on 200 microRNA molecules.

“Forbes” quotes Rosetta Genomics chairman Isaac Bentwich as saying that dark DNA may be even more important than active genes in causing disease. He hopes for new treatments and diagnostic tools for lung cancer, prostate cancer and other diseases. Junk DNA, also called “dark DNA” does not actively encode proteins.

The Human Genome Project, completed in 2001, did not map junk DNA. “Forbes” writes, “But researchers are now finding this junk DNA, overlooked for decades by geneticists, may actually not be junk at all. They are finding hints of an enormous and previously unimagined command-and-control apparatus that regulates what our 25,000 genes do and how the body is assembled.

Junk DNA, when it goes wrong, may be a culprit in major killers, ranging from cancer to diabetes to infectious disease.” “Forbes” quotes David Haussler, a Howard Hughes investigator at UC, Santa Cruz, as saying, "This will revolutionize human genetics over the next few decades.”

Haussler predicts that most disease-causing genetic flaws will be found lurking in our junk DNA. It now appears that some junk DNA is encoded by microRNA, which activates or shuts down, other protein-inducing genes.

For example, microRNA 375, can block insulin secretion and may be involved in diabetes. Another, microRNA 122, is found in the liver and is used by the hepatitis C virus to help it replicate; it could be a target for future drugs for the disease.

“Forbes” writes that microRNA is also involved in a small part of junk DNA activity, and that dark DNA may contain breakthroughs in many areas of medicine.

Bentwich founded the company, which has raised $16 million to date. Investors include Teva Pharmaceutical Industries Ltd. (Nasdaq:TEVA; TASE:TEVA), Leon Recanati, Yair Shamir, Moshe (Mori) Arkin, and Usia Galil. Six months ago, Rosetta signed an important contract with Ambion, a leading US biotechnology company, for a collaborative licensing agreement that will provide Ambion access to proprietary microRNA sequences discovered and owned by Rosetta Genomics. Rosetta Genomics’ science advisory board includes Nobel Prize laureate in Chemistry (2004) Prof. Aaron Ciechanover, former Weizmann Institute of Science president Prof. Michael Sela, Hadassah University Hospital’s Goldyne Savad Gene Therapy Institute director Prof. Eithan Galun, and, its newest member, former head of US Food and Drug Administration’s (FDA) science board Dr. Robert Langer. Rosetta Genomics is the second company founded by Bentwich. He sold Pegasus Medical to HBOC for $15 million in 1995.

[The two biggest problems with "Dark Genes" are that a) "junk DNA" is by definition is *not* gene (in any color). Second, they will not remain in the "dark" - thus the name is obsolete at its emergence. In the International PostGenetics Society there is a reference to "junk DNA" as "PostGenes" implying that "Genetics" after 100 years is here to stay, but in the second Century there is "Genomics Beyond Genes" with emphasis of attention shifting to the 98.7% (human) DNA from the sturdy, but few and far between "genes". In architecture, "PostModernism" did not negate any of the achievements of "Modernism" - just that time often comes to delineate a landmark. The discovery in 2002 that the mouse differs from the human 1% in the genes but 30% in the "junk DNA" was one sobering landmark. Now, after 1st of September 2005 knowing that humans differ from the chimp in 0.1% in the genes but there is a forty times larger 4% difference in the "junk DNA" puts not only our reflection on humanity, on evolution and on genomics, but also puts us in the middle of a massive industrial revolution (far surpassing the significance of the one in the 19th Century). As Juan Enriquez pointed out in his classic book ("As the future hits you") this scientific/technological/economic disruption will re-draw everything - including geopolitics. 15 Founders of International PostGenetics Founders represent 11 countries on 4 continents. Israel has clearly "bet her future" on becoming a pioneer and a major beneficiary of this revolution - Comment by AJP on 27th of November, 2005]

Submitted by one of the Founders of International PostGenetics Society, Mircea Achiriloaie.

["Architecture is not about bricks - or mortar. Architecture is about 'design'" - commentator A. Pellionisz]

Abstract of the Science article:
Vertebrate-type intron-rich genes in the marine annelid Platynereis dumerilii
F. Raible, K. Tessmar-Raible, K. Osoegawa, P. Wincker, C. Jubin, G. Balavoine, D. Ferrier, V. Benes, P. de Jong, J. Weissenbach, P. Bork and D. Arendt.
Science, 25 November 2005

Previous genome comparisons have suggested that one important trend in vertebrate evolution has been a sharp rise in intron abundance. By using genomic data and expressed sequence tags from the marine annelid Platynereis dumerilii, we provide direct evidence that about two-thirds of human introns predate the bilaterian radiation but were lost from insect and nematode genomes to a large extent. A comparison of coding exon sequences confirms the ancestral nature of Platynereis and human genes. Thus, the urbilaterian ancestor had complex, intron-rich genes that have been retained in Platynereis and human.

The earliest animals had human-like genes

Press Release, Heidelberg, Germany, Thursday 24 November 2005

Species evolve at very different rates, and the evolutionary line that produced humans seems to be among the slowest.

The result, according to a new study by scientists at the European Molecular Biology Laboratory [EMBL], is that our species has retained characteristics of a very ancient ancestor that have been lost in more quickly-evolving animals.

This overturns a commonly-held view of the nature of genes in the first animals. The work appears in the current issue of the journal Science. Genes hold the recipes for proteins. The genes of animals usually contain extra bits of DNA sequence, called introns – information which has to be removed as cells create new molecules. The number of introns in genes, however, varies greatly among animals. While humans have many introns in their genes, common animal models such as flies have fewer.

From an evolutionary perspective, it was long assumed that the simpler fly genes would be more ancient. The current study reveals the opposite: early animals already had a lot of introns, and quickly-evolving species like insects have lost most of them. To discover what early animals were like, scientists usually compare their descendents. This is difficult when comparing distantly-related animals such as humans and flies. In these cases, it helps to look at living organisms that have preserved many features of their ancestors. Detlev Arendt's group is doing this with a small marine worm called Platynereis dumerlii. "Similar animals are already found in the earliest fossils from the Cambrium, about 600 million years ago," Arendt explains, "arguing that Platynereis could be something like a 'living fossil'."

This makes it an ideal model for evolutionary comparisons to find out what the common ancestors of humans, flies and worms were like."Until quite recently, such comparisons could only be made by looking at physical characteristics such as the structure of bones, teeth, or tissues. But DNA sequencing now permits scientists to make comparisons of the genetic code and read evolutionary history from it.

An international consortium involving researchers from EMBL, the UK, France and the United States has now sequenced a part of the Platynereis genome. "The fraction of Platynereis genes we have been able to look at tells a very clear story," says researcher Florian Raible, who performed most of the computer analyses.

"The worm’s genes are very similar to human genes. That's a much different picture than we've seen from the quickly-evolving species that have been studied so far."Raible is member of both Arendt's group and a second EMBL lab, that of Peer Bork, whose specialty is analyzing genomes by computer. "Human genes are typically more complex than those of flies," explains Bork. "Classically studied species like flies have far fewer introns, so many scientists have believed that genes have become more complex over the course of evolution. There have already been speculations that this may not be true, but proof was missing. Now we have direct evidence that genes were already quite complex in the first animals, and many invertebrates have reduced part of this complexity."

Not only are the introns there – the team also discovered that their positions within genes have been preserved over the last half a billion years." This gives us two independent measurements that tell the same story," Raible explains. "Most introns are very old, and they haven't changed very much in slowly-evolving branches of life, such as vertebrates or annelid worms.

This makes vertebrates into something like 'living fossils' in their own right."The discovery that Platynereis also represents a slowlyevolving branch of animal life has important implications for the study of humans. "We've already learned an incredible amount about humans from studies of the fly," Arendt says. "The marine worm might well give us an even better look at important conserved processes.

Another thing that this has shown us is that evolution is not always about gain; the loss of complexity can equally be an important player in evolution."

["Complexity" is clearly not the relevant issue - since it arises as a result, as an epiphenomenon in a "bewildering" manner from canonically succint algorithms, such as simply illustrated by FractoGene. The very same fractal algorithm, say Mandelbrot's equation Z=Z^2 + C (simple, itsn't it?) can be used in very few recursions, or the iterative reverberation may go on for any number of millions. Some fractal algorithms quickly develop a "shape" from as simple "bricks" as straight line segments, and their fractal dimension converges extremely rapidly (e.g. the Koch-curve, approaching 1.26 in a 2-dimensions). Other, equally "trivial" algorithms, on the other hand, although also composed of the same kind of sturdy "bricks" of straight line segments, approach their full fractal dimensionality very slowly, needing an enormous number of iterations (e.g. the Hilbert-curve will approach full 2.0 dimensions, completely filling the 2D room, though its "shape" (or "pattern") is increasingly lost after a huge number of reverberative iterations.

Some are bewildered that closely related species ("the pattern looks the same") may have a huge difference in their amount of DNA (clearly, the difference in the "junk DNA"). (Varieties of salamanders, frogs, etc; each can be designed by the same set of fractal algorithms, but pushed to widely different range of iterations). One has to be careful about such "tricks" as the range of iterations, since one design-element, say (in architecture) can be chiseled in "infinite" resolution; e.g. a decorative relief, but another design-element, say a chimney, could result in a disaster if bricklayers keep on repeating their simple routine and the resulting structure is too high).

If "complexity" is an epiphenomenon, what to do? Having labored 100 years on studying "the bricks" (genes) and "mortar" (introns and intergenic junk DNA) in Genetics (1905-2005), in the next century of Genomics (PostGenetics 2005-) focus on the *algorithm* ("design"). When the axiom (dogma, rather) that the "atom is the indivisible smallest unit of matter" collapsed when nuclear fission and fusion became irrefutable facts - there was an inevitable rush to generate quantum mechanics, with its not entirely trivial mathematical underpinning. Genomics is at the same kind of crossroads where physics was when the Coppenhagen Group was forced to take a lead. Genomics will have an increasingly difficult time to proceed without mathematically stated algorithms of "DNA as information".  Theory, however, must be scientific - i.e. must be predictive and thus experimentally supported or falsified. - Comment by A. Pellionisz on 28th of November, 2005]

GTG and APPLERA ask Court time till 5th of December to finalize JunkDNA patent settlement

The Company [GTG] now reports, that on November 22nd, 2005, the Court posted on its website a further joint Stipulation dated the same date that had been signed and filed by the Parties, seeking additional time, until Monday, December 5th, 2005 (US time), in order to complete and execute a binding Settlement Agreement, as well as attendant licenses and a supply agreement. A complete copy of this third Stipulation together with the full ASX Announcement is attached

["The devil is in the details" - GTG at this point pretty much can "name its price" in the last minute escalation.  Since the settlement leaked out, GTG stocks "GENE" on NASDAQ went up by 40% and are now holding steady. (As mentioned above, ALNY catapulted by 80% since the summer). The dominant *existing* technology that will benefit from exploding "junkDNA" R&D and applications is the "microarray" sector. Although the settlement will incur expenses (while Affymetrix bought long ago Perlegen, which was the 4th Company to agree on royalties to GTG...), the leaked news of elimination of a lingering uncertainty sent all leading microarray companies on a rapidly rising course (AFFX up by 20%, Agilent up by 15%, Beckman-Coulter up by 14% since settlement leaked). This is, however, only the "very early part of the curve". Remember when Google was "too high at $80" ? By Thanksgiving, it reached $422 - Comment by AJP on 24th of November, 2005]

Oops - the price of junkDNA just took off ... "junkDNA" is the word ....

The word: Junk DNA
New Scientist
19 November 2005

Magazine issue 2526

DNA may be the building block of life, but the vast majority of it in most species is apparently useless - or is it?

DNA may be the building block of life, but the vast majority of it in nearly all species is apparently useless. The human genome, for example, is made up of 3 billion base pairs of nucleotides arranged in the well-known double helix, yet only 3 per cent of that works as functional genes. The other 97 per cent has been written off as junk. But remarkably, junk DNA may turn out to be as important as genes - if not more so.

What is junk DNA exactly? Simply, it's any DNA that doesn't contain a blueprint for making proteins. Active DNA, the stuff that builds living organisms, works by translating itself into RNA, which provides instructions for building proteins. But most DNA doesn't fit this picture. Take, for example, the sequences of seemingly irrelevant DNA called introns that lurk within genes, and the long stretches of genetic material between genes ...

To continue reading this article, subscribe to New Scientist. Get 4 issues of New Scientist magazine and instant access to all online content for only $4.95

[What made just a mere 512 words long blurb suddenly cost you five bucks? (You can get a GTG share for $12 on NASDAQ - at least that generates you some royalty-money - especially when on the 22nd of November Applera will settle for many tens of $millions... and as CEO Jacobson claims in his audio message, tens and hundreds of $millions will start trickling...)

Suddenly, even a vague notion of what the WORD "junkDNA" might be, became a valuable asset.

Well, you can get plenty of information here, for free. At least for now...

What could be the reason for charging money just for the notion of "junkDNA"? Read on...]

continuation (submitted by IPGS Founder Jules Ruis, The Netherlands)

... between genes that carry no protein-building instructions.

Why the change of heart on junk DNA? A new study by Peter Andolfatto, a biologist at the University of California, San Diego, suggests that junk DNA is preserved over millions of years of evolution (Nature, vol 437, p 1149). If that's true, the junk must be performing some crucial part in the organism's survival and ability to reproduce.

Andolfatto analysed the genome of the fruit fly, 80 per cent of which is junk DNA, and discovered that the rate at which the junk DNA accumulated mutations was far lower than expected. Natural selection had rejected between 40 and 70 per cent of new mutations, effectively putting the brakes on its evolution.

What's so special about junk DNA that ensures it is mothballed in this way? One clue comes from comparing genomes. The biggest differences between species lie not in the number of active genes, but in the amount of junk DNA. Humans have about 30,000 genes, which is a similar number to a mouse, so the number of genes does not correlate with an organism's complexity. But it seems the amount of junk DNA does. The human genome contains the largest proportion of junk DNA of any species. Could it be our junk DNA, rather than our genes, that makes us who we are? [Yes, this is a "big issue" - see Press Release on Oct. 17. but *not* from a business viewpoint... - AJP]

We don't yet know how junk DNA might play that role. It might work by reducing the chance of a mutation hitting an active gene, or by providing raw material for new genetic combinations. Or it could encode vital information that scientists haven't yet unravelled - the more DNA, the higher the capacity to store information and produce complex organisms. One thing is clear. Now that we've mapped our genes, it's time to start exploring the junkyard.

[Yepp, this is where the money is. In business, investors ask two questions before anything else. "Is it too eary?" "Is it too late?" Indeed, the richest person in the world could be the one who rings a bell on Wall Street "this is the moment to get in, prices from now on will rise". The name of the game is to get in before the competitor does. This "word" on junkDNA "time to invest is *now*" is priceless - commentator AJP on 20th of November, 2005]

Further update regarding 'JunkDNA on Wall Street' (GTG settles with Applera) - and implications

GTG now reports that on November 11th, 2005, the Court posted on its website a joint Stipulation dated the same date that had been signed and filed by the Parties, seeking additional time, until Tuesday, November 22nd, 2005 (US time), in order to complete and execute the settlement agreements.

[Since GTG cites that the Court - accidentally - revealed among others that "A Confidential Term Sheet had been executed by the Parties and submitted to the Court" (on the GTG Company web site, see the facsimile of Court Document) the two technicalities outstanding are:

a) the exact time when GTG/Applera will announce their settlement

b) while it is unlikely that the "Confidential Term Sheet" will disclose the exact amount of Settlement - industry experts are likely to gain some insight - especially since GTG is not publicly traded on NASDAQ and thus even their balance sheet is a publicly available document.

For Industry Analysts the most important implications and questions with urgency seem to be:

i) Once cash value of Intellectual Property pertaining to "junkDNA" is a fact, attempts are likely for some industrial giants with foresight to put together via M/A the strongest possible "junkDNA IP portfolio" - before the completion does it.

ii) Beyond Intellecual Property, the "64 million dollar question" is how to "productize" (not mostly just "license" as GTG does it) probably "One of the Biggest R&D and Industry Disruption" -- PostGenetics.

According to the educated opinion of this analyst (Andras J. Pellionisz) the "big winner" (just like with earlier disruptions, like Neural Networks breaking through Artificial Intelligence and Internet Business breaking through Government R&D Projects, to become public, will be private domain Information Technology Companies. At the same time, Government Funding programs as well as Venture Capital Companies will have to overcome the hurdle of conducting "due diligence" at the time of perhaps the most lucrative disruption, ever, when most of them quite unprepared for it . Two examples: Craig Venter's "Synthetic Genomics, Inc." already announced their plans to modify the tiniest genome of the bacterium Mycoplasma Genitaliae to produce hydrogen using solar energy- still, with 12% "non-coding DNA" but without breakthroughs in understanding the role of non-coding DNA any kind of natural or synthetic protein-production, for instance for new materials in Nanotechnology will be handicapped. In Health Services, there will be a tremendous social outrcy (manifesting in Congressional Appropriation Bills) to re-allocate funds from "Gene Discovery" to "PostGene Discovery", since a long list of devastating diseases (with the list getting longer by the day) is *not* caused by "Genes" but by "non-coding DNA". Those millions of taxpayers suffering from proven "non-coding DNA diseases" will not silently wait until all (non-existent) "Genes are searched for" - without even a search-engine to sort through the 98.7% of (human) "non-coding DNA" - Comment by Dr. Pellionisz, 14 November, 2005]

JunkDNA made it to Wall Street - GTG earmarked to escalate to a $2 Billion business alone

[At the website above, listen to GTG Founder, Mr. Jacobsen's audio presentation to the Press in New York City on the 9th of November, 2005.


GTG, with Intellectual Property [[sole authored by Dr. Malcolm J. Simons, not mentioned - comment by AJP]] is now publicly traded on NASDAQ under stock symbol "GENE".

The stock price surged upon the news that GTG, worth USD 167 Million, is to execute a term-sheet for "settlement" against the USD 6 Billion APPLERA.

GTG has presently 20+ licensing agreements worldwide, generating about USD 26 Million revenue from licensing. GTG has a list of about 2000 companies and estimates that about 400 of them need a license. GTG expressed confidence that since APPLERA could not win over issued US patent(s), it seemed unlikely that any other company would - calling the settlement a "watershed", or "a make or break" event. [[If the Company's worth would be directly proportional to the number of licenses a "forward looking" statement might put "value of JunkDNA" over USD 2 Billion - prior to issuance of any of the mathematically stated and thus utilizable e.g. in Nanotechnology "junkDNA patents" - comment by AJP]]

Remember, the worth of "JunkDNA" is by no means equivalent to the worth of the first couple of patents. (The worth of electrical and electronics industry is many-many-many orders of magnitude larger than the revenue was from the "light bulb patent" of Thomas Edison). ]

[ *** Microarray Industry at a point of disruption -
see also the publicly disclosed "Stipulated Revised Case Schedule and Order" on GTG website -AJP ***]

GTG, Applera Look to Be Nearing Settlement

By Graeme O'Neill, Australian Biotechnology News

November 07, 2005 Melbourne-based gene testing company Genetic Technologies appears to be nearing settlement of its long-running court case against U.S. rival Applera Corp. over Applera's refusal to take a licence to use GTG's patents on the use of so-called 'junk' DNA markers for gene testing.

Trading in GTG's shares was halted last Thursday pending an announcement on the case from the U.S. District Court of Northern California, in San Francisco, which has been mediating in the case.

Applera was one of three companies sued by GTG early last year for infringing its non-coding DNA marker technology, and the lone holdout after the other two, Novelo and Covance, agreed to pay license fees to the Australian company.

GTG and Applera underwent two unsuccessful rounds of mediation in September last year, and in February this year, and entered a third round in August, at which the court-appointed mediator, Magistrate Judge Joseph Spero, ordered all details of the mediation be filed under seal -- in effect, that details and documents be kept completely confidential.

According to GTG executive chairman Dr Mervyn Jacobson, legal counsel for Applera and GTG jointly prepared a document to keep the court updated on progress in their negotiations.

The companies learned last Thursday that the court had posted the document on its web site. It reported that the parties have reached an in-principle settlement, and a confidential term sheet has been submitted to the court.

GTG and Applera are now "working diligently" to complete a binding settlement agreement and associated documents, that are expected to be signed no later than Wednesday this week, Jacobson said.

The order did no more than record the progress being made towards effecting a settlement, and according to Jacobson, made it clear a final settlement has not been reached.

[Microarray technologies, since for an array of "reagents" it is indifferent if a particular reagent is signalling a "gene" or "non-coding DNA" ("junkDNA") is presently the leading experimental method suitable for "junkDNA R&D". Therefore, even since the disruptive paradigm-shift became evident that "gene discovery" should yield room for "postgene discovery", the valuation of microarray companies has been more-or-less constantly on a rather spectacular rise. Also - as predicted - at least one microarray product has been craftily re-named, *not* to imply that the technology was meant for "gene discovery". The rather spectacular rise of valuation, however, was occasionally interrupted, as if ongoing litigation on the presently only *issued* USA patents on "junkDNA" might have a potential bearing on valuation. Since the signalled Court-date is tomorrow, momentarily it is a matter of speculation if the stock (presently publicly traded GTG, under stock symbol "Gene" - will rise or fall - and how the stock values of various Microarray Companies are likely to be affected). While this commentator is available with expertise on the matter, one can publicly state the obvious. As long as there is a virtual "monopoly" on issued US "junkDNA" patents, there might be at least a perceived vulnerability if even the about $5 billion worth Applera has to give in - smaller companies are unlikely to prevail. However, the IP contained in the patents is already somewhat dated and new IP, not associated with either GTG or their claims by any means, is available. Thus, in the private opinion of this commentator, a major re-structuring of the "microarray industry" is likely, in which those companies that are responsive to changes imposed by "disruptive technology" will catapult, while those clinging to "sustaining technologies" might run into increasing problems. This perspective is not new and has been "proven" repeatedly (found "scary" by reviewer Intel President Andy Grove); "The Innovator's Dilemma; When New Technologies Cause Great Firms to Fail" by Clayton M. Christensen, Harvard Business School Press, 1997, ISBN 0-87584-585-1 - comment by AJP on November 8th, 2005]

The Heart of Science
The American Heart Association donated about $1.23 million to fund University projects
By Joe Bailey

[This clipping is to be contrasted with the $ zillions that the Government spends on "genetics". To paraphrase the classic quote by Dr. Mattick "overlooking the role of junkDNA in government-funded R&D is probably the biggest mistake in the history of tax dollar appropriation" - comment by AJP]

November 02, 2005

Breaking the code

Voelker, a post-doctoral research associate, is using a $99,000 grant from the AHA to investigate the human genome.

Genes represent only a small portion of the human genome, the rest is made up of non-essential materials that some refer to as “junk DNA,” Voelker said.

Voelker’s research builds on the Human Genome Project, which in 2003 announced that it had successfully mapped out the human genome. “We now have the entire sequence. We know how to read parts of it, and there are a lot of implications that the rest of it — the bulk of it — is important, but we don’t know how to read it,” he said.

Voelker said the human genome has lots of useless information sandwiched between useful information. The body separates the good information from the bad information. He is conducting research to decipher how the body carries out the splicing process.

“A large number of genetic diseases are the results of mistakes in splicing,” he said. “There’s a mistake in recognition of what’s junk and what’s not.”

By collaborating with people from other disciplines such as mathematics and computer science, Voelker is hoping to determine how the body reads its own genetic code.

“Ultimately, the idea is that once we figure out what the error is, we can use some of these methods to go in and repair the mistake,” he said. “I have no doubt that in time humans will figure out how to correct these mistakes.”

[It really looks like a waste of US taxpayers' money to buy hundreds of volumes of books when "we don't know how to read them" (sequencing more and more species when 98.7% of human DNA is still "unread"). As a parent, would you rather buy tons of books to your kid - or would you rather first make sure that he/she learns how to read in the first place? Leaving the job of "cracking the code" for $99k paltry funds coughed up by well-meaning private organizations risks that the grandiose US Genome Program will look like a joke to the World. It is now up to the International PostGenetics Society to rectify this scientific insult - and demand that a re-allocation of resources puts priority on the role of "junkDNA" in devastating diseases - AJP]

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NHGRI's Collins Says US Must Launch Its Own Biobanking Project

SALT LAKE CITY, Oct. 27 (GenomeWeb News) - In light of biobanking projects underway in the UK, Iceland, Estonia, and Japan, the US can ill afford to not invest in its own population-based cohort study, Francis Collins said yesterday.

Speaking at the American Society of Human Genetics conference held here this week, the director of the National Human Genome Research Institute said that the falling cost of genotyping, coupled with the completion of the International HapMap Project, has enabled the US to start generating its own repository of genetic information.

He admitted that it would be an "uphill battle" and that the "cost is likely to be in the hundreds of millions of dollars a year" but said the project would pay off in the form of future research. "It might, in fact, in the long-term be a good investment," he said.

Collins said that current "case-control" studies such as the Framingham Heart Study that look at smaller groups of people are valuable, but that if the US really wants to understand the effect that environmental factors play on genetic diseases, researchers will need a "cohort that's selected to cover all ages, all races" and all states of wellness.

Ideally, Collins said that the project would have a large sample size, perhaps from two to three million individuals, with the "full representation of minority groups and a broad range of ages, and a broad range of genetic backgrounds." He said that significant data about participants' lifestyles would be included, and that that information should be made available to all researchers. "This kind of project would only have value if the maximum number of people would have access to it and can draw inferences from it," he said.

Collins acknowledged the ethical issues and potential privacy concerns of such a project, but said he could imagine that most Americans would want to be involved in the study because it would be an historic undertaking.

