December, 2004
(31 Dec)
"Junk DNA":Top 10 Science Discoveries - 2004 Science Magazine
(28 Dec) Top 10 Science stories, 2004 ["Junk DNA" "shapes the coding for protein production"]
(27 Dec) Sun Gives Grid Cluster to India Institute of Bioinformatics
(27 Dec) Researchers Shed Light On Intron Evolution
(13 Dec) In our Post Gene Era a clear emphasis is put on Information Technology [see Pellionisz-Simons]
(13 Dec) Allen Institute Debuts 'Google for Gene Activity' [$ 100 M]
(10 Dec) DVD: "Junk DNA is not JUNK" [Creationism]
(05 Dec) The Sunday Times - Britain's 10 M Pounds - Chicken genes help crack the dinosaur code
(05 Dec) Tiny microbes make us who we are, scientist says
(04 Dec) Complete chicken genome map revealed [comments by Malcolm J. Simons, IPGS Honorary Chairman]

November, 2004
(26 Nov) German Research Foundation to Fund Collaborative Genomics Project [$ 490 M]

(26 Nov) The Government Funding Dam broke; NSF, NIH programs
(20 Nov) Human gene number slashed [to 20,000]
(15 Nov) Agilent and ExonHit Partner to Develop Microarray for Splice Variants
(11 Nov) Research effort seeks A's to gene expression Q's [Perlegen and J&J]
(03 Nov) US genetics win a shot in the arm [GTG vs. Applera]

October, 2004
(22 Oct) Affymetrix Launches Encode Array to Uncover Hidden Function of Human Genome
(20 Oct) Golden DNA goose [Rosetta Genomics, Israel]

(20 Oct) Mice do fine without 'junk DNA' [Questioned by Haussler, Pellionisz, Simons]
(20 Oct) Fish Tales Solve Genetic Puzzles [Fugu]
(11 Oct) 'Junk' DNA may be very valuable to embryos
(03 Oct) Doctor's race against time [Malcolm J. Simons' GTG and Haplomics patents]
(01 Oct) The Hidden Genetic Program of Complex Organisms [Mattick, Sci. Am.]

September, 2004
(29 Sep) New research shows plants can shuffle and paste gene pieces to generate genetic diversity
(15 Sep) Human chromosome 5 sequence analysis released.Disease genes,regulator elements populate terrai
(02 Sep) Glowing Green Proves Darwin Theory

June, 2004
(29 Jun) Newborn Introns [contributed by IPGS Honorary Chairman Malcolm Simons]

(22 Jun) The Scientist : Lab mouse genome isn't simple
(02 Jun) Junk DNA regulates neighboring gene [contributed by Steve Jurvetson, DFJ]

(10 Oct) The 64-Bit Question

========== NEWS IN DETAIL ==========

"Top 10 Science Discoveries - 2004" Science Magazine

Scientists discovered that “junk DNA,” the base pairs between known genes in the human genetic structure, actually play an important role. Several research teams have found that DNA between genes helps determine how vigorously and often the genes are activated and shapes the coding for protein production. ["Shapes"? Fractal shapes? - comment by Andras Pellionisz]

[Same article, under heading: "Scientific areas to watch in 2005"]

"Hap-mapping: The $100 million international Haplotype Map project, aimed at studying genetic differences among populations, is slated to wrap up by the end of 2005.

[Comment by Andras Pellionisz: The very top "breakthrough item", if there is water on Mars, is extremely unlikely to affect readers' life. However, cure for "junk DNA" diseases, will. - 17th of December, 2004]

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Top 10 Science stories: Mars water evidence leads list ["Junk DNA" "shapes the coding for protein production"]

By Paul Recer, Associated Press | December 28, 2004

The conclusive discovery by a pair of wheeled robots that Mars once had vast pools of water and possibly could have harbored life was chosen by the editors of the journal Science as the most important scientific achievement of 2004.

NASA's two Mars rovers, Opportunity and Spirit, landed on the Red Planet early in 2004 and have since found clear and conclusive evidence that Mars was drenched with water at some time in its history.

The editors of Science, one of the world's leading publishers of peer-reviewed, original research, judged the robotic accomplishment as the top scientific "Breakthrough of the Year."

"Their finds mark a milestone in humankind's search for life elsewhere in the universe," Science said.

The rest of Science's 2004 "breakthroughs of the year" are:

5. THE VALUE OF TRASH: Scientists discovered that "junk DNA," the base pairs between known genes in the human genetic structure, aren't junk after all. Several research teams have found that DNA between genes helps determine how vigorously and often the genes are activated, and shapes the coding for protein production.

[This is the first time when "Junk DNA" is brought into direct connection with "Shape". Next will be, once "genes" and their "shaping" are gone, that the Full Genome becomes "FractoGene". Genes define fractal templates, and the "rest" of the fractal set "shapes" the fractal template into full-blown fractal structure. - Comment by Andras Pellionisz, 28th of December, 2004]

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Sun Gives Grid Cluster to India’s Institute of Bioinformatics

By a GenomeWeb staff reporter

NEW YORK, Dec. 27 (GenomeWeb News) - Sun Microsystems has awarded the Institute of Bioinformatics in India a computing grid cluster under its Academic Excellence Grant, according to a news report.

The Bangalore-based institute uses informatics to study genomics and proteomics. It has recently developed the Human Protein Reference Database, a catalog of all human proteins.

The center currently works with the John Hopkins University, the University of Michigan, Human Proteome Organization and Memorial Sloan-Kettering Cancer Center.

[The "64 bit question" for Information Technology is which company will dominate the exploding "Post Gene" market. In this Alert, SUN Microsystems is already listed as the main provider of IT Platforms for Singapore's Biopolis. With this further penetration, SUN is "head to head" with APPLE and HP for dominance on the "Post Gene Market"- Comment by Andras Pellionisz, 27th of December, 2004]

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Researchers Shed Light On Intron Evolution

Date: 2004-12-27

By comparing four fungal genomes, researchers from MIT and the Broad Institute have described some of the dynamics of the evolution of introns, the non-coding portions of genes that comprise a large proportion of many genomes.

Introns are found in eukaryotic species, which includes all members of the fungi, plant, and animal kingdoms. Although introns were first discovered almost 30 years ago, scientists are still asking [and answering, see FractoGene, comment by Andras Pellionisz, 27th of December, 2004] basic questions about their role.

The researchers studied fungal genomes that together span 400 million years of evolution from a common ancestor.

Their findings, published in the December 2004 issue of the Public Library of Science, describe how an increase in introns plays a significant role in eukaryotic evolution.

"Our results provide clues about two fundamental unanswered questions about genome evolution--how introns are gained and how introns are lost," said Chris Burge, Whitehead Career Development Associate Professor in MIT's Department of Biology.

Introns are one of the basic characteristics of eukaryotic genomes, said James Galagan, a computational biologist at the Broad. "We want to understand what they are doing because they comprise a significant part of our genomic ecosystem," he said.

To paint a more complete picture of intron evolution, the researchers are currently looking at other fungal genomes. With additional data and analysis, they hope to one day apply their whole-genome method to better understand intron evolution in the genomes of higher eukaryotes, including animals and plants.

Also on the study team are Bruce Birren, co-director of the Sequencing and Analysis Program and director of the Microbial Sequencing Center at the Broad; and co-first authors Cydney Nielsen, a graduate student in biology, and Brad Friedman, a graduate student in biology and mathematics.

This research was supported by grants from the National Institutes of Health, National Science Foundation, United States Department of Agriculture, and the Burroughs Wellcome Fund.

A version of this article appeared in the December 8, 2004 issue of MIT Tech Talk (Volume 49, Number 12).
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DVD: "Junk DNA is not JUNK"

Conference lectures from Creation

Dr David A. DeWitt

Ph.D. in neuroscience from Case Western Reserve University in Cleveland, Ohio. Associate Professor of Biology at Liberty University (Lynchburg, Va.) and the associate director of the Center for Creation Studies at Liberty University. His research has focused on Alzheimer's disease, and he has written a number of articles.

[Junk DNA and Evolution. The explosive discovery that "Junk DNA" (98.7% of human DNA) servies a vital regulatory role (defined as iterative fractal recursion by, US Patent Pending) profoundly changes most everything.

Starting from the most important issue (human health), the "old game" (i.e. "gene discovery") will take a second seat to the Next Big Thing; "regulatory DNA research, development and applications in BioTech, NanoTech, InfoTech".

It is also a tremendous business opportunity, given the "Gold Rush" early stage. This fact is certified by the private "Angel" investments of Paul Allen (co-Founder of Microsoft, personal wealth $20 Billion [Forbes]) into several genome companies, most recently $100 M into "Google" to create "Gene Map" (see below).

Practical issues aside, even our philosophy and faith are stirred up, they may be profoundly affected - comment by A. Pellionisz]

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In our Post Gene Era a clear emphasis is put on Information Technology (see Pellionisz-Simons,

[If $100M private investment was available a year ago for GENE activity Information Technology, how many $100 M private investment is available today for GENE and NON-CODING DNA Information Technology? - In human, "genes" are 1.3% of the DNA. 98.7% is ncDNA, formerly "junk DNA". It is possible to expand business 75 times. Thus (the tremendous advancements nonwithstanding over a year, the Private Funding for Non-Coding DNA is to be $7.5 Billion) - comment by Andras Pellionisz, 12/14/04]

Allen Institute Debuts 'Google for Gene Activity'
By Kevin Davies

Bio-IT World (online)

(12/13/04)—The Allen Institute for Brain Science (AIBS) has released its first dataset of gene expression data in the brain for nearly 2,000 mouse genes – the first public release of the Allen Brain Atlas initiative. The institute’s leadership, announcing the release in a teleconference on Monday, believes the data will have important relevance for the study of brain function, disease, and the role of genes in governing human behavior.

“Google for gene activity patterns in the brain” was how Genentech’s Mark Tessier-Lavigne, chairman of the Allen Institute’s scientific advisory board, described the initiative. “It will enable the user to identify all the nerve cells in which a gene is active, and vice versa, for each nerve cell, identify what the complement of active genes is. It will enable users to do more readily what they’re already doing on a gene-by-gene basis.”

Tessier-Lavigne, who is a world authority on neuronal migration, also noted that “having all the information in one place for 20,000 or so genes makes it possible to mine the data, to identify correlations, and make discoveries of novel markers or therapeutic targets in brain regions of interest.”

The debut Allen Atlas release “blurs the distinction between an atlas and a database,” said UCLA’s Arthur Toga, an AIBS advisory Board member. He called the release “a landmark advancement in integrative neuroscience.”

AIBS was founded in September 2003 with $100 million in seed funding from Microsoft co-founder and philanthropist Paul G. Allen. The flagship project is the Allen Brain Atlas, a neurogenomic atlas of the mouse brain. “We wanted to embark on a project that would marry genetic information with neuroanatomic information,” said Allan Jones, senior director of Atlas Operations, at AIBS, who succeeded founding director Mark Boguski earlier this year. “We also need to make the data fully publicly accessible.”

Using a technique called in situ hybridization, the AIBS researchers and collaborators have produced expression data for 2,000 mouse genes so far, in a series of ultra-thin 25-micron brain tissue sections. In aggregate, these produce a 3-D representation of the expression data for thousands of genes. The data, and tools required to analyze them, can be found at the website:

With the Allen Atlas data being made publicly available, the project will help scientists around the world further research into the development and function of the human brain, which in the long term should greatly benefit studies of neurodegenerative disease, addiction disorders, depression, memory, mood, and behavior.

Some genes are already providing extraordinary markers of the “essential building blocks of the brain,” said Ed Lein, the AIBS director of neuroscience. Parkinson’s disease, for example, is a disease of the striatum. “The identification of new genes and markers in dopamine-releasing neurons could have therapeutic consequences down the road,” said Lein.

Caltech professor and Howard Hughes Medical Investigator David Anderson said the amount of work involved could not be underestimated. It would take one person 1-2 weeks by hand to prepare and analyze the expression of one gene in 50 tissue sections. “For 2,000 genes, that would take a single person 77 years, and for all genes, about 770 years! That’s without putting the data into a form in which it can be accessed in a database.”

The AIBS has moved into a new facility with 53 fulltime staff, including mathematics, neuroscience, lab technicians, mechanical engineers, and IT professionals, who face considerably data storage and formatting challenges. “There’s a tendency to generate large amounts of data storage requirements,” said Michael Hawrylycz, AIBS director of Informatics. “The image, in its uncompressed form, is 250 MB, so you need data compression to store the data.”

In its raw state, the complete genome atlas would require 1 petabyte of data, Hawrylycz said. “Today, there’s 17 TB of raw data, but this data is compressed, filtered, etc. Our intent is to provide users with copies of the original data. About one-eighth of the [dataset] is presented on the application, through the filtering and compression technologies.”

The initial analysis of 2,000 mouse genes is just the beginning. It is widely accepted that at least 50 percent of human and mouse genes are expressed in the brain, but Lein believes this is an underestimate, and expects “the final tally may be about 75 percent.”

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A/G BLAST for G4/G5

Apple/Genentech (A/G) BLAST is an enhanced, platform-specific optimization of NCBI's standalone Basic Local Alignment Search Tool (BLAST) developed by Apple's Advanced Computation Group. In particular, we have enhanced BLASTn (which finds similarities between nucleotide sequences) for the PowerPC G4/G5 processors and Mac OS X

For more information about the Advanced Computation Group and its projects, please visit the ACG website. General information about BLAST, including tutorials, can be found at the NCBI website.

For further instructions on building and using BLAST, download NCBI's BLAST demo.

APPENDIX: Licensing Terms

* National Center for Biotechnology Information (NCBI)
* This software/database is a "United States Government Work" under the
* terms of the United States Copyright Act. It was written as part of
* the author's official duties as a United States Government employee and
* thus cannot be copyrighted. This software/database is freely available
* to the public for use. The National Library of Medicine and the U.S.
* Government do not place any restriction on its use or reproduction.
* We would, however, appreciate having the NCBI and the author cited in
* any work or product based on this material
* Although all reasonable efforts have been taken to ensure the accuracy
* and reliability of the software and data, the NLM and the U.S.
* Government do not and cannot warrant the performance or results that
* may be obtained by using this software or data. The NLM and the U.S.
* Government disclaim all warranties, express or implied, including
* warranties of performance, merchantability or fitness for any particular
* purpose.

[Stand-alone 64-bit "hyper-number-crunchers" for non-licenceable NCBI (US Gov.) Internet-database?
FractoGene proposes a different business model (US Patent Pending) - comment by Andras Pellionisz, 2004]

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Why a Pug is Not a Collie

Science Now


Most dogs have five digits, but Great Pyrenees have six. The reason, according to a new study: a gene involved in foot development in this breed is missing 51 bases. That wayward DNA consists of a pattern of three bases repeated over and over again. The gain and loss of these so-called tandem repeats may help explain why dogs have evolved so quickly, researchers now say.

There are more than 100 dog breeds, most of them dating back little more than 1000 years. They all belong to the same species, despite contrasting looks and behavior. Typically researchers expect such differences to arise from mutations. But modern dogs have changed much faster than the pace at which mutations accumulate.

