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Humans have a bit of shark in them

Jennifer Viegas
Discovery News

Some 450 million years ago, sharks and humans shared a common ancestor, making sharks our distant cousins.

And according to recent research, this kinship is evident in our DNA, as at least one shark species possesses several genes that are nearly identical to those in humans.

The elephant shark's genome is so similar to ours that we wind up having more in common with it, genetically speaking, than with other species, such as teleost (bony skeleton) fishes, which are nearer to us on the evolutionary tree.

"This was a surprising finding, since teleost fish and humans are more closely related than the elephant shark is to humans," says lead author Associate Professor Byrappa Venkatesh.

Venkatesh, principal investigator at the Institute of Molecular and Cell Biology in Singapore, and his team determined that sets of genes on chromosomes, as well as actual genetic sequences, are "highly similar in the elephant shark and human genomes".

The researchers not only analysed the elephant shark genome, but also the genes for other animals including puffer fish, chickens, mice and dogs.

Their findings were recently published in the journal PLoS Biology.

The researchers identified 154 genes in humans that have comparable matches in mice, dogs and elephant sharks.

The similarities between people, mice and dogs were expected, given that they are all mammals.

But sharks are cartilaginous fish that seem to bear little physical resemblance to mammals...

Immunune system genes

The researchers also found that shark and human immune systems are very similar, since sharks have all four types white blood cells found in mammals.

Sean Van Sommeran, executive director of the Pelagic Shark Research Foundation in California, says that he was not entirely surprised to learn about the shark-human links.

"The field of genetics is a Pandora's box," Van Sommeran says.

[This and the following article are grouped - since the Cerebellum appeared in the emergence of species with the sharks. Therefore, evolutionary and comparative PostGenetics ("Genomics beyond Genes") may consider the entire genomes (and specific sets of genes) but also may "zoom" on well-identified neuronal networks and even cell(s), the Purkinje neuron, as its development is governed by "similar" (not identical) genomic information. - Pellionisz, 31st of May, 2007]

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Researchers discover gene essencial to cerebellum formation

By Institute for Research in Biomedicine (IRB)

A study published this week in the scientific journal PNAS provides new information on the origin of different cells in the cerebellum, an important component of the central nervous system found in all vertebrates, including humans, and the part of the brain that controls movement. The study was completed by researchers from the Institute for Research in Biomedicine (IRB Barcelona), the Department of Cell Biology of the University of Barcelona (UB), the IMIM-Hospital del Mar, Pompeu Fabra University (UPF) and Vanderbilt University (Nashville, Tennessee, USA). The main authors of the study are Dr. Marta Pascual (IRB Barcelona and UB) and Ibane Abasolo (IMIM-Hospital del Mar-UPF).

Co-author of the study, Francisco X. Real, coordinator of the Research Unit on Cell and Molecular Biology at IMIM-Hospital del Mar and Professor at the UPF, explains that this discovery sheds new light on the mechanisms of brain formation and has potential future applications for regenerative medicine. It provides crucial insight into the manipulation of truncal nerve cells (or stem cells) and their selective differentiation into 'gabergic' neurons, or cells that contain the neurotransmitter gamma-aminobutyric acid (GABA) and that act as inhibitors.

Eduardo Soriano, Principal Investigator of the Developmental Neurobiology and Regeneration laboratory at IRB Barcelona, and professor at the UB, maintains that the study explains two important principles: first, that the protein Ptf1a/p48 is needed for the production and differentiation of Purkinje neurons, the most important cells in the cerebellum; and second, that in the absence of this protein, the progenitor cells that should produce Purkinje neurons do not differentiate correctly and instead produce a different type of neuron, granular cells, indicating that Ptf1a/p48 acts as a molecular switch.

The researchers hypothesized that a transcription factor, whose function is well known in the pancreas and which appears to play a role in the nervous system, is also involved in the development of the cerebellum. In order to test their idea, and characterize the new mechanism of cell differentation, the authors used mice with a disactivated gene that codes for the Ptf1a/48 protein, and compared them with mice that express the gene normally. Their conclusions provide new insight into origin of nerve cells that form the cerebellum in higher organisms.

In a second research project, led by Francisco Real and Eduardo Soriano and funded by the Fundació La Caixa, the scientists aim to explore the potential of this gene to produce Purkinje neurons in a laboratory setting. The researchers will investigate whether the expression of Ptf1a/p48 can induce the production of Purkinje cells from stem cells and neurospheres, progenitor cells of adult neurons. This study is an important step toward understanding rare diseases, such as cerebellar ataxias, which is characterized by the degeneration of Purkinje cells. Producing this type of cell in the lab may lead to future neuronal replacement therapy.

[This author opened the "Pandorra box" of POSTgenetics (Genomics beyond Genes) by making experimentally verified quantitative predictions for the cerebellar Purkinje cells in the fugu fish, as compared to zebra fish and mammals such as the guinea pig, mouse and human. It would be most interesting to see if/how ptf1 is found in the newly sequenced elephant shark and how the arborization of the Purkinje neuron of the cerebellum of elephant shark would appear - Comment by A. Pellionisz, 31st of May, 2007]

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Astrophysicists Find Fractal Image Of Sun's 'Storm Season' Imprinted On Solar Wind

[Our Sun found to be fractal (left), algorithmically fractal planets, Earth from the Moon - and a real bacterium showing fractality ... AJP]

Science Daily — Plasma astrophysicists at the University of Warwick have found that key information about the Sun’s 'storm season’ is being broadcast across the solar system in a fractal snapshot imprinted in the solar wind. This research opens up new ways of looking at both space weather and the unstable behaviour that affects the operation of fusion powered power plants.

Fractals, mathematical shapes that retain a complex but similar patterns at different magnifications, are frequently found in nature from snowflakes to trees and coastlines. Now Plasma Astrophysicists in the University of Warwick’s Centre for Fusion, Space and Astrophysics have devised a new method to detect the same patterns in the solar wind.