He added that similar projects in progress around the globe have left the US behind in biobanking endeavors and warned that if "we wait until we get data to start setting [the project up] then we have waited too long."

[No comment is necessary, perhaps a "here we go, again". Government tried to "solve it all" and the Private Sector beat them to the punch. Repeatedly. Lately, both in "Internet Space", and in the "Genome Sequencing". The issue truly is for the *individual* to be able to have his/her genome sequenced, control its analysis as carefully and privately as they wish - and not to be disclosed at all if undesired. The government - if for nothing else, beause of shere intertia - rarely promotes disruptive R&D. Prediction is that taxpayers will gain control to cut down on egoistic "historic undertakings" and instead enforce helping *individuals* with most common hereditary diseases not even looked at in the protein-coding-DNA - since their origin is in the "junkDNA"! Those in the private domain will take "historical" advantage in the ongoing disruption, and those with excessive inertia will be unable to adjust - comment by 27th of October, 2005 AJP]

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Healthbeat: Social Studies

October 27, 2005

Jen Christensen

Looking at Our Differences

Researchers with the Human Genome Project have found that the genome sequence is nearly 99.9 percent the same for all humans. Despite our genetic closeness, each of us is an individual. The physical differences are obvious. Some have fair skin and hair. Others have dark skin and hair. Some are tall; others are short.

Our personalities are also important in setting ourselves apart from one another. By nature, humans are social creatures. However, some people are very outgoing and enjoy being in groups or meeting new people. Others are shy and prefer to be alone or with just one or two close friends.

There are many different theories about how personality and social behavior develop. Some researchers say we are genetically programmed to behave in the way we interact. Yet, environmental factors can also influence development. Still, a combination of factors may be involved. A family can have two children with completely different social interaction patterns – one being very extroverted and the other being very introverted.

The Role of Junk DNA in Social Behavior

Researchers at the Center for Behavioral Neuroscience and Yerkes National Primate Research Center in Atlanta have been studying rodent behavior and genes to try to find clues to social behavior in humans. Investigators looked at the genetic make-up of two different species of voles (a mouse-like animal). One species of voles tends to be very social, interacting in groups and spending time to caring for each other. The second species prefers to spend time alone.

Previously, investigators discovered that a hormone, called vasopressin, was linked to stimulation of social interaction. In the current research, scientists found the social voles had a gene responsible for encoding a vasopressin receptor in the part of the brain associated with reward. (The vasopressin hormone binds to the receptor and activates the brain.) In the non-social voles, the gene receptor couldn’t be located in that part of the brain.

Further investigation found the social voles had longer sequences of DNA in the vasopressin receptor gene. This “extra” DNA has been called “junk DNA” because it was previously believed to serve no important function. Yet, since the voles with the extra genetic sequences exhibited more outgoing social behavior, this so-called junk DNA may really have some unknown purpose. [Would it make sense to have at least some scientific - predictive and thus refutable - theories on "junkDNA"? - comment by AJP]

Humans also have the vasopressin hormone. The location of the gene and the presence of junk DNA may play a role in social behavior for humans as well as animals. Research suggests 95 percent of the human genome contains junk DNA. Eventually, studying the role of this “non-functioning” genetic material may help scientists learn more about human interaction and lead to treatments for social behavior problems ranging from shyness to autism.

[Some of the most common hereditary diseases will never be found by "Gene Discovery" in the "protein-coding-DNA" ("genes") - because many of them are already known to originate from noncoding regions, "junkDNA". We need "PostGene Discovery". For a known instance:

"Fragile X is a hereditary/genetic condition which can impact families in many ways. It includes fragile X syndrome (FXS), the most common cause of genetically-inherited mental impairment ranging from subtle learning disabilities and a normal IQ, to severe cognitive or intellectual challenges (often still referred to as mental retardation) including autism or "autistic-like" behavior. Symptoms often include unique physical characteristics, behavioral deficits and delays in speech and language development."

"Several disorders in humans are caused by the inheritance of genes that have undergone insertions of a stretch of identical codons repeated over and over. A locus on the human X chromosome contains such a stretch of nucleotides in which the triplet CGG is repeated (CGGCGGCGGCGG, etc.). The number of CGGs may be as few as 5 or as many as 50 without causing a harmful phenotype (these repeated nucleotides are in a noncoding region of the gene). Even 100 repeats usually cause no harm. However, these longer repeats have a tendency to grow longer still from one generation to the next (to as many as 4000 repeats)."

Rather than setting up a hopelessly complex, expensive and socially controversial catalog of "genetic backgrounds" would it make sense for individuals and their families and friends to command at least some of their taxpayer's monies for "junkDNA R&D"? - comment by AJP]

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** Press Release by A. Pellionisz, 17th of October, 2005 - Look for another one within days ("International PostGenetics Society" announced)**

One Believer’s Junk is another Believer’s Treasure;
Quest for Predictive Scientific Theories on the Function of 'junkDNA'

98.7% of the (human) DNA needs more than a national debate if it is 'junkDNA' or a treasure-chest of information. Predictive scientific theories can deliver more than dogmatic belief if they are experimentally testable. Prediction of on the Fugu has been supported by experimentation. Novel predictions, such as the 'Methylation Prediction' are laid bare to test.

(PRWEB) (MEDIAWIRE) (KERALANEXT) (JUNK)(PREDICTIONS)(METHYLATION PREDICTION)(BIOTECHNOLOGY)[Official version here] October 17, 2005 -- Triggered by the hairline difference of 0.1% between the chimp and human “genes”, yet 4% difference in their "non-genes”, scientific theory on the "junkDNA" became “daily news”.

“Genes” amount only to 1.3% of the hereditary material in human. Thus, the "genetic" difference between human and chimp is a slim one in ten thousand, while the difference in “junkDNA” is forty times larger. Is it a matter of belief or of scientific theory whether the 98.7% of the human DNA is “junk” or “a goldmine”?

The national debate about Darwinism (D) contra Intelligent Design/Extraterrestrial Intelligence (ID/ET) see centers on the nature of predictive and thus refutable scientific theories.

Most Darwinists erroneously predicted that 98.7% of the DNA was devoid of function (“junk”), while the ID/ET theory correctly predicted some yet to be decoded function of junkDNA. Debate is obsolete on "existence" of theories, once there is at least one with refutable preditions(s). [The question no loger if there is a function of junkDNA but how is its function mathematized, e.g. useful in biotech, nanotech and infotech engineering]. The scientific challenge is already at its next stage, having stepped over the “existence question” and proceeded with the decoding junkDNA in order to understand its function.

FractoGene was based upon the concept, process and platform that genes and non-genes comprise fractal sets, determining the ensuing fractal hierarchies of complexity;

The first prediction of FractoGene was that the ancient fugu fish, with about one tenth of the amount of "junkDNA" compared to human, should show a specific brain cell (cerebellar Purkinje neuron) with a primitive arborization, hardly more than a stem; mathematically describable as a “fractal template”.

Experimental support of the "Fugu Prediction of FractoGene”, that there should be a mathematically expressible relation between non-gene and ensuing complexity on 28/08/2005 was accepted to publication in the peer-reviewed science journal “The Cerebellum” by the Taylor & Francis Group.

I now announce further predictions based on mathematical theory. The “Methylation Prediction of FractoGene”concerns methylation, one type of genomic event. The prediction is experimentally testable by current technologies such as microarrays and other available means.

The “Methylation Prediction by FractoGene” is, in a rather specific form (while an array of other, more powerful formulations are at hand), that: “A cell (including but not limited to that of the brain cell in which the 1st Prediction was found experimentally supported) should show bursts of methylation, effectively ‘silencing’ perused repetitive and self-similar sets of auxiliary information (‘PostGenes’) of the DNA, such bursts temporally corresponding from stem cell through embryogenesis and through life till death, with the emergence of fractal-like levels of complexity e.g. with the generations of stages of development (including but not limited to, brain cell branching, readily observable by neuromorphology), thereby revealing a new, theoretically sound and experimentally usable method of discovering linkage among specific ‘Genes’ and ‘PostGenes’”.

Further elaboration will be provided immediately in talks with interested parties and in the forthcoming BrowserBook "FractoGene ... decoding junkDNA in PostGenetics" by Dr. Pellionisz.

Predictions will be formulated further and disclosed along yet other aspects, as appropriate. If found experimentally supported also in this next step, FractoGene is expected to result in a method, technology and industry of "PostGene Discovery" beyond existing “Gene Discovery” in the present PostGenetics era of Genomics.

Dr. Andras J. Pellionisz
Silicon Valley, CA, USA
(four zero eight) seven three two 9319 [US phone number spelt out to lessen effect of SPAM by Internet robots]

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Study: Junk DNA is critically important
[Nature, 20th of October]

SAN DIEGO, Oct. 19 (UPI) -- A University of California-San Diego scientist says genetic material derisively called "junk" DNA is important to an organism's evolutionary survival.

Junk DNA is so-called because it doesn't contain instructions for protein-coding genes and appears to have little or no function. [We know all too well, that this is shere nonsense - AJP]. But Peter Andolfatto, an assistant professor of biology, says such DNA plays an important role in maintaining an organism's genetic integrity.

In studying the fruit fly Drosophila melanogaster, Andolfatto discovered such regions are strongly affected by natural selection -- the evolutionary process that preferentially leads to the survival of organisms and genes best adapted to the environment.

Andolfatto says his findings are important because the similarity of genome sequences in fruit flies, worms and humans suggests similar processes are probably responsible for differences between humans and their close evolutionary relatives.

"Sequencing of the complete genome in humans, fruit flies, nematodes and plants has revealed the number of protein-coding genes is much more similar among these species than expected," he said. "Curiously, the largest differences between major species groups appear to be the amount of 'junk' DNA, rather than the number of genes."

He details his research in the Oct. 20 issue of Nature.

[Especially beacuse junkDNA is all of a sudden "critically important" - at the level of Nature magazine - it makes so much sense for many to actually look into the Experimentally Verifiable (or Refutable) "Methylation Prediction of FractoGene" on junkDNA, "curiously" announced in a Press Release on the 17th of October, see above - comment by A. Pellionisz on the 19th of October, 2005]

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[* US TAXPAYER ALERT !! * "Brute force" tax dollars for looking for "genes" causing certain diseases are likely to be intentionally wasteful! Simple reason: 98.7% of the DNA (in human) is "non-gene", and certain diseases are already known *not* to originate in "genes" but in the 98.7% "junkDNA". Since in Genetics "genes" (1.3% of the DNA) have already been extensively looked (and "junkDNA" was suggested "to be left for theologists") how much taxpayer money should be immediately re-directed for looking for causes in the "junkDNA"??? - comment by 21st of October, 2005 AJP]

Large-scale Sequencing Research Network Sets Its Sights On Disease Targets

BETHESDA, Md., Mon., Oct. 17, 2005 - In what promises to be a significant step forward in the genome era, the National Human Genome Research Institute (NHGRI), one of the National Institutes of Health (NIH), today announced plans to devote a portion of its large-scale sequencing capacity to efforts aimed at identifying the genetic roots of specific diseases that have long eluded gene hunters. [Eluded, since it is left for "non-gene hunters" - AJP]

The National Advisory Council for Human Genome Research (NACHGR) recently approved a plan for NHGRI's Large-Scale Sequencing Network that, for the first time, includes a portfolio of "medical sequencing" projects. Projects given the highest priority will use large-scale sequencing over the next few years to identify the genes [how about "non-genes"? AJP] responsible for dozens of relatively rare, single-gene (autosomal Mendelian) diseases [the "one gene, one disease, one billion dollar pill" business model was dead by 2003, AJP]; sequence all of the genes on the X chromosome from affected individuals to identify those involved in sex-linked diseases; and to survey the range of variants in genes known to contribute to some common diseases. The launch of each project will depend on a number of factors, including the strategic selection of specific diseases and the availability of patient samples with appropriate informed consent.

In addition to the new focus on medical sequencing, the plan continues NHGRI's emphasis on using comparative genomic sequencing analysis to understand the structure and function of the human genome and the biological processes at work in human health and disease. The strategy includes a mix of whole genome sequencing, genome mapping and sequencing of genomic regions chosen for their scientific merits. [this is a code-phrase for "letting" a probably minuscle "non-gene" study in. What NIH must urgenty do - responding to taxpayers outcry - is to set up programs with appropriate size for "junkDNA"; e.g. "PostGene Discovery" - AJP]. Additionally, NACHGR approved the refinement of several existing draft genome sequences and targeted a group of seven additional non-mammalian organisms for sequencing.

"Medical sequencing has the potential to make a substantial impact on both biological and medical research. While many of the genes we will initially be pursuing are responsible for rare disorders, what we learn from rare disorders often has profound consequences for our understanding of more common conditions. Thus we expect the cumulative impact of this acceleration in disease gene discovery to be profound, as many of the discoveries will shed new light on the biological pathways involved in human health and disease," said NHGRI Director Francis S. Collins, M.D., Ph.D. [Dr. Collins champions "Gene Discovery" - but who champions "PostGene discovery"? - AJP]

The first medical sequencing project, predicted to begin in the next year, will be a demonstration project to find the genetic variations responsible for seven rare, autosomal Mendelian disorders. The demonstration project will establish the best procedures for obtaining quality samples, for determining the minimum number of affected and control samples needed, and for deciding how the data will be released to the biomedical research community.

Among the demonstration projects under consideration are those to identify the genes responsible for the familial forms of atrial fibrillation, a major risk factor for heart failure and stroke; thoracic aortic aneurysms, which are life-threatening tears in the major artery of the heart; and dominant restrictive cardiomyopathy, another heart disorder. By understanding the familial forms of these diseases, scientists can apply what they learn to uncover the genetic components underlying the more common types of these heart disorders in the human population.

The other demonstration projects will target the genes for four other rare disorders: paroxysmal kinesigenic choreoathetosis, a neurological condition; neovascular inflammatory vitreoretinopathy, a blinding disorder; lymphedema-cholestasis syndrome, a hereditary disorder causing jaundice and leg swelling; and Joubert syndrome, a rare brain and physical development disorder. [What if these diseases have their origins *elsewhere* than in the "genes"? - AJP]

NHGRI estimates that there are at least 50 to 100 additional projects in the scientific community that could benefit from the brute force [Do you know what "brute force" means in governmentese? Translated: "$ ZILLIONS of your Tax Dollars!" - better watch out for your pocket - AJP] and specialized tools of large-scale sequencing. In order to make an accurate assessment and gather community input into this program, NHGRI has issued a Request for Information to seek additional examples of such diseases from investigators around the world. The deadline for responses is Nov. 4. [Seems to be a bit tight to leave room for PostGenetics - AJP]. NHGRI will also hold an open discussion on Oct. 28 during the upcoming meeting of the American Society for Human Genetics in Salt Lake City to seek additional input from the human genetics community. [Oct 28 is exactly one week away - where is the "PostGenetics community?" - AJP]. NHGRI will analyze the input from these sources and determine the ultimate size of this aspect of medical sequencing as well as the best way to select those projects that offer the most promise.

Another medical sequencing project will be an effort to identify the genetic changes that result in diseases known as X-linked disorders. The human genome consists of 22 matching pairs of chromosome, referred to as autosomal chromosomes, plus a non-matching pair referred to as the sex chromosomes. The sex chromosomes, which are called X and Y, determine whether a person is female (XX) or male (XY). Any defects in genes on the X chromosome are often more apparent in males than females because the Y chromosome does not carry corresponding genes to compensate.

While researchers have identified the genes responsible for a number of X-linked disorders, the precise genetic basis for approximately 130 of these disorders remains to be determined. The study would entail completely sequencing all genes on the X chromosomes of individuals affected with the disorders, and looking for variations that consistently correlate with each disorder.

The other medical sequencing project given priority will attempt to characterize the entire spectrum of variation, both rare and common, in a significant number of candidate genes for common diseases. Genes known to influence high blood pressure, cholesterol and body weight will be targeted. Samples would be sequenced from hundreds to thousands of individuals from existing large cohort studies examining specific diseases, such as atherosclerosis or diabetes.

As part of the effort to select medical sequencing projects, NHGRI has included a working group to examine the ethical, legal and social issues relevant to the new medical sequencing projects [How about some science working group on "junkDNA"? - AJP]. Many of these issues, which include obtaining informed consent from volunteers who plan to donate samples or who have already donated samples for other research projects, protecting the privacy of such volunteers, and understanding when, or how to report clinically relevant results back to volunteers, are similar to those encountered in much of human genetics research. The group will also address data release and intellectual property procedures.

In addition to the new focus on medical sequencing, NHGRI is continuing its ongoing effort to sequence other organisms' genomes, with the aim of deepening our understanding of human biology and evolution. Since the human genome and that of other mammalian and non-mammalian genomes have all evolved from a common ancestor, scientists can use the genome sequences of the non-mammalian animals to learn more about how, when and why the genomes of humans and other mammals came to be composed of certain DNA sequences. Such studies also provide new insights into the function of those sequences, the organization of genomes, [another code-phrase for letting a minuscle money spent on e.g. "ultraconservative sequences" in the "junkDNA". Is that "too dirty to mention"??- AJP] and expand our understanding of the biological basis of certain infectious diseases.

NHGRI has selected seven non-mammalian organisms or groups of organisms for the next round of sequencing. Three of the organisms have been targeted for "high-quality draft" sequencing. They are: the green anole lizard (Anolis carolinensis), zebra finch (Taeniopygia guttata) and body louse (Pediculus humanus). Researchers will also construct physical genetic maps and do some targeted genomic sequencing of two sandflies (Lutzomyia longipalpis and Phlebotomus papatasi), and will obtain a low coverage sequence of the Africanized honey bee (Apis mellifera scutellata) for comparison with the honey bee genome sequence. Finally, the genomes of 100 bacteria cultured from the normal human gut will be sequenced. [Sequencing 100 bacteria carries a huge price tag to be paid from your pocket - why don't we make some sense of the "junkDNA" contents of bacteria *already sequenced*??? - AJP]

"We are continuing to focus on those organisms that will reveal the greatest amount of information about the major biological innovations that have occurred throughout evolution, with emphasis on learning more about our own genome. Genomic information from a wide array of species is proving useful in many areas of biomedical research," said Mark S. Guyer, Ph.D., director of NHGRI's Division of Extramural Research. [This is much closer to opening up the gates to "PostGene Discovery" - perhaps could be a little more exlicite with the budget-percentage - AJP]


The latest NHGRI sequencing plan will also support the refinement of the rat, chicken and dog genomes. All are important model organisms, and their genomes are used to identify features that are similar, or conserved, among the genomes of the human and other mammals. Sequences that have been conserved throughout evolution often reveal important functional regions of the human genome. [...]


NHGRI is one of the 27 institutes and centers at NIH, an agency of the Department of Health and Human Services. [...]

[Budget of NIH for 2005 is close to $30,000 million dollars ($30 Billion - would drive even Bill Gates bankrupt in a hurry...) - 100% is from US Taxpayers. Question: What percentage of $30 Billion is spent on "junkDNA" that is 98.7% of the human genome? - comment by AJP on 21st of October, 2005]

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Smoking chimps show similarities to humans
Published in the Athens Banner-Herald on Wednesday, October 12, 2005 - James Hargrove

[*Nothing* replaces science - see comment appended - 12th October, 2005 AJP]

[*** Watch for an imminent announcement, 2005 AJP *** (Press Release on 17th of October, 2005)]

Recently, an Australian chimpanzee named Charlie and a Chinese chimp named Ai Ai have made the news because both smoke cigarettes provided by guests at their respective zoos.

People find it humorous that animals can develop human vices. Well, the same week Hurricane Katrina came ashore, the first DNA sequence analysis of the chimpanzee genome was presented in the science journal called Nature.

Not many people noticed, but one can now directly compare human (Homo sapiens) and chimp (Pan troglodytes) gene sequences at Entrez-PubMed (

If you do so, it will be evident that most chimp genes provide identical or nearly identical protein sequences compared to human genes. Such is not the case if you compare our genes with rodents or fish, for example.

It is gratifying to see the hand of the Intelligent Designer has made us so similar to monkeys that even our brain nicotine receptors are highly similar. Charlie, can I offer you a light, cousin?

James Hargrove

EDITOR'S NOTE [Athens Banner-Herald]: According to an Oct. 5 Associated Press report, Chinese zookeepers are no longer providing cigarettes to Ai Ai, substituting food and music as distractions.

[It is just staggering to watch in what a bizarre way a "national debate" is degenerating. Sometimes it is even hard to tell for some at a glance if "the news of the day" appears "tongue-in-cheek" or takes itself seriously. Articles as above confuse the basics what the issues are all about (in addition that they are often scientifically incorrect or outright erroneous). For instance, it is not the "similarities" that we look for - science looks for the *differences* telling chimps and humans apart. (Most - if not all - organisms are "similar" for instance that the main ingredient is water for all - what does it have to do with the issue?)

If the issue is the "difference" (from the viewpoint of science it is) the answer is loud and clear. The difference in "junkDNA" is a hefty forty times larger than the difference in "genes". This is not only a fact, but is perhaps the most important challenge for science of all times - and science by definition is the only relevant discipline capable of delivering predictive theories. Instead of letting those with a different agenda cloud the "debate" with pseudo-issues or shere nonsense, it is a duty for scientists to speak up. - comment by A. Pellionisz on the 14th of October, 2005]

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The greatest discovery of all time

The chances are there's life out there, but any messages could be thousands of years old and indecipherable. Roger Highfield reports

Aliens are probably common. Because there are billions of trillions of stars in the cosmos, many astronomers think it would be highly improbable for Earth to be the only rock to harbour life.

Whether ET is intelligent is still hotly debated. But no one doubts that the receipt of a signal from another civilisation would be Earth-shattering. "It would surely be the greatest discovery of all time, eclipsing the findings of Newton, Dawin and Einstein combined," says Prof Paul Davies, a British cosmologist from the Australian Centre for Astrobiology at Macquarie University.

"The knowledge that we are not alone would affect people's psyche, and totally transform our world view," he said during a visit to Britain last week. "The mere fact alone would be disruptive. But imagine if we got some serious information from ET. Then all bets are off about what our future would be."

Prof Davies is among the handful of scientists charged with thinking through the implications of what to do in the event of "first contact" with an alien, sitting on one of a clutch of committees led by Dr Seth Shostak of the Seti (Search for Extraterrestrial Intelligence) Institute in California.

The hunt for ET's transmissions has proceeded in fits and starts since 1959, when Cornell University physicists suggested that extraterrestrial civilisations would find it easier to reach out across the galaxy with radio waves than pay a visit. Today, perhaps the best known is being conducted by the Arecibo radio telescope in Puerto Rico. [...]

Some years ago, international astronomical societies agreed on what they call a "Declaration of principles concerning activities following the detection of extraterrestrial intelligence", The first step, it says, is to "verify that the most plausible explanation for the evidence is the existence of extraterrestrial intelligence rather than some other natural phenomenon or anthropogenic phenomenon".

Unlike the events shown in the film Contact (in which Jodie Foster portrays the celebrated Seti researcher Dr Jill Tarter), "there will be no Eureka moment," according to Dr Shostak. Instead, there will follow a painstaking process of checking and verification to discern a hello from the crackle of cosmic radio waves.[...]

Prof Davies points out that, if a signal is shown to be authentically alien, it is most likely from a civilisation that is stupendously advanced compared with our own: by the time we receive it, it is highly likely that the transmitting civilisation will be millions of years in advance of us - if it still survives, of course [...]

Perhaps ET could invent radio technology without ever developing the concept of an atom. But it does seem likely she [ET] would use mathematics to advertise her intelligence, given that it is a universal language. This much was recognised long ago. In the early 19th century, the mathematician Karl Friedrich Gauss suggested etching giant geometric figures in the snow of Siberia as a way of attracting the attention of Martians [...]

The problem is, however, that these signals have only travelled around 80 light years, too little for even the most optimistic Seti sage to raise the chance of meeting up with another civilisation. We may have to wait millennia for a reply, and Prof Davies speculates that it would probably come from an "information processor" that will blur the distinctions we make today between living organisms and artificial non-living machines.[...]

A laser beam could also be used to send a message. Indeed, our cells may carry one, too, Prof Davies speculates. DNA is mostly "junk", but what if it contains a message from an ancient alien civilisation? "We must not close our minds to communication by quite different means," he said. [...]


[Wow! It is not only a "Reverse Monkey Trial" now, but ET joined forces with ID versus Darwinism, culminating in the (hypothetical) "Greatest Discovery of All Time". If it would be truly "discovered" that "junkDNA" (or at least its "ultraconservative regions") are a message from a Higher Intelligence that may exist beyond our Earth, it would really be "Earth shattering" - there is probably no question about that. Short of "discovery", however, it is only a theory. Embarrassingly, it is difficult to exclude a "Higher Intelligence" (now "standing behind" ID), since it is impossible to prove a negative evidence that such ET does not exist (and even somewhat arrogant to say that ET/ID may not exist. Okay, on one end we have this thorny problem, and on the other end some reduce the problem of scientific theory on the function of junkDNA to populism "we want more sex", "throw PostGenes into the junkyard" - or even "scientists, resign from your profession, it is beyond your reach". (There is always plenty that science at any given point can not explain [fully], but in important issues it compells societies to redouble their efforts and resources, rather than "let go"). It is humbly asked that in addition to (or perhaps even instead of...) arguing if there "cannot be" this-or-that theory on junkDNA (not on its existence, but on its actual function.. ) why don't we just take a little time and look what exactly existing scientific theories on junkDNA with experimental prediction say? - comment by A. Pellionisz on the 5th of October, 2005]

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Harmful Mutations Selectively Eliminated
Bioscience Technology

Researchers from the School of Biological Sciences at the University of Edinburgh, UK, conducted a study on the evolution of non-protein coding DNA sequences that are thought to be involved in regulating when and in which tissues genes are turned on. The results indicate that these regions have been conserved during evolution in mouse and rat. However, the level of conservation between human and chimpanzee is much less pronounced.