Physicist Harold Garner and evolutionary biologist John Fondon III from the University of Texas Southwestern Medical Center in Dallas decided to look into tandem repeats as an alternative. Tandem repeat alterations pop up more frequently than mutations because they arise from a sequencing stutter: Enzymes copying repetitive regions of DNA sometimes lose track of where they are, occasionally leaving a few repeats out of the new copy--or adding one or two extra.

The researchers sequenced the repetitive regions in 17 equivalent developmental genes from 92 dog breeds. They also measured the skulls with a laser scanner, and correlated those differences with variations in repeat number.

Several patterns emerged. Toe number was affected by a gene called Alx-4. Snout lengths correlated quite well with the number of repeats in another gene, Runx-2: Breeds with collie-like noses had more of a particular tandem repeat, while those with pug-like faces had more of a different tandem. And when the researchers compared bull terrier DNA, they found that terriers have one more repeat unit than they did in the 1950s, which could explain why the nose used to be droopier, the researchers note. Repeat numbers didn't vary as much in wolves, however, they report online this week in the Proceedings of the National Academy of Sciences.

Breeding can skew "evolution" because breeders select for just a few traits without regard to what their canines need to survive in harsher environments. Thus, in wolves, fewer changes wrought by tandem repeats are likely to hold up. Even so, the findings are still quite appealing, says Robert Wayne from the University of California, Los Angeles. "Tandem repeats, generally regarded as junk DNA, offer a novel mechanism for evolutionary change."


[FractoGene, interpreting structure and function emerging in the recursive interaction of "gene-produced" proteins, "picking up" auxiliary (regulatory) information sets in the (repeat) patterns of "JunkDNA" explains both the consistent set of about 20,000 "genes" throughout the evolution of vertebrates, and also the enormous diversity, found among different dogs (or, for that matter, among people, but let's not touch on this "political hot potato"). DNA "Fingerprinting" relies on the fact that while the set of genes is remarkably solid, the (regulatory) "JunkDNA" differs from individual to individual. It goes without saying that "breeding" humans "select for just a few traits without regard to what they need to survive in harsher environments" - comment by Andras Pellionisz, 12/15/2004]



See -among others- a comparison of the various pieces of coverage of the "Chicken Genome", with Dr. Malcolm Simons' personal comments (highlights) in the forthcoming book on Non-Coding DNA by Andras Pellionisz and Malcolm Simons.



Complete chicken genome map revealed

18:00 08 December 04 news service

The chicken has joined an exclusive but rapidly growing club with the publication of its complete genome sequence by an international consortium on Wednesday. The newcomer is the closest relative of mammals sequenced so far, and should provide a crucial point of comparison in studies of mammalian evolution.

And because the chicken is both a common farm animal and a long-time favourite of developmental biologists, its genome sequence should also help scientists identify the genetic basis of many agriculturally and developmentally important traits.

The chicken genome is much more compact than that of mammals: it has 20,000 to 23,000 genes formed from just one billion DNA letters, compared with about three billion in humans. Chickens have a similar number of genes to mammals, but their genome appears to contain a smaller amount of repetitive “junk” DNA.

In the time since the bird and mammal lineages diverged, chickens have gained genes for the proteins used to make feathers and beaks, while mammals have acquired genes for hair proteins and lost genes related to egg albumin and yolk.

Crucially, comparison of the chicken and human genomes reveals about 70 million DNA base pairs in common. This suggests the genetic material has been conserved since the two species split from a common ancestor about 310 million years ago.

Journal reference: Nature (vol 432, p 695)

Bob Holmes

[Are you a chicken? The chicken and the human has about the same number of genes (20-30 thousand). The "only" major difference is, that humans have more than three times as many regulatory DNA (formerly, "junkDNA") - comment by A. Pellionisz, 12 December, 2004]

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[Spectacular breakthroughs happen most every day in the (former) field of "junk DNA". An avalanche of experimental evidence supports that "it is not only in the genes" (the subtitle of my coming book, "FractoGene"). Clearly, while 99% of our genes are homologs of the genes of the mouse, our 1/3 more "junk DNA" makes us human. How? The genes, rather than "final arbiters" of our hereditary traits, determine no more than "fractal templates", and growth is commanded not a straightforward, but an interative (recursive, fractal) "algorithm". In an embryonic stage, the already built proteins bind to the DNA, and "what to do next" is determined by the incremental (recursive) information, contained (for each iteration) within the self-similar, repetitious "junk DNA". Looking at , especially the human embryo picture that goes through the "mouse", "rabbit", "giraffe" stages (fractal hierarchical steps), the experimental finding shown below is clearly supportive of FractoGene - comment by Andras Pellionisz]


[obsolete by 18:00 P.M. 22nd of November, 2004]

Dear Readers,

I am delighted to advise that Dr. Malcolm Simons, founder/CSO of Simons Haplomics Limited ('Haplomics'), will visit the Bay Area in the week beginning 15 November to discuss association between his Haplomics and my HelixoMetry, Inc., and to pursue funding prospects.

Concerning my "comment" (here, on the 3rd of November), Dr. Simons confirms that the value of his previous inventions on the utility of 'Junk DNA', assigned to Genetic Technologies Ltd (GTG), remains mainly responsible for the company's market valuation of Aus$150m ($115m).

Dr. Simons clarifies that the US District Court hearing of GTG's claim of infringement against Applera concerned claim construction and term definition (Markman hearing). The matter is now scheduled to proceed to trial later next year, unless there is prior settlement. Damages and penalties will depend on the trial outcome.

The corrected website for this news is:

If you would like to meet with Dr. Simons during his visit, or have him present to you, please contact:

Dr. Andras Pellionisz
Tel: (four-zero-eight) 732-9319
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NSF to Award $29M for Phyloinformatics Projects

By a GenomeWeb staff reporter

NEW YORK, Nov. 26 (GenomeWeb News) - The National Science Foundation is soliciting proposals for computational phylogenetics and phyloinformatics projects as part of its "Assembling the Tree of Life" initiative, which plans to construct a phylogeny for the 1.7 million described species on Earth.

NSF has issued a program solicitation seeking "projects in data acquisition, analysis, algorithm development and dissemination in computational phylogenetics and phyloinformatics."

NSF said it plans to award between three and six awards in fiscal year 2005 and again in 2006, with a total of $14 million earmarked for FY 2005 and $15 million for FY 2006. Awards will range up to $3 million each, for durations up to five years.

[The Government Funding dam broke. We reported a few days ago that a US Government Agency (NIST) started to fund "junk DNA" R&D, and predicted that the rest of the Agencies will follow suit. Here is the US National Science Foundation's (NSF) RFP at the rate of $29M. US Agencies that are orders of magnitudes larger (NIH, NIMH, NINCDS, DOE, etc) will not afford to let "junk DNA" R&D spin out from their control. Therefore, from now on the critical question is, which branch of the Government Agencies will take the lead - a challenge to the Administration's Program Directors. The task is difficult because of the interdisciplinary nature (gene and post gene era expertise, information technology expertise, advanced algorithmic expertise) plus because the "Post Gene Era" is clearly a Global horserace. (See "Germany's response", below). Comment by Andras Pellionisz, 26th of November, 2004]

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German Research Foundation to Fund Collaborative Genomics Project

By a GenomeWeb staff reporter

NEW YORK, Nov. 26 (GenomeWeb News) - the German Research Foundation said this week that it plans to support a collaborative project to study gene regulatory networks as part of a €370 million ($490 million) national initiative to establish seven new collaborative research centers in 2005.

The center, "Networks in Genome Expression and Maintenance," will be based at the Ludwig Maximilians University of Munich and will study the function, structure, regulation, and interactions of protein complexes in normal and malignant cells.

Further details on the center were not provided.

[Here is Germany's "response" to the US initiative. Instead of the US $ 6.25+$ 29 M investment, Germany poured in close to half a billion USD into "gene regulatory networks" (a buzzword for "junk DNA" R&D). Soon we'll see US experts awarded by "International Prizes" to Germany, Japan, UK, Singapore, etc. Comment by Andras Pellionisz, 26th of November, 2004]

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The Sunday Times - Britain's 10 M Pounds - Chicken genes help crack the dinosaur code

December 05, 2004
Jonathan Leake and Michael Fox

SCIENTISTS have gained their best idea yet of the genetic code of dinosaurs after drawing up the first complete genome for a chicken — thought to be one of their direct descendants.

The results of a four-year, £10m-plus project to crack the genetic code of chickens will be released this week, along with a full analysis of their evolution and ancestry.

It will strengthen evidence obtained from fossils that birds are the direct descendants of dinosaurs.

Blair Hedges, an evolutionary biologist at Pennsylvania State University said: “It seems clear that birds, like reptiles, go way back, all the way to the dinosaurs.

“The chicken is the first bird or reptile to have its genes sequenced but it is part of a huge group of animals that includes snakes, lizards and crocs, and the dinosaurs. The chicken genome is a unique insight into the ancient history of life on the planet.”

The papers will also reveal that although chickens might seem primitive they have roughly the same number of genes as humans — and far less of the junk DNA that fills the human genome and which can contribute to harmful mutations.

They will also suggest that humans and chickens have a common ancestor, a small reptilian creature that walked the earth — or maybe crawled — around 300m years ago. It would have predated both the dinosaurs and the earliest mammals.

Angela Milner, assistant keeper of palaeontology at the Natural History Museum in London, said that the animal gave rise to the mammal-like reptiles — a line that evolved into mammals, and also to the archosaurs, which produced birds, crocodiles and dinosaurs.

The first bird, archaeopteryx, is thought to have evolved about 147m years ago. Milner said: “The real ancestors of today’s chickens appeared later, probably around 50m years ago.”

However, the chicken genome was also commissioned for practical reasons. “Knowing how their genomes work will lead to many practical applications in medicine and agriculture,” said a researcher for the Biotechnology and Biological Sciences Research Council (BBSRC) who worked on breaking the code.

It could also save the lives of laboratory mice because chicken eggs and embryos share many genes and biochemical pathways with mammals, so they can be substituted for live animals in experiments.

The BBSRC put millions of pounds into this project largely because of the animal welfare benefits and it is already paying off,” said the co-author of some of the research to be published this week in the journal, Nature.

Now the genome is known, scientists hope to accelerate the rate of evolution creating a range of genetically modified birds.

[Here is the United Kingdom's "response" to the US initiative. The UK has been pouring 10M British Pounds just into a single non-coding DNA related project for four years by now. The result is both highly significant scientifically, as well as it is practical, comment by Andras Pellionisz, 5th of December, 2004]

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Tiny microbes make us who we are, scientist says

Posted on Sun, Dec. 05, 2004


The Orange County Register

IRVINE, Calif. - (KRT) - A University of California, Irvine scientist says viruses are much, much more than nasty little microbes that infect us with the flu. If he is right, they have infected all of life - with evolution.

In an astonishing set of papers and a new book, UCI virologist Luis Villarreal contends viruses are largely responsible for shaping how we look, how we speak, even how we think.

In fact, he says, they are an overlooked evolutionary force, one that has been powerfully influencing the shape of living things since life began - actually, since a little before life began.

"I'm saying they are a creative force in the evolution of all life," he said in a recent interview.

Villarreal, 56, is accustomed to challenging traditional ideas and swimming outside the academic mainstream. His unorthodox ideas about teaching, such as favoring immersion, not lectures, earned him rebukes from some colleagues but a presidential award from Bill Clinton.

He has conducted research with some of the biggest names in genetic engineering and microbiology.

And he knows his view of viruses will be hard for many of his scientific colleagues - let alone the public - to accept.

"Most people are blown away when presented with this information," he said.

The first step in understanding his thinking is to throw out most of what we think we know about viruses.

Sure, there are plenty of bad ones. The flu, West Nile, smallpox, polio - these are the bulls in the china shop, as Villarreal sees it. They blunder into the human body and cause pain, damage and disease in their hosts.

But the viruses he is most intrigued by seem to have little or no detectable effects. And we carry a lot of them - most that have been with our species since its beginning.

He calls them "persisting viruses," and says they are, in essence, the engines of evolution.

"Any species will have these parasites that are going to mark that species for what it is," he says.

For evidence, Villarreal's theory does what many of science's "aha!" theories have done in the past: It knits together a variety of mysterious, unexplained and seemingly unrelated observations into one plausible framework.

Not only human genetic material, but that of all animals and plants down to the single-celled varieties, is littered with the remnants of crippled viruses of various types, he says.

It is part of what has long been called "junk DNA," because it does not appear to scientists to do anything. The DNA that serves as instruction kits to build our bodies comes in short segments that make up less than 3 percent of the DNA in our chromosomes. These segments code for the building blocks of cells and bodies, and they are separated by long segments of noncoding DNA.

In reality, Villarreal contends, much, if not all, of this noncoding DNA is really bits and pieces of ancient viruses. They have modified themselves so they can reside comfortably deep inside our cells while avoiding our immune systems.

But they are far from being junk. Viruses mutate far more rapidly than more complex organisms - as much as a million times faster than their hosts, including humans.

That means many viruses are little packages of new genes that can endow an organism with all kinds of new capabilities.

When these viruses settle quietly into the noncoding regions of our DNA, their disease-causing tendencies are suppressed. Eventually they can be harvested by the host for new genes - for example, by reproductive cells.

Big leaps in evolution - such as, for instance, a capacity for language and symbolic thinking among humans - could have happened all at once, with the incorporation into our chromosomes of fresh new genes left behind by old viruses.

This could explain some features of evolutionary history that have puzzled scientists over the past century.

Some important changes seemed to happen very quickly, including the leap to human language, as well as the evolution of mammals, flowering plants and cells that carry a nucleus.

What is puzzling is how evolution, which we normally think of as slow, can sometimes happen in what looks like a geologic eye-blink.

Since Charles Darwin's day, we have known when it comes to evolution, natural selection appears to be in the driver's seat.

Random variations pop up in all living things from one generation to the next - a taller child born here, a plant with shinier leaves born there. Most of these variations, or mutations, are harmful, some do nothing at all, and a few are beneficial.

In nature's cruel but efficient system, the creatures with the beneficial mutations survive to produce more offspring than their contemporaries. The useful mutations gradually spread through the population, generation by generation, until upright primates with little body hair replace the furry knucklewalkers of the past.

But where do these variations come from?

Although Darwin, the originator of modern evolutionary theory, was the first to suggest random mutations provide the raw material nature uses to make its selections, he could say little else; in his day, scientists knew nothing of genes and chromosomes.

Later scientists discovered genes and said the random mutations were occurring among these.

Villarreal thinks that is only part of the story. In "Viruses and the Evolution of Life," a book to be published by ASM Press next month, Villarreal says viral genes get tangled up in our DNA over millions and billions of years of evolutionary time.

Eventually, the genes they leave behind get recruited for new duties.

If Villarreal is right, it means much of the genetic raw material that selection uses to shape organisms, including us, comes directly from viruses that invaded the cells of long-forgotten ancestors.

"This doesn't counteract any of Darwin's thinking," he says. "It explains facts that have been missing."