The researchers, led by Professor Sandra Chapman, have also been able to directly tie these fractal patterns to the Sun’s ‘storm season’. The Sun goes through a solar cycle roughly 11 years long. The researchers found the fractal patterns in the solar wind occur when the Sun was at the peak of this cycle when the solar corona was at its most active, stormy and complex – sunspot activity, solar flares etc. When the corona was quieter no fractal patterns were found in the solar wind only general turbulence.

This means that fractal signature is coming from the complex magnetic field of the sun.

This new information will help astrophysicists understand how the solar corona heats the solar wind and the nature of the turbulence of the Solar Wind with its implications for cosmic ray flux and space weather.

These techniques used to find and understand the fractal patterns in the Solar Wind are also being used to assist the quest for fusion power. Researchers in the University of Warwick’s Centre for Fusion, Space and Astrophysics (CFSA) are collaborating with scientists from the EURATOM/UKAEA fusion research programme to measure and understand fluctuations in the world leading fusion experiment MAST (the Mega Amp Spherical Tokamak) at Culham. Controlling plasma fluctuations in tokamaks is important for getting the best performance out of future fusion power plants.

The research by K.Kiyani, S. C. Chapman, B. Hnat, R. M. Nicol, is entitled "Self- similar signature of the active solar corona within the inertial range of solar wind turbulence" and was published on May 18th 2007 in Phys. Rev. Lett.

How Google wants to know everything about you [Searching in your Junk?]

From Times OnlineMay 23, 2007

Google wants to monitor the queries each individual taps into its search site to advise them on their life decisions

Rhys Blakely

Google says it does not yet “know enough about you” and is stepping up its efforts to collect personal information on the web.

Eric Schmidt, the Google chief executive, said yesterday that the world’s biggest internet search engine is still at a “very early” stage when it comes to gathering your personal data through the web. “This is the most important aspect of Google's expansion,” he added.

He envisaged a day when Google would be able to advise its users on everything from their career moves to how they should spend their free time, based on the collected queries they tap into Google.com.

Google already holds a vast amount of personal information about its users – ranging from the contents of e-mail (from its Gmail service) to credit card details (through Google checkout, its online payment system). The information is held in a vast network of massive “server farms” – the company's fleet of digital data centres into which it is estimated to have pumped billions of dollars.

Such information is key to success in the online advertising industry, the source of Google's massive wealth. The No1 aim is to build up precise portraits of individual consumers to better target campaigns.

As it seeks to broaden its information net, it emerged yesterday that Google is also backing a firm founded by the wife of Sergey Brin, the company’s billionaire co-founder, that aims to help people browse their genetic information online.

Google said the investment was made as the start-up 23andMe’s “goal of developing new ways to help people make sense of their genetic information will help us further our mission of organising the world’s information in this new and important field”.

Google invested about $4 million (£2 million) in the company, co-founded by Anne Wojcicki in 2006.

It is not alone among technology companies aiming to tap the human genome – perhaps the most personal information there is. Larry Ellison, the billionaire software behind Oracle, the database giant, last week told Times Online that he plans to store, track and manipulate consumers’ digital data – including their bank details, their medical records, even their genetic blueprints.

Health companies, for instance, given the opportunity to mine this information using Oracle technology, will be able to pinpoint the most effective drugs for individual patients, he suggested.

“We are getting close to this level of personalisation,” he said, citing work being done in Oracle’s labs.

On another front, applied to credit card and telephone records, a similar meeting of personal data and technology will help the authorities do a “better job in finding terrorists,” Mr Ellison said. The extension of predictive modeling techniques, already used to track markets on Wall Street, to areas such as healthcare “will help make societies more efficient,” he predicted.

Meanwhile, Autonomy, a Cambridge-based search technology specialist, has said it is exploring online “transaction hijacking”, where consumers buying items online are automatically informed, during their transaction, if a better price is offered elsewhere.

A Google spokesman stressed to Times Online that Mr Schmidt’s most recent comments referred only to the company’s web-search histories. Moreover, users have to opt in to Google's new "personalised search" tools and the company says it will not pass data on to third parties - unless ordered to do so by law.

Earlier this year, Google bowed to privacy concerns when it agreed to limit the time it keeps information about internet searches to two years.

However, the idea of Google – or any other company – taking a “big brother” role on the web will leave many civil libertarians feeling uneasy.

Data leaks have already sparked fears over personal information that can be gleaned from search behaviour. Last year, for instance, AOL, the internet portal that is part-owned by Google, accidentally released details of 20 million private search queries from 658,000 of its users to the online public.

The collection, quickly disseminated across the web by bloggers, provides a disturbingly intimate picture of some of AOL's user base. Alongside searches for Angelina Jolie and Britney Spears, darker queries typed into the AOL search engine included: "how to tell your family you're a victim of incest" and "how to kill your wife".

Potentially incriminating entries included: "cocaine in urine".

TechCrunch, a blog, said at the time: "The utter stupidity of this is staggering ... The data includes personal names, addresses, social security numbers and everything else someone might type into a search box."

Genome Is Larger and More Complex Compared to Fruit Fly and Mosquito Species That Carries Malaria

Scientists at J. Craig Venter Institute Publish Draft Genome Sequence From Aedes aegypti, Mosquito Responsible for Yellow Fever, Dengue Fever

ROCKVILLE, Md., May 17 /PRNewswire-USNewswire/ -- The fight against yellow fever and dengue fever was advanced today by an international team of researchers led by Vishvanath Nene, Ph.D. of the J. Craig Venter Institute who sequenced the Aedes aegypti genome, the mosquito that carries these deadly diseases. The research was published in the journal "Science."

This research is the first characterization of the approximately 1.38 billion base pairs of DNA of the Ae. aegypti genome. From this sequence, the team showed that this mosquito species has an estimated 15, 419 protein encoding genes.