The researchers, led by Peter Keightley, PhD, report the study in the journal Genome Research [P. Keightley et al., vol. 15, pp. 1373-1378 (2005)].

The difference in this level of conservation is likely to be a consequence of the accumulation of slightly harmful mutations that would have been eliminated in the much larger rodent populations, they say. Each of these mutations probably has a very small effect, but the cumulative effect could be quite large.

Although conservation between chimp and human in the regions they examined is quite low, it is nonetheless significant, they say, and implies that some harmful mutations have large enough effects to have been eliminated by selection.

They estimate that there have been as many harmful mutations selectively eliminated from the noncoding genomic regions they examined as in known protein coding genes of humans and chimpanzees. During human evolution, they estimate that a total of about three harmful mutations have been selectively eliminated per genome each generation.

According to population genetics theory, the mutations must be eliminated nonindependently in order to eliminate this many harmful mutations from a population each generation. This, say the researchers, in turn implies that sex is necessary for long-term population persistence.

By Elizabeth Tolchin

[Well, let's see where we are. Taking the message of the next clip home, one may be inclined (to go along with Kubrick...) that "more sex solves it all", from theory of common cold to theory of the function of "junkDNA". The practical and by the way long known truism that sexual procreation seems to be a basic mechanism for mother Nature to give a chance for genomic health since a problem on the mother's side might be compensated for from the side of the mother - "sex" probably falls short of as a scientific theory of the function of "junkDNA". So does the declarative dismissal of "junkDNA" by most (not all) Darwinists. Embarrasingly, even Intelligent Design (ID) did better - correctly predicting that "junkDNA" does have a function. There has hardly been such a time-window in the history of human kind when an apparent "void" exists of predictive/non-predictive and experimentally supported/unsupported scientific theories in such a vital matter as 98.7% of our hereditary material - comment by A. Pellionisz on the 5th of October, 2005]

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New Analyses Bolster Central Tenets of Evolution Theory
"You only believe theories when they make predictions confirmed by scientific evidence"

[Experimental support of the First Prediction of FractoGene was accepted for publication and now "In Press" in the peer-reviewed journal of  The Cerebellum, notification received in writing from Editor in Chief on 09/28/2005 - comment by A. Pellionisz, 28/09/05]

Pa. Trial Will Ask Whether 'Alternatives' Can Pass as Science

By Rick Weiss and David Brown
Washington Post Staff Writers

Monday, September 26, 2005; Page A08

When scientists announced last month they had determined the exact order of all 3 billion bits of genetic code that go into making a chimpanzee, it was no surprise that the sequence was more than 96 percent identical to the human genome. Charles Darwin had deduced more than a century ago that chimps were among humans' closest cousins.

But decoding chimpanzees' DNA allowed scientists to do more than just refine their estimates of how similar humans and chimps are. It let them put the very theory of evolution to some tough new tests. [...]

Evolution's repeated power to predict the unexpected goes a long way toward explaining why so many scientists and others are practically apoplectic over the recent decision by a Pennsylvania school board to treat evolution as an unproven hypothesis, on par with "alternative" explanations such as Intelligent Design (ID), the proposition that life as we know it could not have arisen without the helping hand of some mysterious intelligent force.

Today, in a courtroom in Harrisburg, Pa., a federal judge will begin to hear a case that asks whether ID or other alternative explanations deserve to be taught in a biology class. But the plaintiffs, who are parents opposed to teaching ID as science, will do more than merely argue that those alternatives are weaker than the theory of evolution.

They will make the case -- plain to most scientists but poorly understood by many others -- that these alternatives are not scientific theories at all.

"What makes evolution a scientific explanation is that it makes testable predictions," Lander said. "You only believe theories when they make non-obvious predictions that are confirmed by scientific evidence."

Lander's experiment tested a quirky prediction of evolutionary theory: that a harmful mutation is unlikely to persist if it is serious enough to reduce an individual's odds of leaving descendants by an amount that is greater than the number one divided by the population of that species. [...]

"Evolution is a way of understanding the world that continues to hold up day after day to scientific tests," Lander said.

By contrast, said Alan Leshner, chief executive of the American Association for the Advancement of Science, Intelligent Design offers nothing in the way of testable predictions.

"Evolution is a way of understanding the world that continues to hold up day after day to scientific tests," Lander said.

By contrast, said Alan Leshner, chief executive of the American Association for the Advancement of Science, Intelligent Design offers nothing in the way of testable predictions.

"Just because they call it a theory doesn't make it a scientific theory," Leshner said. "The concept of an intelligent designer is not a scientifically testable assertion."

Asked to provide examples of non-obvious, testable predictions made by the theory of Intelligent Design, John West, an associate director of the Discovery Institute, a Seattle-based ID think tank, offered one: In 1998, he said, an ID theorist, reckoning that an intelligent designer would not fill animals' genomes with DNA that had no use, predicted that much of the "junk" DNA in animals' genomes -- long seen as the detritus of evolutionary processes -- will someday be found to have a function.

(In fact, some "junk" DNA has indeed been found to be functional in recent years [...]).[...]

What is hard to understand about this process is that it is essentially passive. The mechanism is called "natural selection" because the conditions at hand -- nature -- determine which accidents are beneficial and which are not. Organisms do not seek ends.

Giraffes do not decide to grow long necks to browse the high branches above the competition. But a four-legged mammal on the savannah once upon a time was endowed with a longer neck than its brothers and sisters. It ate better. We call its descendants giraffes.

That a mechanism driven by random events should result in perfectly adapted organisms -- and so many different types -- seems illogical. [...]

For example, genome sequencing projects have shown that human beings, dogs, frogs and flies (and many, many other species) share a huge number of genes in common. These include not only genes for tissues they all share, such as muscle, which is not such a surprise, but also the genes that go into basic body-planning (specifying head and tail, front and back) and appendage-building (making things that stick out from the body, such as antennae, fins, legs and arms).

As scientists have identified the totality of DNA -- the genomes -- of many species, they have unearthed the molecular equivalent of the fossil record.

It is now clear from fossil and molecular evidence that certain patterns of growth in multicellular organisms appeared about 600 million years ago. Those patterns proved so useful that versions of the genes governing them are carried by nearly every species that has arisen since.

These several hundred "tool kit genes," in the words of University of Wisconsin biologist Sean B. Carroll, are molecular evidence of natural selection's ability to hold on to very useful functions that arise.

Research on how and when tool kit genes are turned on and off also has helped explain how evolutionary changes in DNA gave rise to Earth's vast diversity of species. Studies indicate that the determination of an organism's form during embryonic development is largely the result of a small number of genes that are turned on in varying combinations and order. Gene regulation is where the action is.

Consequently, mutations in regulatory portions of a DNA strand can have effects just as dramatic as those prompted by mutations in genes themselves. They can, for example, cancel the development of an appendage -- or add an appendage where one never existed. This discovery refuted assertions by Intelligent Design advocates that gene mutation and natural selection can, at most, explain the fine-tuning of species. [...]

[The true essence of science is now the daily agenda of even "Washington Post". " You only believe theories when they make predictions confirmed by scientific evidence" - this axiom emerges now as a result of the question of interpretation of the function of "junkDNA". DNA sets of many species have been sequenced, and at least two facts are unescapably clear. 1) "Genes", especially "tool kit genes" (??) are essentially the same in an enormously wide spectrum of species, but in each comprising a mere (but widely differing) fraction of the DNA, 2) JunkDNA was found "functional" (moreover, "regulation where the action is").

"All" we need, at this time, therefore is some theories which can make predictions confirmed by scientific evidence to provide at least one believable new explanation, to make new sense of the above "conceptual meltdown". (A charming oxymoron is, for example, that the only quoted prediction of "Intelligent Design" was that it accurately predicted function to "junkDNA", while - for its biggest embarrassment - the theory of evolution erroneously postulated the (obsolete) notion of "junkDNA", that they are doing nothing yet they are preserved, even "ultraconservatively preserved"! - comment by A. Pellionisz on the 27th of September, 2005]

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NIH Launches Program to Study Genetics and Genomics of Xenopus
By a GenomeWeb staff reporter

NEW YORK, Sept. 26 (GenomeWeb News) - The National Institutes of Health has announced a new program entitled, "Genetic and Genomic Analyses of Xenopus," which is seeking new genetic and genomic tools "to exploit the power of Xenopus as a vertebrate model for biomedical research."

According to a program announcement issued last week, the NIH welcomes proposals "to develop new tools or genetic or genomic resources of high priority to the Xenopus community that will advance the detection and characterization of genes, pathways, and phenotypes of interest in development, organogenesis, and in cell biological processes, such as cell division, signaling and migration."

In the program announcement, NIH outlined a number or resources that have already been developed for X. tropicalis and X. laevis, including cDNA libraries and EST sequences, UniGene clusters, full-insert cDNA clones and sequences, a genetic map, genomic libraries and genomic sequences, a physical map, microarrays, and transgenic and mutant animals. "These diverse data and reagents are being generated by investigators from several different research communities, including geneticists, gene sequencers, gene mappers, cell biologists, developmental biologists, and bioinformatics experts," NIH said, and "can now be used to enhance Xenopus' role as a model system."

NIH said that it has not set aside any special funding for applications submitted in response to the announcement.

The anticipated start dates for new awards will be December, 2007, 2008, and 2009.

The first due date for letters of intent is Dec. 19, and the first due date for applications is Jan. 18, 2006.

"Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary," NIH said.

[What is the difference between "Genetic" and "Genomic" and what kind of "new tools" are required? While the report on experimental support of the First Prediction of FractoGene used the platform of fugu-zebrafish-mouse-man, both the Xenopus - in which the "basic circuit of the cerebellar neural nets" is a model, as well as the nature of the "need for new tools" is discussed. -comment by A. Pellionisz on the 27th of September, 2005]

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Search for genetic origins of disease

The Times, September 26, 2005, By Mark Henderson, Science Correspondent

SCIENTISTS have embarked on a search for the genetic origins of 12 common diseases in the biggest and most comprehensive project of its kind yet undertaken.

The £8.6 million study, funded by the Wellcome Trust, is expected to provide critical clues that will bring new approaches to the treatment of conditions such as diabetes, heart disease and arthritis.

The Case Control Consortium, which includes 25 British research groups, will study the genetic peculiarities of more than 20,000 people to reveal variations in DNA that make them more or less likely to develop particular medical disorders.

The study will cover eight diseases that account for much of the ill health in Britain: coronary heart disease, hypertension, types 1 and 2 diabetes, bipolar disorder, Crohn’s disease, rheumatoid arthritis and tuberculosis.

A subsidiary project will look at a smaller number of genetic variations that play a part in multiple sclerosis, auto-immune thyroid disease, breast cancer and the spinal disorder ankylosing spondylitis.

For each of the main eight diseases, scientists will read the genetic codes of 2,000 sufferers and analyse variations that may play a part in causing or preventing its development.

These variations, which are known as single nucleotide polymorphisms, or SNPs (pronounced “snips”), will then be compared with DNA taken from a control group of 3,000 healthy people.

The scientists believe that they will find patterns not present in healthy individuals.

“The aim is to identify DNA variants which play a role in susceptibility or resistance to these diseases,” said Peter Donnelly, professor of statistical science at Oxford University, who is one of the study leaders. “There may be variants that make it more likely that you will get type 2 diabetes, and other variants that have a protective effect against the same disease. With most of these diseases, we understand little about the causes. If we can learn that this gene makes you more or less susceptible, we get important clues as to how the disease works.”

He added: “Once we understand these diseases better, through the foothold that the genetics provide, the hope would then be that we would see obvious or plausible candidates for drug therapies.”

The work may help to match treatments to patients whose genes may make them more responsive to certain drugs.

Professor Donnelly said: “Many of the things that we think of as one disease may be, when we understand them better, collections of similar symptoms caused by different biological processes. When a car overheats, you would not always try to repair it the same way - you want to find out the reason why it overheated and fix that. At the moment we often have only one or two sets of drugs for these diseases.”

Not all the effects will necessarily come from genes; variations in the so-called “junk DNA” that makes up most of the human genome will also be studied, as it is thought this plays an important role in switching genes on and off [...]

[For just in case a reader is wondering what is meant by "conceptual meltdown", this important illustration provides a deadly serious example. The title to this posting is "Genetic" origins of diseases. However, seemingly as an "afterthought", it is mentioned that "junkDNA that makes up most of the human genome will also be studied". (Some dreadful diseases are already known to originate from "junkDNA" and *not* from "genes" that may be pristine). Aren't we missing out on something "big time"?? First, the title should than be "Genomic" rather than "Genetic", or something filling the gap between the two... Maybe some of the vast amount of money is outright misspent looking for "genes" ("Gene discovery") as the root causes of some (or most...) of diseases. Maybe a focused and targeted approach is needed (perhaps guided by theories that of course should be predictive, and their prediction(s) verified). What is the difference between "Genetic" and "Genomic" and what kind of "new tools" are required? While the report on experimental support of the First Prediction of FractoGene used the platform of fugu-zebrafish-mouse-man, in addition both the Xenopus - in which the "basic circuit of the cerebellar neural nets" is a model, as well as the nature of the "need for new tools" are discussed. -comment by A. Pellionisz on the 27th of September, 2005]

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"There is more to non-coding DNA than meets the eye".
Chromosome 18 Fully Sequenced; Appears to Have Lowest Gene Density of Any Human Chromosome

By a GenomeWeb staff reporter

NEW YORK, Sept. 23. [2005] (GenomeWeb News) - The DNA sequence of human chromosome 18 has been completed, and scientists have concluded that the chromosome appears to have the lowest gene density of any human chromosome completed to date -- an average of 4.4 genes per megabase.

In a paper published in this week's issue of Nature, a group of about 55 scientists led by Chad Nusbaum of the Broad Institute of the Massachusetts Institute of Technology and Harvard reported that chromosome 18, around 76 megabases in length, included 337 gene loci. These broke down into 243 known genes, 49 novel genes, 10 novel transcripts, 11 putative genes, 11 "predicted-plus" genes, and 13 gene fragments.

By comparison, chromosome 19, at 55.8 megabases, includes around 1,500 genes, an average of 26.9 genes per megabase.

The authors noted, however, that despite the low density of genes on chromosome 18, the density of non-protein-coding sequences conserved among mammals was close to the genome-wide average.

The observation that non-coding DNA seems to be evolutionarily conserved across a number of mammalian genomes suggests that there is more to non-coding DNA than meets the eye.

"This [observation] has important implications for the nature and roles of non-protein-coding sequence elements," the scientists wrote.

[When Malcolm J. Simons took a close look at non-coding DNA (1987) "it met his eyes" that there was apparently far too much "pattern in the junk" to be "just junk". Therefore, it has been the axiom since 1987 that "there is more to non-coding DNA than meets the eye". In fact, lately the two paramount challenges became 1) what is "beyond spotting patterns by naked eye" (some deterministic mathematical algorithms, such as FractoGene, with its first quantitative prediction experimentally supported, and a second prediction is to be announced in days, and explained the forthcoming BrowserBook "FractoGene ... decoding junkDNA in the age of PostGenetics". 2) what are the 55 scientists at MIT/Harvard are going to do, if e.g. in a Journal like Nature a "Society" would be announced putting this conclusion on their agenda? Joining might be a logical step - comment by A. Pellionisz on the 23rd of September, 2005]

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Rosetta Genomics raises $6 M in fourth round
The company also signed an agreement granting user rights to its database, which could generate tens of millions of dollars in revenue.

Batya Feldman 13 Sep 05 19:24

Israeli start-up Rosetta Genomics last week raised $6 million from private investors in its fourth financing round, which was expanded, due to excess demand. Yossi Ben-Yosef’s Kadima High Tech, which brings together private life science investors, led the round, with Coronis Greenberg, GlenRock Israel (Leon Recanati's investment company), and others. Many of Rosetta Genomics previous investors participated in the current round.

Rosetta Genomics CEO Dr. Isaac Bentwich founded the company in 2000. Rosetta Genomics is considered a pioneer in discovering microRNA (miRNA) genes, and in developing diagnostic tools and drugs for a number of types of cancer and other important diseases, based on these genes. Discovery of microRNA genes is a new discipline; until recently, these genes, considered an unimportant element of the genome, were referred to as “junk DNA.”

As the financing round was completed, Rosetta Genomics signed its first significant agreement with Ambion, a leading US biotechnology company. Ambion produces innovative RNA-based diagnostic and research tools. The agreement gives Ambion access to Rosetta Genomics’ database, including miRNA sequences, for a variety of medical research applications.

Rosetta Genomics is currently negotiating a cooperation agreement with a number of leading biotechnology companies for development of innovative drugs and diagnostic tools, based on miRNA, for prostate cancer, lung cancer, and a number of viral diseases.

Rosetta Genomics president Amir Avniel said today that the significantly shorter development process required for development of diagnostic tools had led his company to focus on them, in preference to drug development.

Published by Globes [online] - - on September 13, 2005

["A NEW DISCIPLINE IS BORN". The highly successful Israeli Rosetta Genomics continues to be "on the edge" with its journalistic coverage - making the "conceptual meltdown" of what "gene" is (and what "junk" is) evident. In the "traditional" sense, no "genes" were considered "unimportant"; by definition they were the only important part of the Genome (and the rest was "junk"). With Affymetrix, also trying to "re-define" what a "gene" is (see in this compilation, comment on June 22nd), there is something completely new arising from the conceptual wreckage - A NEW DISCIPLINE, see our forthcoming announcement - comment by A. Pellionisz on the 14th of September, 2005]

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'Introns' play key role in RNA formation, Italian team says (ANSA) - Rome, September 5 - Sections of DNA formerly dismissed as junk contain information vital to our genes, a team of Italian researchers has discovered .

Introns, which account for around 25% of the human DNA sequence, play a role in embryonic development and in important cellular processes, according to a study by scientists from the IRCCS Medea Institute near the northern town of Lecco .

The report, to be published in the scientific journals Human Molecular Genetics and Trend Genetics, overturns the long-held belief that introns are "junk" sequences, evolutionary artefacts from the past that have outlived their usefulness .

"We found that far from representing junk, they contain information that is important for the functioning of our 30,000 genes," said one of the study's authors, Uberto Pozzoli .

"It is not so much the number of our genes but how their functions are regulated that makes humans humans, mice mice and worms worms. While this was already understood, it was far from clear that introns also helped make us human." Since their discovery in the late 1970s, introns have been dismissed as useless. Their location scattered along vital protein-coding sequences known as extrons, which account for less than 2% of human DNA, left scientists baffled .

But the full DNA mapping of other organisms - dogs, chimps, mice, pufferfish - has allowed an extensive comparison with human DNA, leading to a scientific re-evaluation of the intron's purpose .

DNA sequences that have a function are preserved during evolution. There is therefore little alteration during successive stages of the evolutionary process, meaning that different organisms today still show very similar patterns .

Given the importance of extrons, [sic] it came as no surprise that their sequences varied little between one species and the next. However, scientists had not expected to discover similar, strong cross-species resemblances in intron sequences .

Taking this discovery as its starting point, the Italian team proved that the location of introns in the DNA sequence suggests they play a role in the correct formation of messenger RNA, molecules that act as "blueprints" for protein synthesis .

Furthermore, they discovered that genes active in the brain have preserved more intron sequences than those anywhere else .

The team also took into consideration other recent studies, showing that genetic diseases can be caused by variations in preserved intron sequences .

"It's therefore clear that the study of these sequences represents one of the great challenges of modern genetics," remarked Manuela Sironi, who co-penned the report .

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Junk RNA Begins To Yield Its Secrets
5 September 2005
Cripps Institute, La Jolla, California

A paper in the journal Science details how a team of investigators from The Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation have discovered a way to screen hundreds of non-coding RNA molecules to discover their functions within cells. Unlike mainstream RNA, which is copied from DNA to build proteins, these non-coding RNA molecules are not translated into proteins. Sometimes referred to as "junk", there are many thousands of these non-coding RNA molecules inside human cells. Scientists believe that even if only a small percentage are functional, this would equate to hundreds of molecules that may play important roles in the control of cellular functions.

It's only recently that scientists have become interested in non-coding RNA. One of the reasons for the turnaround is that they have begun to recognize just how abundant non-coding RNA is. In the same issue of Science, two reports describe the work of other scientists showing that there are far more non-coding RNAs than most researchers would have imagined even a few months ago.

The question scientists have been asking is: why would the cell expend so much energy making RNA if that RNA doesn't do anything? They have speculated that perhaps some non-coding RNAs play cellular roles. And while computational approaches and analysis have been used, nobody has come up with a way of experimentally determining whether the non-coding RNAs have a cellular function. So how can researchers rapidly assess what the function of these non-coding RNAs might be? "That's the million-dollar question," says Neurobiology Professor John Hogenesch, from Scripps. "Until now we have not had a generalized way of answering it."

But now they have. And it appears that the team has established the first proof of a cellular function by non-coding RNA. To apply a high-throughput approach to the problem, the teams began by collecting a library of 512 evolutionarily conserved non-coding RNAs. A technique called RNA interference was then used to silence the non-coding RNA within cells. The researchers then screened for changes, such as the increase or decrease of activity related to a certain cellular protein. In theory, if this change occurs as a sole result of altering the level of a non-coding RNA, then that non-coding RNA could well be involved.

Out of the 512 target non-coding RNAs, eight of them appeared to have a cellular function. Six appeared to affect cell proliferation, one influenced the hedgehog (Hh) signal transduction pathway, and the final one was a strong modifier of nuclear factor of activated T-cells (NFAT) signaling. The researchers decided to examine in detail this last non-coding RNA. Suspecting that it might interact with proteins, they used a technique to trap the proteins with which the non-coding RNA was interacting. There were ten, a few of which were of the class known as "importins," involved in the transport of materials from the cytoplasm to the cell nucleus. Among these was the protein "nuclear factor of activated T cells" (NFAT). The scientists found that when they blocked the non-coding RNA, the activity of NFAT increased dramatically. For this reason, they dubbed the non-coding RNA the non-coding repressor of NFAT "NRON."

The researchers are excited about their new experimental strategy which they say could be ramped up to screen thousands, rather than hundreds, of RNA samples. "You could apply this methodology to look for functions of many other non-coding RNAs," said Scripps researcher Aaron Willingham. "We have only just hit the tip of the iceberg," added Professor Peter G. Schultz, also from Scripps. "There's a whole world of this non-coding RNA."

[Indeed, it is the "million dollar question" to come up with a process and method of experimentally detecting which "protein coding" sequences are working together with which "non-coding" sequences. This is precisely what "FractoGene - 2nd Prediction" will reveal in an imminent Press Release, and will elaborate in the upcoming browserbook of "FractoGene ... decoding junkDNA". - comment by A. Pellionisz on the 6th of September, 2005]

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[The selection of announcements below, pertaining to the sequencing of the DNA of the chimpanzee, with 99.9% identity of the genes with that of the human - while a much larger than expected difference in their "junkDNA" - raises a number of questions that will be answered here in an appropriate manner in due course - comment by A. Pellionisz, 31st of September, 2005.]

By Lisa M. Krieger

San Jose Mercury News, 31st of August, 2005

An international team of scientists today announced the first comprehensive comparison of the genetic blueprints of humans and chimps, an effort that explains what makes us so similar to our closest living relative -- yet so strikingly different.

``The differences shed light on our uniqueness,'' said Dr. Eric Lander, director of the Broad Institute of Cambridge, Massachusetts and one of the principal investigators of the project.

The insights will contribute to medicine, because many of the differences relate to disease susceptibility. Humans die from illnesses like malaria, AIDS and Alzheimer's disease, while chimps are immune.

They could also explain other evolutionary changes that caused the species to diverge -- and gave humans the ability to walk, talk, use tools, ponder the future and build giant societies.

The genetic sequences of the most important parts of the human and chimp genomes are about 99 percent identical, according to the analysis by 67 researchers, including a team from the University of California-Santa Cruz. Part of the chimp genome is not shared by humans; part of the human genome is not shared by chimps.

When the genomes of the two species are compared more broadly, including non-functional ``junk DNA,'' they are 96 percent identical.

While this sounds like a close connection, people are far more closely linked to each other, the scientists explained. There is only a .1 percent difference between individual humans -- in other words, there are 10 times fewer differences between all humans than there are between humans and chimps.

The news, announced at a Washington, D.C., press conference, echoed the excitement of the first complete sequencing of the human genome in 2001.

``It adds great richness to something that was one-dimensional,'' said Dr. Francis S. Collins, director of the National Human Genome Research Institute, who led the human sequencing project.

A large collection of papers, to be published Thursday in the journals Nature and Science, describe a broad range of chimp-based research.

Several papers explore chimp evolution, fossilized remains and their ecological future.

Others, focused on genetics, describe three major accomplishments:

• Sequencing of a genome from a single chimp, named Clint.
Alignment of the chimp genome against a human genome.
Analysis of the two genomes, sifting through data to find areas of similarities and differences.

The final step, which will fuel years of further research, is to understand what these differences mean.

Humans and chimps shared a common ancestor 6 million years ago, then parted ways. How we changed, and why, has long intrigued scientists.

``The similarities between man and chimp have fascinated us across time,'' said LaDeana W. Hillier of the Genome Sequencing Center at Washington University School of Medicine. ``It is a privilege to see those very specific similiarities at the molecular level.''

The DNA differences will offer clues to the mysteries of aging and disease.

The genome comparison finds some of the most dramatic differences in regions thought to cover the immune system. This would explain varying susceptibilities to disease. Other regions, such as those governing the nervous system, seem very similar.