The theory's apparent explanatory power is, of course, no vaccine against defeat. Many big ideas that seemed to explain a lot ended up in history's wastebasket, disproved by later discoveries.

Still, Edward K. Wagner, also a virologist at UCI, called Villarreal's book "seminal" and said so far his work has been well-received in the scientific community and will likely prompt useful debate.

"There will obviously be discussion and controversy over it," he said. "I think these are very exciting ideas. What Luis is attempting to do is show that viruses are a tremendous source of biological diversity and genetic diversity."

And Villarreal's ideas go all the way back to the beginning. Viruses probably have been around as long as life itself. So they have been influencing evolution since Day One.

In all probability, he says, viruses got their start before true life forms evolved, in the "prebiotic" stage postulated by scientists. That is when self-replicating molecules might have begun organizing, eventually to become clothed in protective cells and to earn the name "life."

The idea we are largely a creation of our parasites crystallized slowly for Villarreal, starting when he was a graduate student in the early 1970s. He was doing research at the University of California, San Diego on whether viruses might modify or even disable themselves during infection, altering the outcome of disease. And he began to see evidence of repeated gene sequences that came to be called junk DNA.

The idea these sequences were really bits and pieces of ancient viruses came later.

Villarreal now hopes to conduct further research on these viral bits - including learning more about the individual histories of viral colonization that seem to be unique to each species, including humans.

But he knows while he has had plenty of time to get used to these ideas, they might make a lot of other people uncomfortable.

"There's a very strong cultural, negative response to the concept of a parasite of any kind," he said. "The irony is that if this is such a crucial creative force, that we look at it so negatively. If you want to evolve, you have to be open to being parasitized."

[JunkDNA makes us human? FractoGene said that while our genes are 99% identical to that of the mouse -- or, for that matter with most of the vertebrates -- "JunkDNA" is vastly more in humans than e.g. in the mouse (by over 30%). As Edison used to say "An invention takes 1% inspiration -new genes- and 99% perspiration -improving upon the protein design by "JunkDNA", see by Andras Pellionisz, Dec. 5th, 2004]

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The Hidden Genetic Program of Complex Organisms

Scientific American, Oct. 2004
by JS Mattick

Assumptions can be dangerous, especially in science. They usually start as the most plausible or comfortable interpretation of the available facts. But when their truth cannot be immediately tested and their flaws are not obvious, assumptions often graduate to articles of faith, and new observations are forced to fit them. Eventually, if the volume of troublesome information becomes unsustainable, the orthodoxy must collapse.

We may be witnessing such a turning point in our understanding of genetic information. The central dogma of molecular biology for the past half a century and more has stated that genetic information encoded in DNA is transcribed as intermediary molecules of RNA, which are in turn translated into the amino acid sequences that make up proteins. The prevailing assumption, embodied in the credo "one gene, one protein," has been that genes are generally synonymous with proteins. A corollary has been that proteins, in addition to their structural and enzymatic roles in cells, must be the primary agents for regulating the expression, or activation, of genes....

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Agilent and ExonHit Partner to Develop Microarray for Splice Variants

By a GenomeWeb staff reporter

NEW YORK, Nov. 15 (GenomeWeb News) - Agilent Technologies will combine its microarray platform with ExonHit's alternative RNA splicing in an attempt to develop an array technology that can monitor the expression of splice variants, the companies said today.

The companies presented results from an experimental splicing array of G-protein coupled receptors, which was designed by ExonHit and produced by Agilent, at the Splicing 2004 meeting, held in September in Bethesda, Md.

That array was bale to detect multiple isoforms of several genes, and "showed good reproducibility and specificity," the companies said in a statement today. Agilent and ExonHit "are expected to work with early test sites to generate additional experimental results," the firms said.

Financial terms of the agreement were not disclosed.

[Of course, not. This area is one of the fiercest industrial competitions or our time. Agilent's response to the Affymetrix shift from "Gene Chip" to "Genome Chip" (including ncDNA). Affymetrix and Agilent are head-to-head in this new round of competition. Comment by Andras Pellionisz]

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Research effort seeks A's to gene expression Q's

Medical news today

11 Nov 2004

The National Institute of Standards and Technology (NIST) has launched a new $6.25 million, five-year program to explore and address challenges in measurement, validation and quality control for the rapidly growing field of gene expression profiling.

Enormous quantities of gene-sequence data are pouring out of labs thanks to dramatic gains in DNA sequencing technology, but that's only a start. The real question is how genetic information translates into biological activity. Gene expression---the complex process by which some genes are turned on, others off---is an essential part of the functioning of an organism. It also can indicate, or be a factor in, many diseases. The mechanisms of gene regulation are poorly understood---recent research, for example, suggests that a great deal of gene regulation information may be encoded in long stretches of DNA previously written off as "junk."

Gene expression measurements impact everything from basic bioresearch to drug development and clinical diagnostics. The most powerful tool for studying gene expression is the microarray, a device that uses many thousands of DNA probes to make massively parallel measurements of gene activity. But the technology is beset by large uncertainties and unexplained variability in measurement. One experiment using three different microarray systems to measure the same sample found that under the most stringent criteria the three agreed on only four out of 275 genes identified.

NIST's multidisciplinary Metrology for Gene Expression Program seeks to improve the quality, reliability and comparability of gene expression measurements with microarrays. Working with instrument developers and users, the program will evaluate sources of error and variability in measurement, and will develop reference data, reference materials and measurement methods to enable quality assurance for the chemistry, detection methods and information processing used in microarray analysis.

A key partnership that helped inspire the program is the External RNA Control Consortium, a group of almost 50 organizations from industry, academic labs, federal agencies and other key stakeholders.

Contact: Michael Baum


National Institute of Standards and Technology (NIST) <>

[Government Grants are always the "last indicators" in acknowledging breakthroughs. With the US National Institute of Standards and Technology coming on board with money specifically earmarked for "Junk DNA research", one year after the scientific acknowledgement by Scientific American, the "final seal of approval" - money - is stamped on "Junk DNA" - comment by Andras Pellionisz]

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US genetics win a shot in the arm

The Australian

November 03, 2004

AUSTRALIAN biotech companies not only have to be tough to survive. They usually need to win in the US as well.

That's why the dramatic patent victory in the US courts by the $150 million Australian company Genetic Technologies against the $5 billion US giant Applera Corporation was both a tremendous encouragement and a lesson to other Australian hopefuls.

And in the lead-up to the US Presidential election, the sight of CNN commentator Larry King promoting a vitamin breakthrough by another local company, Phosphagenics - which conducts its Food and Drug Administration approved human trials in Australia - was another boost.

However, I must warn readers that these stocks remain very high-risk - like all Australian biotechs they are not flush with cash, and they incur losses. But both are trying to develop an operating cash source to fund their research. Applera did not take seriously the royalty demands of Melbourne-based minnow Genetic Technologies and its executive chairman and founder Mervyn Jacobson.

Applera now realises it made a mistake - especially as the Australian royalty demands have been increased in the wake of the court's decision.

Genetic Technologies has the patented rights over what was once known as junk DNA. Jacobson took the patents out in the 1980s when most of the scientists of the day thought this aspect of DNA was useless.

Not only was he awarded patents in most countries, but Jacobson took out patent claim insurance with GE, because he realised that eventually a US drug giant would attempt a legal challenge rather than pay royalties to a tiny Australian company.

Connecticut-based Applera believed it could blow Genetic Technologies' patents out of the water, so it refused to settle prior to the hearing.

But in the all-important initial or "Markman" hearings, the US giant lost to the Australian company on every point it raised. Applera could, of course, continue the legal fight, but the GE insurance means that Genetic Technologies has the money to match them.

With a court decision supporting the Aussies, not only will Applera be required to pay higher royalties on its junk DNA research, but hundreds of other companies are now also likely to pay royalties.

Most of the patents run out in 2015 - some in 2010 - so Genetic Technologies will receive a substantial cash flow.

Genetic Technologies burned $5 million last year and has cash of $11 million, so the royalties are vital to take it into the black and justify its market capitalisation.

Genetic Technologies also received a boost from the Olympic Games. The company is a global leader in genetic testing, and was able to quickly and accurately analyse the samples taken from the Australian cycling team.

The results enabled Olympic officials to decide who to take to Athens.

DNA analysis, in both humans and animals, is likely to be a growth market.

Jacobson is advising the Chinese on dairy herd DNA, and that could develop into a major market for the Genetic Technologies techniques.

Meanwhile, like John Laws in Australia, CNN's Larry King also promotes consumer products. One of his clients is the US Zila Group, which has about 10 per cent of the US vitamin C market.

It is moving into Vitamin E supplements using the technology developed by Australia's Phosphagenics.

Vitamin E offers great benefits in healing and heart disease, but is not easily absorbed in the body.

Phosphagenics has developed a skin-applied or oral delivery compound which enables far more Vitamin E to be absorbed in the blood stream than conventional products.

Zila has the Australian product on Wal-Mart shelves - but to stay there, it has to sell. Meanwhile, Phosphagenics aims to use its patented skin-applied delivery compound to deliver other drugs.

In the next three months it will conduct human trials on morphine, where the side effects of the current delivery methods can be very severe on patients.

If the morphine human trials are successful, then the treatment of many terminally ill patients will be transformed. It is no easy process to take Australian technology from the laboratory to human trials and beyond. That is why most sell out to majors.

Just as Gene Technologies shows you must be ready for patent fights, so Phosphagenics is showing that Australian discoveries don't always have to be sold off early to big pharmaceutical companies.

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Affymetrix Launches ENCODE Array to Uncover Hidden Function of Human Genome

Friday October 22, 11:56 am ET

SANTA CLARA, Calif., Oct. 22 /PRNewswire-FirstCall/ -- Today, Affymetrix, Inc., (Nasdaq: AFFX - News) announced early technology access to the GeneChip® microarray used in the NHGRI-funded ENCODE (ENCyclopedia of Complete DNA Elements) initiative -- the next step of the Human Genome Project. The ENCODE project comprises over two dozen international research institutions, many of which are using this array to discover the function for a representative 1% of the human genome specified by the ENCODE project.

(For an interactive version of this press release with additional information, please go to and click on the release title.)

While the complete human genome sequence is now available, nearly all of it (about 98%) has been considered "junk" and its function not studied because there has been no technology available to examine millions or even billions of bases of DNA. The ENCODE project, as outlined in today's issue of Science, has brought together an impressive collection of international laboratories to evaluate strategies and new technologies to tackle what may be the biggest biological question ever asked.

Affymetrix' ENCODE microarray is playing a key role in helping to answer this important question. The ENCODE array contains millions of DNA probes evenly spaced or "tiled" across 35 million base pairs of DNA that was specifically chosen by the ENCODE project as a representative sampling of the complete genome sequence. In an industry first, these "tiling" arrays provide scientists with the only single tool available for genome-wide analyses of many important biological functions, including: transcription, transcription factor binding sites, sites of chromatin modification, sites of DNA methylation and even chromosomal origins of replication.

"In the process of climbing the steps of whole genome research, the ENCODE array is a wonderful tool," said Katsuhiko Shirahige, Ph.D., Division for Gene Research, Tokyo Institute of Technology. "The design content is extremely easy to use for basic research areas such as human transcription, replication and chromatin structure, to name a few."

In addition to Affymetrix arrays being used in large-scale initiatives like the ENCODE project, Affymetrix has established an Early Access program that gives individual researchers the opportunity to purchase tiling arrays for human chromosomes 21 and 22. Affymetrix has also developed high- resolution tiling arrays for the entire human genome and several model organisms, including Drosophila, Arabidopsis, S. cerevisiae and S. pombe. These arrays have been made available to several research groups through a technology access program or through collaborative projects with Affymetrix. A full range of tiling arrays are expected to be commercially available in the second half of 2005.


The results from these papers are changing the way that we understand the genome. For the past 50 years, research has focused almost exclusively on protein coding genes. Using tiling arrays, scientists are beginning to understand the genome is far more complex than that.

"Piece by piece, we are beginning to create a high-resolution map of the human transcriptome, providing detailed information well beyond its basic sequence," said Thomas Gingeras, Ph.D., Vice President of Biological Sciences, Affymetrix Laboratories. "The hope is that one day, scientists can more readily understand the biology of health and disease by correlating sequence of DNA from anywhere in the genome to its function."

About Affymetrix:

Affymetrix is a pioneer in creating breakthrough tools that are driving the genomic revolution. By applying the principles of semiconductor technology to the life sciences, Affymetrix develops and commercializes systems that enable scientists to improve quality of life. The Company's customers include pharmaceutical, biotechnology, agrichemical, diagnostics and consumer products companies as well as academic, government and other non-profit research institutes. Affymetrix offers an expanding portfolio of integrated products and services, including its integrated GeneChip brand platform, to address growing markets focused on understanding the relationship between genes and human health. Additional information on Affymetrix can be found at

["Connector" company of experimental, medical and information technology approaches, Affymetrix is re-structuring for Non-(Directly)-Coding DNA. "Tiles" of gene-chips are the technology. But where is the underlying theoretical basis? (FractoGene) - comment by Andras Pellionisz]

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Golden DNA goose

Rosetta Genomics, a secretive Israeli start-up, reveals a revolutionary genomic research technology, and a long list of celebrity investors.

Batya Feldman 20 Oct 04 17:37

What do the following have in common: Teva (Nasdaq; TASE: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; Yoav Chelouche of the Fantine Group; Nathan Hod, former CEO of DSPC (acquired by Intel); Mordechai Segal, cofounder of Libit Signal Processing (acquired by Texas Instruments); Ami Lidor of Lidor Chemicals; Prof. Moshe Many, former President of Tel Aviv University, and chairman of Teva’s R&D committee; Prof. Michael Sela, Israel Prize laureate and former president of the Weizmann Institute of Science; First International Bank of Israel chairman Dr. Joshua Rosensweig; Adv. Ehud Arad of the Bach, Arad, Scharf, & Co. law firm; and investor Michael Davis?

The simple answer is that they have all invested in Israeli start-up Rosetta Genomics, which was founded four years ago, and is on its way to becoming the jewel in the crown of Israeli biotechnology.

If, however, you ask Rosetta Genomics founder, president, and CEO Dr. Isaac Bentwich, he’s likely to tell you that these people carry non-coding micro RNA genes, which Rosetta Genomics is discovering and patenting, and which it will one day use to cure currently incurable diseases. When that happens, he’ll probably add, if everything goes as planned, all these people will also get a lot richer.

Bentwich puts it like this: “The solution that Rosetta Genomics has found for the puzzle of cell differentiation has enormous medical, human, and economic significance. Yes, certainly, in that order.”

It is easy to dismiss the pretentiousness of Bentwich, 43, and attribute it to the enthusiasm of a scientist-entrepreneur, whose dream company is approaching a critical stage in a young company’s life turning its technology into money. At this stage, favorable newspaper headlines are a vital commodity.