Since both the sequence of the fruit fly, Drosophila melanogaster (sequenced in 1999 and published in 2000) and another mosquito species, Anopheles gambiae, (sequenced and published in 2002) were available, researchers were able to compare these insects to Ae. aegypti to ascertain biological differences between the species.

An. gambiae diverged on the evolutionary tree from the fruit fly about 250 million years ago, and the two mosquito species diverged from one another approximately 150 million years ago. Genomic comparisons revealed greater differences between the fruit fly and the mosquito species, than between the two mosquito species.

An important finding from this analysis is the discovery of certain proteins and genes unique to the Ae. aegypti. These proteins and genes, among many things, infer robustness to the insect. A more thorough analysis of these genes and proteins may lead to improved means to eradicate the mosquito and thereby stop the spread of yellow and dengue fevers.

Another key discovery was that almost 50 percent of the genome consisted of transposable elements. These are movable pieces of DNA that cause mutations and can affect genome size. The researchers showed that likely due to these elements the gene length and the intergenic regions of Ae. aegypti are 4-6 times larger than those of An. gambiae and the fruit fly.

[Scientific American - notorious of their ill-understanding the field of "non-coding DNA" - breaks the same news under this totally misleading title:

Genetic Code of Deadly Mosquito Cracked

No. The genetic code has not been "cracked". The book has been "revealed", but still those thinking in terms of "junk DNA" can not read any of the 2.5 Billion letters but about the same number of genes that is also present from the lowliest creatures up to the genome of humans (1.3% in the human genome)].

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Rosetta Genomics Receives First Ever Patent Supporting MicroRNA-Based Diagnostics and Therapeutics

Company Expects Further Precedent Setting Issuances to Follow

REHOVOT, Israel and NORTH BRUNSWICK, New Jersey, May 15, 2007 /PRNewswire-FirstCall/ -- Rosetta Genomics, Ltd. (NASDQ: ROSG), a leading microRNA company, announced today that on May 15, 2007, the United States Patent and Trademark Office (USPTO) issued Rosetta Genomics U.S. Patent No. 7,217,807. This is the first microRNA composition of matter patent ever issued relating to a human or viral microRNA gene, and the company believes that this issuance sets an important precedent for Rosetta Genomics' entire target patent portfolio.

The patent covers composition of matter directed at a specific microRNA gene found in the Human Immunodeficiency Virus (HIV). The company believes that this patent, as well as the hundreds of other viral and human microRNA-related patent claims filed by the company worldwide, constitutes a broad intellectual property estate surrounding a new class of prospective drug targets with significant therapeutic opportunity. Targeting microRNAs provides the unique potential to either up- or down-regulate key disease causing proteins. The potential to up- or down-regulate protein expression broadly across this prospective target class is a significant advantage. Human and viral microRNA targets are expected to play a role in the regulation of key disease processes in major therapeutic areas such as oncology, metabolism and infectious diseases.

"This is truly a precedent setting event for validating our extensive portfolio in microRNA genes for both therapeutics and diagnostics," said Ranit Aharonov, Ph.D., Executive Vice President IP & Computational Biology at Rosetta Genomics Ltd. "Rosetta Genomics is the first commercial entity to receive a patent on a microRNA gene. Given we have another patent which has been allowed, and many others in active examination, we feel confident that we will continue to see issuances of our patents for both human and viral microRNA gene sequences as well as patents covering microRNA biomarkers and our cutting-edge enabling technologies. We view the USPTO's decision to issue this patent as strong validation of our position as a leader in this rapidly expanding field. "

"This is a landmark occasion for us", said Amir Avniel, President and CEO of Rosetta Genomics Ltd. "This is a significant step towards validating Rosetta Genomics' leadership role in terms of our microRNA intellectual property estate. Moreover, we believe the issuance of this patent, and future such patents, will allow exclusive partnership opportunities and increases the value proposition across our broad product development pipeline for microRNA-based diagnostics and therapeutics."

About microRNAs

MicroRNAs (miRNAs) are a recently discovered, naturally occurring form of RNAi. These small RNAs act as protein regulators and have the potential to form the basis for a new class of diagnostics and therapeutics. Since many diseases are caused by the abnormal activity of proteins, the ability to selectively regulate protein activity through microRNAs could provide the means to treat a wide range of human diseases. In addition, microRNA expression levels have been shown to be correlated with various disease states and to hold significant potential as diagnostics and prognostic markers

About Rosetta Genomics

Rosetta Genomics is a leader in the development of microRNA-based diagnostics and therapeutics. Founded in 2000, the company's integrative research platform combining bioinformatics and state-of-the-art laboratory processes has led to the discovery of hundreds of biologically validated novel human microRNAs. Building on its strong IP position and strategic alliances with leading biotechnology companies, Rosetta Genomics is working to develop a full range of diagnostic and therapeutic products based on microRNAs. The company's primary focus is in the development of microRNA-based products to diagnose and treat different forms of cancer and infectious diseases.

USPTO 7,217,807 Bioinformatically detectable group of novel HIV regulatory genes and uses thereof

The invention claimed is:

1. An isolated nucleic acid consisting of 77 up to 120 nucleotides, wherein the nucleic acid comprises the sequence of SEQ ID NO: 14.

2. An isolated nucleic acid wherein the sequence of the nucleic acid consists of the sequence of SEQ ID NO: 14.

3. A vector comprising an HIV nucleic acid insert, wherein the nucleic acid insert consists of the nucleic acid of claim 1 or claim 2, and wherein said vector does not comprise an HIV nucleic acid insert other than the nucleic acid of claim 1 or claim 2.

4. A probe comprising an HIV nucleic acid insert, wherein the nucleic acid insert consists of the nucleic acid of claim 1 or claim 2, and wherein said probe does not comprise an HIV nucleic acid insert other than the nucleic acid of claim 1 or claim 2.

5. An isolated nucleic acid complement of the nucleic acid of claim 1 or claim 2, wherein said isolated nucleic acid complement is identical in length to the nucleic acid of claim 1 or 2.

