Sirna shareholders approve $1.1 billion sale of company to Merck
[oops, the price of short repetitive sequences just skyrocketed...]

Associated Press
Posted on Thu, Dec. 28, 2006

SAN FRANCISCO - Shareholders of Sirna Therapeutics Inc. on Thursday approved the sale of the tiny biotechnology company to the pharmaceutical company Merck & Co. for $1.1 billion.

In October, the Whitehouse Station, N.J.-based Merck announced it had offered Sirna shareholders $13 per share for a company attempting to turn a Nobel Prize-winning technology into medicines.

The offer represented a 102 percent premium over Sirna's closing stock price on Oct. 30. The stock's previous high for the past year is $8.52, set in April.

Sirna is one of at least half a dozen biotech companies developing drugs that silence genes by interfering with the messenger-carrying RNA. The technique was discovered by this year's Nobel winners, Andrew Fire of Stanford University and Craig Mello at the University of Massachusetts.

The San Francisco company said the acquisition is expected to close when "reasonably practicable."..

MINUTE MANIPULATIONS [piRNA in "Top 10" of Science in 2006]

Small RNA molecules that shut down gene expression have been hot, hot, hot in recent years, and 2006 was no exception. Researchers reported the discovery of what appears to be a new and still-mysterious addition to this exclusive club: Piwi-interacting RNAs (piRNAs). Abundant in the testes of several animals, including humans, piRNAs are distinctly different from their small RNA cousins, and scientists are racing to learn more about them and see where else in the body they might congregate.

PiRNAs made their grand entrance last summer, when four independent groups released a burst of papers describing them. In a sense, their sudden prominence is not surprising. The Piwi genes to which piRNAs bind belong to a gene family called Argonaute, other members of which help control small RNAs known as microRNAs (miRNAs) and small interfering RNAs (siRNAs). Scientists already believed that the Piwi genes regulate the development and maintenance of sperm cells in many species. With the discovery of piRNAs, they may be close to figuring out how that happens.

Particularly intriguing to biologists is the appearance of piRNAs: Many measure about 30 RNA bases in length, compared with about 22 nucleotides for miRNAs and siRNAs. Although that may not sound like much of a difference, it has gripped biologists and convinced them that piRNAs are another class of small RNAs altogether. Also striking is the molecules' abundance and variety. One group of scientists found nearly 62,000 piRNAs in rat testes; nearly 50,000 of those appeared just once.

But beyond characterizing what piRNAs look like and finding hints that they can silence genes, scientists are mostly in the dark. Still to be determined: where they come from, which enzymes are key to their birth, and perhaps most important, what they do to an organism's genome.

Ancient Noncoding Elements Conserved in the Human Genome

[kept for half a billion years]

Byrappa Venkatesh,1* Ewen F. Kirkness,2* Yong-Hwee Loh,1 Aaron L. Halpern,3 Alison P. Lee,1 Justin Johnson,3 Nidhi Dandona,1 Lakshmi D. Viswanathan,3 Alice Tay,1 J. Craig Venter,3 Robert L. Strausberg,3 Sydney Brenner1

Cartilaginous fishes represent the living group of jawed vertebrates that diverged from the common ancestor of human and teleost fish lineages about 530 million years ago. We generated ~1.4x genome sequence coverage for a cartilaginous fish, the elephant shark (Callorhinchus milii), and compared this genome with the human genome to identify conserved noncoding elements (CNEs). The elephant shark sequence revealed twice as many CNEs as were identified by whole-genome comparisons between teleost fishes and human. The ancient vertebrate-specific CNEs in the elephant shark and human genomes are likely to play key regulatory roles in vertebrate gene expression

And in the beginning was RNA

21.12.2006

RNA silencing or RNA interference (RNAi) is a recently discovered process involving RNA molecules, in which, as the name indicates, these molecules interfere and shutdown specific genes.

And now, while studying the mechanism behind RNAi researchers at Oxford and Helsinki University have discovered that the functional core of a key enzyme (enzymes are proteins which promote biochemical reactions in the body) involved in the formation of RNAi molecules is striking similar to an enzyme involved in gene expression.

The research, published in the journal "Public Library of Science Biology", supports the idea that the two enzymes have a common ancestor and gives weight to the theory that life started as self-replicating RNA molecules in a RNA world (as opposed to the present world where molecules of DNA are the basis of life).

In fact, we live in a DNA world, as genes are segments of DNA, and it is the information contained in the genes of an organism that, when translated into proteins, makes up the blueprint for the body structure and function. This process, the expression of genes into proteins, is comprised of two steps: the first by which genetic information in DNA is converted into RNA and the second which is the synthesis of proteins based on the information/instructions contained in the newly made RNA (DNA ? RNA ? protein).

But there is a dent in this apparently perfect process. In fact, for a long time scientists have been puzzled why approximately 32% of the human genome/DNA, although transformed into RNA, does not lead to protein production (DNA ? RNA ? no protein)? So why would this huge amount of “junk” RNA keep being formed instead of being eliminated during evolution? After all, a basic rule of life is that any reaction that costs energy and is not advantageous for the individual must be eliminated. What recent research unveiled is that RNA is a much more multifaceted molecule than previously thought, and some of that “junk” RNA actually plays an important role in gene regulation. One such example is RNAi, a RNA that is capable of blocking the activity of specific genes.

And it was while studying the mechanisms behind RNAi, that Paula S. Salgado, Jonathan M. Grimes and colleagues discovered that the functional core of an enzyme involved in the formation of short RNAi molecules from other RNA molecules (RNA? RNA), was remarkably similar to the one that mediates the formation of RNA from DNA (DNA ? RNA) during the first step of gene expression. This striking similarity suggested a common ancestor and further analysis seemed to indicate that the enzyme involved in the RNAi process had appeared before and so would probably be more similar structurally to the common ancestor.

These results support the idea of life starting in a (RNA) world where self-replicating (RNA?RNA) multifunctional RNA molecules evolved (as well as the enzymes mediating the process) into the present situation where genetic information is contained instead on DNA. In fact, although RNA is chemically similar to DNA it has, as the “originater” of life, two major advantages over the latter molecule: 1- it is easily synthesised from non-complex blocks so it had higher possibility of occurring spontaneously and 2 - it is easy to imagine that it could evolve into DNA, which by being a much more stable molecule would then take over. Furthermore, the idea of a primitive RNA world, if proved, could solve one of biggest conundrums on the origin of life: if life needs both DNA as a source of genetic information and proteins to drive life’s chemical reactions how could have one appeared first without the other? Some scientists believe that the answer lies in this ancient RNA molecule which was capable of supporting life reactions and also contained life’s genetic blueprint and whose existence seems to be consistent with the findings of Salgado, Grimes and colleagues.

In this way, Salgado’s work sheds light not only on the mechanism behind this extremely interesting and important process that is RNAi, but can also help to understand better how life began on earth.

Repetitive Elements Round Up

by Guts

Quite a lot of buzz in the journals these days challenging the views that variations that generate phenotypic differences occur in a more or less random manner and that most, if not all, non-coding DNA has no biological function. More and more evidence shows that genomes are in fact reservoirs of "adaptive phenotypic plasticity". This might go along with the concept of front-loaded evolution which predicts, in my opinion, that adaptive benefits are likely to occur at greater than random frequencies.

Recent findings that the primary source of genome-size variation is in fact repetitive DNA (Brenner et al. 1993; Kidwell 2002) has led to lots of interesting research into the roles and functions of repetitive loci. For example, Biémont & Vieira (2006) and Volff (2006) focus on transposable elements (TEs), and Kashi & King (2006) review the contribution of microsatellite loci.

Tracing the evolutionary history of repetitive elements through the study of nucleotide sequences shows that most, if not all, repetitive DNA is derived from TEs: in Drosophila and Cetaceans (Kidwell 2002), centromeric repeats have been traced to TEs in plants (Henikoff et al. 2002); and microsatellites have been observed to come from TEs in organisms as diverse as fruit flies (Wilder & Hollocher 2001), mosquitoes (Tu et al. 2004), barley (Ramsay et al. 1999) and humans (Deininger & Batzer 2002).

Evidence that transposable elements donate repetitive sequences with unique biological functions to their host organisms (reviewed by Britten 1997; 2006; Biémont & Vieira 2006; Volff 2006) provokes questions about the roles and functions of other repetitive DNA loci. Specific responses to environmental cues have been detected at repetitive loci other than TEs in plants (Ceccarelli et al., 2002), bacteria (Servant, Grandvalet & Mazodier 2000; Kojima & Nakamoto, 2002; Ojaimi et al., 2003) and humans (Uhlemann et al. 2004), indicating that these loci retain the capacity for generation of phenotypic variation.

If environmentally induced beneficial RE mutations are to have evolutionary significance, they must also be passed to subsequent generations. Environmentally mediated changes in REs have been reported in a range of taxa, but most well-known examples focus on situations where phenotypic effects are negative. Little thought seems to have been given to the possibility that such mutations might also have positive effect. This is an open avenue of investigation.

Caporale (2000) has indicated that heritable genomic responses to recurrent classes of environmental challenge are in fact a key mechanism of adaptive evolution. Evidence that repetitive DNA elements are at least one source of such mutations is strong:

- Mutations in and/or transposition of repetitive DNA affect structure and expression of coding genes in many diverse species and play essential roles in fundamental biological processes.

- REs tend to cluster in genes, or genomic regions, involved in or associated with externally triggered processes and show a unique capacity to respond to environmental signals.

- Site-specific mutations at and/or transposition of repetitive loci are associated with adaptive changes of phenotype in natural populations.

Such findings suggest that genomes are composed of genetic units that are larger, and more complex, than previously thought. Rather than being determined by simple point mutations in protein-coding regions, most phenotypic variation is generated and maintained by complex combinations of variation within larger systems comprised of both coding and non-coding elements.

Korea to Invest $14 Billion in Biotech

Annual Fifteen Thousand Million US dollars to them. This is about 810 times the money of the Nobel Prize... For six years, close to 5,000 times the Nobel Prize money...

Korea plans to invest $14.3 billion in biotechnology research and industrialization over the next 10 years to create a $60 billion market by 2016.

This market will push the nation to No. 7 worldwide, from its current ranking of No. 14.

The ambitious plan was unveiled by the Ministry of Science and Technology Wednesday.

The ministry’s ``Bio-Vision 2016’’ plan puts priority on the acquisition of core technologies and the establishment of infrastructure that will help them in the applied industry, a ministry spokesman said.

The detailed plan calls for the integration of bio-technology with related areas such as post-genome studies, gene-to-life research, information technology and nano-technology.
...

Meanwhile, the ministry selected the two ``National Scientists,’’ who will be entitled to the annual financial research support of 1.5 billion won for up to six years. ...

A Cryptologist Takes a Crack at Deciphering DNA’s Deep Secrets

By INGFEI CHEN

New York Times: December 12, 2006

Thirty years ago, Nick Patterson worked in the secret halls of the Government Communications Headquarters, the code-breaking British agency that unscrambles intercepted messages and encrypts clandestine communications. He applied his brain to “the hardest problems the British had,” said Dr. Patterson, a mathematician.

Today, at 59, he is tackling perhaps the toughest code of all — the human genome. Five years ago, Dr. Patterson joined the Broad Institute, a joint research center of Harvard and the Massachusetts Institute of Technology. His dexterity with numbers has already helped uncover startling information about ancient human origins.

In a study released in May, scientists at the Broad Institute scanned 20 million “letters” of genetic sequence from each of the human, chimpanzee, gorilla and macaque monkey genomes. Based on DNA differences, the researchers speculated that millions of years after an initial evolutionary split between human ancestors and chimp ancestors, the two lineages might have interbred again before diverging for good.