Before making that dismissal, however, you should know that Bentwich, who is trained as a physician, has already founded one company, which he sold for $15 million almost ten years ago. Bear in mind too that Rosetta Genomics is currently completing its third financing round, amounting to $5 million, at a value of $25 million before money. Moreover, Rosetta Genomics’ band of celebrity investors did not back the company for reasons of philanthropy and the advancement of medical science - or at least, not solely for those reasons.

Patiently differentiating

The historical Rosetta stone is 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 soldiers found the tablet near the town of Rosetta in northern Egypt, in 1799. 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 suits Rosetta Genomics, which has in effect developed a new discipline that is discovering micro RNA, until recently considered an unimportant part of DNA. Just like hieroglyphics, everyone saw it, but no one could decipher it.

Bentwich thought of the idea behind Rosetta Genomics on a trip to northern India. “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.”

In Bentwich’s case, ideas in this field found a ready listener within his own family. His father is 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. Adv. Arad also joined, and has advised the company since it began.

“Globes”: What exactly did you try to do?

Isaac Bentwich: The goal was to find a solution to the mystery of cell differentiation. Every cell contains the recipe for all possible proteins, and there are 40,000 of them, but each individual cell produces its own specific proteins. The puzzle that we tried to solve is, what makes cells turn into various types. The differentiation process is the key mystery of science. Cancers, for example, are in essence out-of-control cell differentiation. Various neurological diseases, anaemia, and many other diseases are caused by faulty differentiation of cells. Actually, there are practically no diseases that are not linked to differentiation.”

Bentwich, of course, has not stumbled on virgin scientific territory. Scientists all over the world have performed intensive research in this field, mainly as part of stem cell research. Bentwich, however, explains that he has tried to tackle the problem from a new angle: “Science is aware of many factors in cell differentiation. Certain proteins secreted or existing in the cell, and interactions between neighboring cells, are known to cause differentiation.

“The problem that intrigued me was differentiation not linked to these interactions. 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.”

And you suddenly thought, 'Hey, what about the other 98%?'

“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."

Rosetta decided to focus on the 98% of genes that were "useless". 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. Using advanced computer technology, Rosetta Genomics has found a way of using advanced computer technology to reveal the encoding genes through the “unnecessary” genome areas, called micro RNA 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.

How did you do it?

“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."

So the computer finds that a certain gene should exist, and the biological test merely performs the physical search?

“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.”

Genes as intellectual property

Rosetta Genomics’ business model is based on intellectual property. “We register a patent for every gene we discover,” Bentwich says. “Then we grant licenses to use the genes for development of the next generation of drugs and diagnostic devices.”

You’ll need cooperation with the drug manufacturers, and their willingness to pay.

“We’ll work with the world’s leading pharmaceutical manufacturers and biotechnology companies. In fact, we are already talking to several leading biotechnology and nanotechnology companies in fields that are tangential or complementary to our work. Our cooperative ventures will be aimed at using our discoveries for joint development of drugs.”

Teva has invested money in you.

“We’re discussing cooperation with Teva on matters of interest to them. With nanotechnology companies, for example, cooperation is in the area of the discovery of small molecules.”

Bentwich is not alone in his optimism. Prof. Many has invested privately in the company, and is a member of its board of directors. “I was captured by the company’s vision over three years ago, when the idea was presented to me for the first time,” Many says. “I was impressed by the pace of scientific progress, and the moment I realized that I could also contribute, I joined the board.”

What's your role on the board?

Many: I help the company’s CEO and chief scientist, Bentwich, by enabling him to express his scientific creativity.”

Is this a real scientific breakthrough?

“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.”

But Rosetta Genomics has not yet reached the second stage.

“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. In the next stage, which will come soon, we will conduct animal trials on genetic splices. These treatments will be based on micro-RNA, 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. We are collaborating with medical companies, and Rosetta Genomics’ know-how will be the basis for the medical treatments of the next two decades.”

Weizmann Institute of Science Department of Molecular Genetics director Prof. Doron Lancet, one of the heads of Israel’s genome project, agrees. “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.”

How is this expressed?

Lancet: “Until now, Israeli biotechnology companies have rarely tried to change the scientific model. Rosetta Genomics is working in a fairly new field. Its sting lies in its computers. Its system enables it to locate micro-RNA more effectively.

“In addition, it seems that they are also innovating on the qualitative side. When the special functions of RNA were discovered, researchers believed that there were only a few dozen or few hundred. One of Rosetta Genomics’ claims is that there are thousands, and possibly tens of thousands of them. The company’s scientists have set themselves the goal of being the best in the world at detecting micro-RNA. It’s hard to make predictions, but I feel that they have a good chance of achieving their goal.”

A 500,000-page patent application

Bentwich can be described as colorful. He is a physician, an entrepreneur, and a yoga and meditation instructor. He is a potter and poet, who composes "mainly love poems to my wife.” Rosetta Genomics’ workday begins with yoga exercises. Bentwich sometimes leads the session himself. The company’s offices are decorated with his pottery, and every afternoon he meets with the company’s computer programmers and biologists in a Bedouin-style sitting area.

Benwich sold the first company he founded Pegasus Medical for $15 million in 1995, long before Israel’s high-tech boom. “I never actively worked in medicine,” he recalls. “Pegasus dealt with the computerization of medical information, and in fact enabled the creation of the computerized file.” The buyer, HBOC of the US, now McKesson Corporation (NYSE:MCK), has a market cap of $7 billion.

Following the sale of Pegasus, Bentwich was appointed executive vice president at HBOC, where for two years he was responsible for developing computerized medical solutions for doctors. But as has happened to many other serial entrepreneurs, even a fat bank account could not persuade him to rest. “I left after two years, both because I wanted to live in Israel, and because I was more the entrepreneurial than the corporate type. I felt uncomfortable in a large organization. I stayed on for another year in the US, and then went to India.” That’s where the idea of Rosetta Genomics was born.

Rosetta Genomics has raised only $6 million to date. "But with this money," Bentwich proudly says, "we have succeeded in positioning ourselves as a leader in the field of micro-RNA discovery and identification. We’ve filed patents on genes we’ve discovered, and the applications are now awaiting approval.” Rosetta Genomics has definitely achieved one record already: its patent applications are the largest ever to be filed over 500,000 pages.

Rosetta Genomics’ capital structure is also unconventional. Typical start-ups usually begin with one or two venture capital funds. Rosetta Genomics was launched with a large group of private investors. “The company was set up on the basis of an intellectual property strategy,” says Bentwich. “That dictated its structure and what type of investors were suitable.

“Rosetta Genomics’ discoveries were innovative and of extreme significance, right from its initial stages. We had to keep everything under wraps, and preferred not to undergo the disclosure procedures required by venture capital funds when they examine investments. Their due diligence would involve experts, and we wanted to keep everything in strict confidence. In addition, I have a proven track record in founding and developing a company. I don’t need a venture capital fund to hold my hand. In any case, there are advantages in working with private investors. The atmosphere is almost familial. I’ve learned that there’s a great advantage in bringing together a large group of people who contribute not only money, but also experience and vision.”

How were you able to recruit so many celebrities?

Bentwich: “Most of them invested through Yossi Ben-Yossef’s Kadima Hi-Tech, which recruits investors for companies. We reached them through Kadima's extensive network. There was a lot of hype about genomics when we began working. We survived the subsequent crash, and we’ve now emerged from the recession. We’ve managed to survive.”

One of Rosetta Genomics’ best-known investors is Leon Recanati, who invested in the company through his investment company, Glenrock Israel. “The first thing was the company’s conceptual breakthrough,” says Recanati. “Its unconventional thinking could deal with the two paramount problems in biotechnology: increasing predictive power, and, as a result, reducing the time and cost of developing new drugs.

“The second point is that Rosetta Genomics operates in a hot market. Micro-RNA and bioinformatics are the focus of a great deal of interest in academic institutions, venture capital funds, the capital market, and pharmaceutical companies.

“Rosetta Genomics’ business model is based on strong and unique intellectual property, and on collaborative agreements that will enable it to cope successfully with the shortage of money for biotechnology in Israel.”

“A multi-billion dollar market”

Rosetta Genomics has a computer center that Bentwich calls “the biggest and strongest in Israel. Our computer system is ten times stronger than the supercomputer that provides services for the five universities doing research on the human genome, but it cost only a tenth of what that supercomputer cost. It is this computer cluster that enables us to carry out the complex calculations we use in the initial discovery stage.”

Another innovation at Rosetta Genomics is its micro-RNA DNA chip. This is a bioelectronic component that the company developed to identify simultaneously many genes in a tissue sample. The method commonly used now examines individual cells sequentially, until the sought-after gene is found. Rosetta Genomics’ processor can also identify tiny genes.

To illustrate the point, Bentwich explains that, whereas encoding genes comprise tens of thousands of nucleotides, micro-RNA consists of only 22 nucleotides. Only 230 micro-RNA sequences have been published to date, compared with 40,000 encoding genes. “Our computerized approach enabled us not only to find these genes, but also to discover their functions before we went to the lab. We could understand what a particular gene did and what disease it was linked to. This is of course a huge advantage when you want to develop a drug or diagnostic tool. And I’m talking about definitively identified genes. All the genes we’ve discovered are linked to diseases.”

Even during the high-tech crisis, Rosetta Genomics was always able to increase its value at every financing round. Only a few months ago, it began to change from being a self-declared secret company to a company that makes public disclosures. “Our article was accepted by the prestigious journal “Genome Research”, and will be published soon,” says Bentwich proudly. “This groundbreaking article describes the company’s chip platform. We’re also writing five additional articles and sending them to leading journals, and five article abstracts have been submitted to prestigious conferences in our field.”

When will your investors start seeing a return on their investments?

Bentwich does not speak in understatements. “Rosetta Genomics is the goose that lays golden eggs,” he says unhesitatingly. “It has a patented technological platform for detecting genes associated with major diseases with a multi-billion dollar market. This is a new biological stratum that gives hope for a new generation of drugs and diagnoses in huge markets.

“Rosetta Genomics will develop focused drugs with leading companies. The return on the investment will come either from royalties from drugs, or from the acquisition of a subsidiary that will develop drugs that no one intends to sell in the near future.”

Will you continue to be an investor, manager and researcher?

“Rosetta Genomics has reached the stage where it needs a large management team that will allow me to concentrate on the vision and scientific direction.”

Published by Globes [online] - - on October 20, 2004

[Small countries are betting their future on Post-Genetics. Singapore's Biopolis is one example. Israel's latest quest is another shining example - comment by Andras Pellionisz]

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Mice do fine without 'junk DNA' [Questioned by D. Haussler, A. Pellionisz, M. Simons, etc]

Published online: 20 October 2004; | doi:10.1038/news041018-7

Roxanne Khamsi

Deleting non-coding regions from the genome has no apparent effect.

Mice seemed normal even when 3% of their genome had been deleted.

Mice born without large portions of their 'junk DNA' seem to survive normally. The result contradicts the beliefs of many scientists who have sought to uncover the function of these parts of the genome.

More than 90% the genome of organisms such as mice and humans does not appear to code for any proteins. And yet this DNA shows striking similarities between species. If they had no function, over time mutations would scramble the sequences. Why have these bits of the genome remained so highly conserved?

One study, published this month in Developmental Cell1, reports that parts of the non-coding DNA may be involved in embryonic development. Barbara Knowles and her colleagues from the Jackson Laboratory in Bar Harbor, Maine, found that non-coding regions known as transposable elements, which can regulate genes, are highly active in mouse embryos.

Knowles speculates that transposable elements could control embryonic differentiation, activating or reprogramming parental chromosomes. "I think they contain controlling sequences," she says.

Take out the trash

But transposable elements are only a small part of the non-coding regions. And now Edward Rubin's team at the Lawrence Berkeley National Laboratory in California has shown that deleting large sections of non-coding DNA from mice appears not to affect their development, longevity or reproduction.

The team created mice with more than a million base pairs of non-coding DNA missing - equivalent to about 1% of their genome. The animals' organs looked perfectly normal. And of more than 100 tests done on the mice tissues to assess gene activity, only two showed changes. The results are reported in this week's Nature2.

The group has now created mice missing three million base pairs. "We can see no effect in them," Rubin says.

Tough test

Knowles cautions that the study doesn't prove that non-coding DNA has no function. "Those mice were alive, that's what we know about them," she says. "We don't know if they have abnormalities that we don't test for."


Peaston A. E., et al. Developmental Cell, 7. 597 - 606 (2004).
Nobrega M. A., et al. Nature, 431. 988 - 993 (2004)

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[comment by Dave Haussler, UCSC within the above article,
"David Haussler of the University of California, Santa Cruz, who has investigated why genetic regions are conserved, says that Rubin's study gives no hint that the deleted DNA has a function. But he also believes that non-coding regions may have an effect too subtle to be picked up in the tests to far. "Survival in the laboratory for a generation or two is not the same as sucessful competition in the wild for millions of years" he argues. "Darwinian selection is a tougher test"".]

[comment by Andras Pellionisz, HelixoMetry/FractoGene, exclusive to this website. (When citing, please give this URL as reference). Taking out 3% of the "junk DNA" with hitherto uncertain consequences puts the colossal challenge to Information Technology into the limelight. It became today an experimentally investigated theoretical problem, of HOW non-coding DNA regulates gene expression. However, where are the theories? FractoGene (US Patent Pending) is presently the only mathematically expressed utility that explains, based on clear theoretical (axiomatic) basis, HOW the non-coding parts of the DNA constitute a fractal set (together with the genes). The experimental finding that taking out 3% of the non-coding DNA is entirely consistent with the explanation by FractoGene that growth is a fractal (iterative) process, thus with a few iterations lacking the result is the same, although its "precision" (elaboration) is perhaps 3% lesser. As one can see on the fractal diagram on , FractoGene quantitatively predicts that taking out even 30% of the "non coding DNA" would not destroy the "mouse Purkinje cell" - but would result in a Purkinje cell of a "lesser mouse - e.g. a frog". Looking at the photo at of a cute mouse, it may be impossible to tell (I can not distinguish, since even the scale is not given), if it is "a 3% lesser mouse". Does it have 3% less hair? Maybe. Is it 3% smaller (not as full grown)? Maybe. Another example: Taking out 3% of the DNA of the onion (which has a 13-20 times larger DNA information compared to human, may produce an onion with 3% of its so many (fractal like :-) layers. The aggressive cultivation (enforced evolution) of onion, may in fact beautifully explain why the second largest vegetable crop (onion) has such a humongous amount of "junk DNA" - and why has the vegetable onion far to many layers, producing a huge onion, compared e.g. to the tulips (also a type of onion). It is absolutely fantastic that both experimental approaches, as well as comparative anatomy and comparative genomics, plus the sequencing of so many species is already available. However, in the history of science (remember e.g. the fission and fusion of atoms) key experimental questions always triggered rapid developments of scientific theoretical explanations, which, in turn, were absolutely essential to the guidance of experimentation. Nuclear physics is also an example to Post Genomics, that explosive development of theoretical (mathematical) quantum mechanics was equally essential to building a new industry of peaceful and less peaceful nuclear devices, one of the most important branch of modern industries. And yes, experimentation was the ultimate arbiter, if theory and technology was correct, or not. POST GENOMICS IS A COLOSSAL AND BRIGHT CHAPTER IN THE HISTORY OF THEORETICAL AND EXPERIMENTAL SCIENCE, AND INDUSTRIES OF BIOTECH, NANOTECH, INFOTECH]

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Fish Tales Solve Genetic Puzzles

By Kristen Philipkoski

10:00 AM Oct. 20, 2004 PT

A species of puffer fish has helped scientists identify 900 human genes that went previously unnoticed.