[Viral microRNA] - Cancer Virus' Genetic Targets Identified

Science Daily — University of Florida researchers have identified specific human genes targeted by a virus believed to cause Kaposi's sarcoma, a rare form of cancer associated with AIDS and with organ transplants that causes patches of red or purple tissue to grow under people's skin.

Writing May 11 in PLOS Pathogens, the scientists are the first to name human genes that are actually hijacked by a virus wielding minimolecules called microRNAs. Apparently the viral microRNAs silence genes known to influence growth of blood vessels and suppress tumor cells. Scientists believe that with the regulatory genes sidelined, blood vessel growth runs rampant, resulting in the typical markings of Kaposi's sarcoma.

"The hallmarks of Kaposi's sarcoma are red spots full of blood vessels on the necks, arms and legs of patients," said Rolf Renne, Ph.D., an associate professor of molecular genetics and microbiology at the College of Medicine and a member of the UF Shands Cancer Center and the UF Genetics Institute. "We think that the tumor virus is using microRNAs to make sure infected cells are well nourished and protected from the human immune system."

Thought to be little more than cellular debris less than a decade ago, microRNAs are short chemical strands that strategically silence gene activity by binding to RNA within cells. They play a role in healthy development -- no one with a complete set of fingers and toes would want their genes to keep adding new digits -- and they evidently may be involved in the onset of some diseases, including cancer.

Now it seems that even foreign microRNA has a say in human health.

In an effort to identify human gene targets, UF scientists equipped cultured human cells with just 10 genes from the Kaposi's sarcoma virus, thus endowing human cells with the ability to produce viral microRNA. Scientists then screened the more than 30,000 genes that exist within human cells and found that 81 were strongly inhibited in the presence of the viral microRNA.

Five of the most affected genes are known to suppress tumor and blood vessel growth and influence the body's immune response, suggesting that the herpesvirus uses microRNA to create a cancerous environment in which it thrives, undetected by the body's natural defenses.

Researchers confirmed the results of the microRNA gene profiling with tests to detect individual microRNA activity in specific genes. "The data beautifully showed which genes were regulated by the viral microRNA," said Henry Baker, Ph.D., a professor and interim chairman of molecular genetics and microbiology who oversaw the gene screening. "The most exciting thing was one of the most-targeted genes on the list is thrombospondin 1. When something is important in a natural process, there are often a lot of built-in redundancies. In this case all of the viral microRNAs were used to target 34 different binding sites on the human gene, so apparently this is a virus that really wants to down-regulate thrombospondin."

ABSTRACT Kaposi sarcoma–associated herpesvirus (KSHV) is a gamma-herpesvirus associated with Kaposi sarcoma, primary effusion lymphoma, and a subset of muticentric Castleman disease. Recently, it was found that KSHV encodes 12 microRNAs (miRNAs) within its latency-associated region. miRNAs are small 22 nucleotide-long single-stranded RNA molecules that act to inhibit gene expression by binding to target messenger RNAs (mRNAs). Because miRNAs bind to these targets with limited base pairing, it has been difficult to find targets. The goal of our study was to identify cellular mRNAs targeted by KSHV-encoded miRNAs. Microarray analysis of cells expressing the KSHV miRNAs revealed a set of 81 genes that were changed. Several genes are regulators of important functions such as blood vessel growth, cell proliferation, and cell death. One target, thrombospondin 1, is a potent inhibitor of blood vessel growth and is known to be down-regulated in Kaposi sarcoma tumors. Thrombospondin 1, which is targeted by multiple miRNAs, also showed reduced protein levels in our study. To our knowledge, our data describe the first targets for tumorvirus-encoded miRNAs and suggest that these novel regulators may have roles in pathogenesis.

Is the universe a fractal? [With the DNA no exception to the universe? - AJP]

09 March 2007
New Scientist

Written across the sky is a secret, a hidden blueprint detailing the original design of the universe itself.

The spread of matter throughout space follows a pattern laid out at the beginning of time and scaled up to incredible proportions by nearly 14 billion years of cosmic expansion.

Today that pattern is gradually being decoded by analysing maps of the distribution of the stars, and what has been uncovered could shake modern cosmology to its foundations. Cosmology is founded on the assumption that when you look at the universe at the vastest scales, matter is spread more or less evenly throughout space. Cosmologists call this a "smooth" structure.

But a small band of researchers, led by statistical physicist Luciano Pietronero of the University of Rome and the Institute of Complex Systems, Italy, argues that this assumption is at odds with what we can see.

Instead they claim that the galaxies form a structure that isn't smooth at all: some parts of it have lots of matter, others don't, but the matter always falls into the same patterns, in large and small versions, at whatever scale you look. In other words, the universe is fractal.

It is a controversial view, and one that sparked an intense debate over a decade ago. Since then, astronomers have surveyed ever-greater numbers of galaxies, taking larger and larger samples of the universe. Now the biggest galaxy survey ever and a brand new map of the universe's dark matter are adding fuel to the fire.

At stake is far more than the way galaxies cluster. A fractal universe could undermine cosmology's most basic assumptions. "All of the observations we make depend to a greater or lesser extent on the idea that the universe is homogeneous," says David Hogg of New York University, who leads a team of physicists that disputes Pietronero's view.

This idea that matter is spread more or less evenly throughout the universe is embodied in Einstein's cosmological principle. Einstein formulated it after publishing his general theory of relativity, which describes how the distribution of mass bends space-time and creates gravity. It allows cosmologists to use the equations of general relativity to describe the geometry of the whole universe. As a result it has led to a picture of a universe expanding uniformly from the big bang and in which cosmological measurements have defined meanings.

Fractals allow Pietronero to paint a very different sort of picture - one in which the irregular distribution of matter that we see around us never evens out into a smooth structure, but repeats itself at ever grander scales.