The controversial theory was built on the strength of rigorous statistical and mathematical modeling calculations on computers running complex algorithms. That is where Dr. Patterson contributed, working with the study’s leader, David Reich, who is a population geneticist, and others. Their findings were published in Nature.

Genomics is a third career for Dr. Patterson, who confesses he used to find biology articles in Nature “largely impenetrable.” [This is the biggest challenge; without intimate cooperation of biology- and mathematically minded leaders, with a proven record of fruitful cooperation, result is often vasteful or even alienating - AJP]. After 20 years in cryptography, he was lured to Wall Street to help build mathematical models for predicting the markets. His professional zigzags have a unifying thread, however: “I’m a data guy,” Dr. Patterson said. “What I know about is how to analyze big, complicated data sets.” [Actually, by today's standards, a genome can be amazingly small. Human DNA is smaller than a video you rent from Netflix, and e.g. the entire genome of the Mycoplasma fits on a floppy disk (that is so small that nobody uses it anymore). The non-coding fraction of the entire Mycoplasma genome is less than 50k - even a stamp-sized low quality digital picture is much larger amount of information. Complex? "Complexity is in the eye of the bevildered". - AJP]

In 2000, he pondered who had the most interesting, most complex data sets and decided “it had to be the biology people.”

Biologists are awash in DNA code. Last year alone, the Broad Institute sequenced nearly 70 billion bases of DNA, or 23 human genomes’ worth. Researchers are mining that trove to learn how humans evolved, which mutations cause cancer, and which genes respond to a given drug. Since biology has become an information science, said Eric S. Lander, a mathematician-turned-geneticist who directs the Broad Institute, “the premium now is on being able to interpret the data.” That is why quantitative-minded geeks from mathematics, physics and computer science have flocked to biology.

Scientists who write powerful DNA-sifting algorithms are the engine driving the genomics field, said Edward M. Rubin, a geneticist and director of the federal Joint Genome Institute in Walnut Creek, Calif. Like the Broad, the genome institute is packed with computational people, including “a bunch of astrophysicists who somehow wandered in and never left,” said Dr. Rubin, originally a physics major himself. Most have never touched a Petri dish.

Dr. Patterson belongs to this new breed of biologist. The shelves of his office in Cambridge, Mass., carry arcane math titles, yet he can converse just as deeply about Buddhism or Thucydides, whose writings he has studied in ancient Greek. He is prone to outbursts of boisterous laughter.

He was born in London in 1947. When he was 2 his Irish parents learned that he had a congenital bone disease that distorted the left side of his skull; his left eye is blind. He became a child chess prodigy who earned top scores on math exams, and later attended Cambridge, completing a math doctorate in finite group theory. In 1969, he won the Irish chess championship.

In 1972, Dr. Patterson began working at the Government Communications Headquarters, where his research remains classified. He absorbed through his mentors the mathematical philosophy of Alan Turing, the genius whose crew at Bletchley Park — the headquarters’ predecessor — broke Germany’s encryption codes during World War II. The biggest lesson he learned from Dr. Turing’s work, he said, was “an attitude of how you look at data and do statistics.”

In particular, Dr. Turing was an innovator in Bayesian statistics, which regard probability as dependent upon one’s opinion about the odds of something occurring, and which allows for updating that opinion with new data. In the 1970s, cryptographers at the communications headquarters were harnessing this approach, Dr. Patterson said, even while academics considered flexible Bayesian rules heretical.

In 1980, Dr. Patterson moved with his wife and children to Princeton, N.J., to join the Center for Communications Research, the cryptography branch of the Institute for Defense Analyses, a nonprofit research center financed by the Department of Defense. His work earned him a name in the cryptography circle. “You can probably pick out two or three people who’ve really stood out, and he’s one of them,” said Alan Richter, a longtime scientist at the defense institute.

In 1993 Dr. Patterson moved to Renaissance Technologies, a $200 million hedge fund, at the invitation of its founder, James H. Simons, a mathematician and former cryptographer at the institute. The fund made trades based on a mathematical model. Dr. Patterson knew little about money, but the statistical methods matched those used in code breaking, Dr. Simons said: analyzing a series of data — in this case daily stock price changes — and predicting the next number. Their methods apparently worked. In Dr. Patterson’s time with the hedge fund, its assets reached $4 billion.

By 2000, Dr. Patterson was restless. One day, he ran into Jill P. Mesirov, another former defense institute cryptographer, and mentioned his interest in biology. Dr. Mesirov, then director of computational biology at the Whitehead/M.I.T. Center for Genome Research, which later became the Broad Institute, hired him.

“Really, what we do for a living is to decrypt genomes,” Dr. Mesirov said. Cryptographers look at messages encoded as binary strings of zeros and ones, then extract underlying signals they can interpret, Dr. Mesirov said. The job calls for pattern recognition and mathematical modeling to explain the data. The same applies for analyzing DNA sequences, she said.

One common genomic analysis tool — the Hidden Markov Model — was invented for pattern recognition by defense institute code breakers in the 1960s, and Dr. Patterson is an expert in that technique. It can be used to predict the next letter in a sequence of English text garbled over a communications line, or to predict DNA regions that code for genes, and those that do not.

Dr. Patterson said he also has a well-honed instinct about which data is important, after seeing “a lot of surprising stuff that turned out to be complete nonsense.” Dr. Lander of the Broad Institute describes him as a great skeptic, with the statistical insight to tell whether a signal is “simply random fluctuation or whether it’s a smoking gun.”

Making that distinction is one of the great difficulties of interpreting DNA. In studying the human-chimp species split, the genomics researchers strove to rule out possible errors and biases in the data.

Dr. Reich, with Dr. Patterson and Dr. Lander, and two other colleagues, used computer algorithms to compare the primate genomes and count DNA bases that did not match, like the C base in gorillas that had become an A in humans. Because such mutations naturally arise at a set rate, the researchers could estimate how long ago the human and chimp lineages separated from an ancient common ancestor.

A DNA base can mutate more than once, however. To correct for that, Dr. Patterson worked out equations estimating how often it occurred; Dr. Reich revised their computer algorithms accordingly. Two strange patterns emerged. Some human DNA regions trace back to a much older common ancestor of humans and chimps than other regions do, with the ages varying by up to four million years. But on the X chromosome, people and chimps share a far younger common ancestor than on other chromosomes.

After the researchers tested various evolutionary models, the data appeared best explained if the human and chimp lineages split but later began mating again, producing a hybrid that could be a forebear of humans. The final breakup came as late as 5.4 million years ago, the team calculated.

The project was “our hobby” Dr. Reich said of himself and Dr. Patterson said. Their main work, in medical genetics, includes devising a shortcut to scan the genome for prostate cancer genes.

Whether studying disease or evolution, Dr. Patterson noted, genomics differs from code breaking in one key respect: no adversary is deliberately masking DNA’s meaning. Still, given its complexity, the code of life is the most open-ended of cryptographic challenges, Dr. Patterson said. “It’s a very big message.”

What will be the biggest benefit from mapping human genome?

[Yahoo posted this question at the above link. 2144 answers were received from the general public. Sampling the answers (above), it is astounding how overwhelming the answer is "doing away with diseases, improving health". Even more astonishing is that that the general public is much-much more aware of the "Junk DNA" than perhaps even their Congressional Representatives are - as evident from the public citing specific diseases for which the modern era of Genetics could not provide an answer - since they are high on the ever-growing list of strongly suspected "junk DNA diseases". Thus, the ongoing effort of PostGenetics to promulgate Policies for Congress to act may prove to be easier than thought - comment by A.J. Pellionisz, 9th of December, 2006 .]

Peering Into The Shadow World Of RNA

Medical News Today

08 Dec 2006 - 4:00am (PST)

The popular view is that DNA and genes control everything of importance in biology. The genome rules all of life, it is thought. [Journalists need to start "to think outside the box". RNA is determined by the DNA, and is part of the genome - AJP]

Increasingly, however, scientists are realizing that among the diverse forms of RNA, a kind of mirror molecule derived from DNA, many interact with each other and with genes directly to manage the genome from behind the scenes. [Express the genome might be more correct AJP]

In particular, RNA produced by the vast stretches of DNA that do not code for any genes - long considered 'junk' DNA - may in fact be serving vital duty by governing important aspects of gene expression. This type of RNA is called non-coding RNA, meaning that although it may be biologically active, it does not carry the instructions for producing any protein in the body. [This is where dogmatic thinking goes wrong. Insertion of a single word "it does not carry PRIMARY instructions for producing any protein" changes the modern axiom from "straightforward genic protein synthesis" to the postmodern new axiom of "recursive iterative fractal protein synthesis" - where primary instructions are carried by the genes, but "non-coding DNA" does contribute to the "coding", albeit not in in a direct manner - AJP]

The importance of better understanding these non-coding forms of RNA is underscored by the fact that they are known to play roles in such critical processes as embryonic development, cell and tissue differentiation, and cancer formation.

A review of current research in this still-developing area of biology, authored by Kazuko Nishikura, Ph.D., a professor in the Gene Expression and Regulation Program at The Wistar Institute, appears in the December issue of the journal Nature Reviews Molecular Cell Biology [purchase only].

"The essence of gene regulation occurs, of course, at the level of gene transcription," Nishikura says. "Cellular machinery transcribes genetic DNA into messenger RNA from which the proteins of the body are produced. In the last several years, however, scientists investigating the biological meaning of other forms of RNA that don't code for proteins have discovered that they oversee another, more subtle level of genome control."

Nishikura's own research has for many years explored RNA editing mechanisms. In particular, she has studied an enzyme called ADAR that converts specific occurrences of a basic RNA building-block molecule called adenosine into another called inosine. In her laboratory, this simple substitution has been seen to have significant biological effects, altering the expression of certain neurotransmitter genes, for example.

Last year, this work converged with that of researchers investigating an extensive family of small molecules called microRNAs, or miRNAs, non-coding forms of RNA that appear to target and inactivate particular sets of messenger RNAs, thus preventing them from producing protein and effectively silencing the group of genes from which they were transcribed. In that study, Nishikura found that that precursor miRNAs, like messenger RNAs, are themselves subject to specific RNA editing, the result of which is to suppress - or perhaps refocus - miRNA expression and activity (http://www.nature.com/nsmb/journal/v13/n1/full/nsmb1041.html [full text, free]).

"MicroRNAs often target a specific set of genes," Nishikura notes. "But when editing occurs, they may target a completely different set of genes."

In recent years, Nishikura says, a growing number of scientists are discovering other links between RNA editing and the activities of different forms of non-coding RNA.

"We used to believe there were only a limited number of RNA editing sites," she says, but now we think there may be as many as 20,000 sites involving perhaps 3,000 genes. Interestingly, most of the editing sites correlate with non-coding regions of DNA, the so-called junk DNA."

One reason for this, Nishikura and others speculate, may be that the majority of these non-coding regions are composed of repetitive sequences of DNA called transposons. The largest class of transposons, known as retrotransposons, have the remarkable ability to copy themselves into RNA, translate themselves back into DNA, and then reinsert themselves back into the DNA at the new location. If their insertion spot happens to be within the coding region for a vital gene, the result can be destruction of the gene, leading to birth defects and genetic disease.

Over evolutionary history, this ability of transposons to copy themselves to new locations has helped them to dramatically expand their representation in the mammalian genome.

"Transposons occupy as much as half of our entire genome, and they can be dangerous," Nishikura says. "As a result, mechanisms have arisen through evolution to suppress their activity. This is particularly true in the egg and sperm, where maintenance of the genome's integrity is critical."