As scientists compare genomes more closely, they will seek genetic ``outliers'' in individuals -- patterns that do not conform to those in the general population. This would suggest a unique trait, such as suspectibility to a rare disease.

The analysis also depicts evolutionary change. It shows that chimp and human genomes have changed over 6 million years, due to selective pressures of their different environments, said Dr. Robert Waterson, chair of the Department of Genome Sciences of the University of Washington School of Medicine in Seattle.

``I couldn't imagine Darwin hoping for stronger confirmation of his ideas than this,'' said Waterson.
Added Collins: ``We can peek into evolution's lab notebook to see what is going on.''
Yet even this collection of elegant new research will not explain everything about what makes us human, the scientists conceded.
``The real question of what makes us human is more than a biological question,'' said Collins. ``It is also a theological question.

``Knowing how the nervous system acts may not tell us about other aspects of humanity, like how do we know what is right and wrong? And what is the human spirit?''

Contact Lisa M. Krieger at or (408) 920-5565.

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'Life code' of chimps laid bare
BBC News
Wednesday, 31st August, 2005

The genetic code of our closest living relative, the chimpanzee, has been sequenced and analysed by an international team of researchers.

The scientists say the information is a milestone in the quest to discover what sets us apart from other animals. A comparison shows chimps and humans to be almost 99% identical in the most important areas of their "life codes". The team tells Nature magazine that future research will tease out the significance of the few differences. The study was undertaken by an international group called the Chimpanzee Sequencing and Analysis Consortium, which was made up of 67 scientists at 23 research institutions in the US, Germany, Italy, Israel and Spain.

Fundamental questions

The work provides a catalogue of the genetic differences that have arisen since humans and chimpanzees diverged from a common ancestor some six million years ago.

"As our closest living evolutionary relatives, chimpanzees are especially suited to teaching us about ourselves," said the study's senior author, Robert Waterston, chair of the Department of Genome Sciences of the University of Washington School of Medicine in Seattle .

"We still do not have in our hands the answer to a most fundamental question: What makes us human? But this genomic comparison dramatically narrows the search for the key biological differences between the two species."

The researchers hope that by elaborating those few points of separation, they will also increase pressure to save chimpanzees and other great apes in the wild.

The study shows that our genomes are startlingly similar. We differ by only 1.2% in terms of the genes that code for the proteins which build and maintain our bodies. This rises to about 4%, when non-coding or "junk" DNA is taken into account.

The long-term goal of the project is to pinpoint the genetic changes that led to human characteristics such as complex language, walking upright on two feet, a large brain and tool use.

Medical gain

Comparing our genome with other species provides a treasure trove of information for understanding human biology and evolution. "As the sequences of other mammals and primates emerge in the next couple of years, we will be able to determine what DNA sequence changes are specific to the human lineage," said the study's lead author, Tarjei Mikkelsen, at the Broad Institute of the Massachusetts Institute of Technology and Harvard University .

"The genetic changes that distinguish humans from chimps will likely be a very small fraction of this set."

There should be significant gains for medicine. Already, it can be seen that three key genes involved in inflammation - a root cause of many human diseases - appear to be absent from chimps. This could explain some of the known differences between chimps and humans affecting immune and inflammatory responses. Humans, on the other hand, seem to have lost a functioning caspase-12 gene, which may protect other animals against Alzheimer's disease. The DNA for the study came from the blood of a male chimp called Clint, who was housed at the Yerkes National Primate Research Center in Atlanta . The chimp died from heart failure last year but some of his cells have been preserved for future research. The species studied is the common chimpanzee (Pan troglodytes). Its only sister species is the pygmy chimpanzee, or bonobo (Pan paniscus). The chimp's is one of more than two dozen mammalian genomes that have or are currently being sequenced and analysed, including the mouse, the rat, the dog and the cow.

[This article makes it very clear that the main difference between the human and chimpanzee genome is in the "junkDNA". The logical scientific question, therefore, is "what is the 'junkDNA' doing? - comment by AJP on the 1st of September, 2005]

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What does the fact that we share 95 percent of our genes with the chimpanzee mean? And how was this number derived?

Scientific American
J. M. Foxley
Colchester, U.K.

Prescott Deininger of the Tulane Cancer Center in New Orleans explains. There is a significant body of evidence that supports the idea that the chimpanzee is the closest genetic relative of humans. This was first determined through a large number of studies, some of which used genomic DNA hybridization to detect the level of sequence mismatches, as well as analyses of individual protein molecules. These early findings suggested that chimps and humans might typically have sequences that diverge from one another by only about 1 percent.

We now have large regions of the chimpanzee genome fully sequenced and can compare them to human sequences. Most studies indicate that when genomic regions are compared between chimpanzees and humans, they share about 98.5 percent sequence identity. The actual relationship depends on what types of sequences are being compared and the size of the comparison unit. A report published in the Proceedings of the National Academy of Sciences in 2002 suggested that under the most rigorous alignments, the match would be only 95 percent similarity overall. This resulted from the researchers treating changes involving small insertions and deletions of bases differently than previous investigators did over a very large region. A few questions still remain as to whether the chimpanzee genome sequence data are of high enough quality at this point for reliable comparison. In general, however, the overall conclusion is that most genes would share about 98.5 percent similarity. The actual protein sequences encoded by these genes would then typically be slightly more similar to one another, because many of the mutations in the DNA are "silent" and are not reflected in the protein sequence. Given the very strong similarity between the chimpanzee and human genomes, many people wonder how we can be so different. At this point, there have been only a few isolated examples of genes that are functionally present in chimpanzees but not in humans, and vice versa. Thus, chimps and humans may share as many as 99.9 percent of the same genes with most of those genes being 99 percent similar in their sequences. Chromosomes do not exhibit big structural differences either. Although there are a number of small chromosomal changes that rearrange the order of genes on regions of those chromosomes, most of these are thought to leave gene function unchanged. It seems likely that the differences between human and chimpanzee phenotypes depend more on subtle regulatory changes more than on the presence of different genes. For instance, it may be that there are changes in some genes that alter the amount of protein produced by that gene at different stages in the development of a chimp versus a human. Alternatively, there may be small changes to the structures of the proteins (from the 1 percent divergence) that produce changes in how they interact with other cellular components and therefore subtly alter the pathways in which they are involved. At this point, we do not know which types of changes are responsible for the relatively big differences between chimps and humans.

It is worth noting that individual humans generally differ by about 0.1 percent genetically. Thus, chimps differ from humans by about 15-fold more, on the average, than humans do from one another. The 0.1 percent human divergence certainly results in significant variation in physical appearance and traits between different humans. Therefore, perhaps we shouldn't be so surprised that chimps could be 98.5 percent related to humans. Relatively small genetic changes can produce major phenotypic changes.

["Conceptual meltdown" even at the level of Scientific American. Is the the number of our "shared genes" with the chimp 99.9%, 99%, 98.5% or 95%? It may decide on how we (re)define "Gene". One conclusion is certain: "junkDNA" is *not* "non-functional" - the 4% or so difference in "regulatory changes" is more likely to make us human, rather than the one tenth of a single percent difference of "genes". - comment by A. Pellionisz, 1st of September, 2005]

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Sisters under the skin

The Economist
Sept. 1st 2005

The genome of the chimpanzee - mankind's closest living relative- has been sequenced. Comparing it with Man's should help people understand themselves

KARL VON LINNÉ (or Linnaeus, as he is widely known) was a Swedish biologist who devised the system of Latinised scientific names for living things that biologists use to this day. When he came to slot people into his system, he put them into a group called Homo—and Linné's hairless fellow humans are still known biologically as Homo sapiens. But the group originally had a second member, Homo troglodytes. It lived in Africa , and the pictures show it to be covered with hair.

One half of the puzzle has been available for several years: the human genome was published in 2001. The second has now been added, with the announcement in this week's Nature that the chimpanzee genome has been sequenced as well. For those expecting instant answers to age-old questions though, the publication of the chimp genome may be something of an anticlimax. There are no immediately obvious genes - present in one, but not the other - that account for such characteristic human attributes as intelligence or even hairlessness. And while there is a gene connected with language, known as FOXP2, it had already been discovered. But although the preliminary comparison of the two genomes made by the members of the Chimpanzee Sequencing and Analysis Consortium, the multinational team that generated the sequence, did not turn up any obvious nuggets of genetic gold, it does at least show where to look for them.

The two genomes are, indeed, very similar. They differ by only 1.2% over the course of some 3 billion pairs of the genetic "letters" in which the language of the genes is written. In fact, almost a third of the shared genes (each of which is several thousand letters long) are identical in the two species, despite their most recent common ancestor having lived 6m years ago. Many more differ by less than the amount that would be expected if changes were accumulating by random processes. (This suggests that natural selection is actively stopping them changing.)

There were, though, 585 genes that showed differences large enough to have been the result of natural selection for change, rather than stasis, and it is among these that the vital human/chimp differences may be found. Or, at least some of them. For it may be that many of the crucial differences are not in the genes themselves, but in how and when the messages those genes carry are transcribed and translated into the protein molecules that do the work in cells - and thus, ultimately, determine what an organism looks like and how it behaves.

This idea is supported by two observations. One is that a number of genes have been duplicated in humans, but not in chimps. Other things being equal, two copies of a gene turn out twice as much protein as one, and that can make a huge difference to the way a cell works. The other is that a number of the genes that seem to have undergone more rapid evolution in humans than in chimps carry the blueprints for transcription factors. These are special proteins that regulate the transcription of other genes. Change the regulation, and both the amount of protein and the time when that protein is produced may change. If the protein in question is involved in embryonic development, that can have huge consequences for the organism that eventually arises.

[This article raises a most interesting question and recalls a historical parallel. Looking (in vain) for the "gene(s) of intelligence" is a deja vu of a huge science establishment, called "Artificial Intelligence". "AI" was dominated for decades by MIT professor Marvyn Minsky, who even dared to "prove" that looking for biological clues of how the biological brain produces some (even simple) functions, is "theoretically impossible" - all R&D was monopolized by non-biologist "Cybernetists". Minsky's (in)famous paper froze all Government funding of theoretical neurobiology for at least two decades. Exploding "Neuroscience" could only break through this devastating handicap by some determined and devoted scientists (such as National Academy Member John Hopfield and this commentator AJP at the "Neuroscience Study Program" in Boston in the late seventies) to establish a new field (with its International Neural Network Society, Congresses and Journal, leading to Government & other Funding Programs), called "Neural Networks" - with the clear intent of looking for clues of "Intelligence" in the right place (the biological brain).

This commentator (AJP) as the Founder of the International Neural Network Society (INNS) and a Founding Member of Editorial Boards of several Journal of Neural Networks sees an eary parallelism at this time - when Genetics as we know it seems to "give up on biology" in finding answers what makes us human. If the science establishment as we know it (either AI or Genetics) runs out of answers, it must yield to those little new branches of science establishment that could (Neural Networks a quarter of a Century ago, and looking beyond Genetics as we know it, today). It is not altogether impossible, for instance, that "intelligence" is already present in much less complex manner in dogs (versus worms), and human intelligence is a "runaway" regulatory feature of uncontrolled of hierarchical representations of the external word (a primitive form of which is already present in higher mammals). Admittedly, the argument may prove to be totally mistaken for "intelligence", but it is certainly a fact of today, that a good number of deadly diseases (e.g. types of cancer) originate from "regulatory DNA" problems, for which no "gene discovery" is likely to find a solution as there may be no "gene" to look for. In all likelihood, "Genetics" (turning 100 years old in 2006) needs to be redefined. - comment by Andras J. Pellionisz, Sept. 1st, 2005]

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Nature News
Aug 31, 2005

SEATTLE , WA , United States (UPI) -- A study comparing humans and chimpanzee genomes has determined the cause of differences between the two species.

Researchers found much of the genetic difference came about in events called segmental duplications, in which segments of genetic code are copied many times in the genome.

Lead researcher Evan Eichler, associate professor of genome sciences at the University of Washington-Seattle , and colleagues studied the chimp genome, looking for large-scale segmental duplications consisting of as many as 20,000 base pairs.

They found most of the genome change between chimps and humans can be attributed to large segmental duplications. Such large-scale genetic events altered more total base pairs -- about 2.7 percent of the genome -- than differences from single base-pair changes, which total about 1.2 percent of the genome.

"For all the talk of the 1.2 percent single base-pair difference and the importance of those, there`s even more difference between the species due to duplication events," said Eichler. "Now we need to learn the role of those duplication events in species evolution and disease."

[This article comes closest to "calling a spade a spade" when telling the differences in non-coding sequences apart in homo sapiens and the chimpanzee. Clearly, "segments of genetic code are copied many times (more) in the human DNA compared to the chimp. One (AJP) can not help recalling a figure in the "evolution revolution" where it is plainly in view what an additional repeat may do to a brain cell. There is, therefore a "science agenda" - as the 2nd Prediction of Fractogene will be layed out in the upcoming book - comment on the 1st of September, 2005]

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Reading the chimp book of life

By Helen Briggs
BBC News science reporter

Scientists have deciphered another book in the library of life - the genetic recipe of our closest living relative, the chimpanzee.

It is arguably the most valuable genetic blueprint for determining what makes us human. Researchers have already begun to analyse the parts of the life code that are unique to each species. Buried within the 3 billion DNA "letters" are the changes that put our ancestors on the pathway to humanity.

Wealth of new evidence . It is more than a century since Charles Darwin recognised that humans and chimps are related. A wealth of evidence has emerged since then, including the discovery of the first known chimpanzee fossil revealed this week. Researchers hope the comparison of the chimp and human genomes will shed light on the past six million years or so of evolution, since the two species diverged from an apelike common ancestor. In this brief eye blink of evolutionary time, the features that make us human emerged; among them our large brain, complex speech and the ability to walk upright. At the same time, we lost many of the features we associate with our ape cousins such as their dense body hair.

Alterations in the sequences of the chemical "letters" (base pairs) along our DNA should account for the differences.  [This used to be the "axiom"- but the new finding has destroyed the old axiom - AJP]

It turns out that we are both more and less like apes than previously thought. This apparent paradox is a hallmark of the complexity of the mammalian genome. If you take the most meaningful parts of the genome - the genes that code the proteins that build and maintain our bodies - the genetic sequences of man and ape differ by a mere 1% in terms of single letter changes to the genetic code. But in more poorly-understood parts of the genome - regions of DNA that regulate our genes, for instance, or so-called junk DNA with as yet unknown functions - we are somewhat more divergent than we once thought. Duplications and shuffling of stretches of DNA add a further difference of about 3% so, when you compare the two genomes as a whole, we share about 96% of DNA.

Disease defences Many of the 35 million single letter (nucleotide) differences that set us apart from chimps lie in the genes that make proteins involved in our immune response. This is no great surprise, since chimps and humans would have encountered different diseases during evolution. Intriguingly, changes to parts of the human genome may have made us prone to certain diseases. A gene that seems to protect other animals against Alzheimer's appears not to function in our genome. Duplication of others stretches of DNA in humans are implicated in the development disorders spinal muscular atrophy and Prader-Willi syndrome.

In terms of what makes us human, the most promising areas for exploration are six regions that show very little variation among humans but more variation in chimps suggesting they were important in the human line of evolution. One of these regions contains a gene called FOXP2 that seems to be important in speech.

But as yet there is no smoking gun - a protein involved in regulating brain function, say - that may have caused our ape-like ancestors to branch off from chimps. With the genomes of other primates, such as the orangutan, nearing completion, there will soon be other members of the family available for comparison. The researchers who decoded the chimp genome hope that elaborating how few differences separate the species will broaden recognition of our duty to protect apes in the wild. Only a day after their study was published in the journal Nature, the UN's environment and biodiversity agencies warned that some of the great apes - chimps, gorillas, and orangutans - could be extinct in the wild within a human generation.

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Scientists find missing links in chimp genome

Completion of genetic sequence for humans' nearest relatives offers vital new biological clues, while fresh fears are raised for their survival

The Guardian
Tim Radford, science editor
Thursday September 1, 2005

Humans and chimpanzees share "perfect identity" in 96% of their DNA sequence, an international team of scientists reports today. Their findings, a landmark in the scientific study of humans and great apes, are drawn from the completion of the full genome sequence of a chimpanzee. Clint, a 24-year-old male who died of heart failure last year at a research centre in Atlanta , Georgia , now lives on in the world's databases as the fourth mammal - after humans, mice and rats - to yield a full genetic blueprint. The research findings could offer a new way of understanding human biology, and underline once again the close kinship between Pan troglodytes, the larger species of chimpanzee, and Homo sapiens. It also throws new light on the tiny differences that set humankind on a different evolutionary path. "As our closest living evolutionary relatives, chimpanzees are especially suited to teach us about ourselves," said Robert Waterston of the University of Washington in Seattle, a leading member of the research team. " We still do not have in our hands the answer to a most fundamental question: what makes us human? But this genomic comparison dramatically narrows the search for the key biological differences between the species." Scientists have only begun to sample the richness of the genetic information now at their disposal. Comparison between human and ape DNA reveals that some human and ape genes evolved very swiftly, especially those linked to the perception of sound, the transmission of nerve signals and the production of sperm. It shows a pattern of genetic mutations that could leave each species open to disease, but also enable each to make unique adaptations to the environment. And it highlights a pattern of rapid change in a small number of human genes about 250,000 years ago - when Homo sapiens is supposed to have emerged as a distinctive species in Africa . Chimpanzees and humans last shared a common ancestor more than six million years ago. But chimpanzees kill each other, defend their territories, start squabbles and then kiss and make up. They devise tools, use subterfuge, recognise themselves in mirrors and clasp hands when they meet.

The latest studies, published in Nature today, show that the difference between humans and chimps is 60 times less than that between humans and mice. But the difference between humans and chimps is still about 10 times that between any two humans.

Researchers completed an epic race to sequence the first draft of the human genome in 2001, followed by mice and rats. The mammalian sequences have already been compared with the DNA of many other organisms. The first lesson has been that many genes have survived millions of years of evolution, and that small changes have led to sometimes dramatic differences between related species.

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Genetic Efficiency and the Carbon Cycle [a misnomer title - comment by AJP]
Jamais Cascio at August 19, 2005
(also, as seen below: New Scientist, 27 August 2005)

A bacteria known as SAR 11 -- or Pelagibacter ubique -- now has the distinction of being the living organism on Earth with the most efficiently-coded genome. There are no signs of junk DNA, duplicate entries, or viral genes, and the code length itself is only 1,354 genes long (compared to the 30,000 genes in humans, which itself was a surprisingly low number). The only microbes with fewer genes are "obligate parasites" or symbionts, creatures that rely on another organism for some of their physiological processes.

The researchers who figured all of this out argue that this goes a long way to explain why Pelagibacter ubique is the dominant species in the ocean. The mass of Pelagibacter ubique outweighs the combined weight of all the fish in the sea. Moreover, SAR 11 appears to be critical for the function of carbon cycle.

The microbe has evolved into an incredibly efficient form, in terms of both its genome and its behavior -- the DNA is even biased towards base pairs requiring less nitrogen, a relatively hard element to obtain without effort. Pelagibacter ubique only does what it must to survive: eat.

Pelagibacter feeds off dead organic matter that is dissolved in ocean water - lead researcher Stephen Giovannoni of Oregon State University likens it to a very thin chicken soup.The dissolved carbon is always there, so there is no need to build in special metabolic circuits to adjust between periods of feast and famine. Indeed, in laboratory studies, the Oregon biologists have found that adding nutrients to the broth has no effect on the microbe's vigour.

Pelagibacter ubique's role in the carbon cycle is only now becoming clear. It consumes the dissolved organic carbon in the oceans, but in doing so it produces nutrients required by algae for growth; the algae then turn carbon dioxide into oxygen. Ocean algae are responsible for about half the photosynthetic oxygen on the planet.

The research appears in the current Science.


New Scientist
Is no-frills DNA the key to success?· 27 August 2005 · From New Scientist Print Edition

SMALL is beautiful in more ways than one for the ocean-dwelling bacterium Pelagibacter. As well as being among the tiniest of all bacteria, it has now been identified as having the most streamlined genome so far found in a free-living organism.It contains just 1354 genes scattered over 1.3 million DNA base pairs and is almost entirely devoid of "junk" DNA, according to researchers at Oregon State University in Corvallis (Science, vol 309, p 1242).This streamlining could mean the bacterium needs less nitrogen and phosphorus to copy itself, allowing it to grow where nutrients are scarce. This may give it a competitive edge over less thrifty bacteria.

[The plot thickens. Is it true that the Pelagibacter has zero "junkDNA"? No, it is false (the first article says "there are no signs of Junk DNA" while the second says even more cautiously that it is "almost entirely devoid of "junk" DNA").

In fact, the information provided by the lead author of the Science article concludes in this statement:

"There is DNA with no assigned function in the genome, but there is not very much of it. Our last analysis put the coding regions at 96.33% of the nucleotides, and much of the remainder probably functions in transcription initiation and control. Although obvious examples of junk DNA are conspicuously absent, it is likely that some of the 3.77% of "spacer DNA" has no function, and could be characterized as "junk". - Steve Giovannoni"

Wow, this is most interesting. In human, 97.8% is "JunkDNA" - while in total contrast in Pelagibacter 96.3% is "non-JunkDNA". (In other species, the numbers range between these extremes). Clearly, it is the interplay between "coding" and "regulatory" segments of the DNA that results in (not "efficiency" and even more subjective "beautiful" or "streamlined"), but in the measure how "primitive" an organism is - from the point of view of hierarchical development. What needs to be pointed out, is that even the most primitive bacteria (Pelagibacter, or Mycoplasma genitalium) contain almost exactly the same (the minuscule amount of fifty thousand A,C,T,G base-pairs) that will predictably be the most suitable target to pinpoint the way in which "junkDNA" sequences augment the primary information of a particular "gene". The second prediction of FractoGene, to be announced in Press Release in days, provides algorithmic theory-based, yet an experimental methodology of linking a particular gene to the hitherto "dark horse" non-coding sequence (formerly junkDNA) - comment by Andras J. Pellionisz, 27th of August, 2005]

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Newsweek on JunkDNA

The Shape of Things To Come

By Mary Carmichael

Meet four visionary scientists who helped map the human genome and are now blazing new trails.

Summer 2005 - The human genome project may be near completion, but the "real" human-genome project is just getting underway. Scientists now know the sequences of most of our genes. But they don't necessarily know how those genes work or, considering that most of the genome is "junk" DNA that doesn't contribute to the body's normal functioning, whether they work at all. In other words, we've got all the pieces, but we still need to put the puzzle together. Many of the geneticists who worked on the original HGP are now pursuing follow-up projects on their "genes of interest." Here are four who will help give us the complete picture.

The Matchmaker

Leroy Hood is given to car metaphors. "If you want to understand a car, you can't just study the carburetor," he says. "You need to study all the parts and how they function together as the car travels." If that's true, Hood must be the world's best mechanic (metaphorically speaking, of course). When he first went to Caltech in 1970 on a three-year fellowship, he told his department chair that he wanted to spend half his time doing biology and half doing technology development—with the ultimate idea of using that technology to study all the parts of the body simultaneously, as a system, via multiple perspectives. Hood had a vision of devices that could read human DNA and proteins, and computer systems that could analyze the results. "At the end of the three years [the chair] urged me in the strongest possible terms to give up the technology," Hood says. But Hood was stubborn, and he was also right. Now, as president and director of the Institute for Systems Biology—a one-of-a-kind organization based in Seattle and independent of academia—he is a scientific matchmaker, bringing biologists together with chemists, engineers, computer scientists and applied physicists.

Hood's fingerprints are all over modern genetics. He was one of the earliest advocates of the Human Genome Project, at a time when many people thought sequencing the genome was a largely useless, and maybe impossible, goal. He is also one of the people who made the project possible by inventing DNA and protein sequencers, which "read" the molecular contents of those chemicals, and synthesizers, which allow scientists to produce large quantities of them for experimentation. He has played a role in founding several of the country's best-known biotech firms, including Amgen and Applied Biosystems.

Leroy Hood

Institute For Systems Biology

When Hood makes a prediction about the future of science—no matter how outlandish it sounds—he's usually right. He foresaw the joining of biology and technology decades before others did, and his vision of "discovery science" (or research driven by the search for data rather than the formulation of hypotheses) is now epitomized by the Human Genome Project. His new dream is "preventive and predictive medicine," in which drugs are used not to cure, but to prevent disease in the first place. Hood says the advent of this type of medicine could mean that in the next 20 years, the average functional life span will increase by a decade. Lately he's been working on a project that analyzes how protein molecules fold (page 52)—and, as a result, how they interact with other chemicals in the body to either keep systems running, build new bodily components or, alternately, cause disease. If he ever needed proof that technology and biology were made for each other, the protein-folding project is it. The task would take "a hundred thousand years with our computers," Hood says. But he has a corporate partner in IBM and access to the company's Grid system, which uses "brain" power from computers around the world to do immensely complicated math

The Quick Study

When colleagues say there ain't no mountain high enough for Rick Young, they mean it: an avid skier and climber, he's hiked the Himalayas three times. But years from now, they may regard as his true triumph a task that once seemed even more daunting. Young studies transcription factors, which he describes as switches that turn genes on or off. (There are about 2,000 transcription factors in the human body.) A century ago, he says, it would have taken one scientist one century to understand one switch working on one gene. Now, he says, it takes "one person about two weeks to understand what one transcription factor is doing across the entire genome." That's largely because Young has figured out the fastest way to do it.

Rick Young

Massachusetts Institute Of Technology

Young foresees a future in which doctors will test children early in life for flaws in their transcription factors (the "switches" that turn genes on or off), then try to flip those switches. "What we could do is alert parents to the fact that a change in diet or ultimately a particular therapeutic might prevent the development [of the disease]," says Young. "We do this already—you take a prophylactic for malaria when you go to Africa.This isn't that different." It could happen within the next 10 to 15 years, Young says, once scientists figure out how to sequence genetic information from people cheaply and quickly.