Fractals are familiar enough: we see them in the branching of trees, the curves of coastlines, lungs, turbulence and clouds. No matter what scale you look at them, fractal patterns look the same.

Think of broccoli: a tiny branch looks much the same as the whole vegetable. Zoom in or zoom out, the structure looks the same - exquisitely detailed, never smooth. Fractals can be beautiful to look at, but when it comes to galaxies it may be a subversive kind of beauty. Certainly the universe does not look smooth. Some regions contain clusters of matter; others are virtually empty.

Hundreds of billions of stars group together to form galaxies, and galaxies congregate in clusters. Clusters assemble into colossal structures called superclusters that can stretch out for 100 million light years and look uncannily like fractal patterns. Even superclusters string together in long filaments and sheets that stretch like ghostly cobwebs across an otherwise empty sky. The Sloan Great Wall, for example, which was discovered in 2003, spans more than a billion light years. These filaments and sheets seem to encircle huge voids of empty space. The voids range from 100 to 400 million light years in diameter, making the whole assemblage appear as an immense, glowing lattice punctuated by wells of darkness.

No one disputes that the universe is far from smooth on relatively small scales - by which cosmologists mean thousands of light years. But Hogg's team is convinced that if you zoom further out, smoothness reigns. "When you're looking at the size scales of galaxies, groups of galaxies, clusters, superclusters and filaments, it looks like a fractal," says Hogg. "But once you get larger than all of that, then it starts to look homogeneous."

What has convinced him is his team's analysis of the latest data from the Sloan Digital Sky Survey, the largest 3D map of the galactic universe so far. His team insists that the map is proof of smoothness.

The fractal camp, however, are skeptical. In fact, they say the Sloan observations confirm what they've been claiming all along. It might appear to be deadlock, but at least with the Sloan survey the two sides can agree what they're disagreeing about.

For years Pietronero and his team argued that the statistical methods mainstream cosmologists were using to establish homogeneity were flawed because they start off by assuming that matter is evenly spread. The team was mostly ignored until 2004, when Hogg and astrophysicist Daniel Eisenstein of the University of Arizona in Tucson spent a summer in Paris with Pietronero's colleagues, cosmologists Francesco Sylos Labini of the Enrico Fermi Centre and the Institute for Complex Systems, Rome, and Michael Joyce of the Pierre and Marie Curie University, Paris.

"We argued every day about fractals," Hogg says. "Those battles raged over lunch and coffee and finally convinced us by the end of our visit that we should be doing the analysis as they say." When they returned to the US, Hogg and Eisenstein applied the fractal team's methods to a sample of 55,000 luminous red galaxies mapped by Sloan.

They found that the galaxies do form a fractal pattern, but as they looked at bigger and bigger scales, the pattern appeared to disintegrate and smooth out at just over 200 million light years - a scale far larger than most cosmologists had expected.

But Pietronero and Sylos Labini are not convinced. Instead, they believe that if astronomers could continue to zoom out and look at even larger scales, they would find more clustering. They suspect that the apparent smoothness at 200 million light years is not real, but rather an illusion created by statistical effects due to the limited range of the Sloan survey. Hogg's team, though, insist that their evidence of homogeneity is statistically significant. "I think the result really is secure," says Hogg. "I would stake my scientific reputation on that."

Even if the result is real, mainstream cosmologists still have a huge problem on their hands. The fact that the fractal patterning extends to far bigger scales than anyone had expected means that there must be far bigger structures than anyone expected - structures that are even bigger than superclusters.

The fractal team argues that the standard model cannot explain the existence of these galactic giants. "If you look at the galaxy data, you can see enormous objects hundreds of millions of light years across, stuff that's really huge," says Pietronero.

"This is a huge problem. You're going to have to change the story very radically." The usual story runs something like this. In the tiny fluctuations of the nascent universe, matter began to collect in denser regions, setting off a chain reaction of gravitational collapse that has given us the large-scale structure we see today. Gravity has worked from the bottom up, building galaxies first, then collecting galaxies into clusters, then clusters into superclusters and so forth. But while the matter has been clumping together, the universe has been expanding, and thus a battle has ensued: gravity versus expansion.

According to Pietronero, there simply hasn't been enough time since the universe came into being 14 billion years ago for gravity to sculpt structures larger than about 30 million light years across: expansion would have prevented anything larger from forming. "The existence of structures much larger than this implies a crisis of the present view of structure formation," he says. This present view is the "cold dark matter model", in which the glowing masses of stars and galaxies are only the tip of the cosmic iceberg. Luminous matter makes up roughly 15 per cent of all the matter in the universe - the other 85 per cent is mysterious dark matter. Hogg's team says that the new observations do not undermine the standard view as Pietronero claims. Instead, they maintain that the cold dark matter model explains the Sloan data quite accurately. For that to be true, however, Hogg's team have to put a number called a bias parameter into their equations. It reflects the difference between the distribution of matter in computer simulations of the cold dark matter model and the observed distribution of luminous matter. Collisions between particles of ordinary matter help it clump together, but dark matter is thought not to behave in the same way. That suggests it could be spread out in space more evenly than ordinary matter, so cosmologists assume that the distribution of the matter we can see - galaxies, say - is not a true reflection of the distribution of all the matter that is out there.

They believe the structure of the universe is really much "smoother" than it appears to be, because dark matter dominates. In the case of the Sloan survey, the bias is 2: the visible galaxies are clumped twice as densely as the predicted total distribution of matter in the universe. Sylos Labini, however, sees the bias as a fudge that allows cosmologists to discount the observed clustering of galaxies and to assume that the gigantic clusters of superclusters are only half the problem they appear to be. "The bias is a way to hide the size of structures behind some ad hoc parameter," he says. Mainstream cosmologists, however, feel the bias is justified, assuming that galaxies cluster in regions of space that are replete with excess dark matter. According to the standard model, dark matter is everywhere, but galaxies only shine in the rare regions where dark matter is densest. Dark matter also lingers in the voids where no light shines but here it is thinly spread out. In other words, while the luminous galaxies look very clustered, the underlying blanket of dark matter is far smoother, supporting the claim of homogeneity. "If the cold dark matter model is correct, then there should be dark matter in the voids," Hogg says.