One of these suppression mechanisms involves short interfering RNA, or siRNA, a form of non-coding RNA that specifically targets and inactivates the stretch of DNA from which it originated. In the case of transposons, this would effectively limit their ability to act, thus protecting the genome from potential disruption.

Venter hopes to develop drugs from ocean microbes [Scripps, San Diego]

By Bruce Lieberman

UNION-TRIBUNE STAFF WRITER

November 9, 2006

Biologist J. Craig Venter, whose role in the Human Genome Project brought him international fame and fortune, hopes to build a lab at UCSD for developing drugs from ocean microbes, the university's officials and researchers have confirmed.

Regents for the University of California are expected to consider the proposal late this year or early in 2007. Many details of the partnership between the University of California San Diego and the nonprofit J. Craig Venter Institute, based in Maryland, have not been released.

Tony Haymet, the new director of the Scripps Institution of Oceanography, outlined the general proposal.

The University of California would provide land and Venter would pay for the construction of a research lab, Haymet said. The building would be situated between UCSD's main campus and Scripps.

“The whole drug-design business is about optimizing things nature gives us,” Haymet said. “We're not smart enough yet to design things from scratch, and so the marine environment is just a whole other realm of molecules you get to try out.

“We're sort of scratching the surface of the ocean, and with Craig's leadership, we have this window into the (genetic) information of the ocean.”

Venter earned a bachelor's degree in biochemistry in 1972 and his doctorate in physiology and pharmacology three years later, both from UCSD.

He has been a pioneer in the field of genomics – the study of how DNA is organized in various organisms and how that genome, or genetic blueprint, may hold clues for treating diseases. Using powerful computers and other instruments, Venter and his colleagues have developed ways to rapidly sequence, or map out, the genomes of numerous organisms.

More recently, Venter has traveled the world aboard his private yacht, Sorceror II, to catalog the genomes of microbial life in all the world's seas.

He could not be reached for comment yesterday.

The proposed venture would be the latest of several between Venter and San Diego scientists.

Venter's institute has joined with UCSD, the Salk Institute, The Scripps Research Institute, all in La Jolla; the Battelle Memorial Institute in Columbus, Ohio; and Iowa State University to apply for a 10-year, $500 million grant from British Petroleum for studying how to convert organic matter into fuel.

As part of the grant bid, Venter's institute and his biotech company, Synthetic Genomics, have leased about 18,000 square feet of lab and office space in Torrey Pines.

Also this year, Venter and UCSD announced a joint venture to accelerate research into the DNA of ocean microbes and build a computer infrastructure to manage the vast amount of information generated from that effort. The project is titled CAMERA, short for Community Cyberinfrastructure for Advanced Marine Microbial Ecology Research. It is being funded by a $24.5 million grant from the Gordon and Betty Moore Foundation.

“The ocean represents a frontier for Venter and for us, and collaborating on this is a smart thing to do,” said John Orcutt, UCSD's associate vice chancellor for government research relations and director of research innovation initiatives.

The Scripps Institution of Oceanography runs a research program on the genetics of marine life. The newly proposed partnership with Venter would elevate what many already see as a world-class program, said Bill Gerwick, a lead researcher at the institution's Center for Marine Biotechnology & Biomedicine.

“We're going to make use of (Venter's) incredible ability to sequence genes,” said Gerwick, who is also a professor at UCSD's Skaggs School of Pharmacy and Pharmaceutical Sciences. “We have just dozens of projects awaiting sequencing.”

Gerwick studies the DNA of cyanobacteria, a marine algae that someday may be used in the development of drugs. Scripps has compiled one of the world's largest – if not the largest – collections of cyanobacteria, and researchers are eager to map out the DNA of these organisms, Gerwick said.

“(Venter) is a very high-profile scientist and will bring a lot of talent and recognition with him,” Gerwick said. “Things are snowballing.”

The Scripps Institution is already one of the most prestigious oceanographic labs in the world, Haymet said, and accelerating work in ocean genomics will further elevate its profile.

“It's just a way of reinforcing La Jolla as one of the centers for modern marine science,” he said.

New Technology Used To Construct First Map Of Structural Variation In Human Genome

Beyond the simple stream of one-letter characters in the human genome sequence lies a complex, higher-order code. In order to decipher this level of architecture, scientists have developed powerful new experimental and algorithmic methods to detect copy number variants (CNVs)--defined as large deletions and duplications of DNA segments. These technologies--reported in the journal Genome Research--were used to create the first comprehensive map of CNVs in the human genome, concurrently published in Nature. A related article appears in Nature Genetics.

CNVs are responsible for genetic changes in Alzheimer's and Parkinson's, susceptibility to HIV-1, some forms of color blindness, and many other diseases. They lead to variation in gene expression levels and may account for a large amount of phenotypic variation among individuals and ethnic populations, including differential responses to drugs and environmental stimuli. Mechanisms underlying the formation of CNVs also provide insight into evolutionary processes and human origins.

Using microarray technology, scientists can scan for CNVs across the genome in a single experiment. While this is a cost-effective means of obtaining large amounts of data, scientists have struggled to accurately determine CNV copy number and to precisely define the boundaries of CNVs in the genome. Two papers published today in Genome Research present groundbreaking approaches to address these issues.

One paper describes a new whole-genome tiling path microarray, which was constructed from the same DNA used to sequence the human genome in 2001. The array covers 93.7% of the euchromatic (gene-containing) regions of the human genome and substantially improves resolution over previous arrays. The array was employed in a process known as comparative genomic hybridization (CGH), which involves tagging genomic DNA from two individuals and then co-hybridizing it to the array. Data from the array were assessed with a new algorithmic tool, called CNVfinder, which accurately and reliably identified CNVs in the human genome.

"This method helped us to develop the first comprehensive map of structural variation in the human genome," says Dr. Nigel Carter, one of the lead investigators on the project. "We used it to help identify 1,447 CNVs, which covered 12% of the human genome."

The other paper presents a new multi-step algorithm used with the Affymetrix GeneChip® Human Mapping 500K Early Access SNP arrays. The specificity of the algorithm, coupled with the increased probe density of these arrays, permitted the identification of approximately 1,000 CNVs, many of which were below the detection size limit of alternative methodologies. Furthermore, the algorithm more accurately estimated CNV boundaries, thereby permitting a detailed comparison with other genomic features.

"This new approach will be useful in understanding the role of CNVs in disease pathology--not only copy number changes in cancer cells, but also possible association of CNVs with common diseases," explains Dr. Hiroyuki Aburatani, one of the scientists who led the development of the algorithm. "We'll be able to develop diagnostic tests with sub-microscopic resolution, and because the analysis detects SNPs--single-nucleotide polymorphisms--in addition to CNVs, it will find widespread use among researchers performing disease-association studies."

Both projects were part of the International Structural Genomic Variation Consortium's Copy Number Variation Project (http://www.sanger.ac.uk/humgen/cnv). The Principal Investigators on this project were Hiroyuki Aburatani (University of Tokyo); Nigel P. Carter, Matthew E. Hurles, and Chris Tyler-Smith (Sanger Institute); Keith W. Jones (Affymetrix); Charles Lee (Harvard Medical School); and Stephen W. Scherer (Sick Kids Hospital, Toronto, Canada)

[PostGenetics will re-vamp the information technology - comment A. J. Pellionisz, 27th of November, 2006]

Junk DNA in Y-chromosome control functions

Hyderabad, Nov. 24 (PTI): Scientists at the Centre for Cellular and Molecular Biology (CCMB) here have demonstrated that junk DNA in human Y-chromosome control the function of a gene located in another chromosome...

"The study, published in the international journal Genome Research, will open up a new approach to unravel the function of the non-coding DNA in our genome," CCMB Director Lalji Singh, who led the research effort, told reporters here today.

The Y-chromosome is present only in men. Two-thirds of it contains repetitive DNA that has been thought of as junk or useless.

However, the CCMB study clearly demonstrated that the Y-chromosomal junk DNA interacts and controls the function of a gene located in another chromosome that is not limited to a sex.

"The study shows unequivocal evidence, for the first time, that 40 mega base repeat block of the Y-chromosome, which was earlier perceived as junk DNA, is transcribed into RNA and controls the expression of a protein by a mechanism described as trans-splicing," Singh said.

New diversity discovered in human genome [welcome again to PostGenetics...]

[See entire Nature article here , select "full text" in upper right corner]

BEIJING, Nov. 23 (Xinhuanet) -- The assumption that humans are genetically almost identical is wide of[f] the mark -- and the implications could be resounding, according to a new international study.

Current thinking, inspired by the results five years ago from the Human Genome Project, is that the six billion humans alive today are 99.9 percent similiar when it comes to genetic content and identity.

But major research, published Wednesday in the British journal Nature, suggests humans are genetically more diverse -- and the repercussions could be far-reaching for medical diagnosis, new drugs and the tale of human evolution itself.

Until now, analysis of the genome has focussed overwhelmingly on comparing flaws, or polymorphisms, in single "letters" in the chemical code for making and sustaining human life.

The international consortium of scientists has taken a different t[r]ack and believe they have uncovered a complex, higher-order variation in the code.

This better explains why some individuals are vulnerable to certain diseases and respond well to specific drugs, while counterparts swiftly fall sick or never respond to treatment, the authors believe.

Their focus has been to dig out deletions or duplications of code among relatively long sequences of DNA and then compare these so-called copy number variations (CNVs) across a range of volunteers of different ancestry.

The researchers were astonished to locate 1,447 CNVs in nearly 2,900 genes, or around one eighth of the human genetic code.

"Each one of us has a unique pattern of gains and losses of complete sections of DNA," said Matthew Hurles of Britain's Wellcome Trust Sanger Institute, one of the project's partners.

"The copy number variation that researchers had seen before was simply the tip of the iceberg, while the bulk lay submerged, undetected. We now appreciate the immense contribution of this phenomenon to genetic differences between individuals."

̊ll the same, there are widespread differences in CNVs according to the three geographical origins of the samples. This implies that, over the last 200,000 years or so, subtle variants have arisen in the genome to allow different populations of humans adapt to their different environments, according to the researchers.

This new study is based on two technical breakthroughs: one in faster, accurate sequencing of DNA and the other in a powerful software programme to spot the CNVs.

DNA methylation profiling of human chromosomes 6, 20 and 22

Researchers discovered characteristics of sections of DNA previously thought of as ‘junk’.

The epigenome is the interface where genetics and the environment meet. Environmental factors and lifestyle can permanently alter our genetic code, leaving some more susceptible to certain diseases than others. Such factors can alter DNA bases through the addition or removal of certain compounds, such as a methyl group, according to the Sanger Institute.

To examine how and where DNA modification might take place, researchers looked at the presence or lack of a methyl group, or the methylation of DNA. They discovered that to a large extent, methylation is binary, i.e. it is either there or it isn’t, rather than occurring in varying concentrations. They also discovered little difference in methylation across age groups, as was previously thought to be the case. It had been believed that methylation associated with aging was the cause of certain disease processes. The research also showed that there was no difference between sexes.

“Our data show DNA methylation to be stable, specific and essentially binary (that is, on or off) - all key hallmarks of informative clinical markers,” explained Dr Stephan Beck, Project Leader at the Wellcome Trust Sanger Institute. “Our conclusion is that epigenetic markers will be a powerful addition to the current repertoire of genetic markers for future disease association studies, particularly where non-genetic factors are known to play a role, for example in cancer, and where they are suspected, as in autoimmune disease.”

They discovered that regions called evolutionary conserved regions (ECRs), lying distant from genes, out in the ‘junk’ DNA, had high concentrations of methylation. This may indicate that these regions have an undiscovered role to play in gene or chromosome activity, according to the scientists.