Young's lab can take a living cell "going about its business," he says, and freeze it in action by adding formaldehyde. The chemical cross-links the transcription factors to DNA in the nucleus, capturing them where they're acting (the factors do their work by binding to the DNA strands as the genetic material is copied). Then all Young has to do is break the cells open and identify which DNA sequences the transcription factors are stuck to.

Armed with Young's techniques, scientists of the future should someday be able to study diseases that stem from problems with transcription factors—including diabetes, cancer and immune dysfunction. With luck, pharmaceutical companies will then be able to create drugs that simply turn the relevant switches on or off. And "someday" may be just a few years away, says Young, particularly for diseases like diabetes that are controlled by a particular type of transcription factor called a nuclear hormone receptor. Transcription factors in this group can often be induced to drastically change their activity if they bind to other molecules. One nuclear hormone receptor called HNF4alpha even binds to fatty acids, which are part of a regular diet. Francis Collins, the leader of the Human Genome Project, recently published papers suggesting that HNF4alpha plays a major role in diabetes. "So here is a factor that's controlling the genes in your pancreas and liver, and it senses what you eat," says Young. "What we don't know yet is, how would you modify your diet to have a beneficial effect?" Given how fast Young usually works, it probably won't be long until we do.

The Math Magician

It's a truism that some scientists are stymied by an inability to communicate their ideas to people outside their fields. Eric Lander isn't one of them. Here he is on modern medicine: "It's like taking your car to a mechanic who has no idea what's under the hood and is trying to fix the car based on listening to the noises it makes." (What is it with geneticists and cars, anyway?) And here's Lander on trying to study big problems with tools made for a small scale, which is largely what science has been doing all along: "It's like trying to see continental drift by walking around Cape Cod." And on the genome: "Evolution has been carrying out experiments for the last 3.5 billion years. It gets up every morning and says, 'Let's change a few letters.' And then it leaves us notes."

Lucky for us, Lander knows how to read those notes. A Rhodes scholar originally trained as a mathematician, he is now quite possibly the country's leading molecular geneticist, the founder of one of the world's first and best genome-sequencing centers (the Whitehead Institute/MIT Center for Genome Research) and one of a small coterie of visionaries behind the Human Genome Project. Unlike many scientists, he puts his snappy metaphors to frequent use—he's a beloved teacher on the MIT campus, and he's got awards to show for that, too. He won the Westinghouse Prize when he was just 17 for a paper proving that quasi-perfect numbers exist only in theory. Oh, and he's a really nice guy. In short, he's the sort of scientist you'd think would exist, well, only in theory.

Not bad for someone who started his scientific career as a dabbler, auditing a biology course at Harvard along with younger students and "moonlighting, cloning fruit-fly genes in labs at night." (During that time he was also teaching economics at Harvard Business School, even though, he admits, he knew very little about the topic and his degree was actually in math.) In the early 1980s, he happened to meet an MIT geneticist who was working on ways to scan human DNA for genes that were the sole causes of specific diseases. The real trick, though, was figuring out which genes were involved in more-complex diseases with multiple causes like cancer. Lander wasn't really a scientist, but he had an idea for a statistical technique that might help. Within two years he had launched his genome-research institute. And that was pretty much the end of teaching econ.

Massachusetts Institute Of Technology

When Lander visualizes the future, one image comes to mind: scornful doctors. "When people tried to treat infectious disease 150 years ago, they had no clue what the cause was—namely that there were these nasty microorganisms that caused the disease," he says. "They were just shooting in the dark. That's what we still do." Doctors of the future will look on our medicine with "bemusement and horror," he says, just as we look at the use of leeches. "They'll sit around, saying, 'Can you believe they gave poisons to people to kill their cancers?' " says Lander. "And that is the reward we'll get—we will be considered medieval."

The Whitehead Institute would go on to lead the effort to map the human and mouse genomes. Lander essentially provided the mathematical scaffolding for the full human-genome sequence, giving scientists a template by which to organize their data. His techniques have also helped other scientists identify genes involved in cancer, diabetes and inflammation, among others. These days Lander has returned to his mathematical roots. With the genome sequenced, he says, his job now is "purifying the information away from the molecules," trying to understand DNA at a submolecular level with sophisticated mathematical techniques. He still focuses on multigene diseases—for example, tracking down all the mutations that can cause cancer. "That's a finite problem—a big one, but big shouldn't scare us anymore," he says.

The Optimist

Inder Verma is one of very few people with anything good to say about HIV. "It becomes part and parcel of the chromosome and stays there for years," he says. "And it has learned the trick of allowing itself to grow in cells that aren't dividing." Neither of which is a good thing if you're an HIV patient, of course. But if you're Verma, and your goal is to "take a virus and convert it into a friend," then HIV is your best buddy. Several years ago Verma was pondering one of the biggest problems with gene therapy—how to introduce genes into existing cells. "You can't inject billions of new cells with a needle," he thought. "You can give [drugs], but that's a very inefficient process." Viruses, over millions of years of evolution, have solved the problem by insinuating themselves into cells and co-opting the cellular-reproduction machinery—without killing their new hosts. So why not use them to our advantage? Verma's lab decided to strip down a virus, removing the disease-causing components while making use of the cellular-hijacking machinery. But which virus? The obvious choice was HIV, since scientists already knew a great deal about it. The result was a "friendly" HIV strain that could (theoretically, at least) introduce new genes into patients who lacked properly working versions of them.

Salk Institute

Working in the field of gene therapy can turn any scientist into a visionary. But Verma also knows the pitfalls he testified before Congress in 2000 after a young patient named Jesse Gelsinger was treated with a modified adenovirus, then sank into a coma and died. Verma says the field has learned a great deal since then. He sees a future in which gene therapy will treat Parkinson's disease, cystic fibrosis and even cancer. If a patient today has a tumor on the optic nerve, a surgeon often can't remove it without destroying the patient's eyesight. In the future, Verma says, it will be possible to inject the tumor with a virus, introducing genes that will kill the tumor cells without infiltrating the optic-nerve cells, leaving sight intact.

Since then, scientists have commandeered a number of other viruses for therapeutic purposes. Verma admits that the field still faces some major challenges. Ironically, one of them is the question of how to overcome a patient's immune system—the very thing HIV's disease-causing parts, now removed, would normally target. (The short-term solution is suppressing the immune system with drugs.) Producing gene-therapy viruses on a large scale is another ongoing problem. Nonetheless, Verma says he expects to see gene therapy available for cancer patients with-in the next 10 years. "We don't want to get too cocky," he says. "Yes, man made it to the moon, but the physical principles, like gravity, were already known," whereas even the basic principles of gene therapy are still somewhat hazy. On the other hand, he adds, "we have to be optimistic. Usually timetables are beaten. I went to a meeting in India recently, and the title was 'Can Cancer Be a Chronic Disease?' Who would have even thought to ask?"

[It is not unprecedented that major newsmagazines take leadership in the field of Genomics. Time Magazine organized in 2003 an eminently successful meeting to celebrate the "50th Anniversary of the Discovery of Double Helix". Time may be ripe for another landmark meeting & associated developments - comment by Andras J. Pellionisz, 30th of July, 2005]

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Genomics study highlights the importance of "junk" DNA in higher eukaryotes

14 Jul 2005

A landmark comparative genomics study appears online today in the journal Genome Research. Led by Adam Siepel, graduate student in Dr. David Haussler's laboratory at the University of California, Santa Cruz, the study describes the most comprehensive comparison of conserved DNA sequences in the genomes of vertebrates, insects, worms, and yeast to date.

One of their major findings was that as organism complexity increases, so too does the proportion of conserved bases in the non-protein-coding (or "junk") DNA sequences. This underscores the importance of gene regulation in more complex species.

The manuscript also reports exciting biological findings regarding highly conserved DNA elements and the development of a new computational tool for comparing several whole-genome sequences. It was authored by multiple investigators from leading research institutions, including Penn State University (University Park, PA), Washington University School of Medicine (St. Louis, MO), Baylor College of Medicine (Houston, TX), and the University of California, Santa Cruz.

One of the most powerful approaches for pinpointing biologically relevant elements in genomic DNA is to identify sequences that are similar across multiple species. Such approaches are particularly useful for analyzing non-protein-coding sequences - sometimes called "junk" DNA. Although "junk" DNA is poorly understood, the increasing availability of whole-genome sequences is rapidly enhancing the ability of scientists to ascertain the biological significance of these non-protein-coding regions.

"Looking for functional elements in mammalian and other vertebrate genomes is like looking for needles in a haystack," explained Siepel. "By focusing on conserved elements, you get a much smaller haystack. It's not guaranteed to have every needle in it, and not everything in it is a needle, but you're much more likely to find a needle if you look in this smaller haystack than if you look in the big one."

Siepel's team aligned whole-genome sequences for four groups of eukaryotic species (vertebrates, insects, worms, and yeast). The vertebrates included human, mouse, rat, chicken, and pufferfish, and the insects included three species of fruit fly and one species of mosquito. Two worm species and seven yeast species rounded out the set.

To help ease the gargantuan task of identifying conserved elements in multiple alignments of whole-genome sequences, the researchers developed a new computational tool called phastCons. In contrast to traditional tools that compute conservation levels based on sequence similarity at each nucleotide position, phastCons allows for multiple substitutions per site, accounts for unequal rates of substitutions for different nucleotides, and considers the phylogenetic relationships of the species involved.

After applying phastCons to multiple alignments of each of the four groups of eukaryotic species, the researchers estimated that only between 3-8% of the human genome was conserved in the other vertebrate species. On the other hand, the more compact genomes of insects were more highly conserved (37-53%), as were those of worms (18-37%) and yeast (47-68%).

The scientists also observed that the proportion of conserved sequences located outside of protein-coding regions tended to increase with genome length and with the species' general biological complexity.

Most strikingly, the researchers discovered that two-thirds or more of the conserved DNA sequences in vertebrate and insect species were located outside the exons of protein-coding genes, while non-protein-coding sequences accounted for only about 40% and 15% of the conserved elements in the genomes of worms and yeast, respectively.

"The conserved noncoding story seems to be fairly similar in vertebrates and insects, but looks quite different in worms and yeast," explained Siepel. "These findings support the hypothesis that increased biological complexity in vertebrates and insects derives more from elaborate forms of regulation than from a larger number of protein-coding genes." He noted that the results for the worm group should be interpreted cautiously because the analysis was based on the genomes of only two quite divergent worm species.

"We still understand remarkably little about the function and evolutionary origin of these elements," Haussler added. But the locations of the conserved elements will provide the scientists with some key clues to the potential functions of these sequences.

Some of the strongest sequence conservation in vertebrates was observed in the 3' untranslated regions (3'UTRs) of genes, which indicates that post-transcriptional regulation may be a widespread and important phenomenon in more complex species. The scientists found positive associations between highly conserved elements (HCEs) in known genes and RNA editing, as well as between HCEs and microRNA targets.

Interestingly, the researchers discovered that many HCEs in vertebrates may encode functional RNAs. The HCEs in introns and intergenic regions in vertebrates were significantly enriched for statistical evidence of local RNA secondary structure, which indicates that many may function as RNA genes.

"There really does seem to be a lot more going on at the RNA level than people would have guessed a few years ago," commented Siepel.

HCEs were also associated with "gene deserts" - long regions of the genome that are devoid of protein-coding genes. This indicates that some of the conserved elements may function as long-range transcriptional regulatory elements.

For genomic scientists, the current study is a major contribution to the field. Not only will the new bioinformatics tool phastCons help researchers identify evolutionarily conserved DNA elements, the reported conserved elements are represented as conservation tracks in the widely used UCSC Genome Browser. "With phastCons and with the conservation tracks in the browser," says Siepel, "we're trying to make it as easy as possible for researchers to home in on functionally important DNA sequences."

Adam Siepel, first and corresponding author on the manuscript, has agreed to be contacted by e-mail ( or by phone (+1-831-423-0863) for further information. David Haussler, Ph.D., is the principal investigator on this work and can be reached at or +1-831-429-9472. Information about Haussler's Genome Bioinformatics Group at the University of California, Santa Cruz can be accessed at

This work will be published in the August print issue of Genome Research. It will also appear online on July 15 as a "Genome Research in Advance" article at Its citation is as follows:

Siepel, A., Bejerano, G., Pedersen, J.S., Hinrichs, A.S., Hou, M., Rosenbloom, K., Clawson, H. Spieth, J., Hillier, L.W., Richards, S., Weinstock, G.M., Wilson, R.K., Gibbs, R.A., Kent, W.J., Miller, W., Haussler, D. 2005. Evolutionary conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15: 1034-1050.

[Well, it did not take long since yesterday's comment on "California Gold Rush selling shovels". Today, essentially the first "shovel" for digging for "JunkDNA" is out ! There are two business problems, however. The first is, that publicly supported genome data centers (University of California, USA govenment institutions, etc) not only don't run business as a tight ship, but are not designed to make any profit . (Nor do they respond, therefore, to "customers' supply and demand dynamics"). Worse, "public money" (governments) are traditionally helpful mostly in the early (not profitable) stages of R&D (say, NASA - but even aerospace flight is sliding now into the private sector...) . For the "Internet boom", it took a Jim Clark to snatch Marc Andresson from University and ignite the private domain hyper-escalation of a brand new Industry.

The second problem has already been proven outright devastating. Internet "tools" can be incredibly helpful - but those who run the servers can (and usually do) monitor every single search in their databank. If you look up the showtime in the movie theater nearby, you might not mind revealing what you are looking for. However - as some of the Genome Database companies listed in the July 13th posting can testify - many went bankrupt because the user of a "super-tool" better not give away by Internet service*where* is he/she looking. You would not buy a shovel when going for the gold, if you knew that there is a GPS on it, telling the seller the exact location where you searched AND FOUND the biggest golden nuggets, would you???

Therefore, while the "JunkDNA tools" are already on the march (actually, since March...) the Business Model is clearly *not* the sale of data over the Internet -nobody is buying raw data, the market needs knowledge, not information- nor is it providing tools for the use over the Internet. Indeed, Big Pharma, or Nanotechnology would be crazy to "officially leak" where they are looking.

If "the party is over" for both "free rides", where is the Business Model of Regulatory DNA? - Commentator Dr. A. Pellionisz has agreed to be contacted by e-mail ( or by phone (+1-408-732-9319) for further information. July 14th, 2005.

P.S. Oh, yes. There is also the "algorithm challenge". When dealing with "JunkDNA", some mathematical postulates, processes and platfroms for its interpretation might help (such as FractoGene, the experimentally supported fractal geometrical generalization of the "gene concept"). Drs. A. Pellionisz and M. Simons are looking into the merits of such a venue, and the fractal approach to DNA was endorsed by Mandelbrot by his Keynote Lecture at Stanford, 2004 Aug., and in 2004 December by Rothemund, Papadakis and Winfree at Caltech, bringing in further endorsements of John Hopfield (Neural Networks, Genomics Institute at Princeton), Ned Seeman (author of "Nanotechnology and the Double Helix", Scientific American 2004), Len Adleman (proponent of DNA-based infotech).]

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Dueling Databases

Can companies still make money selling genomic and molecular information?

[The reader can skip the article if lacking time. The answer is "NO money for data, $$$ for proprietary tools" - AJP]


Jul. 4, 2005 By Ted Agres

Celera Genomics made hundreds of millions of dollars by selling access to its proprietary genome sequence information. But this month, Celera discontinued its database subscription service and made its 30 billion base pairs of genomic data of humans, rats, and mice freely available through GenBank, operated by the US National Center for Biotechnology Information.

Some see Celera's decision to exit the sequence business as proof of the adage that information wants to be free, and yet another sign that selling access to data is no longer a viable business model. "The trend is perfectly clear. It would be surprising to find any company setting up a business plan that was based on a subscription database of precompetitive information," says Francis Collins, director of the National Human Genome Research Institute and leader of the Human Genome Project, Celera's publicly funded rival in the race to sequence the human genome.

During the past few years some database companies (such as Incyte Genomics and Celera) have transitioned to drug discovery and development, while others (such as DoubleTwist) have simply gone out of business. Still, dozens of large and small companies worldwide continue to sell subscriptions to genome databases and molecular libraries, either alone or in combination with other services.

Some of these companies are information providers, such as the American Chemical Society's Chemical Abstracts Service (CAS) and Biobase, a commercial biological database vendor in Germany. Others, such as Integrated Genomics in Chicago and Inpharmatica in London, combine databases with proprietary software and other informatics tools to facilitate discovery of drug candidates.

Making a profit from research-generated data is not an easy matter, says Frank Allen, executive director of Cambridge Crystallographic Data Center, a nonprofit institute spun off from the University of Cambridge. "Some people sit back in their chairs and say, 'It's my divine right to use data that's in the public domain.' Well, it certainly is, but there's a price involved in turning that data into something that's usable. It's either going to come from the public purse or from subscription income." The CCDC maintains the Cambridge Structural Database, a repository of small molecule crystal structures.

Dozens of large and small companies worldwide continue to sell subscriptions to genome databases and molecular libraries. Their challenge is to find ways to maintain value amid growing competition from public sources.

"Science is moving towards greater openness in terms of data," says Eric Campbell, professor of health policy at Harvard Medical School. "The issue comes down to protecting one's competitive advantage. You have to have a way to uniquely profit from discoveries and prevent free-riders from hopping in at the end."


Some companies, such as Biobase in Germany, are trying to increase value by curating, annotating, and extending the reach of their databases. Others, like the American Chemical Society's Chemical Abstracts Service (CAS), are attempting to maintain market exclusivity by keeping potential competitors at bay. Novartis and Perlegen Sciences, on the other hand, believe they will generate more business if they allow other researchers access to their proprietary databases. "We don't know if it's collaboration or competition or some combination that will drive science the fastest," Campbell says. "Nobody has studied it before."

Celera knew that its genomic information was a perishable commodity. "There is a time component to the value of information," says Tony Kerlavage, Celera's senior director of online business. In the company's early days, when Celera held a near-monopoly on human genome sequences, pharmaceutical companies and research institutions paid big bucks to access the raw data to locate novel genes and drug targets.

At its height, more than 200 institutions and 25 drug and biotech companies subscribed to the Celera Discovery System (CDS), paying annual fees ranging from thousands to millions of dollars, depending on the number of researchers. Over the years, the CDS was supplanted by such resources as GenBank and Ensembl – a project of the European Bioinformatics Institute and the Sanger Institute. Today, the CDS is useful primarily as a reference source, hence the company's willingness to place it in the public domain. Kerlavage declined to say how many subscriptions expired July 1, closing the service for good.

Three years ago, Celera's parent company, Applera Corp., decided to shift from information to drug discovery and development, and to selling gene expression arrays and diagnostic tools. The move may have been prescient. "If you have complementary services, it may be better to have your data freely available so you can sell more of those other services, whether they are machines or other things," says Arti Rai, a Duke University law professor who focuses on intellectual property in the life sciences.


Not anxious to see its Chemical Abstracts Service Registry follow in the footsteps of Celera's database, the American Chemical Society (ACS) is aggressively lobbying federal officials to curtail development of PubChem, a free online resource on the biochemical structures and properties of some 650,000 small organic molecules. PubChem was initiated in September 2004 as part of the National Institutes of Health Roadmap and is maintained by the National Center for Biotechnology Information.

The 159,000-member ACS claims PubChem is exceeding its mandate and has become a "mini-replica" of the Chemical Abstracts Service Registry, a database of more than 25 million organic and inorganic substances and more than 56 million sequences. "That replica will, over time, pose an insurmountable threat to CAS's survival," simply because it is publicly funded, the ACS said in a statement. That PubChem data are already in the public domain "is completely irrelevant," the ACS added. "If a scientist obtains this data from PubChem, there is no reason to purchase it from the CAS Registry."

NIH officials say PubChem will complement, not compete, with the CAS. The data overlap will be minimal, they say, and PubChem will not offer the detailed manual curation that makes the CAS valuable to its subscribers.

"It's all about money," Collins fumes. "It's hard to see how this very small effort on the part of NIH could represent a significant threat. I am astonished by their very strong negative reaction, especially for a database that's run by a supposedly scientific society."

Revenues from the Registry and other publications yield more than half of the ACS's annual funding, said CAS president Bob Massie in an E-mail. Massie says the CAS has discussed the matter with congressmen from Ohio, where the company is located. The House budget bill for NIH that was drafted in June acknowledges the controversy and "urges NIH to work with private sector providers to avoid unnecessary duplication and completion."

"Twelve people at NIH will put 1200 people at ACS out of business? That's absurd," says Stephen Heller, a consultant and expert in numerical databases who has extensive U.S. government experience. "There is minor overlap between PubChem and the CAS Registry, but basically they are two separate things. One is for chemists and the other is for biologists, and they are two different cultures and they don't talk to each other let alone use the same computer systems and databases," he says. And he notes that the ACS received millions in funding from the National Science Foundation in the late 1950s and early 1960s to develop the technical infrastructure for the CAS Registry system.

"There are structural changes going on in the dissemination of scientific information because of the Internet and because everything has become computer-readable. It's not the same sort of business it used to be," says Heller. "Either you adjust or you have problems."


For years, researchers had enjoyed access to the Yeast Protein Database, a detailed curation of Saccharomyces cerevisiae compiled by James I. Garrels at Proteome Inc., in Beverly, Mass. In 2000, Incyte Corp. (then Incyte Genomics) acquired Proteome for $77 million and began charging for what had previously been free, triggering an outcry from researchers.

Incyte sold Proteome in January 2005 to Biobase, a commercial biological database vendor in Germany, a move that completed Incyte's transition to drug discovery and development. For Biobase, acquiring Proteome's BioKnowledge Library increases the company's depth of offerings – which also include transcription factors and signal transduction databases – and helps solidify its competitive position in the marketplace. "The synergism between Biobase's traditional database portfolio and the BKL range of products will open unprecedented opportunities for the customers to optimally exploit their investments in novel high-throughput approaches," said Biobase President Edgar Wingender in a statement.

Taking a completely different tactic, Perlegen Sciences, a biotech company in Mountain View, Calif., will donate its proprietary database of 1.6 million single nucleotide polymorphisms to the International HapMap Consortium by the end of the year. Perlegen believes that having a completed HapMap will enable it to scan for and develop drugs for specific diseases and patient populations more quickly and effectively than if it kept its database secret.

In an effort to elucidate the underlying genetic basis for type 2 diabetes, and subsequently create therapies to treat it, Novartis is partnering with the Broad Institute to create a public database of genetic variants associated with the disease.

"It's very likely the answers we get will be complex and require a lot of work," says Tom Hughes, head of the diabetes and metabolism disease areas at Novartis Institutes for BioMedical Research in Cambridge, Mass. "We believe it's important to get the best minds to the problem, and the best way is to share data and get people working on it."

Novartis will contribute $4.5 million to the collaboration, which will also involve Leif Groop at Lund University in Sweden, who has collected thousands of genetic samples from diabetes patients. The first data will be posted later this year. "It makes good sense to get the data out there to help the field mature," Hughes says. "It will help us define better what the medicine should look like. We can't do it on our own."


1. TM Powledge "Can sequences turn a profit?" The Scientist Daily News May 16, 2002

[In the "California Gold Rush" the quickest money was *not* the business model of purchasing land. After all, who knew exactly where the gold was? The land was free. However, the shrewedest investment was to sell shovels (see below)*.  The same is (will be) true in Genomics. As long as sequences were difficult to get, they carried a price - no longer. We are awash with data - yet few of us has any specific idea of what the 98.7% ("Junk") is doing, and how. "The golden shovels" carry a huge price tag. Comment by Dr. A. Pellionisz on 13th of July, 2005]

* The gold rush needed a booster, and Sam Brannan was the man. A San Francisco merchant, Brannan was a skilled craftsman of hype. Eventually, the gold rush would make him the richest person in California--but Sam Brannan never mined for gold.

He had a different scheme--a plan he set into motion by running through the streets of San Francisco shouting about Marshall's discovery. As proof, Brannan held up a bottle of gold dust. It was a masterstroke that would spark the rush for gold--and make Brannan rich.

Brannan keenly understood the laws of supply and demand. His wild run through San Francisco came just after he had purchased every pick axe, pan and shovel in the region. A metal pan that sold for twenty cents a few days earlier, was now available from Brannan for fifteen dollars. In just nine weeks he made thirty-six thousand dollars.

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'Champion of "the Human Genome Project" does it again from scratch':
Venter, Launching New Company, Hopes to Synthesize Genome to Create Bacterium

By a GenomeWeb News reporter

NEW YORK, June 29 (GenomeWeb News) - Nearly four years after being shown the door at Celera Genomics and creating a family of nonprofits, Craig Venter has founded a new company that aims to create an organism from synthetically crafted and oriented genes.

The company, Synthetic Genomics, is in the process of building a "minimal genome" that can be inserted into the shell of a bacterium, in this case the 517-gene Mycoplasma genitalium, which scientists may eventually genetically engineer to perform specific industrial tasks.

Though the company is still developing the technology, and its applications are speculative, Venter suggests one potential application is in the production of alternate energy sources.

Synthetic Genomics builds on the success Venter and colleagues had two years ago after they synthesized a genome to create the bacteriophage phiX174. Though other researchers managed to build an organism from the genome up before Venter -- in 2002, a team from the State University of New York at Stony Brook used off-the-shelf oligos to create poliovirus -- Venter founded the new company to create the first man-made bacterium.

Synthetic Genomics' technology is still being developed. The company, based in Rockville, Md., is sponsoring and working with researchers from Venter's nonprofit, the J. Craig Venter Institute, to remove genes from M. genitalium "to identify the minimum set of genes necessary for an organism to survive in a controlled environment," according to the company's website.