The million-dollar question is: what is the real distribution of dark matter?

Is dark matter smooth or fractal? Is it clustered like the galaxies, or does it spread out, unseen, into the great voids? If the voids are full of dark matter, then the apparent fractal distribution of luminous matter becomes rather insignificant. But if the voids are truly empty, the fractal claim requires a closer look. Astronomers are now providing our first glimpse into the voids and our first look at the pattern of invisible matter. Richard Massey of the California Institute of Technology in Pasadena and others in the Cosmic Evolution Survey project have just created the first 3D map of dark matter in the universe (New Scientist, 13 January, p 5). They were able to find the dark matter by observing its gravitational effect on any light streaming past it. Combining data from the Hubble Space Telescope, the Subaru telescope in Hawaii and the Very Large Telescope in Chile, they mapped the distribution of dark matter at scales ranging from 23 million to 200 million light years across. Massey's team found that the dark matter distribution is nearly identical to the luminous matter distribution. "The first thing that strikes me is the voids," Massey says. "Vast expanses of space are completely empty. The dark matter makes up a criss-crossing network of strings and sheets around these voids. And all the luminous matter lies within the densest regions of dark matter."

Although this distribution of dark matter seems to favour the idea that the universe is fractal, Hogg isn't convinced. "It is interesting," he says, "but measurements of dark matter are much less precise than measurements of galaxy distributions." "The result is very new," Massey agrees. "It demonstrates a very exciting new way of looking directly at dark matter and will be vital in future work, but hasn't yet been subject to all the analysis that has been applied to galaxy surveys." When asked if the dark matter exhibits an explicitly fractal structure, Massey replies, "We don't know yet."

"The universe is not a fractal," Hogg insists, "and if it were a fractal it would create many more problems that we currently have."

A universe patterned by fractals would throw all of cosmology out the window. Einstein's cosmic equations would be tossed first, with the big bang and the expansion of the universe following closely behind. Hogg's team feel that until there's a theory to explain why the galaxy clustering is fractal, there's no point in taking it seriously. "My view is that there's no reason to even contemplate a fractal structure for the universe until there is a physical fractal model," says Hogg. "Until there's an inhomogeneous fractal model to test, it's like tilting at windmills." Pietronero is equally insistent. "This is fact," he says. "It's not a theory." He says he is interested only in what he sees in the data and argues that the galaxies are fractal regardless of whether someone can explain why. As it turns out, there is one model that may be able to explain a fractal universe. The work of a little-known French astrophysicist named Laurent Nottale, the theory is called "scale relativity" (see "Fractured spacetime"). According to Nottale, the distribution of matter in the universe is fractal because space-time itself is fractal. It is a theory on the fringe, but if the universe does turn out to be fractal, more people might sit up and take notice. A resolution to the fractal debate will only come with more data. Sloan is currently charting more galaxies and will release a new map in the middle of 2008. According to Sylos Labini, this will cover over 650 million light years and should tell us if the apparent transition to homogeneity extends beyond 200 million light years. For now, the pattern of the world, imprinted at the origin of the universe, remains a secret glimpsed only in the knowing shimmer of the stars.

Fractured space-time

French astrophysicist Laurent Nottale has developed a theory that takes fractals to a whole new level. A researcher at the Meudon Observatory in Paris, Nottale set out to extend Einstein's principle of relativity - in which the laws of physics remain the same regardless of the motion of an observer - to a theory in which the laws of physics would remain the same regardless of the scale at which the universe is being observed. He found that the underlying space-time of such a theory would have to be fractal. In Nottale's theory, called scale relativity, the underlying fractality of space-time is most noticeable in the quantum world. Quantum behaviour, he claims, can be understood geometrically - particles move along fractal trajectories. On large scales, his model could explain a fractal pattern of the galaxies. The most profound question in physics today is how to unify the really small with the really big - and when it comes to matters of scale, fractals may turn out to be a key ingredient.

Opossum Provides Insight into Human Evolution

First Decoded Marsupial Genome Reveals "Junk DNA" Surprise

Stefan Lovgren

for National Geographic News

May 10, 2007

The genome of a marsupial—the tiny short-tailed opossum (Monodelphis domestica)—has been sequenced for the first time.

The study reveals a surprising role in human evolution for "jumping genes"—parasitic bits of "junk DNA" that until now were thought to be nothing more than a nuisance—and may also lead to a number of medical breakthroughs.

In particular, the study highlights the genetic differences between marsupials such as opossums and kangaroos and placental mammals like humans, mice, and dogs.

Marsupials typically spend their youths tucked in a mother's pouch, while placental females maintain a temporary organ called the placenta to nourish their embryos.

"The opossum is a wonderful comparison to the human," said Eric Lander, director of the Broad Institute of MIT and Harvard University in Cambridge, Massachusetts, which led the sequencing project.

The study, which appears in today's issue of the journal Nature, helps to explain the evolutionary origins of human DNA, Lander pointed out. (Read a genetics overview.)

And opossums are often used as models in a wide variety of research on human health and disease, including the malignant melanoma form of skin cancer. (Related: Macaque Genome Deciphered; May Herald Medical Breakthroughs" [April 12, 2007].)

The new findings show that marsupials have a much more complex immune system than previously thought.

Jumping Genes

Marsupials are the closest living relatives of placental mammals. The two groups split from a common ancestor about 180 million years ago.

Scientists were able to pinpoint the genetic elements that are present in placental mammals but missing from marsupials to learn more about what makes the two groups different.

The researchers were surprised to find that placental and marsupial mammals have largely the same set of genes for making proteins. Instead, much of the difference lies in the controls that turn genes on and off.