In addition, analysis of methylation led the team to portions of DNA previous thought to be relatively inactive. Some portions of DNA, known as pseudogenes, appear to have lost function or their exact function is unknown because they have not yet been experimentally studied. Researchers found that these regions were approximately 90 percent methylated, leading them to suspect that methylation might contribute to the inactivity of such genes.

--- [end of popularization - here is the Abstract from PubMed] ---

Florian Eckhardt1, Joern Lewin1, Rene Cortese1, Vardhman K Rakyan2, John Attwood2, Matthias Burger1, John Burton2, Tony V Cox2, Rob Davies2, Thomas A Down2, Carolina Haefliger1, Roger Horton2, Kevin Howe2, David K Jackson2, Jan Kunde1, 3, Christoph Koenig1, Jennifer Liddle2, David Niblett2, Thomas Otto1, Roger Pettett2, Stefanie Seemann1, Christian Thompson1, Tony West2, Jane Rogers2, Alex Olek1, Kurt Berlin1 & Stephan Beck2

1 Epigenomics AG, Kleine Präsidentstrasse 1, 10178 Berlin, Germany.

2 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

3 Present address: Schering AG, Müllerstr. 178, 13342 Berlin, Germany.

DNA methylation is the most stable type of epigenetic modification modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of six annotation categories showed that evolutionarily conserved regions are the predominant sites for differential DNA methylation and that a core region surrounding the transcriptional start site is an informative surrogate for promoter methylation. We find that 17% of the 873 analyzed genes are differentially methylated in their 5' UTRs and that about one-third of the differentially methylated 5' UTRs are inversely correlated with transcription. Despite the fact that our study controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.

NLM Awards $75M for Biomedical Informatics Training Programs

[November 21, 2006]

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) - The National Library of Medicine today said it has awarded a series of grants totaling more than $75 million to fund training in biomedical informatics.

The 18 grants awarded by the NLM, a branch of the National Institutes of Health, will fund five-year programs around the country in a number of areas, including healthcare and clinical informatics, bioinformatics and computational biology, translational informatics, public health informatics, and imaging and signal processing.

NLM director Donald B Lindberg described the training programs as “vital” for areas such as human genome research, applied genomics in treatment and diagnostics, and in maintaining health records.

The training will target physicians, biologists, computer scientists and engineers, the NLM said.

Training centers funded by the NLM include Johns Hopkins University, Rice University, Harvard University, the University of Washington and 16 other education institutions.

Recipients of the funding are responsible for selecting trainees and implementing program specifics, the NLM said.

Taking 'chips' to the next level of [non]-gene hunting

Researchers at the Johns Hopkins' High Throughput Biology Center have invented two new gene "chip" technologies that can be used to help identify otherwise elusive disease-causing mutations in the 97 percent of the genome long believed to be "junk."

A variety of DNA microarray technology, one of the two new chips, called the TIP-chip (transposable element insertion point) can locate in the genome where so-called jumping genes have landed and disrupted normal gene function. This chip is described online this week in the Proceedings of the National Academy of Sciences.

The most commonly used gene chips are glass slides that have arrayed on them neat grids of tiny dots containing small sequences of only hand-selected non-junk DNA. TIP-chips contain on them all DNA sequences. Because each chip can hold thousands of these dots - even a whole genome's worth of information - scientists in the future may be able to rapidly and efficiently identify, by comparing a DNA sample from a patient with the DNA on the chip, exactly where mutations lie.

"With standard chips, we're missing a big piece of the picture of mutations in humans because they look only at the meaty parts of genes, but the human genome is only 3 percent meaty parts," says Jef Boeke, Ph.D., Sc.D, professor of molecular biology and genetics and director of the HiT (High Throughput Biology Center), who spearheaded both studies at the Institute of Basic Biomedical Sciences at Hopkins. "The other 97 percent also can contain disease-causing mutations and is often systematically ignored," he says.

Boeke and his team have focused particularly on transposable elements, segments of DNA that hop around from chromosome to chromosome. These elements can, depending on where they land, wrongly turn on or off nearby genes, interrupt a gene by lodging in the middle of it, or cause chromosomes to break. Transposable elements long have been suspected of playing a role vital to disease-causing mutations in people. Boeke hopes that the TIP-chip eventually can be used to look for such mutations in people.

The new TIP-chip contains evenly sized fragments of the yeast genome arrayed in dots left to right in the same order as they appear on the chromosome. Boeke's team used the one-celled yeast genome as starting material because, unlike the human genome, which contains hundreds of thousands of transposable elements of which perhaps a few hundred are actively moving around, the yeast genome contains only a few dozen copies.

Like a word-find puzzle, where words are hidden in a jumbled grid of letters, the TIP-chip highlights exactly where along the DNA sequence these elements have landed. By chopping up the DNA, amplifying the DNA next to the transposable elements and then applying these amplified copies to the TIP chip, the researchers were able to map more than 94 percent of the transposable elements to their exact chromosome locations.

The second new chip, described in a separate report published in the Nov. 3 issue of Nature Methods, contains twice the amount of genetic information of current DNA chips.

"This one lets us look at twice as much as we could in the past, which means essentially that all chip experiments become faster and cheaper and can be done on an ever larger scale," says Boeke. The chips his team currently uses cost about $400 per experiment. If the amount of information can be quadrupled, "it would be four experiments for the price of one," he says.

Standard chips contain one layer of DNA dots that read from left to right, like the across section of a crossword puzzle. Boeke's new double-capacity chips hold two layers of dots, a bottom layer that reads across and a top layer that reads down, again using the crossword analogy. So if their experiment lights up a horizontal row of dots, the researchers learn that the data maps to the region of the genome contained in the bottom layer; likewise, if the experiment highlights a vertical row, the data correspond to the top layer.

Says Boeke, "It's so easy to differentiate the top and bottom layers. Next we're going to try adding another layer reading diagonally" to triple the amount of genomic information packed onto the tiny chips.

God vs. Science

We revere faith and scientific progress, hunger for miracles and for MRIs. But are the worldviews compatible? TIME convenes a debate

DAVID VAN BIEMA

There are two great debates under the broad heading of Science vs. God. The more familiar over the past few years is the narrower of the two: Can Darwinian evolution withstand the criticisms of Christians who believe that it contradicts the creation account in the Book of Genesis? In recent years, creationism took on new currency as the spiritual progenitor of "intelligent design" (I.D.), a scientifically worded attempt to show that blanks in the evolutionary narrative are more meaningful than its very convincing totality. I.D. lost some of its journalistic heat last December when a federal judge dismissed it as pseudoscience unsuitable for teaching in Pennsylvania schools.

But in fact creationism and I.D. are intimately related to a larger unresolved question, in which the aggressor's role is reversed: Can religion stand up to the progress of science? This debate long predates Darwin, but the antireligion position is being promoted with increasing insistence by scientists angered by intelligent design and excited, perhaps intoxicated, by their disciplines' increasing ability to map, quantify and change the nature of human experience. Brain imaging illustrates--in color!--the physical seat of the will and the passions, challenging the religious concept of a soul independent of glands and gristle. Brain chemists track imbalances that could account for the ecstatic states of visionary saints or, some suggest, of Jesus. Like Freudianism before it, the field of evolutionary psychology generates theories of altruism and even of religion that do not include God. Something called the multiverse hypothesis in cosmology speculates that ours may be but one in a cascade of universes, suddenly bettering the odds that life could have cropped up here accidentally, without divine intervention. (If the probabilities were 1 in a billion, and you've got 300 billion universes, why not?)

Roman Catholicism's Christoph Cardinal Schönborn has dubbed the most fervent of faith-challenging scientists followers of "scientism" or "evolutionism," since they hope science, beyond being a measure, can replace religion as a worldview and a touchstone. It is not an epithet that fits everyone wielding a test tube. But a growing proportion of the profession is experiencing what one major researcher calls "unprecedented outrage" at perceived insults to research and rationality, ranging from the alleged influence of the Christian right on Bush Administration science policy to the fanatic faith of the 9/11 terrorists to intelligent design's ongoing claims. Some are radicalized enough to publicly pick an ancient scab: the idea that science and religion, far from being complementary responses to the unknown, are at utter odds--or, as Yale psychologist Paul Bloom has written bluntly, "Religion and science will always clash." The market seems flooded with books by scientists describing a caged death match between science and God--with science winning, or at least chipping away at faith's underlying verities.

Finding a spokesman for this side of the question was not hard, since Richard Dawkins, perhaps its foremost polemicist, has just come out with The God Delusion (Houghton Mifflin), the rare volume whose position is so clear it forgoes a subtitle. The five-week New York Times best seller (now at No. 8) attacks faith philosophically and historically as well as scientifically, but leans heavily on Darwinian theory, which was Dawkins' expertise as a young scientist and more recently as an explicator of evolutionary psychology so lucid that he occupies the Charles Simonyi professorship for the public understanding of science at Oxford University.

Dawkins is riding the crest of an atheist literary wave. In 2004, The End of Faith, a multipronged indictment by neuroscience grad student Sam Harris, was published (over 400,000 copies in print). Harris has written a 96-page follow-up, Letter to a Christian Nation, which is now No. 14 on the Times list. Last February, Tufts University philosopher Daniel Dennett produced Breaking the Spell: Religion as a Natural Phenomenon, which has sold fewer copies but has helped usher the discussion into the public arena.

If Dennett and Harris are almost-scientists (Dennett runs a multidisciplinary scientific-philosophic program), the authors of half a dozen aggressively secular volumes are card carriers: In Moral Minds, Harvard biologist Marc Hauser explores the--nondivine--origins of our sense of right and wrong (September); in Six Impossible Things Before Breakfast (due in January) by self-described "atheist-reductionist-materialist" biologist Lewis Wolpert, religion is one of those impossible things; Victor Stenger, a physicist-astronomer, has a book coming out titled God: The Failed Hypothesis. Meanwhile, Ann Druyan, widow of archskeptical astrophysicist Carl Sagan, has edited Sagan's unpublished lectures on God and his absence into a book, The Varieties of Scientific Experience, out this month.

Dawkins and his army have a swarm of articulate theological opponents, of course. But the most ardent of these don't really care very much about science, and an argument in which one party stands immovable on Scripture and the other immobile on the periodic table doesn't get anyone very far. Most Americans occupy the middle ground: we want it all. We want to cheer on science's strides and still humble ourselves on the Sabbath. We want access to both MRIs and miracles. We want debates about issues like stem cells without conceding that the positions are so intrinsically inimical as to make discussion fruitless. And to balance formidable standard bearers like Dawkins, we seek those who possess religious conviction but also scientific achievements to credibly argue the widespread hope that science and God are in harmony--that, indeed, science is of God.

Informed conciliators have recently become more vocal. Stanford University biologist Joan Roughgarden has just come out with Evolution and Christian Faith, which provides what she calls a "strong Christian defense" of evolutionary biology, illustrating the discipline's major concepts with biblical passages. Entomologist Edward O. Wilson, a famous skeptic of standard faith, has written The Creation: An Appeal to Save Life on Earth, urging believers and non-believers to unite over conservation. But foremost of those arguing for common ground is Francis Collins.

Collins' devotion to genetics is, if possible, greater than Dawkins'. Director of the National Human Genome Research Institute since 1993, he headed a multinational 2,400-scientist team that co-mapped the 3 billion biochemical letters of our genetic blueprint, a milestone that then President Bill Clinton honored in a 2000 White House ceremony, comparing the genome chart to Meriwether Lewis' map of his fateful continental exploration. Collins continues to lead his institute in studying the genome and mining it for medical breakthroughs.