Once that has been accomplished, Synthetic Genomics will attempt to synthesize the genome, "add the desired biological capabilities," and insert it into an environment "that allows metabolic activity and replication - the creation of a synthetic cell," the company said.

After designing and producing a synthetic chromosome -- M. genitalium has just one -- the team plans to develop a proof of concept in either of two bio-energy applications: hydrogen or ethanol.

Though the technology is still being developed, what is well-known is the way Venter's team was able to create the bacteriophage phiX174. As GenomeWeb News reported in 2003, researchers at what was at the time known as the Institute for Biological Energy Alternatives used short oligonucleotides and adapted PCR into a technique called polymerase cycle assembly, or PCA, to build this genome in 14 days. Like PCR, PCA produces double-stranded gene sequences from single-stranded templates.

Researchers on that study included Ham Smith, who is now executive vice president and co-chief scientific officer at Synthetic Genomics, and Clyde Hutchison, of the University of North Carolina, Chapel Hill, who is president of the company's scientific advisory board. Juan Enriquez, founding director of Harvard Business School's Life Sciences Project, is president.

At a 2003 press conference announcing results from that research, Venter stressed that his team would not commercialize PCA, nor would he file patents on it. "We'd rather wait till the next stage when there's a clear-cut application: for instance if we have something that produces hydrogen that might hold some value."

[Wow ! "something that produces hydrogen that might hold some value".... The understatement of the 21st Century. He is talking about a global impact by creating the first "protein-based nanotechnology miracle". When Craig Venter told the USA government that he'd finish "the Human Genome Project" cheaper, better, faster in the private sector, nobody believed him (and he/his Celera delivered what he promised). I am convinced that Craig Venter will pull it off again.

And some more. The bacterium that he focuses on is one of the smallest genome and is very stingy on "non-coding" (formerly "junk") DNA. Yet, bacteria, while poor in "JunkDNA" still have some, e.g. the bacterium Venter picked has 8% (typically, bacteria have over 10% "junk" occasionally a huge amount, see table). Thus, this commentator expects that that precious little "junkDNA" in the "hydrogene producing bacterium" will actually catapult the understanding of the "regulatory" role of "JunkDNA", since it will be so much easier to focus on the critical little amount of 8%. Indeed, it has been known both that total elimination of "junk" kills the living system, as well as that Nanotechnologists (attempting to synthesize protein-based new materials) simply can not do without "regulatory DNA". Now the task is reduced to revealing what less than 50 kb information does! While at the 50th Anniversary Meeting in Montery 2002 Dr. Venter held the view that "JunkDNA" is just that (junk...) - one wonders if JunkDNA will be a stumbling block for Dr. Venter's spectacular project (possibly patenting the pollution-free global source of energy...) , or he will bring us to a much quicker revealing of how the fractal iterative genesis regulates the functioning of DNA. Ad the cyclical program that starts with gene regulation through transcription, translation, post-processing and back into regulation" - Comment by Dr. A. Pellionisz on 30th of June, 2005]

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Founders of "the Human Genome Project" are ready to "re-thinking it all"... The Uncertain Future for Central Dogma

The Scientist
Vol. 19. Issue 12, pp. 20.
June 20th, 2005

The Uncertain Future for Central Dogma

Uncertainty serves as a bridge from determinism and reductionism to a new picture of biology

By Arnold F. Goodman, Claudia M. Bellato and Lily Khidr

Nearly two decades ago, Paul H. Silverman testified before Congress to advocate the Human Genome Project. He later became frustrated when the exceptions to genetic determinism, discovered by this project and other investigations, were not sufficiently incorporated in current research and education.

In "Rethinking Genetic Determinism,"1 Silverman questioned one of the pillars of molecular genetics and documented the need for determinism's expansion into a far more valid and reliable representation of reality. He would receive correspondence from all over the world that reinforced this vision.

Silverman firmly believed that we needed a wider-angled model, with a new framework and terminology, to display what we know and to guide future discovery. He also viewed this model as being a catalyst for exploring uncertainty, the vast universe of chance differences on a cellular and molecular level that can considerably influence organismal variability. Uncertainty not only undermines molecular genetics' primary pillars of determinism and reductionism, but also provides a bridge to future research.


Arnold Goodman (left) is an associate director of the Center for Statistical Consulting at the University of California, Irvine. Cláudia Bellato (center) is an independent researcher at CENA, University of São Paulo, Brazil. Lily Khidr (right) is a PhD candidate at UC-Irvine. They dedicate this article to the memory of Paul Silverman and thank Nancy, his wife, for her assistance.

Various commentaries detail deviation from determinism within the cellular cycle. Here we use the term cellular cycle not in the traditional sense, but rather to describe the cyclical program that starts with gene regulation through transcription, translation, post-processing and back into regulation.

Richard Strohman at UC-Berkeley describes the program in terms of a complex regulatory paradigm, which he calls "dynamic epigenetics." The program is dynamic because regulation occurs over time, and epigenetic because it is above genetics in level of organization.2 "We thought the program was in the genes, and then in the proteins encoded by genes," he wrote, but we need to know the rules governing protein networks in a cell, as well as the individual proteins themselves.

John S. Mattick at the University of Queensland focuses upon the hidden genetic program of complex organisms.3 "RNAs and proteins may communicate regulatory information in parallel," he writes. This would resemble the advanced information systems for network control in our brains and in computers. Indeed, recent demonstrations suggest that RNA might serve as a genetic backup copy superseding Mendelian inheritance.4

Gil Ast of Tel Aviv University writes: "Alternative splicing enables a minimal number of genes to produce and maintain highly complex organisms by orchestrating when, where, and what types of proteins they manufacture."5 About 5% of alternatively spliced human exons contain retrotransposon Alu sequences. These elements represent an engine for generating alternative splicing.

Thus we see a genetic control system regulated by protein products, RNAs, and interventions from DNA itself. Yet throughout, the consideration of genetic uncertainty as a bridge to cellular behavior is conspicuously absent.

Genetic reductionism, the other pillar of molecular genetics, has many challengers. Among them is Stephen S. Rothman at UC-Berkeley, who described the limits of reductionism in great detail within his comprehensive and well-constructed book.6

A more recent publication by Marc H.V. Van Regenmortel at France's National Center for Scientific Research updated this assessment by discussing not only the deficiencies of reductionism, but also current ways of overcoming them. "Biological systems are extremely complex and have emergent properties that cannot be explained, or even predicted, by studying their individual parts."7


Molecular genetics appears to be at a crossroads, since neither determinism nor reductionism is capable of accurately representing cellular behavior. In order to transition from a passive awareness of this dilemma to its active resolution, we must move from simply loosening the constraints of determinism and reductionism toward a more mature and representative combination of determinism, reductionism, and uncertainty.

To facilitate this expansion, we propose a model for the cellular cycle. Although only a framework, it provides a vehicle for broader and deeper appreciation of the cell. The figure on page 25 provides a novel structure for understanding current knowledge of the cycle's biological stages, as well as a guide for acquiring new knowledge that may include genetic uncertainty.

Organismal Regulation: The organism specifies its cellular needs (bottom red) for the cell to act upon. It converts the comparison of proteins with organismal needs into metabolic agents. The organism then defines its cellular needs (top red). It employs metabolic effects to alter the extra-cellular matrix and signal other needs.

Cellular Regulation: Within the bounds of a cell's membrane, cellular needs transmission (top blue) directs the cell in various ways, including proliferation, differentiation, and programmed cell death. It uses such factors as receptors and enzymes to yield molecular messengers. In the cell's nucleus, chromatin remodeling (bottom blue) then rearranges DNA accessibility by uncoiling supercoiled DNA and introducing transcription factors.

Transcription: Transcription (left green) DNA serves as the template for RNAs, both regulatory sequences and pre-messenger RNAs. It transcribes polymerases and binding partners into heterogeneous nuclear RNAs. Pre-messenger RNAs then undergo highly regulated splicing and processing (right green). They turn pre-messenger RNAs into mature messenger RNAs.

Translation: Within the cytoplasm, messenger RNAs and ribosomes translate 2D-unfolded proteins (left magenta). Secondary structuring and thermodynamic energy (right magenta) then enable physical formations that complete the process with folded proteins and oligonucleotides.

Postprocessing: Again within the cytoplasm, tertiary structuring and modification (top aqua) use assemblers, modifiers and protein subunits to supply regulated proteins. Then feedback regulation (bottom aqua) produces heritable gene expression from small RNAs, proteins and DNA. The proteins and gene expression, rather than being an endpoint, now begin the whole process over again by signaling other cells, altering and maintaining the genome, and editing RNA transcripts.


Model for the Cellular Cycle

Click for larger version Click for larger version

Helen M. Blau was a keynote speaker at the recent UC-Irvine stem-cell symposium in memory of Paul Silverman and Christopher Reeve.8 She observed: "Where we look and how we look determine what we see." Although only a brief prescription, we now propose an approach to the exploration for uncertainty that involves both where we look and how we look. We examine those cellular-cycle outputs having a relatively high likelihood of diversity and its frequent companion, uncertainty.

As an example of exploring for uncertainty in a cellular cycle, consider the following example: Suppose an organismal regulatory program for cellular differentiation might alter the signaling milieu in the extracellular matrix. The signal is internalized by a cell, which might, in turn, alter transcription, produce mature messenger RNAs, produce the 3D-folded proteins, and feed back to alter gene expression for all daughter cells.

Now suppose the ECM signaling milieu is altered with a probability p1; the signal is internalized by a cell with a probability p2; transcription will change with a probability p3; mature mRNAs are produced with a probability p4, producing the 3D-folded protein with a probability p5 and altering heritable gene expression with a probability p6. The probabilities p2, p3, p4, p5, and p6 are all conditional on results from the step preceding them, so that the resulting probability of altered heritable gene expression is the product of all of them. Although this probability may be small, is it not preferable to know its form and to later estimate it, than to simply ignore its existence?

When we consider all possible stage alterations, the diversity of outputs and complexity of our probability calculations will increase. If we also consider all possible interactions, the diversity of outputs and complexity of probability calculations will increase quite substantially.

The implications reach far beyond the regulation of a single cell or organism. Sean B. Carroll of the University of Wisconsin, Madison, summarizes evolutionary developmental biology,9 invoking Jacques Monod's landmark Chance and Necessity, and the Democritus quote upon which it is based: "Everything existing in the universe is the fruit of chance and necessity."

Why wouldn't chance also be included in our observations of biology at the molecular level? We've proposed a brief overview of the "what" and "how" for constructing an uncertainty bridge from genetic determinism and reductionism to actual cellular behavior. We hope and believe it meets the spirit of Paul Silverman's prescient vision, as well as his final wishes.


1. PH Silverman "Rethinking genetic determinism," The Scientist 18(10): 32-3.May 24, 2004

2. R Strohman "A new paradigm for life: beyond genetic determinism," California Monthly 2001, 111: 4-27.

3. JS Mattick "The hidden genetic program of complex organisms," Sci Am 2004, 291: 60-7.

4. SJ Lolle et al, "Genome-wide non-mendelian inheritance of extra-genomic information in Arabidopsis," Nature 434. March 24, 2005

5. G Ast "The alternative genome," Sci Am 2005, 292: 58-65.

6. SS Rothman Lessons from the Living Cell: The Limits of Reductionism New York: McGraw-Hill 2001.

7. MHV Van Regenmortel "Reductionism and complexity in molecular biology," EMBO Reports 2004, 5: 1016-20.

8. HM Blau "Stem-cell scenarios: adult bone-marrow to brain and brawn," Developing Stem-Cell Therapies: A Symposium in Memory of Paul H. Silverman and Christopher Reeve University of California, Irvine, October 20, 2004.

9. SB Carroll Endless Forms Most Beautiful New York: W.H. Norton 2005.

["the cyclical program that starts with gene regulation through transcription, translation, post-processing and back into regulation" is identified by FractoGene as the geometrical re-conceptualization, a generalization of the "Gene Concept" to include "JunkDNA" into the repetitive (fractal) hierarchical procedure. Any "re-thinking" might as well be algorithm-based in the 21st Century in order to tap the Information Technology resources, without which "decoding JunkDNA..." simply will not happen. In terms of Fractal Geometry, the pseudo-controversy between determinism, genetic conservation on one hand and mind-boggling diversity within even the single human species (with uniqueness of each individual) on the other hand, is totally resolved. Not only conceptually, but in exact mathematics - Comment by Dr. A. Pellionisz on 29th of June, 2005]

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After Lead Newsmagazine (The Economist), JunkDNA is now on National Television - "Extra DNA Makes Voles Faithful"

By Rossella Lorenzi, Discovery News

June 23, 2005— A little extra DNA makes for faithful males, at least when they are male prairie voles, new genetic research found.

In a study published in the current issue of Science, Larry Young and Elizabeth Hammock of Emory University in Atlanta, Ga., show that fidelity in male voles depends on the length of a particular genetic sequence in a stretch of DNA between their genes.

Voles, mouselike rodents, look pretty much the same, yet they feature dramatic species differences in social behaviors.

Prairie voles (Microtus ochrogaster) form lifelong attachments with a mate, are biparental and highly social, whereas the closely related montane voles (M. montanus) are solitary and promiscuous.

Hammock and Young focused their study on "microsatellites," repetitive DNA sequences that have been long considered junk DNA as they do not produce proteins.

"Most people have considered these microsatellites as not having any function in the genome ... On the contrary, these highly repetitive, unstable DNA sequences are a mechanism generating diversity in behavior - I really think that they have a very important evolutionary function," Young told Discovery News.

The researchers bred two groups of male prairie voles with short and long versions of microsatellite DNA. The scientists put the voles in three situations. They added soiled bedding from unknown females to their cages; put young males into their cages; and allowed males to mate with females for 18 hours.

Then they carried a partner-preference test by adding new females.

It emerged that long sequences activated vasopressin — a hormone produced by mammals that regulates social behavior — in the brain. Voles with the longer strand of DNA spent more time investigating and approached strangers more quickly.

They also were more likely to form bonds with mates, and they spent more time nurturing their offspring.

The longer the microsatellite, the more attentive males were to their female partner and their offspring.

"This is an extraordinary example of research linking gene variation to brain receptors to behavior," said Thomas Insel, director of the U.S. National Institute of Mental Health.

Since people have the same DNA variability as voles, the research might help explain human behavior and behavioral disorders as well.

Said Young: "I'm afraid a DNA test would not be a very accurate predictor for identifying cheating partners. That said, there is a very real possibility that variations in the gene do contribute to these types of behavior. This is something that we are trying to study now."

[This piece of publicity - see earlier posting on the science - is a major landmark from two viewpoints. First, once "JunkDNA" hit a lead Newsmagazine - The Economist - now the news is on National Television.  Second, and more importantly, the science study was financed by the lead USA Government Health R&D Agency -NIH/NIHM. An earlier posting here (Nov. 26, 2004) reported that NIH already started to finance "JunkDNA" R&D (at a level even more minuscle than what Germany spent on the same day). With the hard evidence that diversity in behavior hinges on JunkDNA there will be an unbelievable pressure on the US Government to pour very serious money into JunkDNA. People with their Representatives to Congress will demand (instruct) them to vote money not for exploring the Mars, but to launch a campaign comparable only to the "Genome Project" - this time to probe the very foundation of human behavior. Program Administration of such a historical shift will face colossal challenges. - Comment by Dr. A. Pellionisz on 25th of June, 2005]


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Rosetta Genomics identifies hundreds of novel human microRNAs

Medical Research News

Published: Tuesday, 21-Jun-2005

In a study published online this week and to be published as a cover story in the July issue of Nature Genetics, Rosetta Genomics' scientists report identification of hundreds of human microRNA genes, including the first report of primate specific microRNAs.

Using a novel methodology, the researchers successfully cloned and sequenced 89 human microRNAs, nearly doubling the number sequenced in man to date.

MicroRNAs are a recently discovered class of tiny regulatory genes, comprised in the 98% of the genome that does not encode proteins, which until recently were considered 'Junk DNA'. Numerous recent studies have shown microRNA genes, far from being 'junk', are in fact of central importance, regulating at least 30% of all proteins, and involved in a wide range of diseases, including diabetes, obesity, viral diseases, and various types of cancer.

"The finding of large numbers of primate specific microRNAs is exciting because it supports the notion that microRNAs may indeed play an important role in the evolution of complexity of higher organisms," said Aaron Ciechanover, Nobel prize laureate 2004, and Chairman of Rosetta Genomics' Scientific Advisory Board. "We believe that these genes may serve as an important basis for next generation diagnostics and therapeutics."

"We are extremely pleased to report our success in nearly doubling the number of human microRNAs sequenced to date, results which we believe establish Rosetta Genomics as a leading player in discovery of microRNA genes," said Isaac Bentwich MD, founder and chairman of Rosetta Genomics and lead investigator of the study. "We are now aggressively pursuing partnerships for development of diagnostics and therapeutics based on this huge group of novel microRNAs."

MicroRNAs are a recently discovered group of non-protein-coding regulatory genes, shown to be involved in a wide range of diseases in addition to neuronal and stem-cell differentiation. MicroRNAs currently are an intensely researched area, and are believed potentially to be the basis for a new class of therapeutic and diagnostic products.

[The science content of this news is not new (see clipping on Rosetta Genomics posted below on May 30th). What is mind-blowing, that the "Gene concept" (approaching 100 years) and crisply defined for the last 50 years or so (protein-coding DNA sequence) has spectacularly fallen apart. In fact, it is dead as a doornail. Big Pharma is frozen on its (very expensive) tracks of "gene discovery" since the real discovery is in the 98.7% of (human) DNA that was called "junk" (by definition "non-gene"). Affy's "Gene Chip" would be "out of fashion" - but it is already re-designed to "Genome Chip". The highlighted last sentence of this spectacular piece of journalism now re-defines the axiom, talks about "non-protein-coding regulatory genes". The conceptual meltdown of the "Gene" and "Junk" misconceptions absolutely, and without any question requires not a journalistic but *mathematical* re-definition of the Genome. This is exactly what FractoGene is, and what it does. FractoGene only conceptually generalizes (by fractal geometry) the Gene and JunkDNA misconceptions (brings the disjointed thesis and antithesis into a meaningful synthesis), but provides the mathematical/information technology to generate (now #1 is experimentally supported) quantitative predictions. The 2nd Prediction, coming out in "FractoGene - Decoding JunkDNA" BrowserBook will provide with the experimental-information technology procedure, not only to "print" the Genome DNA sequence, but also "how to read them". Imagine if in the Bible someone declared that only "verbs" make sense, the rest of the words were "junk". Nonsense. Nouns, adjectives (etc) are also essential, and even much-repeated "the" serves a purpose in forming the information. the "finding reported [in Science] will blow open the 'social studies'" of animals, and eventually of the human race. Sooner than anyone thinks, Time Magazine will herald that "if behavioral diversity is determined by the - formerly - 'junkDNA', humanity must invest in finding out what is the clue, 'the mechanism'". "FractoGene - Decoding JunkDNA". - comment by Dr. A. Pellionisz on 22nd of June, 2005]

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Junk DNA makes voles better dads

Jun 21, 2005, 22:50 GMT

ATLANTA, GA, United States (UPI) -- Scientists in Georgia have found that male voles with a certain strand of junk DNA are more attentive mates and better fathers.

Larry Young and Elizabeth Hammock of Emory University bred strains of prairie voles with different lengths of micro satellite DNA in a gene coding for a hormone. They found that the voles with the longer strand of DNA were more attentive to their mates and spent more time with their pups.

Microsatellites are strands of repetitive DNA that do not encode for proteins and thus are considered junk. About 95 percent of human DNA is junk.

But Young said that junk strands of DNA appear to have a purpose.

"They can be a mechanism for rapid evolution and adaptation," he says.

[It was expected - in fact predicted: the "finding reported [in Science] will blow open the 'social studies'" of animals, and eventually of the human race. Sooner than anyone thinks, Time Magazine will herald that "if behavioral diversity is determined by the - formerly - 'junkDNA', humanity must invest in finding out what is the clue, 'the mechanism'". "FractoGene - Decoding JunkDNA". - comment by Dr. A. Pellionisz on 22nd of June, 2005]


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Helpful junk

Jun 16th 2005
From The Economist print edition

Brain development may be influenced by genetic parasites

THE brain is the most complicated object known. How it gets that complicated is, however, almost completely unknown. But part of the answer may turn out to be junk—at least that is the conclusion of a study led by Fred Gage of the Salk Institute in La Jolla, California, which has just been published in Nature.

One of the puzzling features of the human genome is that although genes are numerous they actually form less than 5% of the DNA in a cell nucleus. The rest was thus, rather cavalierly, dubbed “junk DNA” by those who discovered it. Gradually, a role for some of this junk has emerged. In particular, parts of it regulate the activity of genes, and thus which proteins are produced and in what quantities. That has implications for what a cell does—or, to put it another way, what type of cell it is. One of the most puzzling sorts of junk, though, is something known as a LINE-1 retrotransposon. This is junk that won't stay in one place.

Retrotransposons are sometimes known as “jumping genes”. They pop from chromosome to chromosome with gay abandon. The assumption has been that they are genetic parasites. They resemble retroviruses, which certainly are parasites (HIV, the cause of AIDS, is a retrovirus). And the effect of a string of irrelevant LINE-1 DNA popping into the middle of a functional gene is indeed traumatic. The gene in question stops working.

The parasite hypothesis is supported by the fact that although bits of DNA that look as if they have once been part of a LINE-1 element make up 20% of the human genome (ie, they are more than four times as abundant as real genes), only 100 retrotransposons are actually able to leap around, and only ten of those leap often. By and large, the parasites have been disabled, suggesting they are such bad news that evolution has eliminated them. Dr Gage and his colleagues, however, suspect that at least some of those that have not been disabled have been allowed to live on for a purpose. Instead of being destroyed, they have been subverted—and what they have been subverted to do is to create complexity in the brain.

Light fantastic

The researchers were led to this idea when they scanned the stem-cell precursors of nerve cells with a device called a gene chip. This detects the activity of genes by measuring the presence of the molecular messengers they send into the cell to do their bidding. To their surprise, the researchers discovered a lot of LINE-1 messengers, suggesting that retrotransposons are active in these precursor cells.

To find out what was going on, Dr Gage and his colleagues built a piece of DNA that included a human LINE-1 retrotransposon; a gene for a molecule called green fluorescent protein (GFP); a genetic switch to turn the whole lot on; and a special sequence of DNA that keeps the switch in the “off” position unless the retrotransposon jumps from one place to another. The result of all this genetic engineering was a system that produces light in cells in which a retrotransposon has jumped. And GFP glows green, as its name suggests, so such cells are easy to spot.

The researchers spliced their creation into the DNA of nerve-cell precursor cells from rats (which they then grew as laboratory cultures). They also spliced it into the DNA of a line of mice, so that it was present in every cell in the mice's bodies.

Nerve-cell precursors can turn into two types of brain cell besides nerve cells. These other two types have supporting, rather than starring roles in the brain, and cannot transmit nerve impulses. The rat-cell work showed that LINE-1 jumping happens only in precursors that turn into nerve cells, and that it seems to be regulated by a protein called Sox2 that is already known to play a crucial role in the formation of nerve cells. The mouse work showed that LINE-1 was not jumping in any other parts of the body (except, oddly, the sex cells—a result that had been seen before). That suggests it is happening in the brain for a purpose.

The mouse work also showed that the retrotransposons were jumping mainly into genes that are active while precursor cells are changing into their destined cell types. The team identified a dozen and a half such genes that were affected by LINE-1, and followed up one of them, PSD-93, in detail. PSD-93 makes a protein found in the places where nerve cells touch each other and pass their signals on. When LINE-1 jumped to a location in the genome near PSD-93 it increased production of the protein. That increase, at least in cell cultures, made it likelier that a developing precursor cell would turn into a nerve cell.

So much is observation. This is where the speculation comes in. Brain formation is an incredibly wasteful process. About half of the nerve cells created in a developing brain have died by the time that brain has formed. Many researchers think that which cells live and which die is decided by a process similar to natural selection. Cells with the right properties in the right places flourish; those without wither. But natural selection requires random variation to generate the various properties.

Retrotransposons could provide that variation, by affecting gene expression at random, depending on where they pitch up. Changing the quantities of proteins such as the one made by PSD-93 would probably change the nature of the affected cell quite radically, and might even be responsible for generating the different types of nerve cell that are known to exist. Certainly, the brain has many more different types of cell in it than any other organ.

A similar idea about generating variation has been proposed in the past, to explain the activity of LINE-1 elements in sex cells. This, the theory goes, would bolster variety in an individual's offspring above and beyond the variation already provided by sexual reproduction. That is an interesting idea. But the thought that the complexity of the mammalian brain—and the existence of human intelligence—depends on variety induced by a tamed genetic parasite is truly audacious. Whether it is true remains to be seen.

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Rodent Social Behavior Encoded in Junk DNA

A discovery that may someday help to explain human social behavior and disorders such as autism has been made in a species of pudgy rodents by researchers funded, in part, by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH) and National Center for Research Resources (NCRR).

The researchers traced social behavior traits, such as monogamy, to seeming glitches in DNA that determines when and where a gene turns on. The length of these repeating sequences — once dismissed as mere junk DNA — in the gene that codes for a key hormone receptor determined male-female relations and parenting behaviors in a species of voles. Drs. Larry Young and Elizabeth Hammock, Emory University, report on their findings in the mouse-like animals native to the American Midwest in the June 10, 2005 Science.