"Twenty percent of all the regulatory instructions in the human genome were invented after we part ways with the marsupials," Lander said.

"That was the first really important surprise about evolution—it's tinkering much more with the controls than it is with the genes themselves."

The scientists were also surprised to find that these regulatory sequences have in large part been distributed across the human genome by so-called jumping genes.

These genes have hopped through chromosomes for more than a billion years, leaving behind many copies of themselves. So until now the genes had been widely regarded by scientists as parasites, or "junk DNA," that played no creative role in evolution.

"It was a surprise that quite a significant proportion of all the new regulatory controls in the genome were coming from jumping genes," Lander said.

"It looks like [they are] a pretty major force for evolutionary innovation."

Advanced Immune System

The short-tailed opossum is native to South America and is also known as the Brazilian opossum and rain forest opossum.

The individual whose genome was sequenced came from a colony housed at the Southwest Foundation for Biomedical Research in San Antonio, Texas.

The animals have many features that make them ideal for scientific research, especially during early development, experts point out.

"Their biology is fascinating," said Jenny Grace, a biologist and marsupial expert at the Australian National University (ANU) in Canberra.

"Their young are born very tiny, the size of a penny."

The creatures are the only other mammals known to develop melanoma skin cancer solely from exposure to ultraviolet light, the cause of melanoma in most human cases.

Newborn opossums can also repair damage to their spinal cords, making them a focus of research into regenerative medicine.

"This shows us that it may not be that hard to grow spinal cords," said Lander, the Broad Institute director.

"Once you have a marsupial that can do something that a human or mouse can't do, you can compare the two," he added. "We're saying, wait, wait, it may not be that hard to grow spinal cords. Our closest cousins can do it. Let's see what tricks [they] have."

Scientists had also believed that marsupials have a primitive immune system.

"The genome project knocked that firmly on its head," ANU's Grace said.

"It turns out that marsupials have a very complicated immune system. It's just different from us."

Thursday, May 10, 2007

Led by researchers from Harvard and MIT, a team of scientists sequenced the DNA of the gray South American short-tailed opossum -- the first marsupial to have its genome sequenced.

Marsupials are closely related to placental mammals, the group that includes humans, but their evolutionary lines diverged 180 million years ago during the dinosaur age.

Interestingly, the team found that the majority of differences were found not in genes coding for proteins, but in the non-coding regions that has been popularly described as "junk DNA".

A fifth of the human genome's key functional elements arose after the divergence from marsupials, the research found. Most of these innovations occurred not in protein-coding genes but in areas of the genome that do not contain genes and until recently [until International PostGenetics Society formally abandoned the misnomer "Junk" DNA - AJP] had been derided as junk DNA, they found.

[Science Daily] ... It has been the regulation of their genes - when they turn on and off - that has changed dramatically.

"Evolution is tinkering much more with the controls than it is with the genes themselves," said Broad Institute director Eric Lander. "Almost all of the new innovation ... is in the regulatory controls. In fact, marsupial mammals and placental mammals have largely the same set of protein-coding genes. But by contrast, 20 percent of the regulatory instructions in the human genome were invented after we parted ways with the marsupial."

The research, released Wednesday (May 9) also illustrated a mechanism for those regulatory changes. It showed that an important source of genetic innovation comes from bits of DNA, called transposons, that make up roughly half of our genome and that were previously thought to be genetic "junk."

The research shows that this so-called junk DNA is anything but, and that it instead can help drive evolution by moving between chromosomes, turning genes on and off in new ways.

The research - the first time a marsupial genome was decoded - involved the gray, short-tailed opossum, a native of South American rain forests that is small enough to fit in the palm of one's hand. Marsupials, which include kangaroos and koalas, have young that do much of their development in a pouch outside the mother's body instead of in an interior womb as in humans and other "placental mammals."

It had been initially thought that most of a creature's DNA was made up of protein-coding genes and that a relatively small part of the DNA was made up of regulatory portions that tell the rest when to turn on and off.

As studies of mammalian genomes advanced, however, it became apparent that that view was incorrect. The regulatory part of the genome was two to three times larger than the portion that actually held the instructions for individual proteins.

"The official textbook picture of how genes work really didn't appear to be right," Lander said. "There was much more of the genome standing around shouting instructions than actually producing proteins."

That raised a question of how evolution actually works on the genome, Lander said. With so much of the genome devoted to regulation, it became apparent that evolution could work by simply changing the instructions rather than changing the protein-coding genes themselves.

The opossum genome provided an important point of comparison because it is more distantly related to humans than other mammals whose genomes had been studied. While the common ancestor of humans and opossums split 180 million years ago, the common ancestor of humans and mice split just 80 million years ago.

The research will also prove useful for those seeking to understand opossum biology, according to other researchers involved in the project. Opossums are important models for human disease studies because they're the only animal other than humans who develop melanoma - skin cancer - after exposure to ultraviolet radiation. They are also used in nervous system research because baby opossums can regenerate their spinal cord tissue after it is cut and regain the ability to move their limbs.

[Los Alamos] Genome Institute Reaches Milestone with a Mighty Microbe [to neutralize Uranium pollution]

Shewanella baltica OS185 is a tiny, ocean-dwelling microbe that could be an answer to cleaning up certain kinds of radioactive contamination, but for a few days this month the microbe is in the spotlight at Los Alamos for another reason. Los Alamos scientists working as part of the Department of Energy's Joint Genome Institute (JGI) recently finished the genetic code of Shewanella baltica OS185 as its 100th genomic sequence.

Finishing a genome is the process of finding and eliminating any gaps in sections of genetic code that were not initially sequenced correctly by automated sequencing methods.

"The finishing of S. baltica is being celebrated as a Los Alamos milestone for a couple reasons," said Chris Detter, leader of the JGI Sequencing Technology Team, "Not only is it our 100th completed genomic sequence, but it's also appropriate because S. baltica has shown potential for use in confining and cleaning up uranium-contaminated areas, such as the Laboratory's legacy waste sites. The microbe might someday be put to work right here at Los Alamos for the bioremediation of uranium contamination at nuclear waste sites because of its unique abilities."