He is also a forthright Christian who converted from atheism at age 27 and now finds time to advise young evangelical scientists on how to declare their faith in science's largely agnostic upper reaches. His summer best seller, The Language of God: A Scientist Presents Evidence for Belief (Free Press), laid out some of the arguments he brought to bear in the 90-minute debate TIME arranged between Dawkins and Collins in our offices at the Time & Life Building in New York City on Sept. 30. Some excerpts from their spirited exchange:

TIME: Professor Dawkins, if one truly understands science, is God then a delusion, as your book title suggests?

DAWKINS: The question of whether there exists a supernatural creator, a God, is one of the most important that we have to answer. I think that it is a scientific question. My answer is no.

TIME: Dr. Collins, you believe that science is compatible with Christian faith.

COLLINS: Yes. God's existence is either true or not. But calling it a scientific question implies that the tools of science can provide the answer. From my perspective, God cannot be completely contained within nature, and therefore God's existence is outside of science's ability to really weigh in.

TIME: Stephen Jay Gould, a Harvard paleontologist, famously argued that religion and science can coexist, because they occupy separate, airtight boxes. You both seem to disagree.

COLLINS: Gould sets up an artificial wall between the two worldviews that doesn't exist in my life. Because I do believe in God's creative power in having brought it all into being in the first place, I find that studying the natural world is an opportunity to observe the majesty, the elegance, the intricacy of God's creation.

DAWKINS: I think that Gould's separate compartments was a purely political ploy to win middle-of-the-road religious people to the science camp. But it's a very empty idea. There are plenty of places where religion does not keep off the scientific turf. Any belief in miracles is flat contradictory not just to the facts of science but to the spirit of science.

TIME: Professor Dawkins, you think Darwin's theory of evolution does more than simply contradict the Genesis story.

DAWKINS: Yes. For centuries the most powerful argument for God's existence from the physical world was the so-called argument from design: Living things are so beautiful and elegant and so apparently purposeful, they could only have been made by an intelligent designer. But Darwin provided a simpler explanation. His way is a gradual, incremental improvement starting from very simple beginnings and working up step by tiny incremental step to more complexity, more elegance, more adaptive perfection. Each step is not too improbable for us to countenance, but when you add them up cumulatively over millions of years, you get these monsters of improbability, like the human brain and the rain forest. It should warn us against ever again assuming that because something is complicated, God must have done it.

COLLINS: I don't see that Professor Dawkins' basic account of evolution is incompatible with God's having designed it.

TIME: When would this have occurred?

COLLINS: By being outside of nature, God is also outside of space and time. Hence, at the moment of the creation of the universe, God could also have activated evolution, with full knowledge of how it would turn out, perhaps even including our having this conversation. The idea that he could both foresee the future and also give us spirit and free will to carry out our own desires becomes entirely acceptable.

DAWKINS: I think that's a tremendous cop-out. If God wanted to create life and create humans, it would be slightly odd that he should choose the extraordinarily roundabout way of waiting for 10 billion years before life got started and then waiting for another 4 billion years until you got human beings capable of worshipping and sinning and all the other things religious people are interested in.

COLLINS: Who are we to say that that was an odd way to do it? I don't think that it is God's purpose to make his intention absolutely obvious to us. If it suits him to be a deity that we must seek without being forced to, would it not have been sensible for him to use the mechanism of evolution without posting obvious road signs to reveal his role in creation?

TIME: Both your books suggest that if the universal constants, the six or more characteristics of our universe, had varied at all, it would have made life impossible. Dr. Collins, can you provide an example?

COLLINS: The gravitational constant, if it were off by one part in a hundred million million, then the expansion of the universe after the Big Bang would not have occurred in the fashion that was necessary for life to occur. When you look at that evidence, it is very difficult to adopt the view that this was just chance. But if you are willing to consider the possibility of a designer, this becomes a rather plausible explanation for what is otherwise an exceedingly improbable event--namely, our existence.

DAWKINS: People who believe in God conclude there must have been a divine knob twiddler who twiddled the knobs of these half-dozen constants to get them exactly right. The problem is that this says, because something is vastly improbable, we need a God to explain it. But that God himself would be even more improbable. Physicists have come up with other explanations. One is to say that these six constants are not free to vary. Some unified theory will eventually show that they are as locked in as the circumference and the diameter of a circle. That reduces the odds of them all independently just happening to fit the bill. The other way is the multiverse way. That says that maybe the universe we are in is one of a very large number of universes. The vast majority will not contain life because they have the wrong gravitational constant or the wrong this constant or that constant. But as the number of universes climbs, the odds mount that a tiny minority of universes will have the right fine-tuning.

COLLINS: This is an interesting choice. Barring a theoretical resolution, which I think is unlikely, you either have to say there are zillions of parallel universes out there that we can't observe at present or you have to say there was a plan. I actually find the argument of the existence of a God who did the planning more compelling than the bubbling of all these multiverses. So Occam's razor--Occam says you should choose the explanation that is most simple and straightforward--leads me more to believe in God than in the multiverse, which seems quite a stretch of the imagination.

DAWKINS: I accept that there may be things far grander and more incomprehensible than we can possibly imagine. What I can't understand is why you invoke improbability and yet you will not admit that you're shooting yourself in the foot by postulating something just as improbable, magicking into existence the word God.

COLLINS: My God is not improbable to me. He has no need of a creation story for himself or to be fine-tuned by something else. God is the answer to all of those "How must it have come to be" questions.

DAWKINS: I think that's the mother and father of all cop-outs. It's an honest scientific quest to discover where this apparent improbability comes from. Now Dr. Collins says, "Well, God did it. And God needs no explanation because God is outside all this." Well, what an incredible evasion of the responsibility to explain. Scientists don't do that. Scientists say, "We're working on it. We're struggling to understand."

COLLINS: Certainly science should continue to see whether we can find evidence for multiverses that might explain why our own universe seems to be so finely tuned. But I do object to the assumption that anything that might be outside of nature is ruled out of the conversation. That's an impoverished view of the kinds of questions we humans can ask, such as "Why am I here?", "What happens after we die?", "Is there a God?" If you refuse to acknowledge their appropriateness, you end up with a zero probability of God after examining the natural world because it doesn't convince you on a proof basis. But if your mind is open about whether God might exist, you can point to aspects of the universe that are consistent with that conclusion.

DAWKINS: To me, the right approach is to say we are profoundly ignorant of these matters. We need to work on them. But to suddenly say the answer is God--it's that that seems to me to close off the discussion.

TIME: Could the answer be God?

DAWKINS: There could be something incredibly grand and incomprehensible and beyond our present understanding.

COLLINS: That's God.

DAWKINS: Yes. But it could be any of a billion Gods. It could be God of the Martians or of the inhabitants of Alpha Centauri. The chance of its being a particular God, Yahweh, the God of Jesus, is vanishingly small--at the least, the onus is on you to demonstrate why you think that's the case.

TIME: The Book of Genesis has led many conservative Protestants to oppose evolution and some to insist that the earth is only 6,000 years old.

COLLINS: There are sincere believers who interpret Genesis 1 and 2 in a very literal way that is inconsistent, frankly, with our knowledge of the universe's age or of how living organisms are related to each other. St. Augustine wrote that basically it is not possible to understand what was being described in Genesis. It was not intended as a science textbook. It was intended as a description of who God was, who we are and what our relationship is supposed to be with God. Augustine explicitly warns against a very narrow perspective that will put our faith at risk of looking ridiculous. If you step back from that one narrow interpretation, what the Bible describes is very consistent with the Big Bang.

DAWKINS: Physicists are working on the Big Bang, and one day they may or may not solve it. However, what Dr. Collins has just been--may I call you Francis?

COLLINS: Oh, please, Richard, do so.

DAWKINS: What Francis was just saying about Genesis was, of course, a little private quarrel between him and his Fundamentalist colleagues ...

COLLINS: It's not so private. It's rather public. [Laughs.]

DAWKINS: ... It would be unseemly for me to enter in except to suggest that he'd save himself an awful lot of trouble if he just simply ceased to give them the time of day. Why bother with these clowns?

COLLINS: Richard, I think we don't do a service to dialogue between science and faith to characterize sincere people by calling them names. That inspires an even more dug-in position. Atheists sometimes come across as a bit arrogant in this regard, and characterizing faith as something only an idiot would attach themselves to is not likely to help your case.

TIME: Dr. Collins, the Resurrection is an essential argument of Christian faith, but doesn't it, along with the virgin birth and lesser miracles, fatally undermine the scientific method, which depends on the constancy of natural laws?

COLLINS: If you're willing to answer yes to a God outside of nature, then there's nothing inconsistent with God on rare occasions choosing to invade the natural world in a way that appears miraculous. If God made the natural laws, why could he not violate them when it was a particularly significant moment for him to do so? And if you accept the idea that Christ was also divine, which I do, then his Resurrection is not in itself a great logical leap.

TIME: Doesn't the very notion of miracles throw off science?

COLLINS: Not at all. If you are in the camp I am, one place where science and faith could touch each other is in the investigation of supposedly miraculous events.

DAWKINS: If ever there was a slamming of the door in the face of constructive investigation, it is the word miracle. To a medieval peasant, a radio would have seemed like a miracle. All kinds of things may happen which we by the lights of today's science would classify as a miracle just as medieval science might a Boeing 747. Francis keeps saying things like "From the perspective of a believer." Once you buy into the position of faith, then suddenly you find yourself losing all of your natural skepticism and your scientific--really scientific--credibility. I'm sorry to be so blunt.

COLLINS: Richard, I actually agree with the first part of what you said. But I would challenge the statement that my scientific instincts are any less rigorous than yours. The difference is that my presumption of the possibility of God and therefore the supernatural is not zero, and yours is.

TIME: Dr. Collins, you have described humanity's moral sense not only as a gift from God but as a signpost that he exists.

COLLINS: There is a whole field of inquiry that has come up in the last 30 or 40 years--some call it sociobiology or evolutionary psychology--relating to where we get our moral sense and why we value the idea of altruism, and locating both answers in behavioral adaptations for the preservation of our genes. But if you believe, and Richard has been articulate in this, that natural selection operates on the individual, not on a group, then why would the individual risk his own DNA doing something selfless to help somebody in a way that might diminish his chance of reproducing? Granted, we may try to help our own family members because they share our DNA. Or help someone else in expectation that they will help us later. But when you look at what we admire as the most generous manifestations of altruism, they are not based on kin selection or reciprocity. An extreme example might be Oskar Schindler risking his life to save more than a thousand Jews from the gas chambers. That's the opposite of saving his genes. We see less dramatic versions every day. Many of us think these qualities may come from God--especially since justice and morality are two of the attributes we most readily identify with God.

DAWKINS: Can I begin with an analogy? Most people understand that sexual lust has to do with propagating genes. Copulation in nature tends to lead to reproduction and so to more genetic copies. But in modern society, most copulations involve contraception, designed precisely to avoid reproduction. Altruism probably has origins like those of lust. In our prehistoric past, we would have lived in extended families, surrounded by kin whose interests we might have wanted to promote because they shared our genes. Now we live in big cities. We are not among kin nor people who will ever reciprocate our good deeds. It doesn't matter. Just as people engaged in sex with contraception are not aware of being motivated by a drive to have babies, it doesn't cross our mind that the reason for do-gooding is based in the fact that our primitive ancestors lived in small groups. But that seems to me to be a highly plausible account for where the desire for morality, the desire for goodness, comes from.