The discovery is the latest in a two decades-old scientific quest for the neural basis of familial behavior begun at the NIMH Intramural Research Program in the mid l980s by now NIMH director Thomas Insel, M.D. By l993, his team had discovered that the distribution of brain receptors that bind to the hormone vasopressin differed dramatically between monogamous and polygamous vole species and accounted for their divergent lifestyles. Yet, how such behavioral differences could have evolved in animals that otherwise appear almost identical remained a mystery.

“This research appears to have found one of those hotspots in the genome where small differences can have large functional impact,” explained Insel. “The Emory researchers found individual differences not in a protein-coding region, but in an area that determines a gene’s expression in the brain. This is an extraordinary example of research linking gene variation to brain receptors to behavior.”

Hammock and Young were particularly intrigued with microsatellites, repeating sequences of letters in the genetic code peppered throughout these regulatory areas of the vasopressin receptor gene.

“It was considered junk DNA because it didn’t seem to have any function,” noted Hammock.

Each animal species has its own signature microsatellites; for example, the repeating letter sequences are much longer in monogamous than in polygamous vole species. But even within a species, there are differences in the number of letters in the sequence among individuals.

The researchers first showed in cell cultures that the vole vasopressin receptor microsatellites could modify gene expression. Next, they bred two strains of a monogamous species, the prairie vole — one with a long version of the microsatellites and the other with a short version. Adult male offspring with the long version had more vasopressin receptors in brain areas involved in social behavior and parenting (olfactory bulb and lateral septum). They also checked out female odors and greeted strangers more readily and were more apt to form pair bonds and nurture their young.

“If you think of brain circuits as locked rooms, the vasopressin receptor as a lock on the door, and vasopressin as the key that fits it, only those circuits that have the receptors can be ‘opened’ or influenced by the hormone,” added Hammock. “An animal’s response to vasopressin thus depends upon which rooms have the locks and our research shows that the distribution of the receptors is determined by the length of the microsatellites.”

Prairie voles with the long version have more receptors in circuits for social recognition, so release of vasopressin during social encounters facilitates social behavior. If such familial traits are adaptive in a given environment, they are passed along to future generations through natural selection.

Variability in vasopressin receptor microsatellite length could help account for differences in normal human personality traits, such as shyness, and perhaps influence disorders of sociability like autism and social anxiety disorders, suggest the researchers. The Emory researchers have found that the bonobo, an ape noted for its empathic traits, unlike its relative the chimpanzee, has a microsatellite with a sequence similar to that of humans. Two studies have found modest associations between alterations in this microsatellite and autism in some families. As subgroups of autism spectrum disorders are characterized, a stronger connection may emerge.

Far from being junk, the repetitive DNA sequences, which are highly prone to mutate rapidly, may ultimately exert their influence through complex interactions with other genes to produce individual differences and social diversity, according to Young.

In addition to NIH, the research was also supported by the National Science Foundation.

NIMH and NCRR are part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

[This article in the highly reputable Science on research done in the most prestigeous NIH is a landmark with a colossal impact. Ever since both the human (2000) and the mouse (2002) genome were revealed, with 99% of their "protein coding" content virtually identical (homologue), and such "genes" amounting only 1.3% of the 3.2 Megabasis-long DNA sequence, some of us were certain that only our 30% (!) more "JunkDNA" makes us not only human - but creates an enormous range of diversity from one human individual to the next. ("Genetic Fingerprinting" is based on the fact that while the genes are identical, "JunkDNA" varies in each individual). FractoGene, with the mathematical generalization of the "geneconcept" accounts for the facts found (see also experimental support of the 1st prediction of FractoGene submitted for peer-review by M.J. Simons and A.J. Pellionisz on 27/4/2005, and the 2nd prediction coming out in the FractoGene BrowserBook by Pellionisz). While the "2nd prediction" will directly impact "microarray technology" (from an Algorithmic Mathematical & Information Technology viewpoint), the finding reported here will blow open the "social studies" of the human race. Leadership of NIH will no doubt re-vamp the funding system of "JunkDNA" R&D. - comment by Dr. A. Pellionisz on 10th of June, 2005]


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Affy to Buy ParAllele for $120M in Stock; Deal Expected to Close in Q3

By a GenomeWeb staff reporter

NEW YORK, May 31 (GenomeWeb News) - Affymetrix said today that it plans to acquire privately held ParAllele BioScience for approximately $ 120 M in stock.

The acquisition, which will marry ParAllele's genotyping assays and Affy's GeneChip platform, is expected to close in the third quarter of 2005.

"The potential for ParAllele's technology goes far beyond genotyping," said Stephen Fodor, CEO of Affymetrix, in a statement. "We will combine both companies' technologies to accelerate discovery and product development in a wide variety of areas, from basic research to the clinic."

The acquisition grew out of a long-standing collaboration between the two firms. In 2003, Affy began providing its GeneChip platform for use with ParAllele's genotyping assays, which are based on its Molecular Inversion Probe technology - a process that enables up to tens of thousands of reactions to be multiplexed in a single tube.

Last year, Affy and ParAllele extended the collaboration into a distribution partnership under which ParAllele agreed to design assays for Affymetrix to market for use with the GeneChip platform.

Earlier this year, ParAllele announced plans to partner with Eli Lilly and Genaissance to design and market its upcoming MegAllele DME-T assay panel, which will run on Affy's platform and will test around 160 genes that are involved in drug metabolism and transport pathways.

Affymetrix said it expects the acquisition of ParAllele to be "financially neutral" to its operating results in 2006 and accretive to net income in 2007.

The company expects to incur a merger-related charge of around $15 million in fiscal 2005 for in-process R&D, as well as operational charges in the range of $4 million to $7 million. These operational charges include non-cash amortization of about $2 million.

[The Agilent/Affymetrix cut-throat duel is escalating by the day - each mopping up Intellectual Propery left and right. Now we also know the "price tag" of ongoing M/A - measured in hundred millions of dollars per scoop. What is the value of "profile matching in the (obviously) non-Eculidean space?" - comment by Dr. A. Pellionisz on 1st of June, 2005]


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Agilent, Rosetta Biosoftware to Integrate Gene Expression Analysis Software

By a GenomeWeb staff reporter

NEW YORK, May 31 (GenomeWeb News) - Agilent Technologies and Rosetta Biosoftware are integrating the Rosetta Resolver and Agilent GeneSpring software packages for gene expression analysis.

The integration is being facilitated by the Resolver Software Development Kit, the companies said. Further details were not disclosed.

Agilent is the exclusive distributor of the Rosetta's gene expression analysis software.


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Biochemistry Graduate Student Receives UCR Award for Outstanding Research

Rosaleen Gibbons, a Ph.D. student in the Biochemistry and Molecular Biology Graduate Program received the Mary and Randolph Wedding Award for 2005

(May 27, 2005)

RIVERSIDE, Calif. – – Rosaleen Gibbons, a PhD student in the Biochemistry and Molecular Biology Graduate Program, received the Mary and Randolph T. Wedding Annual Prize for her paper examining DNA differences between humans and great apes, published in the Journal of Molecular Biology in 2004.

Gibbons received the prize, which carries a $2,000 cash award, at a reception and brief ceremony between Boyce and Webber Hall on Wednesday May 25. Professor Wedding’s son, Randolph E. Wedding, presented the award; daughter Sheila was also in attendance. Gibbons competed with fellow graduate students in the Biochemistry and Molecular Biology Graduate Program for the award. Randolph T. Wedding was one of six founding professors in the then Department of Plant Biochemistry in 1960, which became today’s Department of Biochemistry in 1962.

Wedding played a leadership role in the development of the Biochemistry Department and of the graduate program in Biochemistry. The program’s first students enrolled in the fall of 1962. Wedding was chair of the Department of Biochemistry from 1966 to 1975, teaching and mentoring graduate students and conducting research into plant enzymes until his retirement in 1993.

I’m very surprised and very encouraged by this very generous support,” Gibbons said. “I want to continue my research as a postdoctoral fellow, hopefully.”

A Moreno Valley High School graduate, Gibbons, who transferred from Mt. San Jacinto Community College in 2000 to complete her undergraduate studies at UCR, is scheduled to receive her Ph.D. in June. She has carried out her research under the direction of Professor Achilles Dugaiczyk, a distinguished scientist researching the role of the Alu DNA in primate evolution. Alu DNA are short, interspersed elements, often referred to as “junk DNA” because they don’t code for any particular proteins, which drives how DNA makes cells behave.

Gibbons’ research has made major strides in analyzing the role of the Alu repeats in the organization of the human genome and the architecture of human chromosomes.

My paper found a 250-fold increase in the differences between human and chimpanzee DNA than had been previously thought,” Gibbons said. “Although 98 percent of DNA is identified with differences between humans and chimps, we looked at that remaining 2 percent.”

That 2 percent, and the differences, are likely involved with developmental processes in humans and chimpanzees, Gibbons said. She hopes to do her postdoctoral work in cancer research at either Loma Linda University Medical Center or at the Scripps Research Institute in San Diego.


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Israel’s Rosetta Genomics - Cracking the RNA Code

By Sharon Kanon

IHC Abstract

Israeli company Rosetta Genomics has developed a way of discovering micro-RNAs (gene regulators). Until now, all DNA research has concerned itself with the two percent of the DNA that encodes proteins. Micro-RNAs (once called junk DNA) are the other 98% of DNA. They were considered to have no function.

Rosetta has discovered and identified specific micro-RNAs associated with prostate cancer, lung cancer, HIV and Herpes Simplex Virus. It is their main goal that their discoveries will lead to the development of products for the diagnosis and treatment of diseases in humans.

The conventional approach to studying RNA was first to remove it from the cell. Rosetta, however, has developed a computer system that enables them to identify genes by analyzing the genomic formats. Only afterwards do they verify their existence in the biological laboratory. A second stage is to link segments of genes to diseases. Then an effort can be made to devise treatments for the diseases from these segments.

Rosetta Genomics has attracted wide interest in both the scientific and business communities.

The IHC recommends you read the article in full.

[The Israeli effort is spectacular from more than one viewpoints. Not only that the enterprise is noteworthy because it is focused on the (more than) 98% of the DNA (maiden name "JunkDNA"), but the effort is outstanding since it is clearly aimed at answering the challenge on the turf of Information Technology. Given the top expertise of Israel both in Genomics and in Information Technology, one can safely predict that the "Rosetta stone" of "Post Gene Genomics" will increasingly be 4-faceted; four areas competing for leadership; Silicon Valley, Israel, Singapore and India . - comment by Andras J. Pellionisz, 30 May, 2005]


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Agilent to Acquire Informatics Company Scientific Software for Undisclosed Amount

By a GenomeWeb News reporter

NEW YORK, May 25 (GenomeWeb News) - Agilent Technologies plans to acquire informatics company Scientific Software for an undisclosed sum, the company said today.

Through the acquisition, Agilent aims to marry analytical instrumentation, data systems, and services with SSI's chromatographic data systems and informatics. The deal would give Agilent one of the largest installed bases of chromatographic data systems -- SSI has more than 120,000 installations - and a broad portfolio of laboratory informatics software in the life science and chemical industries.

The acquisition would enable Agilent to provide a "family" of software products that "addresses the complete life cycle of analytical information, from data acquisition to knowledge management and retention." It will also allow scientists "to collaborate across laboratory operations, linking information from a wide range of instrument platforms and data sources," Jim Miller, director of software for the Life Sciences and Chemical Analysis business, said in a statement.

SSI had annual sales of more than $18 million in 2004. Based in Pleasanton, Calif., the company employs about 80 people, most of whom are expected to join Agilent, the company said.

The company's "key" products include: OpenLAB, a Web-based software framework that joins a chromatography data system with comprehensive Enterprise Content Management and Business Process Management; EZChrom Elite, a chromatography data systems with more than 60,000 licenses installed and the ability to control more than 290 instruments from 26 vendors; Enterprise Content Manager, a software platform that provides a secure, central repository and content services that enable organizations to "capture, manage, legally sign, archive, and re-use business-critical information; and Business Process Manager, a workflow product for "streamlining and automating laboratory business processes."

Agilent has been the exclusive distributor of SSI's ECM since July 2004, and is currently using the technology in-house. An Agilent spokesperson said the unit expects to "expand the application" of this technology within the business group.

More broadly, Agilent said that following the acquisition it plans to "continue development and support of each of these product lines with a commitment to open systems, industry standards, and interoperability with other instrument hardware and software providers." Agilent also plans to support and enhance SSI Instrument OEM partnerships, the company said.

Agilent did not say when it expects the acquisition to close, but the spokesperson said it will likely take one month.


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Israel's Rosetta Genomics - cracking the RNA code

By Sharon Kanon May 22, 2005

The historical Rosetta stone was found by French soldiers near the town of Rosetta in northern Egypt, in 1799. It was a basalt tablet inscribed in 196 BCE with a decree of Ptolemy V of Egypt in two languages (Egyptian and Greek), using three scripts (hieroglyphic, demotic, and Greek). French scholar Jean-Francois Champollion used it to derive a key for translating Egyptian hieroglyphics.

Since that time, Rosetta has been used as a term for the ability to crack previously indecipherable codes.

The name truly suits the Israeli biotech startup Rosetta Genomics, which has developed a new discipline: discovering microRNA, which until recently, was considered an unimportant part of DNA. Just like the historic hieroglyphics from which the company drew its name, everyone saw it, but for a long time, no one could decipher it.

Rosetta Genomics kicked off Israel's 57th Independence Day celebrations a day early with a reception and conference called 'Leading the MicroRNA Revolution' last week. Held at the Weizmann Institute of Science in Rehovot, the conference brought together scientists and investors interested in learning about the developments and discoveries of the company which until recently, had been kept confidential.

The young, Rehovot-based company has good reason to celebrate. Rosetta has now discovered and identified more micro RNAs (gene regulators) than any other research center in the world. The company has identified specific microRNAs associated with prostate cancer and lung cancer (currently engaged in pre-clinical animal studies), Epstein Bar Virus, HIV, and Herpes Simplex Virus.

"From the start, our goal was to achieve a scientific breakthrough that would lead to the development of products for diagnosis and treatment of disease in humans," said Dr. Isaac Bentwich, founder and CEO of Rosetta.

Most genomic research has been concerned with proteins, and the genes that encode proteins and turn them into cells of a certain type. The DNA region that encodes these proteins, however, constitutes only 2% of DNA. Up until two years ago, the other 98% of the genome was considered to serve no function. It was even known as 'junk DNA'.

"For 40 years, research has focused on protein encoding DNA, because it was assumed that all the rest was just there, serving no purpose," said Bentwich. "We focused our attention on a field that was rather neglected. The basic idea was to look for a new group of genes that did not encode proteins. The amazing thing is that we found them."

Bentwich calls what followed "a scientific earthquake."

"All of a sudden, it turned out that what were thought to be useless genes were of decisive importance. They are far from being junk DNA. A series of discoveries proved that extensive regions of junk DNA (that do not encode proteins) are produced by the cell, and preserved throughout its evolution. This is evidence that they have a function."

Rosetta Genomics has found a way of using advanced computer technology to reveal the encoding genes through the microRNA genes. This is now one of the hottest topics in biology. Published research in the field shows that these genes are linked to, and affect, a variety of diseases, such as diabetes, cancer, anemia, and neurological disorders.

Rosetta Genomics' great innovation is that it has managed to find a large number of genes that couldn't be identified through known technological means, Bentwich says.

The breakthrough has attracted a slew of high profile Israeli investors: Pharmaceutical gian Teva, Leon Recanati and his investment company Glenrock Israel; VCON Telecommunications CEO and former Scitex CEO Yair Shamir; Agis Industries president and chairman Moshe Arkin; Israeli high tech pioneer Uzia Galil; and Prof. Michael Sela, Israel Prize laureate and former president of the Weizmann Institute of Science.

Bentwich first got his idea to focus on the role of microRNAs while studying meditation in the Himalayas in 1999.

"I've spent long periods in India," he says, "I studied Tibetan Buddhism and various meditation techniques related to tantra. The inspiration came at the end of four months of studying meditation in the Himalayas, not far from the city of Dharamsala. The idea was linked to a puzzle that has preoccupied me since I was 15 years old. I'm referring to the basic puzzle of biology how every cell in the body has the same DNA, yet different cells are differentiated into various types: muscle cells, nerve cells, brain cells, etc. Science still doesn't know the full answer to the central question of what causes cells to function differently," he told Globes.

He established Rosetta in 2000, with the support of his father, Prof. Zvi Bentwich, an immunologist, and one of the world's leading AIDS researchers. Isaac Bentwich returned to Israel, told his father about his idea, and started to promote it. His father joined the effort, and is currently both chief scientist of the company and chairman of its scientific advisory board.

Speaking at last week's conference, the elder Bentwich proudly gave a brief summary of the scientific discoveries that have marked Rosetta's journey.

"We have discovered 180 microRNAs, and hundreds are in the pipeline. Rosetta is in a position to own 80% of all the known microRNAs," he said.

"The company began looking for microRNAs several years before other scientists believed they existed. It gave us an edge," the younger Bentwich added.

According to him, Rosetta's other edge in the field is its computer system.

"Up until now, the conventional approach was biological, based on the removal of RNA from the cell. Our approach is innovative in that it identifies genes by computer, and only afterwards verifies their existence in a biological laboratory. The success is primarily thanks to Rosetta's teamwork. We are blessed with an amazing group of talented, creative, dedicated young people, computer people and biologists, who have succeeded in tackling the huge technical challenges we faced."

"The computer finds these genes by analyzing the genomic formats. That's what's 'exotic' about our story. Only after finding them in a dry run do we look for biological verification to confirm the discovery."

"Rosetta Genomics has combined scientific disciplines in an original way. The combination of biotechnology and bioinformatics with genetics is innovative and revolutionary. So is the idea of trying use a computer to predict genes, and proving the prediction in a laboratory only afterwards. In the second stage, we're trying to take segments of genes, and link them with diseases. After verification, we can try to devise treatment for the diseases from those segments."

According to Bentwich, the first stage that of gene prediction and verification has been achieved. There are already patents and several dozen genes have already been proven. The company is now linking genes to diseases.

"These treatments will be based on microRNA, which scientists until recently thought were junk genes. It is now clear to everyone that they are goldmines. Rosetta Genomics has reached the applications stage. In this stage, we'll conduct animal trials on genetic splices. We are collaborating with medical companies, and Rosetta Genomics' know-how will be the basis for the medical treatments of the next two decades."

Zvi Bentwich jut returned from a conference in Boston at the beginning of May, and he reported on a rising interest in the field, noting an exponential explosion of articles published on microRNAs since 2001. In the year 2002, Time magazine wrote that microRNAs was one of the ten most important discoveries of the year.

"One scientist [at the conference in Boston] who had said that there were probably only about 255 microRNAs, now admitted that he was wrong. He put the number on the blackboard, and crossed it out. Now the scientific community has accepted the fact that there are a large number of microRNAs," he said.

After keeping their operation secret for a number of years, Rosetta is beginning to make noise with its discoveries. An article on Rosetta?s chip platform has been accepted by the prestigious journal Genome Research, and will be published soon

Showing the relationship between the DNA, RNA, and protein on a slide, the senior Bentwich commented: "MicroRNAs are a small part of the RNA. They connect with the messenger (mRNA) to create protein. All microRNAs come into the world to regulate the process of creating proteins."

"Picking out microRNAs was like finding a needle in a haystack. Bioinformatics was the basis of Rosetta when it was first established. The company also developed a proprietary system to detect and identify microRNA signals (they light up) on a chip, and also a biological system to locate microRNAs in a sequence."

"What can we do with it? When we see that there are 18 times more microRNAs in a diseased tissue as compared to a normal tissue, which can happen in cancer, we have the possibility of intervening."

A recent press release was distributed to participants at the conference last week: Rosetta Genomics scientists found that if they silence one microRNA in a cluster in an EBV infected cell, there is a dramatic reduction in the infection of human cells by EBV.

Prof Bentwich stated: "This is the first proof that viral encoded microRNAs are important for viral replication and has immediate relevance to development of antiviral drugs."

Keynote speaker at the conference was Technion Professor Aaron Ciechanover, co-winner of the Nobel Prize in Chemistry in 2004, and Chairman of the Scientific Advisory Board of Rosetta, a position he took before he won the Nobel Prize.

"When I first heard about the company, I was a skeptic; then, I became a believer; and now I am very enthusiastic," said Ciechanover. "When it started off as a small software company in Jerusalem, I said you won't get any place without a wet lab. Now the company is well organized - with a strong bioinformatics branch; and labs that validate their identifications."

Among the guests at the conference was Uzia Galil, a pioneer in industry in Israel. Galil, most of whose investments are in consumer electronics told ISRAEL21c that Rosetta is the only biotechnology company in which he is investing. "It is the most promising."

Dr. Joshua Rosensweig, Chairman of the First International Bank of Israel (and now a member of the Rosetta Genomics Board), commented that when the company first came to him for financial advice, he gave advice and then asked: "How can I invest?"

"We have had a burst of business activity," said Sharon Kaspi, VP Business Development. "The company is currently in the midst of negotiations for several important contracts for commercialization and collaboration."

Weizmann Institute of Science Department of Molecular Genetics director Prof. Doron Lancet, one of the heads of Israel's genome project, had the final word.

"Rosetta Genomics is working in the hot new field of genome research. It is utilizing scientific discoveries that have changed the previous paradigm. That's a revolution."

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Debating the Merits of Intelligent Design

The Stanford Review

by Tristan Abbey (Pro) and Paul Laddis (Con)

Deputy Editor and Staff Writer

Are Darwinists Chickens?

Tristan Abbey

Let’s suppose you hold two Ph.D.s in evolutionary and theoretical biology. You edit the Proceedings of the Biological Society of Washington, a peer-reviewed journal affiliated with the Smithsonian Institution. You’ve had dozens of articles published in peer-reviewed journals, including the Journal of Morphology and the Journal of Biological Systems. You’ve lectured, spoken, or taught at universities across the United States , from Northern Michigan University to the University of South Carolina . You are not a proponent of intelligent design, but your research has led you to conclude neo-Darwinian mechanisms are not sufficient to account for the complexity of life. As you prepare to resign as scheduled from the Proceedings, you also approve publication of a scientific paper written by a Cambridge-trained philosopher of science theorizing that an intelligent designer played a role in the origin of animal body plans. What happens?

You’re asked if you’re a “right-winger,” accused of being a “creationist,” and prevented from continuing research. The Biological Society of Washington quickly does damage control and publicly explains that the paper was an “inappropriate” mistake, discounting the fact that you pursued the peer-review process. Your career as a scientist hangs in the balance.

Believe it or not, this actually happened to a researcher named Rick Sternberg. The paper in question was “The Origin of Biological Information and the Higher Taxonomic Categories” by Stephen C. Meyer. This is a classic, and scary, case of censorship by orthodox Darwinians, who are afraid of any sort of critique of their sacred methodological naturalism, the philosophical bias permeating much of the scientific community that prevents any non-natural explanation from being considered. No controversy exists, they tell us.

But what of the facts? Darwinists have failed to explain how animal body plans arose, where the precursors to the Cambrian phyla are, how cooptation actually worked to produce irreducibly complex systems, and countless other problems with standard theory. Hundreds of scientists have signed petitions and letters criticizing neo-Darwinism, asserting that it cannot explain everything it pretends to. Many have written books pointing out where Darwinian mechanisms have failed to explain some aspects of biology. The peer-reviewed literature is bursting with examples of papers written by scientists who do not endorse intelligent design, but nonetheless critique aspects of evolutionary theory. If this is not a scientific controversy, what is?

The attraction of intelligent design is its broad scope. Astrophysicists, for example, have explored the fine-tuning of the universe and of the Earth, theorizing that because so many aspects had to be just right that an intelligent designer is responsible. Origins of life researchers, on the other hand, can point to the decades of failures that have not shown that life can originate spontaneously by purely natural processes. Geneticists can look at “junk” DNA, ask what it does, and discover various functions for allegedly useless sequences. Development biologists can observe embryological development and conclude that generative entrenchment suggests body plans didn’t evolve from a universal common ancestor. Molecular biologists can determine various biological systems are irreducibly complex. And on, and on…

This is not to say that intelligent design is necessarily the truth. Years from now intelligent design may indeed be a laughable idea and its proponents relegated to the dustbin of crackpot theories, alongside the Flat Earth and Marxist-Leninist “science.” But let’s wait and see.

It is regrettable that so much of the work in intelligent design is kept hush-hush. There are many scientists, professors, and biology students who keep that aspect of their lives a secret, for fear of ruining their careers with a careless phrase or foolish affiliation with a controversial organization like the Discovery Institute. The cases of Rick Sternberg, Roger DeHart, Jonathan Wells, and others seem to indicate that their careers would, indeed, be at the very least adversely affected were they to come out of the closet.

Which brings us to a very simple question: If the evidence is so strongly in favor of evolution, and if intelligent design is so clearly wrong, what is the Darwinian establishment afraid of?

Tristan Abbey is the director of the Intelligent Design Undergraduate Research Center (

The Dogmatists' New Clothes

Paul Laddis

Creationism is an example of what Richard Dawkins calls a “virus of the mind,” a cultural parasite which spreads simply because it is good at spreading, not because it benefits its host. Just last month editorials in Science and Nature warned of a newer, more insidious strain called “Intelligent Design.”