An international team of researchers has published the genetic map of the puffer fish Tetraodon nigroviridis in the Oct. 21 issue of Nature. Unlike the Fugu puffer fish, Tetraodon is not poisonous and is common at pet stores.

Both the Fugu and the Tetraodon are interesting to scientists because they are chock-full of genes and not much so-called "junk" DNA, which doesn't make up genes. When researchers compare the fish genomes with the human genome, they know matching strands of DNA are genes, not junk (although researchers increasingly believe junk DNA likely has an important function).

"By comparing Tetraodon genes to the human genome, we found about 900 new human genes that had been missed because they were difficult to find using conventional methods," said Hugues Roest Crollius, a researcher at École Normale Supérieure in Paris.

The Tetraodon has the smallest known vertebrate genome, with 21 chromosomes and more than 300 million letters of DNA.

The researchers found that the fish underwent a strange transformation during its evolution. Most human genes have two counterparts in the Tetraodon genome, which proves that the fish at some point duplicated its entire genome, giving it a double set of genes and an evolutionary advantage.

"The fact that it actually occurred in fish may explain why fish are the most successful living vertebrates, with more than 25,000 species that have colonized such diverse environments as the dark and cold depths of the oceans as well as the rivers of Tibet," said Roest Crollius.

John Postlethwait at the University of Oregon has found evidence that the zebra fish and the medaka fish have also taken advantage of whole genome replication.

"It gives them a lot of flexibility so they can take some of those redundant genes and redirect them to new functions," said Dan Rokhsar, a genome researcher at the Joint Genome Institute in Walnut Creek, California, who led the Fugu puffer fish genome-sequencing project.

Eventually, some of the duplicates will die if the fish doesn't find a use for them.

Researchers don't know why some species have undergone whole genome duplications, but they say the events are an important evolutionary phenomenon that facilitated the emergence of many vertebrate lineages.

After confirming that the Tetraodon had duplicated its genes, the scientists found another surprise when they reconstructed what the fish genome looked like before it underwent duplication. What they ended up with was the genome of humans' common ancestor with fish, which lived 450 million years ago in the Paleozoic era.

"It is very exciting to have a first look at this genome which belongs to a species that has disappeared from Earth a long time ago, but from which we descend," Roest Crollius said. "We now understand a little better where we come from."

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Human gene number slashed


Human beings have far fewer genes than originally thought, a consortium of scientists have claimed in Nature.
The researchers compared the draft human genome with the "gold standard" version, published last year, to work out how they are different.

They found the most up-to-date human genome contains only 20,000 to 25,000 genes
- which is about 10,000 less than indicated in the draft.

This suggests that gene regulation is far more important than gene number.

"It means that each gene can be used in a variety of different ways depending on how it is regulated," said Dr Tim Hubbard, of the Human Genetics group at the Sanger Institute in Cambridge, UK.

"The big thing is regulation."

Modest materials

Genes are the DNA templates that code for proteins, which then build and maintain our bodies.

When the draft human genome was published in 2000, and researchers guessed it contained between 30,000 and 40,000 genes, many people were surprised that something as complex as the human body could be built with such modest materials.

Now the gene number has been revised downwards even further, and scientists suspect that the key to complexity lies not in the genes, but in the gaps between them.

They are gradually discovering that the way genes are controlled - how, when and where they are activated - is a magnificently important and intricate process.

It is as if each gene were a Swiss army knife - they can do several jobs, depending on how they are handled.

At the moment the puppet masters, the bits of DNA that control the genes, are something of an enigma.

"There may be a whole lot of stuff in the genome that we just don't know how to extract yet," said Dr Hubbard. "There is a big international collaboration trying to find out what there is apart from protein coding genes.

"The genome contains tiny regulatory sequences, and these little 'actors' are important in the control system - but they are extremely hard to spot."

Pufferfish genome

In a separate development, scientists have sequenced a second pufferfish genome. The near-complete sequence of the spotted green pufferfish, Tetraodon nigroviridis, was also published in the journal Nature.

Scientists had previously sequenced the genome of the poisonous Japanese pufferfish, Takifugu rubripes.

Tetraodon's 21 chromosomes, which together contain more than 300 million letters of DNA, tell a twisting evolutionary tale, and even shed light on our own genetic make up.

By matching the genes on the pufferfish chromosome, to related genes on the human chromosome, the authors were able to peer into the genome of our shared ancestor - a primitive bony fish that lived hundreds of millions of years ago.

Tetraodon's genome is interesting because it is about one sixth the size of ours, even though it has a similar number of genes.

This means it has less of the shady DNA that hides in the gaps between genes - the very stuff that scientists are puzzling over in the human genome.

Quite why the pufferfish can do without it, while humans and other mammals apparently cannot, is something of a mystery.

"The pufferfish has managed to get rid of the so-called junk - all of the gaps between the fragments are shorter," explained Dr Hubbard. "This kind of implies - since you get a perfectly reasonable fish out of it - that you can delete a lot of it."

[comment by Andras Pellionisz, exclusively on this website (please cite/link the URL): No, it is not a mystery, according to FractoGene (see Pufferfish was stuck in the evolutionary ladder 400 million years ago. There is an extremely well-established correlation between evolution and the size of the amount of "junk DNA", see Fig. 1. by Taft and Mattick, ]

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'Junk' DNA may be very valuable to embryos

Public release date: 11-Oct-2004

Contact: Heidi Hardman


Cell Press

A new study sheds light on events orchestrating the changes when mammalian eggs are fertilized and become embryos. Researchers have discovered that expression of genes in mouse eggs and very early embryos is activated in part by regions of DNA called retrotransposons, which may have originated from retroviruses.

These regions, found in DNA of human, mouse, and other mammals in hundreds of thousands of copies, are called retrotransposons because they have the ability to propagate and insert themselves into different positions within the genome. The research, published in the October issue of Developmental Cell, suggests that retrotransposons may not be just the "junk DNA" once thought, but rather appear to be a large repository of start sites for initiating gene expression. Therefore, more than one third of the mouse and human genomes, previously thought to be non-functional, may play some role in the regulation of gene expression and promotion of genetic diversity.

Dr. Barbara B. Knowles and colleagues from The Jackson Laboratory in Bar Harbor, Maine, found that distinct retrotransposon types are unexpectedly active in mouse eggs, and others are activated in early embryos. Surprisingly, by acting as alternative promoters, retrotransposon-derived controlling elements drive the coordinated expression of multiple mouse genes. "To our knowledge, this is the first report that such elements can initiate synchronous, developmentally regulated expression of multiple genes," says Dr. Knowles. "Also, random insertions of these elements can introduce variation in genes, potentially altering their function."

The researchers think that expression of retrotransposons during very early stages may contribute to the reprogramming of the mammalian embryonic genome, a prerequisite for normal development.

Anne E. Peaston, Alexei V. Evsikov, Joel H. Graber, Wilhelmine N. de Vries, Andrea E. Holbrook, Davor Solter, and Barbara B. Knowles: "Retrotransposons Regulate Host Genes in Mouse Oocytes and Preimplantation Embryos"

Publishing in Developmental Cell, Volume 7, Number 4, October 2004, pages 597–606.

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Doctor's race against time

03 Oct 04

MALCOLM Simons is fighting for his life and his life's work and the Geelong scientist's two struggles are linked by a poignant coincidence.

Dr Simons' work on DNA has saved thousands of lives around the world but now the internationally renowned researcher is dying of a cancer that originates in so-called Junk DNA - the field in which he is an expert.

And he knows he has limited time to complete his latest research before he succumbs to the cancer in his bone marrow.

"The cancer I happen to have occurred in the area in which I am a specialist, just by chance," Dr Simons, 64, said.

"But I am clinically well. I am not suffering, I am thriving.

"Contrary to the general impression, I am actually thriving with this cancer and it is one of the best phases of my life."

Dr Simons came to international prominence more than a decade ago through DNA discoveries that provided science with clues to the causes of breast, ovarian and skin cancer, HIV, Alzheimer's and heart disease.

Now the immunologist is researching revolutionary methods of using gene testing to find more accurate bone marrow donor matches and to screen individuals for the likelihood of diseases. But his sickness has created new imperatives.

"It is a time pressure," Dr Simons said. "I am giving myself three years to live and I am aiming to have the science advanced sufficiently within the next six months so that if I die in six months instead of three years, some of my colleagues can run with it."

He was diagnosed with multiple myeloma 21 months ago and has undergone a bone marrow transplant and chemotherapy.

The cancer he is suffering from has a 50 per cent mortality rate within the first three years but Dr Simons said he was coping with the disease.

He added that while his main objective was to get his research to a stage where other scientists could take over if he died, the question of a lack of funding was more of a hindrance to the work than his illness.

"The difficult thing is that it is unfunded and I have got to rely on the goodwill of scientist friends to do what I can do," he said.

Dr Simons' first breakthrough came in the late 1980s when he revolutionised scientific thinking with the discovery that so-called Junk DNA was vital to the process of life.

His discovery cleared the way for international medical researchers to begin work on life-saving tests that can identify an individual's risks of cancer and other diseases.

Regarded as something of an eccentric, Dr Simons has been married five times and was a champion squash player who represented Australia.

His original discovery has been surrounded by controversy because a company Dr Simons co-founded patented the use of Junk DNA, which meant researchers have had to pay to use the knowledge.

Dr Simons said his latest work, which he has named "haplomics", was designed to collect more accurate information from genes.

"Current genetic testing, whether it be matching for transplantation or for disease risk, usually analyses the pair of genes as a mix," Dr Simons said.

"But the goal of haplomics is to meet the world understanding that if you could analyse those genes separately on each of the pairs of chromosomes, the information would be more valuable."

[The communication above is of historical significance. Dr. Malcolm Simons is the true pioneer of "Junk DNA" -- and other than his heroic achievements, his "story" calls for an immediate and compelling investment reason. Dr. Simons' three "Junk DNA" patents in the USA have been fully acquired by an Australian firm that fetch steep - $15 million for 2003 - from USA genome firms, in royalties. Dr. Simons is on record, see for commenting on the "over-reach" of the Australian company (GTG) that acquired his patents. In the humble opinion of this commentator, Dr. Simons could be invested for a fraction of the yearly $15 million USD, as the original inventor, and now with a new "crop" of Dr. Simons' patents that can be used to cut dependency on the GTG patents. Any US Information Technology conglomerate would reap extreme financial benefits - as well as straightening the Intellectual Property history - by cornering the IP rights of "Junk DNA" for the USA, having Dr. Simons deposit a testimony regarding the non-infringement of his new patents with his earlier accomplishments. - comment by A. Pellionisz, for further analysis, call Four-Zero-Eight-732.9319]

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New research shows plants can shuffle and paste gene pieces to generate genetic diversity

Public release date: 29-Sep-2004
Contact: Kim Carlyle

University of Georgia

A team of researchers at the University of Georgia has discovered a new way that genetic entities called transposable elements (TEs) can promote evolutionary change in plants.

The research, published Sept. 30 in the journal Nature, was led by Dr. Susan Wessler, a Distinguished Research Professor of plant biology at UGA.

The Wessler lab studies TEs, which are pieces of DNA that make copies of themselves that can then be inserted throughout the genome. The process can be highly efficient. Almost half of the human genome is derived from TEs and, this value can go to an astounding 95 percent or even higher for some plants, such as the lily.

"Normally transposable elements just copy themselves, said Wessler, "But there were a few anecdotal reports of plant TEs that contained fragments of plant genes that the TE had apparently captured while it was copying itself. The fact that these instances were so rare suggested that this was not an important process."

In analyzing the TE content of the entire rice genome, Ning Jiang and Xiaoyu Zhang, two postdoctoral fellows in the Wessler lab along with Zhirong Bao, a graduate student in the lab of Dr. Sean Eddy of Washington University in St. Louis, discovered that capturing rice gene fragments is a way of life for one type of TE called MULEs.

MULEs with captured gene fragments were called Pack-MULEs. The study identified more than 3000 Pack-MULEs that contained over a thousand different rice gene fragments. Many of the Pack-MULEs have two or three gene fragments picked up from different genes but now fused together into a new gene combination.

"There are only a few mechanisms known for evolving new genes, and one is genetic recombination, which can bring fragments of different genes next to each other," said Wessler. "A second is the duplication of an existing genes followed by mutation of one of the pair until it evolves into another function, though this is not the usual fate because the duplicate copy usually mutate into oblivion."

The discovery of thousands of Pack-MULEs in the rice genome indicates that this may be an important mechanism to create new genes and new functions in rice and in other plants where MULEs are known to flourish. Recent studies indicate that species evolve through the generation of new genes and/or gene variants that help a population adapt to a changing environment, for example, or to inhabit a different niche.

Why are transposable elements so successful? Some think that they are simply "junk" that, much like viruses, they can make lots of copies but do little to help the host. There is mounting evidence, however, that TEs help organisms evolve by making it easier to generate the sort of genetic novelty that is necessary for them to cope with a changing world.

Thus, instead of being beasts of burden, Pack-MULEs may serve rice as a tool of evolutionary change.

[About this new discovery of Transposable Elements (TEs) "Some think that they are simply "junk" that, much like viruses, they can make lots of copies but do little to help the host. There is mounting evidence, however, that TEs help organisms evolve by making it easier to generate the sort of genetic novelty that is necessary for them to cope with a changing world" Thus, instead of being beasts of burden, Pack-MULEs may serve rice as a tool of evolutionary change". Thus, more and more direct evidence accumulates - see also the Sept 15. discovery of David Gilbert, that "junk DNA" plays a crucial role in evolution. It is particularly noteworthy of mentioning that "transposable elements" are over-abundant in the lily and rice. This is a reason why the "onions" (including lily) have 13-20 times bigger DNA (compared to human) and the DNA of rice is also several times larger than the human DNA. Repetition of "Transposable Elements" "speeds evolution" - especially of essential crops and vegetables. Transposable Elements (self-similar repetitions of fractals) gain easy explanation by FractoGene. - Comment by Andras Pellionisz]

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Human chromosome 5 final sequence analysis released to public.
Disease genes, important regulatory elements populate vast terrain

Public release date: 15-Sep-2004
Contact: David Gilbert
DOE/Joint Genome Institute

WALNUT CREEK, CA-- Four years after publicly revealing the official draft human genetic sequence, researchers have reached the halfway point in dotting the i's and crossing the t's of the genetic sentences describing how to build a human. The newly finalized chromosome 5 is the 12th chromosome polished off, with 12 more to go. As the new sequence reveals, this chromosome is a genetic behemoth containing key disease genes and a wealth of information about how humans evolved.