COLLINS: For you to argue that our noblest acts are a misfiring of Darwinian behavior does not do justice to the sense we all have about the absolutes that are involved here of good and evil. Evolution may explain some features of the moral law, but it can't explain why it should have any real significance. If it is solely an evolutionary convenience, there is really no such thing as good or evil. But for me, it is much more than that. The moral law is a reason to think of God as plausible--not just a God who sets the universe in motion but a God who cares about human beings, because we seem uniquely amongst creatures on the planet to have this far-developed sense of morality. What you've said implies that outside of the human mind, tuned by evolutionary processes, good and evil have no meaning. Do you agree with that?

DAWKINS: Even the question you're asking has no meaning to me. Good and evil--I don't believe that there is hanging out there, anywhere, something called good and something called evil. I think that there are good things that happen and bad things that happen.

COLLINS: I think that is a fundamental difference between us. I'm glad we identified it.

TIME: Dr. Collins, I know you favor the opening of new stem-cell lines for experimentation. But doesn't the fact that faith has caused some people to rule this out risk creating a perception that religion is preventing science from saving lives?

COLLINS: Let me first say as a disclaimer that I speak as a private citizen and not as a representative of the Executive Branch of the United States government. The impression that people of faith are uniformly opposed to stem-cell research is not documented by surveys. In fact, many people of strong religious conviction think this can be a morally supportable approach.

TIME: But to the extent that a person argues on the basis of faith or Scripture rather than reason, how can scientists respond?

COLLINS: Faith is not the opposite of reason. Faith rests squarely upon reason, but with the added component of revelation. So such discussions between scientists and believers happen quite readily. But neither scientists nor believers always embody the principles precisely. Scientists can have their judgment clouded by their professional aspirations. And the pure truth of faith, which you can think of as this clear spiritual water, is poured into rusty vessels called human beings, and so sometimes the benevolent principles of faith can get distorted as positions are hardened.

DAWKINS: For me, moral questions such as stem-cell research turn upon whether suffering is caused. In this case, clearly none is. The embryos have no nervous system. But that's not an issue discussed publicly. The issue is, Are they human? If you are an absolutist moralist, you say, "These cells are human, and therefore they deserve some kind of special moral treatment." Absolutist morality doesn't have to come from religion but usually does.

We slaughter nonhuman animals in factory farms, and they do have nervous systems and do suffer. People of faith are not very interested in their suffering.

COLLINS: Do humans have a different moral significance than cows in general?

DAWKINS: Humans have more moral responsibility perhaps, because they are capable of reasoning.

TIME: Do the two of you have any concluding thoughts?

COLLINS: I just would like to say that over more than a quarter-century as a scientist and a believer, I find absolutely nothing in conflict between agreeing with Richard in practically all of his conclusions about the natural world, and also saying that I am still able to accept and embrace the possibility that there are answers that science isn't able to provide about the natural world--the questions about why instead of the questions about how. I'm interested in the whys. I find many of those answers in the spiritual realm. That in no way compromises my ability to think rigorously as a scientist.

DAWKINS: My mind is not closed, as you have occasionally suggested, Francis. My mind is open to the most wonderful range of future possibilities, which I cannot even dream about, nor can you, nor can anybody else. What I am skeptical about is the idea that whatever wonderful revelation does come in the science of the future, it will turn out to be one of the particular historical religions that people happen to have dreamed up. When we started out and we were talking about the origins of the universe and the physical constants, I provided what I thought were cogent arguments against a supernatural intelligent designer. But it does seem to me to be a worthy idea. Refutable--but nevertheless grand and big enough to be worthy of respect. I don't see the Olympian gods or Jesus coming down and dying on the Cross as worthy of that grandeur. They strike me as parochial. If there is a God, it's going to be a whole lot bigger and a whole lot more incomprehensible than anything that any theologian of any religion has ever proposed.

RNA polymerase III transcribes human microRNAs [FractoGem-s are miR-acle sites?]

Prior work demonstrates that mammalian microRNA (miRNA or miR) expression requires RNA polymerase II (Pol II). However, the transcriptional requirements of many miRNAs remain untested.

Our genomic analysis of miRNAs in the human chromosome 19 miRNA cluster (C19MC) revealed that they are interspersed among Alu repeats. Because Alu transcription occurs through RNA Pol III recruitment, and we found that Alu elements upstream of C19MC miRNAs retain sequences important for Pol III activity, we tested the promoter requirements of C19MC miRNAs.

Chromatin immunoprecipitation and cell-free transcription assays showed that Pol III, but not Pol II, is associated with miRNA genomic sequence and sufficient for transcription. Moreover, the mature miRNA sequences of approximately 50 additional human miRNAs lie within Alu and other known repetitive elements. These findings extend the current view of miRNA origins and the transcriptional machinery driving their expression.

TCAG - The Institute for Genomic Research, Venter Institute, Venter Science Foundation Consolidate

Claire Fraser-Liggett, Ph.D., is TIGR Division President, Robert Strausberg, Ph.D., is named President of TCAG Division

ROCKVILLE, MD — October 16, 2006 — The Boards of Directors of the J. Craig Venter Institute (JCVI), The Institute of Genomic Research (TIGR) and the J. Craig Venter Science Foundation (JCVSF) today announced the consolidation of these affiliated organizations into one organization, the J. Craig Venter Institute. The research organization formerly known as JCVI will be renamed The Center for the Advancement of Genomics (TCAG).

J. Craig Venter, Ph.D., was named as the Chairman and Chief Executive Officer of the new JCVI. TIGR, now a division of the JCVI, will continue to be led by Claire Fraser-Liggett, Ph.D., as President. Eric Eisenstadt, Ph.D., will remain as VP for Research at TIGR. TCAG will also be a division of the JCVI and will be led by new President, Robert Strausberg, Ph.D., with Marv Frazier, Ph.D., maintaining his role as VP of Research at TCAG. Both operating divisions will retain their existing research and administrative staff members.

With six buildings and more than 250,000 square feet of lab space for combined assets of more than $200 million, the consolidated JCVI is now one of the largest independent research institutes in the United States. Total number of employees is 520, 392 of whom are dedicated to research and 124 of those having doctoral degrees. The new organization also boasts one Nobel Laureate and three members of the National Academy of Sciences.

Drs. Venter, Fraser-Liggett, Strausberg, Eisenstadt, and Frazier made the following statement about the consolidated organization:

"After much planning and discussions over the last year we and our boards of directors decided that consolidating all the affiliated organizations into one not for profit research institute was a very financially, administratively and scientifically prudent step for us. We are excited by the potential new collaborations and funding opportunities the consolidated J. Craig Venter Institute affords us. While TIGR and the former JCVI have been leading the way in genomic breakthroughs for more than 15 years, we are now confident that our unified organization will be an even greater scientific force in genomic research."

[Genomics, either as a "zero sum game" or as a "hyper-escalating field" absolutely demands major consolidation at a time of global re-alignement of resources, in coping with "coding" versus "non-coding DNA" paradigm-shift. If "Genomics" resources stay steady, there will be a tremendous tension between "Dogmatic Genetics" trying to push PostGenetics into "n-th priority" (for instance, keep spending on sequencing without a first priority on decoding already sequenced DNA, or keep spending on "Gene Discovery" instead of switching to "PostGene Discovery"). This tension, if alternative paradigms slice one single pie in different ways in competing for funds, would break apart loose structures - unless consolidated. However, with "Genetics beyond Genes" hyper-escalating, the pool of resources is likely to rapidly expand, favoring consolidated entities that are set up for "whole genome analysis". The biggest winners are likely to be those centers that put "non-coding DNA into priority number one" - since they will have the competitive edge- comment A. J. Pellionisz, 8th of November, 2006]

Study to genotype six common ["junk DNA"] diseases

Science Daily

WASHINGTON, DC, United States (UPI) -- Six common diseases have been selected as the first to undergo whole genome analysis by the U.S. Genetic Association Information Network.

The Foundation for the National Institutes of Health says the type of analysis to be obtained is designed to identify the genetic contributions to common illnesses that affect the public health.

The six diseases are: psoriasis, attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, major depression and anxiety, and diabetic nephropathy.

Using biological samples collected during earlier clinical studies, GAIN will evaluate the subtle differences between the genomes of approximately 1,000-2,000 healthy volunteers and the genomes of 1,000-2,000 patients with the condition being studied. Scientists say identifying genetic differences between the two groups will speed development of methods to prevent, diagnose, treat and even cure common conditions.

The Genetic Association Information Network is a public-private partnership involving the National Institutes of Health; Pfizer Inc.; Affymetrix Inc., of Santa Clara, Calif.; Perlegen Sciences Inc. of Mountain View, Calif.; Abbott Laboratories of Abbott Park, Ill.; and the Broad Institute of the Massachusetts Institute of Technology and Harvard University.

[Note that all six are "junk DNA diseases", and 5 out of 6 are "CNS diseases", with a leading industrial component focusing on "microarray technology". Prediction is that the effort will create a focus for competition for "PostGene Discovery" by pattern (rather than SNPs) analysis, towards identification of non-genic (non-coding DNA) causes of diseases apparently without any single "gene" responsible - comment A. J. Pellionisz, 7th of November, 2006]

MIT's anti-microbial 'grammar' posits new language of healing

Custom peptides punch holes in anthrax, staph bacteria

Anne Trafton, News Office

In most languages, sentences only make sense if the words are placed in the right order. Now, MIT researchers and an IBM colleague have used grammatical principles to help their search for new antimicrobial medicines.

After identifying "grammatical" patterns in naturally occurring antimicrobial peptides, the researchers custom-designed molecules that proved extremely effective in killing microbes, including anthrax bacteria. The research could lead to new medicines to combat deadly drug-resistant bacteria.

"In the last 40 years, there have been only two new classes of antibiotic drugs discovered and brought to the market," said graduate student Christopher Loose, lead author of a paper on the work that appears in the Oct. 19 issue of Nature. "There is an incredible need to come up with new medicines."

Loose, research associate Kyle Jensen and Professor Gregory Stephanopoulos of the Department of Chemical Engineering are focusing their attention on antimicrobial peptides, or short strings of amino acids. Such peptides are naturally found in multicellular organisms, where they play a role in defense against infectious bacteria.

The researchers' newly designed peptides were shown to be effective against dangerous microbes such as Bacillus anthracis (anthrax) and Staphyloccus aureus, a bacteria that spreads in hospitals and is frequently drug-resistant. The peptides may also be less likely to induce drug resistance in these bacteria, according to the researchers.

Antimicrobial peptides act by attaching to bacterial membranes and punching holes in them, an attack that is general to many different types of bacteria and is difficult for them to defend against. "There's no quick easy mutation fix for a bacteria to get around this non-specific membrane attack," said Loose.

The peptides are generally short, consisting of about 20 amino acid building blocks. The molecules naturally fold into a helix, with positively charged areas running along one side of the helix and hydrophobic (water-resisting) areas along the other side. The charged ends allow the peptides to latch onto the bacteria by attracting the negative charges of the bacterial membrane, while the hydrophobic ends punch holes in the membrane.

Because there are 20 naturally occurring amino acids, there are about 1026 possible peptide sequences of length 20. Some of those kill microbes with varying levels of effectiveness; the overwhelming majority have no effect.

With such a mind-boggling number of possible combinations, it is extremely difficult to find effective antimicrobial peptides by using traditional methods such as testing random sequences or slightly tweaking naturally existing peptides. "Designing them from scratch is quite difficult," said Loose.

Instead, the researchers decided to take a more strategic approach, based on grammatical patterns in the peptide sequences.

At its essence, a "grammar" is a simple rule that describes the allowed arrangements of words in a given language. As it applies to peptides, the sequence can be thought of as a sentence, while the individual amino acids are the words. For example, the sequence QxEAGxLxKxxK, where x is any amino acid and Q, E, A, etc. are specific amino acids, is a pattern that occurs in more than 90 percent of a certain class of insect antimicrobial proteins known as cecropins.