Why do the editors of Nature consider ID “a threat to the very core of scientific reason?” (Nature 434; 1053) ID is nothing but creationism dressed up as science. But this disguise makes it alarmingly effective in slipping past Americans’ defenses in sound bytes and presentations like Michael Behe’s recent lectures, which were part of the “Veritas Forum at Stanford,” and causes considerable confusion about the nature of science. Strip away the rhetoric, and ID is completely devoid of scientific merit. Behe’s argument may be summarized as follows:

1. Everyone agrees that living things appear designed.

2. There are “structural obstacles” to the evolution of biological systems.

3. Therefore, the best explanation is that these systems were in fact designed by an intelligent being.

The “structural obstacles” refer to Behe’s infamous notion of “irreducible complexity.” A structure is irreducibly complex if removing one component causes it to stop functioning completely. If the structure minus one component does nothing, it could not have evolved, or so the argument goes. After all, natural selection can only favor intermediate forms if they confer some sort of advantage. Otherwise, the whole structure would have to come into being fully-formed, which as just about any scientist will tell you, is absurdly improbable. Darwin himself acknowledged that his theory could not account for any structure that could not be produced by a series of “small successive changes” to existing components, but could find no such example.

Behe presented as his sole example a bacterial flagellum. Flagella are whiplike complexes of thirty-odd proteins which function like outboard molecular motors. However, he neglected to point out the large number of published examples of homologous structures, or proto-flagella, which show that small subsets of the proteins that make up the flagellum could have a selectable function. Any doubt that Behe is aware of this fact was erased when students brought up a prominent example, the Type Three Secretory System, after the lecture. Basically, the TTSS is the same as the mechanism used to export flagellar components to the exterior of the cell, but it is part of another pathway that secretes bacterial toxins.

Even if the flagellum were “irreducibly complex,” it could still have evolved. In treating the protein components of the flagellum as irreducible black boxes, Behe once again conveniently omits basic facts of which he is obviously aware. These include Darwin ’s reason for believing all biological structures can be produced by gradual change: evolution co-opts existing structures for new purposes.

It may be improbable that a protein component would suddenly arise ex nihilo. But the structure of proteins and the way they function together often changes gradually, e.g. through comparatively small “point mutations.” The ancestral form of the complex could very well have done its job with fewer components.

To visualize how this works, imagine a simpler system consisting of a protein A which performs some function, and a protein B which makes A more effective. Over evolutionary time, this system undergoes a series of “small, successive changes,” i.e. point mutations: A becomes A2, B becomes B2, A2 becomes A3, and so on. It is quite possible for natural selection to favor such stepwise improvements in the system, even if A becomes increasingly dependent on B, to the point where An and Bn have no selectable function individually.

There are also many mechanisms for the addition of new components. For example, gene duplications are quite common, and redundant copies of A will tend to diverge into specialized forms. In many cases this also explains the origin of B. Far from being impossible in principle, we should expect that many of Behe’s “irreducibly complex” structures evolved from just one protein!

Stripped of its main premise, Behe’s argument goes nowhere. However, a more fundamental problem for the “theory” of ID is that it mostly consists of pointing to things that evolution supposedly can’t explain. This tends to draw attention away from the fact that ID can’t explain anything.

What I mean is this: any scientific theory must be testable. Since Behe has not put forward any model of the “designer,” his “theory” makes no predictions, only ad hoc suppositions. In short, ID is not science. True, evolutionary theory has yet to produce a complete, detailed account of the history of life (hence, it continues to be a productive area of research.) By presenting ID as a viable alternative, Behe propagates an absurd double-standard of proof which undermines real scientific understanding. Ostensibly, the purpose of the Veritas Forum was to discuss religious issues. I would be the last person to advocate “censoring” anyone’s personal beliefs, although private Universities have that right. However, I wish the organizers had chosen speakers who know where belief ends and scientific fact begins. University policy dictates that Stanford’s resources be used to further its basic mission of producing and disseminating knowledge. Why have those resources been used to elevate pseudoscience? The Stanford community deserves an explanation.

["Intelligent Design" (or "Creation contra Evolution") is not at all a new debate - and it focuses not even on science (but on politics). It is not new since it is arguable if e.g. trees are "intelligently designed" since the same blueprint to grow one leaf can be used to grow many, or the "design" is not that intelligent, since lots of trees "junk" all their leaves in the fall. (Or if "built-in obsolence" may be the truly intelligent design e.g. for the car industry, perhaps Nature is "intelligent" likewise?) The vehemence (vitriol, rather) of the new flare-up of an old debate around "junkDNA" is portrayed here only to show that the "Junk/Regulatory DNA" scientific and technological explosion leaves no stone unturned. Fortunately, Stanford "deserves an explanation" mainly of the regulatory function of 98.7% of (human) DNA... Comment on the 18th of May, 2005 by A. Pellionisz]

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Gene researchers find variations by ancestry

By Lisa M. Krieger and Esther Landhuis
Posted on Fri, Feb. 18, 2005 Mercury News

Under the skin, we're all the same. That's been the warm-and-fuzzy wisdom of modern genetics, based on the first efforts to sequence the human genome.

But a closer look by Mountain View biotech company Perlegen Sciences has found small genetic differences that vary in prevalence among people of different ancestries -- suggesting that nature may not be colorblind, after all.

The goal of the new information is to help prevent and treat common diseases. The first comprehensive map of genetic variation among several ethnic groups, published in today's issue of the journal Science, shows patterns of genetic variation that could explain differences in health, disease and response to medication. This is a key step toward the possibility of personalized medicine based on genetic variations.

``We think this is a very powerful new resource for identifying the genetic determinants of complex traits,'' said David Hinds, statistical genetics analyst at Perlegen. He spoke to reporters Thursday in Washington, D.C., at the annual meeting of the American Association for the Advancement of Science, which publishes Science.

Although it is not their goal, the Perlegen scientists have found differences that suggest ``race'' has biological significance.

Critics fear that the identification of biological differences among races could bolster cranks and demagogues, allowing scientists to play into the hands of racists. Many anthropologists, sociologists, geneticists and population biologists consider race a social construct.

But scientists and doctors say the idea of race-based medicine has new respectability -- and that identifying tiny differences could help reduce health disparities among the races.

It is known, for instance, that hypertension affects black Americans at a higher rate than white Americans. And white Americans sometimes take longer to clear certain drugs from the liver than East Asians.

Life's genetic blueprint is 99.9 percent similar from person to person.

The remaining 0.1 percent consists of single-letter DNA variations called SNPs (pronounced SNIPS), or single nucleotide polymorphisms.

Most patterns of genetic variation are common and found in all populations.

But others are less common -- and are likely to determine a person's vulnerability to disease and response to medications, as well as other traits, such as eye or hair color, height and body type.

Uncommon SNPs occur in different frequencies in different populations. For instance, 70 percent of African-Americans might have a nucleotide represented by the letter A; 30 percent might have a letter T. At the same spot, the percentage may be flipped in European-Americans. The difference in frequency of a specific letter could make a population more susceptible to disease.

Finding those differences, and identifying whether they have any clinical significance, is the goal, said Paul Cuzenza, who oversees research collaborations at Perlegen.

The Perlegen researchers analyzed nearly 1.6 million SNPs across 71 unrelated individuals.

They found that most of the SNPs were common to the three human populations in the study. But 94 percent of the study's SNPs were found in African-Americans, 81 percent in European-Americans and 74 percent in Chinese-Americans.

The presence of these patterns allowed the scientists to create the first picture of the structure of human genetic variation.

``Our paper in no way makes any sort of a scientific statement or definition of race,'' said David Cox, Perlegen's chief scientific officer. ``When you look at any group of individuals, you'll see differences in their DNA.''

Perlegen is now working to generate an even better map, describing variation across individuals of Japanese, Chinese, Nigerian and European ancestry.

The company hopes to include 4 million SNPs in 270 individuals by the end of the year.

In a related and even more significant project, it is comparing the genetic variants of sick and healthy people. Their blood samples come from people with Alzheimer's, Parkinson's, breast cancer -- even nicotine addiction. This research is not yet published.

``The challenge going forward is to translate this technology into something that's efficient and informative,'' said Lawrence Lesko, chair of pharmacogenomics at the U.S. Food and Drug Administration.

[Several aspects beyond the "mass appeal issue" (differences between groups) are also noteworthy. One is, that the familiar SNPs occurring in the regulatory DNA ("junk DNA") are increasingly in the interest of Affymetrix, the parent company of Perlegen. Thus, with the migration of Affymetrix from "gene chip" to "full genome chip", bringing their capacity to into the limelight by a "controversial issue" may serve business purposes. Second, the question "Does Race Exist? Genetic Results May Surprise You" has been answered before (December 2003 Cover Article of Scientific American) - Comment on the 18th of February, by A. Pellionisz]

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New Theory of Life's Digital Complexity

By Graeme O'Neill

Australian Biotechnology News (online)

(02/14/05)—Functionally, the genomes of humans and other higher life forms have more in common with the intricate circuitry of a computer processor chip than with the simple genomes of bacteria, according to a new theory advanced by Australian researchers.

In a paper in the current issue of Science, John Mattick and Michael Gagen, of the Institute of Molecular Bioscience at the University of Queensland, argue that all regulatory networks, whether in biology, engineering or society, belong to a class of complex systems called accelerating networks.

Accelerating networks are highly interconnected, and operate in a globally responsive way that requires complex regulatory systems to coordinate the operation of their functional components — proteins, in the case of plant and animal genomes, Mattick and Gagen say.

The requirement for rapid, global responsiveness imposes an upper limit on the complexity of accelerating networks — Mattick has previously suggested that the human genome, which has about 25,000 genes coding for as many as 250,000 different proteins, may approach the limit of complexity.

The limit is imposed by the costs incurred by the need for increasing numbers of connections between the individual functional components or 'nodes' in the network, and the number of regulatory layers required to coordinate their activity.

The Science paper expands on Mattick's hypothesis, developed over the past two decades, that the proteins encoded by the 25,000-odd genes of the mammalian genome are the components of an analogue machine, which is operated by a digital control system coded in RNA, that he calls the 'R-nome'.

Evidence for Mattick's hypothesis has emerged with the discovery that the long tracts of non-protein-coding DNA within and between genes, once dismissed as 'junk' DNA, in fact codes for myriad RNA molecules that regulate and integrate the activity of proteins.

These non-protein-coding tracts of DNA are a basic difference between eukaryotic and prokaryotic genes, which do not have introns, and are arranged end-to-end without intervening tracts of non-coding DNA.

Mattick and Gagen suggest that the transition from the prokaryotic system, which is analogue and protein-based, to a digital, RNA-based control architecture, was the critical step that enabled the evolution and development of complex, multicellular organisms, leading ultimately to the so-called 'Cambrian explosion' around half a billion years ago.

They say most studies of networks to date have focused on simple, usually large connectionist systems like telephone networks and the Internet, which are generally scale-free — they look structurally similar at any scale, in terms of the average number and distribution of the connections for each node.

"These networks can become large precisely because they have no need to rapidly integrate information from, or respond globally to, the current state of their nodes," Mattick and Gagen say.

"For example, it does not matter to the overall function of the Internet whether any individual is connected or not, and the state of one node is quite irrelevant to most of the others, although the system as a whole is vulnerable to damage to very highly connected nodes."

With functionally organised systems that rely on the integrated activity of any or all of their component nodes, like a stock exchange, an office, or a computer processor, the number of informative connections must increase with the size of the network.

As a result, the number of connections between nodes scales more rapidly than the number of nodes — in an accelerating network, the number of interconnections scales quadratically, not linearly, imposing an upper size limit on the network's functional complexity.

"We contend that accelerating networks are far more common in the natural world than has hitherto been appreciated," Mattick and Gagen write.

The interconnectivity eventually reaches saturation, or the accelerating proportional cost the connections becomes prohibitive. At this point, an accelerating network can only continue increasing in size if the number of interconnections is reduced, resulting in a loss of coordinated function and fragmentation — as seen in the social transition from small communities to large cities.

But an accelerating network can continue to grow if some technical breakthrough allows an increase in connectivity — such as evolution's 'invention' of the eukaryotic genome's RNA-based digital control system.

Mattick and Gagen say computer systems are the pre-eminent example of accelerating networks — the millions of components on an integrated chip must be interconnected by shared bus lines that require hundreds of metres of metal wires to be arranged in multiple layers across a thumbnail-sized chip.

Mattick and Gagen say their theory may explain the observation that the number of regulatory proteins controlling gene expression in bacteria increases quadratically with gene number and genome size.

"In any competitive system, whether biological of industrial — the speed and efficiency of organization, and the sophistication of responses to changing circumstances, are critical determinants of the system's survival and success. We suggest that this is the imperative that results on biological regulatory networks scaling quadratically with system size to maintain optimal integration."

The researchers say there are few, if any, fully scalable technologies: "Biological organisms are a collection of technologies optimal in some respects, but sub-optimal in others, which limits life's potential.

"Understanding where the points of regulatory saturation and technological limitation occur will be necessary to break through present and future complexity barriers."

Featured report: J S Mattick and M J Gagen, Accelerating Networks, Science February 11, 307, 856-858 (2005).

[Mattick and Gagen continue to pursue their interest in academic research of introns and RNA. Their paper 4 years ago may not be obvious to Bio*IT World: "The evolution of controlled multitasked gene networks: The role of introns and other noncoding RNAs in the development of complex organisms", J. S. Mattick and M. J. Gagen, Molecular Biology and Evolution, 18 (9), 1611-1630 (2001). - Comment by A. Pellionisz on 18th of February, 2005]

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Power tools for the gene age
Affymetrix chips digging deeper into the genome

Bernadette Tansey, Chronicle Staff Writer
Monday, February 7, 2005

At first glance, the luminous image rolling across a conference room wall at Affymetrix Inc. looks like mysterious transmissions from an alien race using an intricate language we don't understand.

But it's a readout of an experiment on Earth, it soon becomes clear -- a graph of the thicket of coded messages sent out by the human genome and proof to the company's founder of his technology's power to uncover the secrets of biology.

In 1989, Stephen Fodor led a scientific team that invented a new way to ask questions of the genetic code and receive quick answers. The team developed a gene chip that can rapidly detect the presence of a gene or slice of genetic code in a sample of blood or tissue. Such data can reveal the genetic causes of disease, plumb the degree of our kinship with animals and tell us how different we are from distant populations.

In this building in Santa Clara, Affymetrix was born as an independent company in 1992. Soon it was selling GeneChip arrays that could test for genetic variations that were being discovered through the Human Genome Project and other research. As that knowledge exploded, Affymetrix eventually created chips that span the entire human genome.

Now, one of its most powerful chips is being used to explore remaining frontiers, such as the so-called dark regions of the human genome being scanned on the conference room wall.

Long stretches of DNA, where no known gene exists, are showing countless purple spikes of activity in the rolling graph.

Those mysterious regions, once dismissed as junk DNA, are pumping out chemical messages and lending support to scientists who believe these little- explored DNA sequences might emit signals that help build and control the human body

Fodor has spent more than a dozen years expanding the information- gathering power of Affymetrix' gene exploration tools, then convincing researchers they need the upgrades to get real answers to questions about the genetic code and its role in disease.

Only a few years ago, experts estimated the number of human genes at as few as 30,000 -- occupying a mere fraction of the DNA sequence. Fodor says the count could be substantially higher, depending on how a gene is defined.

"There might be upwards of a million,'' said Fodor, who is chief executive officer of the firm.

At a pace similar to the progress in computer data storage, Affymetrix has expanded the analytic power of its GeneChip arrays -- an arrangement of DNA probes on a quartz chip.

Affymetrix's early days coincided with the historic race to figure out the sequence of all 3 billion chemical "letters'' that make up the DNA chains that comprise the human genome.

Now that the Human Genome Project is complete, an even greater task is under way. Scientists are trying to identify all the strings of chemical letters that spell out a gene. Each gene is a program for the manufacture of a molecule that helps control a function of the body.

Affymetrix benefited immensely from the publication of DNA sequences discovered by the Human Genome Project and other studies. It used many of these known sequences to create the DNA probes on its gene chips.

The first widely marketed GeneChip, released in 1994, contained 16,000 different types of DNA probes. A single chip now holds as many as 2.5 million. The upward curve will continue this year. Affymetrix plans the limited release of a new set of gene chips that will each carry 6.5 million varieties of DNA probes.

The company has also been stuffing more information onto every chip. In 2003, it marketed a chip that samples across the entire human genome.

And the cost has plunged. For the price scientists paid a few years ago to search through one region of genetic variation, they can now analyze 100.

The company is using more-powerful non-commercial chips in some of its own research collaborations, which are intended to determine what genes are switched on to produce the chemical signals that control the functions of a cell.

Using the same chips that revealed purple spikes of activity in the genome's dark regions, scientists at Harvard, Affymetrix and MIT recently reported intriguing evidence of previously unknown structures that might help turn genes on or off.

Pioneer ranks first

Affymetrix, a pioneering startup when it began independent operations in 1992, is still first in a DNA microarray market now estimated at $800 million in annual revenues. Trailing Affymetrix, which expects revenue of $405 million this year, are much larger firms like Agilent Technologies Inc. of Palo Alto; Amersham Biosciences of New Jersey, a unit of GE Healthcare; and Applied Biosystems of Foster City, a division of Applera Corp.

"Affymetrix clearly dominates,'' said Steven Bodovitz, principal at the San Francisco consulting firm Bioperspectives. "You can look at Affymetrix's numbers as an excellent bellwether for the market (in DNA microarrays).''

The company's products are primarily used for research, but Affymetrix recently branched into a potentially lucrative new use for its gene chips. In a partnership with Roche, Affymetrix won the first Food and Drug Administration approval of a diagnostic test using DNA microarrays.

Roche's Amplichip CYP450 test identifies patients with unusual genes that make them vulnerable to dangerous side effects from commonly prescribed drugs -- information that could guide a doctor's treatment decisions.

The Affymetrix gene chip, an ingenious combination of DNA molecules and semiconductor technology, doesn't store programs or data like a computer chip. It's actually a highly miniaturized, semi-automated version of a lab test to find out if certain genes exist in a sample of blood or tissue. The chips can also detect RNA, a form of chemical signal programmed by DNA.

This technology can be used in many ways. Researchers compare the genes of sick and well people to see if an abnormal inherited gene boosts the risk of disease. This knowledge could lead to the development of better medicines.

Scientists can also compare the DNA sequences of viral strains to see if they are developing mutations that make them resistant to drugs. And they can monitor the output of the DNA code -- RNA -- to see which genes are switched on in healthy or sick people.

Chips save time

Such projects used to take years as researchers at universities or drug companies laboriously performed their tests one gene at a time. For that reason, they first tried to figure out which few genes or regions on the genome could lead to an illness, then focused their experiments narrowly on those.

Gene chips make it possible to conduct wider genetic surveys in mere days or hours. As the number of DNA probes per chip increases and the cost per chip drops, Fodor said, scientists can fish the whole genome rather than a few target areas suggested by a hypothesis that might be right or wrong.

With this approach, surprises can crop up in unexpected quarters.

"There's an enormous amount of the genome being actively turned into messages,'' Fodor said.

Affymetrix is taking this fishing tactic further. While its commercial gene chips cluster their DNA probes around known genes or known areas of genetic variation, Affymetrix has created a different kind of chip for its research collaborations. These chips have probes spaced at regular intervals along the length of a chromosome, including the dark regions.

That's how the unexpected purple spikes of activity -- a barrage of RNA messages -- were found.

"What's really happening here for the first time is you can ask unbiased questions,'' Fodor said.

Throughout Affymetrix's history, some of its scientists have been tempted to take off from its role as a biotech toolmaker and pursue some of the intriguing leads that gene chips have revealed about genes and disease, said Robert Lipshutz, an executive who has been with the firm almost from the beginning.

Staying the course

But Affymetrix's leaders chose to stick to the company's original mission rather than pursue other paths like drug development, which might bring the firm into direct competition with its customers, he said.

However, in 2000 Fodor co-founded a spin-off called Perlegen Inc., which uses chip technology to map genetic variations among human populations.

Meanwhile, Affymetrix is thriving in its horizontal niche as other companies seek a share of the growing market. Applied Biosystems, for example, just announced the release of its Human Genome Survey Microarray V2.0, claiming that its system covers more genes than other commercial arrays and offers greater sensitivity.

Bodovitz said many drugmakers and academics like the systems created by Affymetrix's competitors, but Affymetrix still benefits from its first mover advantage.

"All the major drug companies have invested heavily in Affymetrix,'' he said. Tests done with one manufacturer's chips and scanners are not easily compared with results from another firm's, he said.

Affymetrix, which says it has shipped more than 1,200 of its systems worldwide, reported record sales for the fourth quarter of 2004 and a 69 percent jump in profit.

Fodor said the improvements in gene chip technology gained by serving the medical market will open fresh opportunities in new fields like environmental monitoring.

"We're rapidly getting to a point where there are lots of commercial applications,'' he said. "A lot of these markets become real as the technology costs decrease.''


Affymetrix makes miniaturized lab tests called gene chips that can detect the presence of certain genes in a sample of blood or tissue. Researchers use gene chips to explore genetic differences among people. This can yield clues about the causes of disease and may lead to better drugs. For example, scientists look for genes that appear in patients withcancer but do not exist in healthy individuals.

-- How it works

1. Blood or tissue samples are taken from a group of sick patients and a group of healthy people.

2. Each sample is fed into a small cartridge containing an Affymetrix GeneChip. The DNA in the sample sticks to any matching DNA probes on the GeneChip.

3. The gene chips are placed in a scanner that detects all the spots where matching DNA sequences have stuck together. As shown below, the pattern for sick people may be very different from the pattern for healthy test subjects.

4. Scientists analyze the genetic differences. Their work may lead to a new drug that blocks the action of a gene linked to a disease.Source: Affymetrix

[Affymetrix may "redefine" the "gene", such that they can continue calling their "gene chip". Or, they may "rename" their chip into "genome chip". Or, their competition may seize upon some algorithmic approach such as FractoGene, not only to make the interpretation of measurement less of a "brute force" and more of an "understanding", but also becoming the industrial champion of "Regulatory DNA Chips" - Comment on the 7th of February, by A. Pellionisz]

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[INFOTECH. Affymetrix' stocks catapulted by nearly 60% in the last six months, since the Company obviously made the key decision of "going after the regulatory, formerly JunkDNA". Comment on the 27th of January, 2005 by A. Pellionisz]

Scientists Find Genome Structure Responsible for Gene Activation

Press Release Source: Affymetrix, Inc.

Thursday January 27, 12:48 pm ET

SANTA CLARA, Calif., Jan. 27 /PRNewswire-FirstCall/ -- The first high-resolution analysis of the key feature that controls the activation of genes on human chromosomes was reported today in the journal Cell, by researchers from the Broad Institute of MIT and Harvard and Affymetrix Inc. (Nasdaq: AFFX - News). The study is pioneering in its large scale and surprising in its results. It reveals previously unknown domains of gene regulation in human chromosomes and also suggests the existence of many novel functional elements in the human genome.

The research team used Affymetrix GeneChip(R) microarrays, each containing millions of distinct DNA fragments to examine "chromatin," the intricate structure that packages the genome and makes certain genes accessible and others inaccessible to the cell. Using these microarrays, the researchers surveyed two entire human chromosomes (chromosomes 21 and 22) as well as additional regions in both the human and mouse genomes.

Despite rapid progress in identifying human genes based on the completed sequence of the human genome, the genome's complex regulatory network -- the mechanisms that turn genes on and off -- still remains poorly understood. "Chromatin is a key part of the regulatory network that controls how genetic information is translated into a cell or an organism. Understanding chromatin is important because many of its components are implicated in cancer and other diseases," said Dr. Brad Bernstein, a research associate at the Broad Institute and instructor of pathology at Harvard Medical School, who co-led the study.

With the ability to perform genome-wide analysis, it should now become possible to gain very general insight into the structure and function of chromatin, said the researchers. In particular, such studies may be useful for understanding how gene regulation becomes defective in certain diseased tissues and cells, they said.

In the January 28 issue of Cell, the researchers report that:

-- Much of the human genome is organized into small chromatin structures

that are remarkably similar to those found in single-celled budding


-- Striking exceptions are found, however, for certain clusters of genes

that control the body plan of the developing embryo. These "Hox" gene

clusters are organized into huge active chromatin domains.

-- Both the small and large chromatin structures are nearly identical in

humans and mice, indicating that they have important functions that

have been preserved over nearly 100 million years of evolution.

The chromatin data "will be an invaluable resource in our effort to define the regulatory network of the genome," said Michael Kamal, co-lead author on the study and a computational biologist at the Broad.

"This project illustrates the power of high-throughput technologies on our understanding of biology," said Stuart Schreiber, who is a member of the Broad Institute, a professor at Harvard University, and an expert on chromatin research.

"These experiments underscore the importance of analyzing the whole genome -- including the parts thought to be unimportant 'junk' DNA -- when looking for functional domains like sites of chromatin methylation," said Thomas Gingeras, Ph.D., Vice President of Biological Sciences, Affymetrix Laboratories. "High-density microarrays allow us to interrogate the genome without making any assumptions of what parts are important and what parts aren't. Using this unbiased investigational approach, we're finding that there may be much less 'junk' DNA in the genome than we thought." [Re-labeling them as "regulatory", the "Junk" will dissipate... Comment by AJP]

"The human genome still has many surprises lurking within it," said Eric S. Lander, director of the Broad Institute and senior author on the study. "One of the most important is the mystery of how genes are turned on. The ability to take global views of chromatin in human cells holds tremendous promise for unraveling this mystery."

Dr. Bernstein is also affiliated with the Brigham and Women's Hospital and is a postdoctoral researcher in the Howard Hughes Medical Institute lab of Stuart L. Schreiber at the Department of Chemistry and Chemical Biology at Harvard University.

The authors also include:

At the Broad Institute: Kerstin Lindblad-Toh, Dana J. Huebert, Scott McMahon, Elinor K. Karlsson, and Edward J. Kulbokas.

At Affymetrix: Stefan Bekiranov, Dione K. Bailey and Thomas R. Gingeras.

The research was supported by funds from the National Institutes of Health, the Howard Hughes Medical Institute and Affymetrix, Inc.