Chromosome 5 is the second of three chromosomes that the Department of Energy Joint Genome Institute (JGI) has finalized in collaboration with colleagues at the Stanford Human Genome Center (SHGC). The final sequence analysis will be published in the Sept. 16 issue of Nature.

"This extremely accurate sequence will be a powerful tool for scientists trying to understand human disease," said Secretary of Energy Spencer Abraham. "I'm pleased that the Department of Energy, which launched the human genome project in the mid-1980s, could help make this important contribution."

Lawrence Berkeley, Lawrence Livermore and Los Alamos national laboratory scientists and staff comprise the JGI, one of the world's largest and most productive public genome sequencing centers. JGI, in partnership with SHGC, completed the sequencing of three of the human genome's chromosomes--numbers 5, 16 and 19--which together contain some 3,000 genes, including those implicated in forms of kidney disease, prostate and colorectal cancer, leukemia, hypertension, diabetes and atherosclerosis. The chromosome 19 sequence was published in the April 1, 2004, issue of Nature.

"I am confident that the interesting features that we have identified from this sequence information are data that the research community can trust and put to good use," said Richard M. Myers, Professor and Chair of Genetics, who is also the director of the Stanford Human Genome Center.

Chromosome 5, the largest to be completed thus far, is made up of 180.9 million genetic letters – the As, Ts, Gs, and Cs that compose the genetic alphabet. Those letters spell out the chromosome's 923 genes, including 66 genes that are known to be involved in human disease. Another 14 diseases seem to be caused by chromosome 5 genes, but they haven't yet been linked to a specific gene. Other chromosome 5 genes include a cluster that codes for interleukins, molecules that are involved in immune signalling and maturation and are also implicated in asthma.

The spaces between the genes are as important as the genes themselves, said Eddy Rubin, JGI's director. "In addition to disease genes, other important genetic motifs gleaned from vast stretches of noncoding sequence have been found on Chromosome 5. Comparative studies conducted by our scientists of the vast gene deserts where it was thought there was little of value have shown that these regions, conserved across many mammals, actually have powerful regulatory influence."

These gene-free stretches were previously considered "junk DNA," but in recent years those seemingly barren regions have taken on greater prominence as researchers have learned that they can control the activity of distant genes. Some of the noncoding regions have also stayed remarkably consistent compared with those in mice or fish rather than accumulating mutations over the course of evolution.

"If you have such large human regions that stay conserved over vast evolutionary distances, it strongly supports the idea that they must contain something important," said Jeremy Schmutz, the informatics group leader at SHGC. Any mutation that appeared in those conserved regions was likely to have either killed the animal or made it less able to reproduce, preventing the mutation from making it to the next generation. So far, nobody has shown what role the conserved regions play. "What this says is that we don't know as much about this conserved stuff as we think we do," Schmutz said.

Hidden in the chromosome 5 sequence are clues to how humans evolved after branching away from chimpanzees. On average, the chromosome is more than 99 percent similar between chimpanzees and humans, with the greatest similarity found in genes that cause diseases when mutated.

Despite similarities in the overall sequence, the human and chimpanzee chromosomes compared have some structural differences, including one large section that is flipped backwards in humans compared to chimps. Such an inversion makes it impossible for the two chromosomes to pair up when the cell divides to create sperm and eggs. Over time, that incompatibility could have driven a reproductive wedge between the evolving populations.

Moving evolutionarily further away, about one-third of chromosome 5 is similar to a chicken chromosome that determines the chicken's sex, much like the X and Y chromosomes in humans. This finding backs up previous research suggesting that before mammals and birds split 300 million years ago, the sex chromosomes had not yet evolved. After the split, mammals and birds developed their own methods of creating males and females.

One duplicated region on chromosome 5 could eventually help explain how spinal muscular dystrophy is inherited. Researchers had known that deletions in the gene for survival of motor neurons, (SMN) caused the disease, but people with the same deletion can have much more or less severe forms of the disease. It turns out that the region contains many duplications and other rearrangements and varies considerably between people. Schmutz said that, with the sequence for this region in hand, researchers can now study how variations in the number of deletions or repetitions influences the disease severity.

For the chromosome 5 effort at JGI, Susan Lucas led the sequencing and Joel Martin the mapping and analysis efforts. Additional Stanford contributors included Jane Grimwood, the finishing group leader, and Mark Dickson, the production sequence group leader.

The DOE launched the historic quest to discover the human genetic blueprint and also developed cost-effective sequencing and computational technologies that enable on-going contributions to the expanding discipline of genomics. Information about these achievements can be found on the partner sites:

The DOE Joint Genome Institute (JGI):
The Stanford Human Genome Center (SHGC):

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Glowing Green Proves Darwin Theory

By Jennifer Viegas, Discovery News

Sept. 2, 2004 - A glowing green protein has provided researchers with the first direct proof for a Charles Darwin theory that predicts complex structures evolve over time through an accumulation of small improvements.

The findings, published in the current issue of the journal Science, add to the growing body of evidence that supports the theories of British naturalist Darwin (1809-1882

A Color Tree

Our study represents the first time that one particular principle of Darwin's theory of evolution has been proved at the molecular level.

The Book of Life: Learn how the human genome works.

Read about researchers working in the field featured in our Discovery Quest series.

In the future, the research might also lead to better methods for preserving coral reefs, where the fluorescent green protein naturally occurs in coral. It also occurs in the crystal jelly jellyfish.

Scientists studied three colors, formed by protein molecules, in the great star coral (Aequorea victoria). The three colors were cyan (a shade of blue), red and green. The fluorescent green shade is unique because, unlike other colors, it is coded for by a single gene.

The researchers synthesized the ancestral genes that correspond to each of the coral colors, and determined that red evolved from green. Red also turned out to be a more complex color. It takes only two reactions for green to synthesize its fluorescent structure, but red requires three.

Three also is the number of steps that the researchers were able to identify by which fluorescent green evolved into red. The mother of all greens was a shortwave color. It then led to a longwave green that, in turn, produced red, according to the study.

Red, along with other colors, likely holds biological benefits for the colorful marine animal.

"There is pretty strong evidence that coloration diversity is beneficial to coral," explained Mikhail Matz, one of the authors of the Science paper and a research assistant professor at the University of Florida's Whitney Laboratory for Marine Bioscience, and in the Department of Molecular Genetics and Microbiology.

"Corals consist of little algae living inside tissues, and we believe that color is related to the symbiosis, the interface, between the algae and the coral. We plan to address that topic in a future research paper."

It is unclear when coral green first arose.

"It appeared in the mists of time," Matz said, before he added that the original green led to its longwave form that became the ancestor to all other coral colors, including red, around 300 million years ago.

"Our study represents the first time that one particular principle of Darwin's theory of evolution has been proved at the molecular level," Matz told Discovery News.

Previously, only computer models proved Darwin's hypothesis that structures that are more complex can arise from simpler ones over time as improvements build up.

Darwinism has yet to pass all scientific tests, however. Another study, published in a recent issue of the Journal of Molecular Biology, suggests that the 19th century scientist's ideas about natural selection might need some additional tweaking.

For this second study, University of California at Riverside biochemists examined DNA in apes and in humans to determine how we can be so different from our furry ancestors, when we share over 98 percent of the same genes.

The researchers found that humans have more Alu DNA, so-called junk DNA, than apes, such as chimpanzees and gorillas.

The junk DNA sections of our genetic code are prone to sudden and frequent changes, which the researchers believe led to many of the physiological differences that separate humans from apes.

According to Achilles Dugaiczyk, one of the paper's authors and a professor of biochemistry at UCR, the proliferation of junk DNA did not occur randomly and was not subject to environmental selection, as per Darwin's theory.

Dugaiczyk said, "We are not contending that natural selection does not exist, but that in this instance it is a chemical process within human chromosomes that explains why humans have an explosive expansion of DNA repeats, and primates do not."

Dugaiczyk and his colleagues continue to study DNA, while Matz and his team hope that the probable link between color and coral health will lead to visual, noninvasive, methods of studying corals.

The fluorescent green protein also is being used in medical research to track cancer growth and to better understand other cell activities.

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June 29, 2004
Worms reveal intron insights

Team finds "newborn" introns by comparing C. elegans and C.
briggsae genomes | By Nicole Johnston

Irish researchers have discovered 122 novel introns that
appeared in the genomes of Caenorhabditis elegans and Caenorhabditis
briggsae since the two species diverged 80 to 120 million years ago,
shedding light on how new introns arise and are subsequently spread among

The genomes of both worms contain roughly 100,000 introns, of
which more than 6000 are unique to one species or the other. Kenneth Wolfe
and Avril Coghlan identified 81 new introns in C. elegans and 41 new introns
in C. briggsae. Of these, 13 are found in genes implicated in premRNA
processing, the authors report in the June 28 PNAS early online edition.

"We used BLAST [Basic Local Alignment Search Tool] to identify
orthologous genes across all the species (animal and nematode), and by
comparison of all genes, we were able to find intron sites present in one of
the nematodes, but absent in all other species," Wolfe, from Trinity College
Dublin, told The Scientist. "We therefore inferred that these gained introns
must be less than 100 million years old."

Their results represent two major findings, said John Logsdon,
an evolutionary biologist at the University of Iowa. One of these is the
finding that introns are changing a lot, both in terms of gain and loss.
"The more incredibly novel part, is that this is some of the first evidence
of how one intron can give rise to another," he said. Even more significant
is the fact that the authors used actual sequence data to infer the process
by which introns were gained, rather than relying on phylogenetic arguments,
the conventional approach to studying intron evolution, he added.

Just where these novel introns had settled in the worm genomes
was evidenced by a stretch of DNA called an exon splice site consensus
sequence. "With these new introns, the consensus sequence is stronger than
the consensus sequence around any of the other introns," said Wolfe. "This
suggests that this splice site was the target site these new introns were
inserted into. We verified this to be true."

Their findings help provide answers to ongoing controversy over
where introns come from. "It's very significant since it goes to the heart
of the debate about the discovery of introns-have they always been around or
have they been added to the genome recently," Michael Purugganan, an
evolutionary geneticist at North Carolina State University in Raleigh, told
The Scientist. "What this paper shows, very nicely, is that there is
evidence that certain introns have been gained very recently. It gives
credence to the notion that organisms can gain introns in their genes."

"It's considered very important to find very young newborn
introns just inserted into a gene," said Eugene Koonin, a computational
biologist at the National Center for Biotechnology Information in Bethesda,

Md. "These researchers seem to be presenting the youngest ones detected [to
date]. It's potentially important because you can look at features of these
introns and compare how they differ from older ones."

So far, similar studies in mammals have failed to detect
evidence of any new introns. Bacteria, on the other hand, lack introns
altogether, leading scientists to wonder if they were lost from bacteria
early on in their evolution.

Two unusual findings in the latest study, according to Wolfe,
were the discovery of copies of introns elsewhere within the same genome and
duplicate copies of an intron within the same gene. The authors attribute
the anomalies to a process called reverse splicing, whereby an excised
intron somehow inserts into a different site within the same mRNA template.
Reverse transcription of the mRNA then gives rise to DNA containing the
reinserted intron, becoming part of the genome.

But Koonin is not entirely convinced of this conclusion. "What
I'm less enthusiastic about is the likely mechanism [proposed by the
authors] of the insertion of these new introns," he said. "They specifically
claim reverse splicing of preexisting introns in the same or other genes. I
find the evidence insufficient on that count."

The problem is that similarity between new introns always
includes repetitive sequences. "The authors see that and claim that is
evidence of common origin," Koonin said. Purugganan agreed, "It's not an
easy mechanism to invoke in this case."

"We'll learn more if we try to detect even younger introns by
analyzing them from plants and other organisms," added Koonin.

Links for this article
C. Holding, "Caenhorabditis comparative genomics," The
Scientist, November 17, 2003.
Kenneth H. Wolfe
A. Coghlan, K.H. Wolfe, "Origins of recently gained introns in
," PNAS, DOI: 10.1073/pnas.0308192101, June 28, 2004.
John M. Logsdon, Jr.
Michael D. Purugganan
Eugene V. Koonin

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The Scientist : Lab mouse genome isn't simple

The patterns of variation between genomes of standard laboratory inbred mice
are not as simple as generally - 26k - Jun 22, 2004
Lab mouse genome isn't simple

June 22, 2004 Previous | Next

Lab mouse genome isn't simple

High-resolution study shows complex structure is bad news for QTL mapping | By Cathy Holding

The patterns of variation between genomes of standard laboratory inbred mice are not as simple as generally believed, according to a team reporting in PNAS. The results suggest that researchers will be forced to use other methods in quantitative trait loci (QTL) mapping, as gene identification will become "not impossible, but more challenging," said Richard Mott, who led the study with Jonathan Flint at the Wellcome Trust Centre for Human Genetics, Oxford.

|"Inbred strains are great in the sense that they're completely homozygous," said Mott. But laboratory mice were bred originally by amateur scientists who used anything they could catch, said Mott. "They weren't created, generally speaking, for genetic research. The question is, if you look at the genomes of these inbred strains in detail, how do they differ?"

Mott and his team sequenced about 12% of a 4.8-megabase region known to contain a QTL affecting anxiety in each of eight inbred strains, in pieces distributed fairly uniformly to ensure a good sampling of the region at high resolution. "Essentially, we were sampling every 10 kb," said Mott.

Mott's team investigated whether the same group of strains of inbred mice showed one variant while the other group showed a different variant—the simplest picture of genome variation—based on data from low-level scans of the mouse genomes.

However, instead of a picture of clear haplotype blocks—well defined boundaries showing a shift from one pattern of differences between strains to a different pattern—Mott's team found a structure of haplotype sharing that resembled a mosaic of ancestral trees. Different regions showed a different phylogenetic tree relating the eight strains. "You would see straight distributions which were consistent with the particular family tree linking the eight strains—but that family tree would change as you went along," Mott said.

One of the main conclusions was that "we are going to need—if not the full sequence of inbred strains—we are going to need data at a very high resolution. It won't be enough just to sample steps at every few hundred kb—which is what people are doing at the moment," said Mott.

"It is one of the first papers to take a serious look at detailed sequence comparison across a large number of strains, and I think the results make a great deal of sense," said Mark Daly, research fellow at the Whitehead Institute, "particularly since we have done a very similar study with concordant results." That study is in press, Daly said.

The different conformations of single nucleotide polymorphisms across the eight strains that they looked at show that 99% of the variation amongst the strains is captured by 13 different patterns, said Daly, who was not involved in the study. "It does in fact offer a very optimistic outlook for how much work will be required in these positional cloning projects in mice," he said.

"I think that this is an important message, and it relies on accurate sequencing and accurate knowledge of the true base pair sequences in the mouse. And I think it's true that that information is not completely accurate yet," said Tamara J. Phillips, professor and vice-chair in the Department of Behavioral Neuroscience, Oregon Health and Science University. "How likely it is that we are going to have the resources to go at it the way that they did? That's another question."

"Perhaps the title says it is 'unexpected complexity,' but I think that's in part because there have been some very naïve proposals and naïve interpretations of genetic variation data," said Daly. "I think that more sophisticated readers will not find this complexity necessarily unexpected.