In this case, the researchers, led by Jensen and Isidore Rigoutsos of IBM Research (Rigoutsos is also a visiting lecturer in the Department of Chemical Engineering), used a pattern discovery tool to find about 700 grammatical patterns in the sequences of 526 naturally occurring antimicrobial peptides.

To design their new peptides, the researchers first came up with all possible 20-amino acid sequences in which each overlapping string of 10 amino acids conformed to one of the grammars. They then removed any peptides that had six or more amino acids in a row in common with naturally occurring peptides. Then, they threw out sequences that were very similar to each other and chose 42 peptides to test.

About half of the peptides displayed significant antimicrobial activity against two common strains of bacteria -- Escherichia coli and Bacillus cereus. That is a much higher success rate than one would expect from testing randomly generated sequences, and much higher than the success rate for peptides with the same amino acids as the designed sequences, but in a shuffled order.

"We've been able to focus our shotgun approach so that half of the time, we get a hit," said Loose.

In further tests, two of the designed peptides showed very high effectiveness against two types of especially dangerous bacteria, S. aureus and anthrax.

The researchers have already begun using their technique to further refine the most effective peptides by tinkering with the sequences and altering traits like charge and hydrophobicity. They hope this process will eventually lead to new, more effective antimicrobial medicines.

The research was funded by the Singapore-MIT Alliance, the National Institutes of Health and the Fannie and John Hertz Foundation.

Human Epigenome Project generates DNA methylation profiles of three chromosomes

Towards a Global Map of Epigenetic Variation
29 October 2006

A new DNA map, published in Nature Genetics today, provides the first large-scale study of biological inheritance in human that is not DNA-sequence based. The map of human chromosomes 6, 20 and 22 shows that as many as one in six of our human genes might be subject to modifications that could alter their activity by epigenetic changes - under the influence of the environment. Understanding these modifications will be important in diagnosis, drug development and disease study.

The epigenome is the interface of genetics and environment, where plasticity of epigenetic changes modifies the hard wiring of our genetic code. Increasingly it is thought that at this interface lie clues to how lifestyle and the environment affect our susceptibility to many diseases.

Epigenetic changes include modification of DNA bases, through addition or removal of simple chemical tags, such as a methyl group, and similar changes of the proteins that are closely entwined with DNA to form chromatin, the functional form of the genome. Collectively, these modifications are also referred to as the 'epigenetic code' which researchers believe defines how different genetic programmes can be executed from the same genome in different tissues.

To examine how and where DNA modification might vary, the team from the Wellcome Trust Sanger Institute and Epigenomics AG measured levels of DNA methylation across three chromosomes in twelve different tissues. The results, from almost two million measurements, looked for differences between tissues as well as differences that might be linked to age or sex.

Although DNA methylation can vary over a wide dynamic range, the study revealed the majority of sites to have on/off status (e.g. being unmethylated or methylated) and identified distinct regions in the genome where methylation differs between tissues but no significant differences were found between two age groups - average age 26 years old and average age 68 years old. Age has been suspected to influence the plastic changes in methylation, and perhaps influence disease processes, but these remarkable results suggest methylation states are more stable than previously thought. The authors do emphasize that discrete changes may occur in regions or tissues not examined here.

Moreover, the two sexes showed indistinguishable patterns of methylation of regions not on the sex chromosomes, X and Y, or part of imprinted regions which are known to have parent-of-origin specific methylation patterns. Except for those regions, the global patterns of methylation are thus the same in males and females.

"There is much less noise in the system than we feared," explained Dr Stephan Beck, Project Leader at the Wellcome Trust Sanger Institute, "Our data show DNA methylation to be stable, specific and essentially binary (that is, on or off) - all key hallmarks of informative clinical markers. Our conclusion is that epigenetic markers will be a powerful addition to the current repertoire of genetic markers for future disease association studies, particularly where non-genetic factors are known to play a role, for example in cancer, and where they are suspected, as in autoimmune disease."

Analysis of the global epigenetic landscape revealed methylation to be tissue- and cell-type specific with sperm showing the greatest difference (up to 20%) when compared to other cell types, emphasizing the extensive epigenetic reprogramming during gametogenesis.

The team found that tissue-specific methylation of one in three genes they studied was associated with changed levels of gene activity. Intriguingly, tissue-specific differences were enriched in regions called evolutionary conserved regions (ECRs), lying distant from genes, out in the 'junk' DNA. ECRs were more often differentially methylated than regions close to genes, suggesting they might have an undiscovered role in gene or chromosome activity.

The study also looked at predicted genes that have decayed and appear to have lost function - so-called pseudogenes - or lack experimental verification. The control regions for almost 90% were methylated, suggesting that methylation plays a role in silencing such genes and that many of the predicted genes might also be non-functional.

In 70% of cases, the patterns of methylation were also conserved between mouse and human tissues. Less than 5% differed to a great extent, supporting previous studies that suggest some epigenetic states to be conserved between these two species.

This stage of the HEP has defined the extent of methylation on a chromosomal scale and identified new possible roles for regions of the genome that we understand only poorly. But its importance goes beyond that.

"This is by far the most comprehensive study in understanding epigenetic differences," commented Professor Peter Jones, Director at the University of Southern California/Norris Comprehensive Cancer Center and a member of the Advisory Board of Epigenomics AG. "It is a breakthrough: we now have a sense of chromosome-wide epigenetics and this study shows what can be done to unravel this complex and clinically important process."

"The achievements serve to emphasize the need for genome-wide analysis of epigenetics - not only the study of methylation differences of DNA but also of chromatin changes. We know from individual studies that these changes are important in some diseases and we need now to establish a comprehensive study programme. The recently initiated international Alliance for Human Epigenomics and Disease (AHEAD) project by the American Association for Cancer Research can be expected to be invaluable for our understanding how genomes function and to take us toward a truly integrated (epi)genetic approach to common disease."

MicroRNA evolution put to the test

Two Nature Genetics papers probe evolution and functionality of microRNAs and their target sites
The Scientist
By Jeffrey M. Perkel
[Published 30th October 2006 02:43 PM GMT]

Nikolaus Rajewsky [from New York City to Berlin, Germany - AJP]

MicroRNA genes and their target sites are under Darwinian selection and continue to evolve, according to a pair of papers out this week in Nature Genetics. Nikolaus Rajewsky used genotyping data to show that predicted microRNA target sites are under negative Darwinian pressure, while Ronald Plasterk used a massively parallel sequencing approach to identify several hundred candidate microRNAs, many of which are restricted to humans, primates, or vertebrates in general.

"My reaction is, this is why we put the genomes out there," said Bob Waterston, chair and professor of genome sciences at the University of Washington, who helped generate many of the genome sequences used in the Plasterk paper. "You can see these papers taking advantage of the wealth of sequence information... I find it very gratifying."

"It's an advance for evolutionary biologists and systems biologists who are interested in how humans are wired," added Phillip Zamore, Gretchen Stone Cook Professor of Biomedical Sciences at the University of Massachusetts Medical Center. "It gives them another variable for their models."

MicroRNAs are short, non-coding RNAs that post-transcriptionally repress gene expression either by blocking translation or inducing the degradation of targeted mRNAs. Several hundred miRNAs and tens of thousands of potential targets have already been identified or predicted, but two basic questions remained: how many more miRNAs are there, and which of the predicted target sites are functional?

"The whole issue of being able to both predict microRNAs and then to predict their targets is a big challenge," said Waterston.

Plasterk, professor of developmental genetics at the University of Utrecht, the Netherlands, used massively parallel sequencing technology to produce 400,000 sequence reads from small RNAs found in human fetal brain and adult chimpanzee brain. After filtering out irrelevant reads such as tRNAs, rRNAs, and other known miRNAs, Plasterk's team was left with 244 novel human and 230 novel chimpanzee candidate miRNAs, most of which were expressed at very low levels.

The team then used comparative genomics to examine the conservation of these transcripts over hundreds of millions of years of evolution. Eight percent of the novel human miRNAs identified in this study were restricted to humans, more than half were restricted to primates, 30% were limited to mammals, and 9% were restricted to nonmammalian vertebrates or invertebrates. In several cases, said Plasterk, the genomic location of the miRNA genes was found to be dynamic across evolutionary time; for instance, there might be a single gene at the human miRNA locus, but two genes at the corresponding chimp position. "I like to see that, because microRNAs could be an important factor in sculpting development in evolution," he said.

"The idea that microRNAs can contribute to species identity has been bandied about for some time, and this is nice confirmation of that," said Zamore. "We're beginning to home in on what makes us, us."

In the second paper, Rajewsky, of the Max Delbruck Center for Molecular Medicine in Berlin, looked over a much shorter stretch of evolutionary time to determine whether predicted miRNA target sites are under negative Darwinian pressure. Rajewsky used single nucleotide polymorphism data from the HapMap and Perlegen genotyping projects, which effectively are limited to the time since humans radiated out of Africa, to analyze the allele frequencies of human polymorphisms in predicted miRNA binding sites from the 3' untranslated regions of mRNAs.

Rajewsky found that SNP density and allele frequencies were indicative of negative selective pressure acting on these target sites. Importantly, the team observed such selective pressures both on sites that are evolutionarily conserved and on those that are restricted to humans. "That's very cool, because previously people thought those [non-conserved] sites might not be functional," said Zamore.

"This new approach lets us estimate the number of predicted sites that do make a contribution to human fitness, not only for evolutionarily conserved predicted targets, but also for sites specific for humans," said Rajewsky. Based on his data, Rajewsky estimates that about 85% of conserved miRNA target sites are likely to be functional. In addition, "we showed that if microRNAs and their targets are coexpressed, then 30% to 50% of [nonconserved] predicted sites are likely to be functional," Rajewsky said. "That's kind of neat, because it is a population genetics technique applied to making statements about a whole layer of gene regulatory control and its evolution in humans."

The negative pressure on these miRNA target sites suggests mutation in these sites could lead to disease, said Rajewsky. "We now have a couple hundred candidates for investigating human disease, because we found variations in sites that are presumed to be functional." Next, he will apply his technique to other non-coding, regulatory elements, such as transcription factor-binding sites.

The net result of these two studies, according to Zamore, is a novel method for predicting and validating human-specific (that is, nonconserved) miRNA target sites.

"If you have a microRNA that is unique to humans, how would you find its target computationally? All the really robust algorithms rely on conservation, so by definition they cannot be used to find targets of human-specific microRNAs," said Zamore. "Now you use the SNP data among humans from the Rajewsky method to look for negative selection against loss of microRNA target complementarity."

Genetic Repair Mechanism Clears The Way For Sealing DNA Breaks

Scientists investigating an important DNA-repair enzyme now have a better picture of the final steps of a process that glues together, or ligates, the ends of DNA strands to restore the double helix.

The enzyme, DNA ligase, repairs the millions of DNA breaks generated during the normal course of a cell's life, for example, linking together the abundant DNA fragments formed during replication of the genetic material in dividing cells.

"Our study shows that DNA ligase switches from an open, extended shape to a closed, circular shape as it joins DNA strands together," says the study's senior author Tom Ellenberger, D.V.M, Ph.D., the Raymond H. Wittcoff Professor and head of the Department of Biochemistry and Molecular Biophysics at Washington University School of Medicine in St. Louis. "The ligase resembles a wristwatch that latches around the DNA ends that are being joined."

DNA is surprisingly reactive and under continuous assault from environmental toxins and reactive cellular metabolites. A means of repairing DNA damage is vital to maintaining the integrity of the genetic blueprint.

When these repair processes go awry, cells can malfunction, die or become cancerous, so researchers would like to know how "DNA mechanics" do their jobs. DNA ligases are attractive targets for the chemotherapy of cancer and other diseases.