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Messages from intergenic space

A non-protein-coding RNA regulates a neighboring gene by simply being turned on

By David Secko, Daily News

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Junk DNA regulates neighboring gene

Junk DNA Yields New Kind of Gene
Regulates Neighboring Gene Simply By Being Switched On

Boston--June, 2004--In a region of DNA long considered a genetic wasteland, Harvard Medical School researchers have discovered a new class of gene. Most genes carry out their tasks by making a product--a protein or enzyme. This is true of those that provide the body's raw materials, the structural genes, and those that control other genes' activities, the regulatory genes. The new one, found in yeast, does not produce a protein. It performs its function, in this case to regulate a nearby gene, simply by being turned on.

Joseph Martens, Lisa Laprade, and Fred Winston found that by switching on the new gene, they could stop the neighboring structural gene from being expressed. "It is the active transcription of another gene that is regulating the process," said Martens, HMS research fellow in genetics and lead author of the June 3 Nature study.

"I cannot think of another regulatory gene such as this one," said Winston, HMS professor of genetics. The researchers have evidence that the new gene, SRG1, works by physically blocking transcription of the adjacent gene, SER3. They found that transcription of SRG1 prevents the binding of a critical piece of SER3's transcriptional machinery.

The discovery raises tantalizing questions. How does this gene-blocking occur? Do other regulatory genes work in this fashion? Does the same mechanism occur in mammals, including humans?

At the same time, SRG1 provides clues to a recent puzzle. Researchers have lately begun to suspect that the long stretches of apparently useless, or junk, DNA might possess a hidden function. In the past year, evidence has been pouring in, not just from yeast but from mammals, that these apparently silent regions produce RNAs, which are associated with transcriptional activity (see Focus, March 5, 2004). Yet no one has found associated protein products. "For us it is easy to look at those findings and say, 'Well maybe those are examples of what is going on here in yeast,'" said Martens.

If so, the findings would carry an important message for the post­human genome era--namely, that researchers' attempts to turn the masses of data churned out by the Human Genome Project into an understanding of what actually happens in the human body may be even more complex than they anticipated. One of the main challenges for that effort is to figure out how and when genes are turned on and off during normal development and disease. Rather than look only at how genes are regulated by proteins, they would have to turn their attention to a new, and possibly more-difficult-to-detect form of control. And given that junk DNA makes up 95 percent of chromosomes, the mechanism could be fairly common.

"I think if nothing else, this sends up an alert that this likely occurs in other cases," said Winston. "When people are looking to understand regulation of genes from whatever organism--humans, flies, mice, yeast--they cannot just look for proteins that are acting there. It might be that it is simply the act of transcribing that is causing regulation."

Like many researchers, Winston and his colleagues may have known in the back of their minds that someday they would have to contend with junk DNA, but it was not their intention to map a new gene in those wild and relatively uncharted regions of the chromosome. If anything, the yeast SER3 gene was their lodestar. What intrigued them about the gene, which is involved in the synthesis of the amino acid serine, was its unusual expression pattern. To be turned on, genes must first be bound by an activator molecule. A common activator in yeast is a molecule called Switch/Sniff. While most genes are turned on by Switch/Sniff, SER3 is turned off by the complex.

In the course of exploring how this repression happens, Martens came across an even more surprising result. "The usual story when a gene is transcriptionally repressed is that RNA polymerase, TATA binding protein and a host of other factors associated with active transcription, will not be there," he said. He, Laprade, a research associate, and Winston conducted a series of experiments and found that the factors were all present and active, and they were located just upstream of the SER3 promoter--as was a jot of DNA needed for the onset of transcription, the TATA element.

Thinking that the TATA element might signify the beginning of a new gene, one associated with both the active RNA polymerase and SER3 repression, Martens mutated it. "We no longer saw the RNA, and we found transcription of SER3 was de-repressed," he said. "That is when we thought, 'OK, we have got a new regulatory gene.'" After characterizing SRG1, which turned out to be 550 base pairs long, they tackled the question, How is it regulating SER3? They put the question on the table during a lab retreat atop a downtown skyscraper. "Everybody talks, and they are not allowed to show any data," said Winston. Out of that intellectual free-for-all, three models emerged.

The first held that RNA transcripts produced from SRG1 were being recruited to SER3 and were somehow repressing transcription. The researchers assumed that if this were true, it would not matter where the RNA came from. As it turned out, SER3 was repressed only when the RNA was produced by an adjacent SRG1. The second model, which proposed that the SRG1 promoter outcompeted the SER3 promoter for transcription factors, also did not hold up to experimental scrutiny.

There had been hints all along favoring the third model. In this one, transcription of the nearby SRG1 somehow prevents an activator from binding the SER3 promotor. Using chromatin immunoprecipitation, a powerful method for imaging the location of molecules in living cells, the researchers found that this was exactly what happened: a well-known activator fell off the SER3 promotor when SRG1 was turned on. In fact, when SER3 was replaced by a reporter gene, the same thing happened--the turning on of SRG1 prevented the activator from binding to that gene as well.

As for how this interference actually occurs, one possibility is that the machinery required to transcribe SRG1--RNA polymerase, TATA-binding proteins and other factors--somehow spills over to the nearby SER3 promotor, physically preventing it from being approached by an activator. "It is also possible that active transcription alters chromatin structure and modifies things in other ways," said Winston.

As for the molecule that got them started in the first place, Switch/Sniff, the researchers now think it may activate SRG1 and in that way bring about SER3's anomalous repression. "That is our current thinking," Winston said. It is a view he expects will be revised. "Every time we thought we understood everything going on here, we have been wrong. There are additional layers of complexity."

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The 64-Bit Question

New chips bring more speed and much more memory.
But choosing the right processor for life science work involves more than just wanting to go faster.


BACK IN THE day when dinosaur microcomputers roamed the Earth, their brains could handle only 8 bits of data at a time, and their memory capacity was a paltry 64 kilobytes. Then Intel came along with a chip, the 8086, that doubled the amount of instructions a computer could chew on at once, and expanded the amount of memory a program could access to a whopping 1 megabyte. Deciding to upgrade was a no-brainer.

Now we're at another historic juncture. Intel, AMD, and Apple/IBM have introduced new 64-bit processors that will power the next generation of high-performance computing systems. The challenge for life scientists is figuring out which processor will deliver the best price/performance to meet their computing needs.

The new 64-bit chips are the Itanium from Intel, the Opteron from AMD, and the PowerPC G5, based on IBM's design and starring in Apple's new G5 PowerMac. In theory, all three offer substantial raw performance improvements over 32-bit processors.

In practice, the true performance will depend on many factors, including the amount of memory a company is willing to purchase and whether applications are optimized to take advantage of the processor's capabilities. Additionally, if the 64-bit systems are part of a cluster, the efficiency and performance of the interconnection software and switches in the cluster will also affect performance.

That said, the main advantage of using a 64-bit system is that much more data can be put into memory — which means faster results.

A 32-bit system can access only 4 gigabytes of memory. (There are ways around this limitation, but these solutions are typically complicated and expensive.) In many common life science applications — searches of a huge database, for example — this 4GB limit can be a real performance stopper.

[This article, that appeared Oct. 10, 2003, on the occasion of AMD's 64-bit "Octeron" chip, provides the backdrop against which the cut-throat IT competition should be evaluated - comment by Andras Pellionisz, Dec. 5th 2004]

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Junk DNA Revisited. Silicon Valley startup claims to have unlocked a key to its hidden language

Hal Plotkin, Special to SF Gate Thursday, November 21, 2002

When the human genome was first sequenced in June 2000, there were two pretty big surprises. The first was that humans have only about 30,000-40,000 identifiable genes, not the 100,000 or more many researchers were expecting. The lower -- and more humbling -- number means humans have just one-third more genes than a common species of worm.

The second stunner was how much human genetic material -- more than 90 percent -- is made up of what scientists were calling "junk DNA." The term was coined to describe similar but not completely identical repetitive sequences of amino acids (the same substances that make genes), which appeared to have no function or purpose. The main theory at the time was that these apparently non-working sections of DNA were just evolutionary leftovers, much like our earlobes.

But if biophysicist Andras Pellionisz is correct, genetic science may be on the verge of yielding its third -- and by far biggest -- surprise.

In addition to possessing an honorary doctorate in physics, Pellionisz is the holder of Ph.D.'s in computer sciences and experimental biology from the prestigious Budapest Technical University and the Hungarian National Academy of Sciences respectively -- institutions that together have produced nearly a dozen Nobel Prize winners over the years.

In a provisional patent application filed July 31, Pellionisz claims to have unlocked a key to the hidden role junk DNA plays in growth -- and in life itself.

Rather than being useless evolutionary debris, he says, the mysteriously repetitive but not identical strands of genetic material are in reality building instructions organized in a special type of pattern known as a fractal. It's this pattern of fractal instructions, he says, that tells genes what they must do in order to form living tissue, everything from the wings of a fly to the entire body of a full-grown human.

Another way to describe the idea: The genes we know about today, Pellionisz says, can be thought of as something similar to machines that make bricks (proteins, in the case of genes), with certain junk-DNA sections providing a blueprint for the different ways those proteins are assembled.

The notion that at least certain parts of junk DNA might have a purpose appears to be picking up steam. Many scientists, for example, now refer to those areas with a far less derogatory term: introns.

Other investigators are also looking into introns from a variety of perspectives. A group at UC Berkeley, for example, recently won $14 million from the National Institutes of Health to study the role introns might play in cardiovascular disease. Other researchers have begun looking at similar questions, with most focusing on intron strands located near genes whose functions are better understood. Scientists at UCLA, for example, recently made a promising association between what appears to be an intron abnormality and spinocerebellar ataxia, which is similar to Huntington's disease.

What makes Pellionisz' approach different is his suggestion that fractals will be found to play a critical role not only in these conditions but also in tens of thousands of others that have not been studied yet. His patent application covers all attempts to count, measure and compare the fractal properties of introns for diagnostic and therapeutic purposes.

"It's certainly possible that such a patent could be granted," says C. Anthony Hunt, Ph.D., a holder of nine patents who heads the Hunt Lab in the Department of Biopharmaceutical Sciences and Pharmocogenomics at the University of California at San Francisco.

To win a patent, Hunt notes, all an inventor must do is describe or teach some new skill that is not obvious.

"And this would certainly qualify as non-obvious," he says. "If it works, [fractal intron analysis] could become a very important tool."

Hunt adds that most biologists simply don't know enough about fractals or the advanced math behind them to understand how they might apply to the field of genetic medicine.

"We need someone to tap us on the shoulder and explain it to us," he says. "But if it clicks as a tool, we would be more than happy to use it."

"Overall, we know very little about what is referred to as 'junk DNA,'" he adds. "But every year that goes by, there are more insights into the possible role they might play."

Staking His Claim

Pellionisz hopes his patent application will help him launch his company and make him one of the field's key players. The provisional application lets him put the words "patent pending" on any related creations for one year, after which he must file a complete application. Like other inventors, he's also free during that time to disclose his concept through other means, such as in professional journals or at scientific gatherings.

In a move sure to alienate some scientists, Pellionisz has chosen the unorthodox route of making his initial disclosures online on his own Web site. He picked that strategy, he says, because it is the fastest way he can document his claims and find scientific collaborators and investors. Most mainstream scientists usually blanch at such approaches, preferring more traditionally credible methods, such as publishing articles in peer-reviewed journals. Scientists who don't follow that tradition are usually treated with suspicion.

But Pellionisz' credentials and prior accomplishments make him much harder to dismiss than the average cyberspace sci-fi wacko.

A biophysicist by training, the 59-year-old is a former research associate professor of physiology and biophysics at New York University, author of numerous papers in respected scientific journals and textbooks, a past winner of the prestigious Humboldt Prize for scientific research, a former consultant to NASA and holder of a patent on the world's first artificial cerebellum (a part of the brain), a technology that has already been integrated into research on advanced avionics systems. Because of his background, the Hungarian-born brain researcher might also become one of the first people to successfully launch a new company by using the Internet to gather momentum for a novel scientific idea.

The Hidden Fractal Language of Intron DNA

To fully understand Pellionisz' idea, one must first know what a fractal is.

Fractals are a way that nature organizes matter. Fractal patterns can be found in anything that has a non-smooth surface (unlike a billiard ball), such as coastal seashores, the branches of a tree or the contours of a neuron (a nerve cell in the brain). Some, but not all, fractals are self-similar and stop repeating their patterns at some stage; the branches of a tree, for example, can get only so small.

Because they are geometric, meaning they have a shape, fractals can be described in mathematical terms. It's similar to the way a circle can be described by using a number to represent its radius (the distance from its center to its outer edge). When that number is known, it's possible to draw the circle it represents without ever having seen it before.

Although the math is much more complicated, the same is true of fractals. If one has the formula for a given fractal, it's possible to use that formula to construct, or reconstruct, an image of whatever structure it represents, no matter how complicated.

Basically, Pellionisz' idea is that a fractal set of building instructions in the DNA plays a similar role in organizing life itself. Decode the way that language works, he says, and in theory it could be reverse engineered. Just as knowing the radius of a circle lets one create that circle, understanding the more complicated fractal-based formula that nature uses to turn inanimate matter into a heart might -- in theory, at least -- help us learn how to grow a living heart, or simpler structures, such as disease-fighting antibodies. At a minimum, we'd get a far better understanding of how nature gets that job done.

The complicated quality of the idea is helping encourage new collaborations across the boundaries that sometimes separate the increasingly intertwined disciplines of biology, mathematics and computer sciences.

Thinking about whether junk DNA has a purpose "is a rather obvious question for scientists to ask," says UC Berkeley mathematics Professor Jenny Harrison, a world-renowned expert on fractals.

When Harrison examined the strings of amino acids involved, the idea that had also dawned on the mathematically inclined Pellionisz, in addition to several other theorists, immediately jumped out at her: If junk DNA really is junk, some of it is certainly organized in a pretty peculiar pattern, one that looks amazingly like a fractal.

"This is a fractal form of nature that must stop at some stage," Harrison says simply, adding that the fractal pattern looks exactly like others that appear in nature. She's been batting the topic around with Pellionisz recently, and is continuing to think about it.

"I'm not sure he has the right answer," she says, "but he is asking a very important question."

Pellionisz has been working on understanding the possible linkages between math and physiology since his earliest days as a college student in Hungary, when he first decided to devote his life to understanding how the brain works. It's that pursuit that has helped lead him to his latest ideas, he says.

"When you consider how the brain tells the fingers to pick up a pencil -- all the many different muscles involved, the senses, vision, touch, the distances involved, and how it is all managed by the brain -- you quickly realize there has to be some form of math involved to coordinate everything," he explains. "I always knew from my earliest days that it had to be math, and I knew it wasn't calculus, because of the distances involved [e.g. from the brain to the tip of the finger]. So it had to be a form of geometry, but it had to be a very special kind of geometry."

Pellionisz has dubbed his new company Helixometry Inc. The name ("helix" refers to the unique spiral folded-over shape of the DNA molecule) alludes to what he says is the fractal math at work inside DNA.

His theory is highly speculative. But there is at least one other important piece of anecdotal evidence that he might be on the right track: As organisms become more complex, they seem to have more intron DNA.

"It's not a perfect correlation," says UCSF's C. Anthony Hunt, "but it is a trend. It's as if the more advanced organisms had made a larger number of steps to get to where they are now."

In other words, although people are made up of the same basic stuff as other organisms, the instructions for making a person should in theory be more complex, which could account for the large amount of intron DNA found in humans.

What's Next

While they remain generally cautious, a number of top biomedical researchers and other scientists say Pellionisz might be onto something really big.

Experts generally agree that a breakthrough in figuring out the role junk DNA plays, if any, would represent a spectacular advance in our understanding about how DNA in general turns inanimate matter into living organisms. If that happens, humanity would take a giant leap toward gaining control of the machinery of life itself, which would open up a wild new frontier in medicine and science that could lead to everything from growing new organs designed for specific patients to preventing and curing any health- or age-related problems that have a genetic origin or component.

Pellionisz says his main goal is to set the stage for the next and even more promising generation of research into genetics. Given the fact that he may be the first person to assert a patent on intron fractal counting and analysis, it's also conceivable that Pellionisz could wind up with related commercial rights worth billions of dollars. If he's wrong, of course, any patent he might receive will be worthless. And even if he's right, he could have to contend with other inventors who may also have recently filed similar patent claims that, like his, have not yet been fully disclosed.

Meanwhile, Pellionisz has several additional patent applications in the works that he says will build on and further protect his original claims. At the same time, he's also looking for the investments he says he needs to move forward more quickly, including completing his formal patent application by the deadline, as well as ramping up his company's first commercial applications, which other researchers would use.

Wary of all the startup horror stories Pellionisz has heard, he's hoping to avoid working with a traditional venture-capital company. Instead, he says he's looking for a single "angel" investor, ideally someone knowledgeable and connected in the biosciences and database worlds who can help him develop his patent portfolio and formulate a business plan that links his efforts with those of some larger organization in a related field. Pellionisz even has a short list of names of specific people who he thinks would be ideal partners at this stage. He is, he says, more interested in building a successful company than in selling the idea for a quick buck. Given the stakes, additional competitors seem certain to join the fray.

It could be years, even decades, before the dust settles and Pellionisz learns whether his patent application has any real merit, as well as whether someone else beat him to the punch with an earlier enforceable patent claim.

"All I know is that I'm in a race," Pellionisz said last week. "And the clock is already ticking."

[SF Gate featured the above on their website - not archived - in late November, 2002 - comment by Andras Pellionisz]

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FractoGene Patent on Mathematical Language of Genetic Code
Sunnyvale, CA, September 3, 2002

HelixoMetry, inc. announces that its FractoGene USPTO patent (pending) on the mathematical language of genetic code is available for exclusive or non-exclusive licensing.

Dr. Andras Pellionisz, Founder and CEO, is USPTO customer 32892, Associate Member of the National Association of Patent Practitioners, NAPP. He electronically submitted patent application called FractoGene and received hard copy confirmation.

When the human genome was mapped out little over a year ago, up to 97% of the DNA was found to contain, instead of genes, so-called non-coding sequences, termed in acute embarrassment "junk genes" says Andras Pellionisz, inventor of FractoGene. "One person's junk is an other person's treasure", he continues. Now he is proud to have incorporated his HelixoMetry Company, and to have submitted a Provisional patent application to protect FractoGene, his invention for the mathematical language of highly repetitious genetic code.

Dr. Andras J. Pellionisz, a former University Professor of New York University, 1976-1990 and Senior Research Fellow of the National Academy of the USA to NASA, 1990-1993, later senior Executive of Silicon Valley Internet Companies (of Ernst & Young, inc.). Subsequently, he was Chief Intelligence Officer and Chief Software Architect of Fabrik, inc, Verge, inc, Xmarksthespot, inc, and Mindmaker, inc. Dr. Pellionisz incorporated HelixoMetry in early 2002 in Sunnyvale. He is an internationally renowned inventor-scientist who pioneered pattern recognition neural network technology. His first patent was obtained in 1984, and in 1990 he received the Alexander von Humboldt Prize for Senior Distinguished American Scientist from Germany for his pioneering in neural networks...

Pending Patent of FractoGene is a utility to count the extremely repetitive number of base-pair sequences in the genetic code, based on the axiom that - contrary to current belief held by many - these supranumerary genes are not "junk" but constitute fractal sets. In turn, body organs and organelles (brain cell arborizations, coronaries, lungs, bowels) that are known to be most suitably modeled by fractal mathematics, develop in self-similar "generations", where the basic template determined by the undifferented genetic information encapsulated in the "stem cell" , and physiological and pathological differentiation governed by regular- or erroneous number of base-pair repetitions.

FractoGene Patent will be used to protect the intellectual property...

Information regarding the use of fractal mathematical language of genetic code is available in the websites

Accomplishments of the inventor of FractoGene are shown in

[The FractoGene approach was conceived on the 17th of February, 2002; one year and one day after the revelation that the already patented 140,000 human genes - were a myth. A. Pellionisz, an Information Technologist, never accepted either the notion (see below) that the paltry 30,000 genes [by 2006, only 19,000] contained enough information to determine a human, or that the paucity of the number of genes were compensated by "nurture". Most importantly, both from an Information Science viewpoint the "Junk DNA" notion of 98.7% of (human) DNA were rejected by AJP, and based on Evolution it was unthinkable that Nature carried in the most compact information depository (DNA) 98.7% "junk". Moreover, the patterned nature of "Junk" was already recognized as not random, see patents by Malcolm J. Simons, conceived from 1987. Thus, (in part motivated by his own research published in 1989) the original FractoGene concept went beyond the state of art drawing practical utilizations of the causal relationship of DNA as fractal sets and the organismal fractality determined by them. From this core, the Intellectual Property of FractoGene Patent Group developed by 2006 - comment by Andras Pellionisz]

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The news that shocked the world: We have only about twice as many genes as your average fruit fly.

Nature vs Nurture Revisited
by Kevin Davies

The most shocking surprise that emerged from the full sequence of the human genome earlier this year [16 February, 2001] is that we are the proud owners of a paltry 30,000 genes -- barely twice the number of a fruit fly.

After a decade of hype surrounding the Human Genome Project, punctuated at regular intervals by gaudy headlines proclaiming the discovery of genes for killer diseases and complex traits, this unexpected result led some journalists to a stunning conclusion. The seesaw struggle between our genes -- nature -- and the environment -- nurture -- had swung sharply in favor of nurture. "We simply do not have enough genes for this idea of biological determinism to be right," asserted Craig Venter, president of Celera Genomics, one of the two teams that cracked the human genome last February. [With all due respect, Craig Venter drew the wrong conclusion from the paucity of genes, clouded by the 1972 "Junk DNA" notion of Ohno - comment by A. Pellionisz]

Indeed, Venter has wasted little time in playing down the importance of the genes he has catalogued. He cites the example of colon cancer, which is often associated with a defective "colon cancer" gene. Even though some patients carry this mutated gene in every cell, the cancer only occurs in the colon because it is triggered by toxins secreted by bacteria in the gut. Cancer, argues Venter, is an environmental disease. Strong support for this viewpoint appeared last year in the New England Journal of Medicine. Researchers in Scandinavia studying 45,000 pairs of twins concluded that cancer is largely caused by environmental rather than inherited factors, a surprising conclusion after a decade of headlines touting the discovery of the "breast cancer gene," the "colon cancer gene," and many more.

But can the role of heredity really be dismissed so easily? In fact, the meager tally of human genes is not the affront to our species' self-esteem as it first appears. More genes will undoubtedly come to light over the next year or two as researchers stitch together the final pieces of the human genome. [In fact, the exact opposite happened. The original 30,000 genes melted to about 19,000 by 2006 - comment by A. Pellionisz]. More importantly, human genes give rise to many related proteins, each potentially capable of performing a different function in our bodies. A conservative estimate is that 30,000 human genes produce ten times as many proteins in the human body, and figuring out what these proteins do will be a challenge for a century or more. "This is just halftime for genetics," says Eric Lander, a leading member of the public genome project, alluding to decades of work ahead to unravel the function of all the proteins in the body... [Eric Lander was half right about halftime. Bateson originated the word "Genetics" in 1905. From 2001-2003 we lived in a "twilight zone" (between the revelation of human whole genome in 2001 to the 50th Anniversary of the discovery of Double Helix, in 2003). By 2005, "Genetics" became a 100-year old and demonstrably overly focused discipline - and PostGenetics was born. What a Century of PostGenetics will bring about, is entirely impossible even to envision. Only one axiom seems certainly clear. The question is not "all the proteins in the body" - but a re-conceptualization how *any* protein-structure is shaped, by the whole genome. By 2005, FractoGene's first ("Fugu") Prediction on recursive hierarchies became experimentally supported and was published in a peer-reviewed science journal - comment by Andras Pellionisz, 2006]

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"Junk DNA" can not be "Junk" - a challenge to Dogmatic Darwinism (Malcolm Simons, 1987)

[The notion "Junk DNA" reigned unchallenged for a mere 15 years, from 1972 to 1987. A Darwinist, Malcolm J. Simons, challenged not one, put two dogmas, in contradiction to one-another in 1987. Malcolm is anything but dogmatic. He knows a dogma when he sees one, and is not afraid to say so, regardless of consequences.

The story can be best recalled by the "Genius of Junk" multiple award-winning science documentary by the Australian Broadcast Corporation (a 20-minute short masterpiece that has never been aired on USA Television, for reasons we might understand by reading its verbatim transcript [AJP].

Narrator: "There is no doubt that our investigation of what was called the coding region of DNA has revolutionized science and the world. But the coding part of DNA makes up less than 5% of our entire genome. Because the rest of our DNA didn’t seem to have any known function it was dubbed non-coding, or Junk DNA.

Malcolm Simons couldn’t believe that evolution would be so wasteful. In 1987, despite having no formal training in genetics, he had a moment of remarkable insight that convinced him that Junk DNA was serving a vital function; it provided markers that indicated susceptibility to disease. At a Workshop in the United States, he saw patterns emerge from the non-coding DNA. He realised that whatever was going on in non-coding DNA was not random. Malcolm Simons, "There was order in the 95%. If there was order there was likely to be function. Maybe this was a way to also contribute to understanding the function of genes and therefore their malfunction in disease and in so doing help diagnosis - make earlier diagnosis - help save lives." When he posed his radical theory that this junk might actually have a critical role in diagnosis, his peers announced, "Malcolm, you're off your friggin' head."

This video was presented in the Press Room of the International Genomics meeting in Melbourne, July 6-10 of 2003, in the presence of eg. Wayt Gibbs, who wrote the Scientific American article later in 2003, and it was in this video where John S. Mattick, director of the Institute for Molecular Bioscience at the University of Queensland in Brisbane, Australia was then filmed saying :

[verbatim quotes again]

John Mattick: The failure to recognize the implications of the non-coding DNA will go down, I think, as the biggest mistake in the history of molecular biology.

... Narration: The “coding regions” became the major focus of genetic research… Even though they account for less than 5% of our entire DNA. All the rest - the other 95% - was assumed to be genetic gibberish with no known function. So they called it ‘non-coding’ or 'Junk' DNA.

Dr Mervyn Jacobson: The word junk was applied and it stuck and people who came along thereafter saw that it was junk and took that as a message that there was no point looking in that area. So it became almost a convenience that instead of looking at 100% of a DNA you only need to worry about looking at 5%. But even that was daunting.

Prof John Mattick: What people should’ve done was take stock at that point. Instead they simply swept the observation under the intellectual carpet.

Narration: For decades this thinking dominated mainstream genetics. But Malcolm Simons couldn’t believe that evolution would be so wasteful. He believed that non-coding DNA must serve some sort of function.

Dr Malcolm Simons: Under Darwinistic notions you would think that junk would drop off under the theory of natural selection just like species drop off if they hit ecological niches which is incompatible with survival. If they can adapt to those niches, then those that can survive and those that can’t die. There’s the notion. If you apply that to the DNA sequence, then the coding region genes which survived have a function and by the way the non coding sequences have survived as well. So the proposition would have to be that if they’re there, they’ve got a function.

Malcolm is anything but dogmatic. He knows a dogma (or two...) when he sees them glaring - and is not afraid to say so, regardless of the severe consequences. With the above 2003 recollection of his 1987 realization, "Dogmatic Darwinism" got into a self-contradiction IF "junk DNA" was found to have some function. Likewise, by finding function of "junk DNA", that notion is also a dogma. Those who suspected all along that both dogmas just might be exposed and thus dismissed/superseded, fell largely into two classes. Those who were frozen into a deafening silence, and those who singularly focused on the scientific challenge of revealing function of (formerly) "junk" DNA. As of today (2006), it is crystal clear that "Dogmatic Darwinism" can not explain "Junk" DNA, and that not only clearly identified function (and malfunction) was found at least for part of the "junk", but also that at least one algorithmic (mathematical) explanation exists (experimentally supported), where the FractoGene concept is based on the deterministic fractal geometry, governing the mathematical "design" of how hierarchies of organisms emerge. Instead of debating "dogma", first let's do (and second, debate...) science of the functional explanation of 98.7% of (human) DNA ... [comment by A. Pellionisz, 6 December, 2006].

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Origin of the term "Junk DNA" (Susumu Ohno, 1972)

Biopharmaceutical DNA glossary

[...The late] Dr. Susumu Ohno, writing in the Brookhaven Symposium on Biology in 1972 in the article "So Much ‘Junk DNA' in our Genome" is credited with originating the term. But his paper was focused "mainly on the fossilized genes, called pseudo genes, that are strewn like tombstones throughout our DNA. But as the term caught on in the 1980’s, its meaning was extended to "all non-coding sequences, the vast stretches of DNA that are not genes and do not produce proteins" (about 95% of the genome) [98.7% of human DNA - AJP]… some [scientists] have begun the scrap the notion that all non-coding DNA is junk … "I don't think people take the term very seriously anymore" says Eric Green [NHGRI] whose group is mapping chromosome 7. [B. Kuska "Should Scientists Scrap the Notion of Junk DNA?" JNCI 90(14): 1032-1033 July 15 1998]

["Junk DNA" thus is a historical brand name, not unlike "Coca-Cola", where "water" is perhaps 1.3% of "soft drinks" - and at an early time "soft drinks" were almost without competition the mysterious and never defined "Coca-Cola". The "generic" contents of "Coca-Cola" change from time-to-time, and today are even different in the USA and in Europe. Presently, the historical brand name "Junk DNA" is a "scientific misnomer" which was essentially abandoned as early as 1987 when Dr. Malcolm J. Simons' patents were conceived, that the part of DNA that were not "genes" show far too much "pattern" to be random; usually meant by "junk". Although Malcolm J. Simons did not know what their function was, he assumed that that it had to have some function. For his realization, Dr. Malcolm J. Simons is recognized as the Honorary Chairman of the International PostGenetics Society - comment by Andras J. Pellionisz]