DNA ligase works in concert with another ring-shaped protein known as a sliding clamp. Sliding clamps, such as the human PCNA protein, are master regulators of DNA repair, providing docking sites that recruit repair enzymes to the site of damage.

"When ligase stacks against PCNA and encircles the DNA, we think this interaction ejects other repair proteins from PCNA," says Ellenberger. "In this role, ligase may serve as the final arbiter of DNA repair, certifying that the DNA is in pristine condition and ready for the final step of DNA end joining."

In this study of DNA ligase, published in the Oct. 20 issue of Molecular Cell, Ellenberger's research group teamed with scientists from The Scripps Research Institute (TSRI), the University of Maryland School of Medicine and Lawrence Berkeley National Laboratory (LBNL).

To visualize the complicated and dynamic structures of DNA ligase and PCNA, both separately and in a complex, Ellenberger and his group worked closely with LBNL scientists to take advantage of the intense X-rays and advanced technologies of the SIBYLS synchrotron beamline at the Berkeley lab Advanced Light Source.

The researchers used a combination of X-ray crystallography and small angle X-ray scattering (SAXS). They conducted their studies with a model organism called Sulfolobus solfataricus that has many of the same biochemical characteristics of multicelled organisms, including humans.

"We expected that DNA ligase would latch shut when bound to the ring-shaped PCNA protein," says Ellenberger. "However, the SAXS experiment clearly shows that ligase remains in an open conformation enabling other repair proteins to bind PCNA until the DNA is engaged and ligase snaps shut."

Co-author John Tainer, Ph.D., professor at LBNL and TSRI, says the results reveal for the first time how these proteins can dynamically assemble and change their shape to join DNA ends during replication and repair.

The closed conformation of DNA ligase bound to DNA was imaged in a separate study previously reported by Ellenberger's group. Ellenberger says that the challenge for the future is to study the molecular choreography of ligase, PCNA and DNA in the same experiment, which will require new methods of analyzing the SAXS data.

"The SAXS methods offer a powerful means of visualizing large proteins and protein complexes that are difficult or impossible to crystallize," says Ellenberger. "Imaging of complex processes will require a variety of tools that address different levels of biological organization from the molecular level to whole animals."

Research on biological imaging is one aspect of the University's BioMed21 initiative, which calls for converting knowledge of genetic mechanisms into practical applications.

NSF awards UGA $4.1 million grant to study so-called 'jumping genes' in maize

Transposable elements, popularly called "jumping genes" when they were discovered more than half a century ago, are sequences of DNA that can move around chromosomes in a cell. At first thought to be molecular "junk," they are now recognized as important, even crucial parts of the blueprints of plants and animals.

The National Science Foundation has awarded a grant of $4.1 million to the University of Georgia to identify all the transposable elements (TE's) in maize and to generate an annotated database that will assist all future research in this crop plant crucial across the globe.

"The collective experiences of the team that will work on this puts us in a unique position," said Susan Wessler, Regents Professor of plant biology at UGA and principal investigator. "Maize is the organism of choice for understanding how TE's contribute to gene and genome evolution."

All information from the project, which is expected to take five years, will be made freely available to the Maize Genome Sequencing Project and to long-term repositories such as the Maize Genome Database.

"The scientific goals of this project and the familiarity of maize also provide outstanding opportunities for student training and for connections between the research community and the broader public," said Wessler. "This project will dedicate more than 15 percent of its resources to the development of web-based, traveling and local museum exhibits that describe the history of maize as a crop, as a model organism for research and as a key component for many Native American cultures."

To this end, collaborations have been established with the UGA Museum of Natural History, the Smithsonian Institution and the U.S. Botanic Garden.

Genomes differ dramatically in the percentage of TE's in their genomes. For instance, half of human DNA is transposable elements, while in some plants, the amount is more than 90 percent. About 80 percent of maize genomic DNA is derived from TE's.

The project also has an in-lab minority outreach component. Each participating institution has a commitment to the education of undergraduates, high school students and other members of the broader community, especially in the representation of under-represented groups.

Scientist Barbara McClintock discovered the first TE's in maize in 1948, work that led to her winning the Nobel Prize in 1983.

International PostGenetics Society European Inaugural; misnomer "Junk DNA" is formally abandoned

Malcolm J. Simons (right) accepts Honorary Chairmanship of IPGS

International PostGenetics Society held its highly successful European Inaugural on the 12th of October, 2006 in Budapest, Hungary. Dr. Malcolm J. Simons accepted "Honorary Chairmanship" of IPGS, and Originator (AJP) was also decorated by BCII2006 Chairman Prof. Falus (center). The scientific program featured presentations by 9 of the 41 Founders of IPGS. The ranks of Members swell unexpectedly by the 500+ participants of BCII2006. IPGS will publish its Proceedings edited by American Editor A. Pellionisz, AsiaPacific Editor M. Simons and European Editor A. Falus.

A small gathering after the European Inaugural

Broad Institute to study causes of cancer as part of $100 million award

Genome Center Shares In Grant
Published On Monday, September 25, 2006 2:00 AM

By KUNAL P. RAYGOR

The Starr Foundation will award $100 million to five leading cancer research institutes in November, including the Broad Institute of MIT and Harvard.

The Broad Institute—a research coalition among MIT, Harvard, and several Harvard-affiliated hospitals, including the Dana-Farber Cancer Institute—will share the five-year grant with four New York research centers. The recipients include Cold Spring Harbor Laboratory, Memorial Sloan-Kettering Cancer Center, Rockefeller University, and Weill Medical College of Cornell University.

The New York-based foundation has donated to Harvard in the past—including a $5 million gift for financial aid in 2004. The new money will fund the development of technology designed to investigate the molecular causes of cancer and, in turn, use this technology to create viable treatment options for patients, according to the Starr Foundation.

A far loftier goal of the grant is to encourage up-and-coming scientists to think outside the box.

"It’s really a call to the next generation to take the tools and apply them in a bold way. It’s an opportunity for young scientists to think big," said Eric S. Lander, director of the Broad Institute. "The [National Institute of Health] budget has fallen 12 percent, and it’s sending a message to young scientists that [ambition is] not valued. This could not be further from the truth."

And institutes cannot go it alone—any projects funded by the money must involve scientists from at least two of the five research centers.

"Our goal in launching the Starr Cancer Consortium is to bring these exceptional institutions together in a manner that assures maximum efficiency and the greatest firepower in targeting cancer,” said Maurice R. Greenberg, the chairman of the Starr Foundation, in a press release. “This will enable us to achieve tangible results more quickly and decisively than any one or two members of the consortium could accomplish working alone.”

The Starr Foundation—along with representatives from the five institutions—will divvy up the offer this November based on research plans proposed by the recipients.

The Broad Institute has been analyzing the loss and amplification of parts of the genome, and it has been conducting sequencing experiments to identify key mutations in genes—springing the institute to the forefront of cancer research.

But collaboration is still necessary, Lander said.

“We need to combine clinical medicine, computational science, chemistry, and molecular biology. No one person and no one research group has all these tools,” he said. “The medicine of the future will be led by bringing together teams to tackle a specific problem.”

Time Aping over Human-Chimp Genetic Similarities

The current issue of Time features a cover story preaching evolution to the skeptical public and editorializing that humans and chimps are related. Though the cover graphic (below) shows half-human, half-chimp iconography, University of North Carolina, Charlotte anthropologist Jonathan Marks warns us against "exhibit[ing] the same old fallacies: ... humanizing apes and ape-ifying humans" (What It Means to be 98% Chimpanzee, pg. xv [2002]). The over-graphic commits both fallacies:

The article also claims that it's easy to see "how closely the great apes--gorillas, chimpanzees, bonobos and orangutans--resemble us," but then observes in a contradictory fashion that "agriculture, language, art, music, technology and philosophy" are "achievements that make us profoundly different from chimpanzees." Perhaps Michael Ruse was wise to ask "[w]here is the baboon Shakespeare or the chimpanzee Mozart?" (The Darwinian Paradigm, pg. 253 [1989]).

Common Descent, or Common Design?

The article predictably touts the 98-99% genetic similarity statistic between humans and chimps, assuming that the similarity demonstrates common ancestry. Can common ancestry explain shared functional genetic similarities between humans and chimps? Sure, of course. But so can common design: designers regularly re-use parts that work when making similar blueprints. The article ignores that shared functional similarities between two organisms do not rule out design in favor of descent.

Evolutionary Miracle Mutations

The article also discusses a "mutation" that could allow a loss in jaw-muscle strength, which evolutionary biologists hypothesize allowed the human braincase to grow larger. It's a nice just-so story, but paleoanthropologist Bernard Wood explained why simply identifying these genetic differences does not provide a compelling evolutionary explanation where natural selection would preserve the mutations:

"The mutation would have reduced the Darwinian fitness of those individuals … It only would've become fixed if it coincided with mutations that reduced tooth size, jaw size and increased brain size. What are the chances of that?"

(quoted in Joseph Verrengia, "Gene Mutation Said Linked to Evolution" Union Tribune, 03-24-04)

The article also makes the unbelievable claim that two mutations could account for "the emergence of all aspects of human speech, from a baby's first words to a Robin Williams monologue." Are they joking? If human speech evolved via Darwinian means, it would require slowly evolving a suite of highly complex characteristics lacking in animals—a feat some experts think is impossible:

Chomsky and some of his fiercest opponents agree on one thing: that a uniquely human language instinct seems to be incompatible with the modern Darwinian theory of evolution, in which complex biological systems arise by the gradual accumulation over generations of random genetic mutations that enhance reproductive success. ... Non-human communication systems are based on one of three designs [but] ... human language has a very different design. The discrete combinatorial system called "grammar" makes human language infinite (there is no limit to the number of complex words or sentences in a language), digital (this infinity is achieved by rearranging discrete elements in particular orders and combinations, not by varying some signal along a continuum like the mercury in a thermometer), and compositional (each of the infinite combinations has a different meaning predictable from the meanings of its parts and the rules and principles arranging them).

(Pinker, S., Chapter 11 of The Language Instinct (1994).)

While Pinker believes that human language can be explained by Darwinism, human speech and language is exceedingly complex compared to animal language. Claiming it could evolve in two mutations is unbelievable.

Functional Non-Coding DNA: The Evolutionists' New Best Friend?

Ironically, the article admits that stark differences between humans and chimps may stem from functional non-coding DNA, which regulates protein production. In an elegant analogy, Owen Lovejoy explains that the 98-99% similarity in coding-regions of DNA ("bricks") may be irrelevant because it's "like having the blueprints for two different brick houses. The bricks are the same, but the results are very different."

Darwinists often cite similarities in non-coding DNA as evidence of chimp-human common ancestry. Yet the Time article explains that non-coding DNA has function—perhaps holding the functions responsible for the differences between humans and chimps:

Those molecular switches lie in the noncoding regions of the genome--once known dismissively as junk DNA but lately rechristened the dark matter of the genome. ... "But it may be the dark matter that governs a lot of what we actually see."

Though the article still asserts much of the genome is junk [!!!! *** !!! - AJP], Richard Sternberg and James A. Shapiro wrote recently that "one day, we will think of what used to be called 'junk DNA' as a critical component of truly 'expert' cellular control regimes" ("How Repeated Retroelements format genome function," Cytogenetic and Genome Research 110:108–116 [2005]).

Evidence of function in non-coding DNA not only casts doubt upon whether the 98-99%-protein-coding-DNA-similarity statistic is relevant to assessing the degree of genetic similarity between humans and chimps, but it also shows that similarities in human and chimp non-coding DNA could be explained by common design.