While solid in most forms, uranium can break down over time in the natural environment leading to the possible contamination of groundwater. Taken from the depths of the Baltic Sea, the S. baltica microbe has a unique ability to convert uranium dissolved in groundwater into an insoluble form called uranium dioxide, or uraninite, which prevents the uranium from mixing with water and from migrating into and with groundwater flows.

Los Alamos specializes in developing techniques to take raw sequence data from the high-throughput JGI facility in Walnut Creek, California, and transform it into finished genomes. The Laboratory began finishing sequences for JGI in 2003. Making advancements in genome technology and chemistry over the years, more components of the process have become automated, speeding up finishing rates as a result.

In addition to Detter, other leaders in the JGI-LANL include David Bruce, Tom Brettin, and Cliff Han, and 35 exceptional scientists, technicians, and support staff.

The Next Human Genome Project: Our Microbes [MetaGenomics and PostGenetics; Common computer algorithms]

George Weinstock, Baylor University, Houston, TX

By Emily Singer
Wednesday, May 02, 2007

A proposed project to sequence the microorganisms that inhabit our bodies could have a huge impact on human health.

Much as we might like to ignore them, microbes have colonized almost every inch of our bodies, living in our mouths, skin, lungs, and gut. Indeed, the human body has 10 times as many [kind of?] microbial cells as human cells. They're a vital part of our health, breaking down otherwise indigestible foods, making essential vitamins, and even shaping our immune system. Recent research suggests that microbes play a role in diseases, such as ulcers, heart disease, and obesity.

While microbes make up such an intimate part of us, most of our microbial inhabitants remain a mystery. The bacteria in the human body are very difficult to study, since only about 1 percent of them can be grown in the lab. Now a proposed new project to sequence all our microbial residents could change that.

"This is completely unexplored territory that is likely to have a large impact on our understanding of human health and disease," says George Weinstock, codirector of the Human Sequencing Center at the Baylor College of Medicine, in Houston. "We hadn't been able to approach it because of the scale of the problem. But now we are finally able to open that door."

Thanks to ever-improving methods to sequence DNA, scientists can now analyze the genomes of entire microbial communities, a field known as metagenomics. By comparing microbial communities in people of different ages, origins, and health statuses, researchers hope to find out precisely how microorganisms prevent or increase risk for certain diseases and whether they can be manipulated to improve health.

Several metagenomics projects are under way or have been completed, including analysis of the microbes living in the human gut and on the skin. But a true snapshot of our microbial menagerie will require a massive effort, along the lines of the Human Genome Project. "Even though a microbial genome is one-thousandth the size of the human genome, the total number of microbial genes in [the human] body is much greater than human genes because you have so many different species," says Weinstock.

The National Institutes of Health (NIH) is now considering such a project. Metagenomics experts and government officials met last week to determine if the proposal, dubbed the human microbiome, will become an NIH "Roadmap" initiative. These NIH-wide programs identify major gaps in biomedical research and provide financial support on a much larger scale than typical grants. A final decision is expected this month.

"At the end of the day, we'll end up with another perspective on the evolution of our species, our human-microbial selves," says Jeffrey Gordon, a microbiologist at the Washington University School of Medicine, in St. Louis.

Recent research from Gordon's lab hints at the potential public-health impact of a clearer understanding of our microbial tenants. Gordon and his colleagues have shown that obese people harbor different microbial communities than lean people. And as obese people lost weight, their microbes began to look more like their lean counterparts' microbes.

Researchers aren't yet sure what triggers the differences, but they found in a similar study in mice that the microbial populations of obese mice could more effectively release calories from food during digestion than could microbes of their lean littermates.

While exciting, Gordon's research also illustrates the challenges of cataloging microbes. To truly interpret the human microbiome, scientists will need to look at the variation in microbial communities among many people and a variety of populations. Complicating the problem is that, while an individual's human genome is static, a person's microbial composition--and thus his or her microbiome--fluctuates over time. So an accurate picture of one person's microbiome could require multiple resequencing efforts.

These types of studies could yield the biggest reward, revealing whether different organisms are correlated with different health states. Gordon and others hope that a microbial analysis will ultimately become a routine part of medical exams, perhaps used to diagnose different diseases.

Scientists are still debating whether the microbiome will become a road-map project, and if so, what the final goals of the project will be: should they focus on generating complete sequences of dominant microbes, for example, or devote equal energy to the complex task of studying microbial variation?

In the meantime, microbiologists are getting ready. Three large sequencing centers--at Baylor, the Broad Institute, and Washington University--have garnered funding to sequence the genomes of a few of the gut microorganisms that can be grown in the lab, which will be crucial in later studies. Ultimately, says Gordon, "we'll get a much more transcendent view of ourselves as a supraorganism with traits acquired from our microbial partnerships."

MicroRNA found in unicellular organism

Yijun Qu, China's National Istitute of Biological Sciences

BEIJING, April 30 (UPI) -- A Chinese-led international team of scientists has, for the first time, identified microRNAs in a unicellular organism.

The team, led by Yijun Qi of China's National Institute of Biological Sciences, made the discovery in green alga Chlamydomonas reinhardtii.

"The finding changes the dogma that miRNAs only exist in multicellular organisms and adds an important piece into the blooming small RNA world," said Qi. "A pressing question we have now is what these miRNAs are exactly doing in the green alga. I hope we will know the answers soon."

The finding shows unicellular miRNAs share functional characteristics with plant miRNAs, in so far as they can direct the cleavage of target mRNAs in vitro and in vivo.

Furthermore, the scientists found miRNA expression patterns changed during gamete differentiation, suggesting a possible role in regulating sexual reproduction.

The discovery also has evolutionary implications, suggesting the miRNA pathway arose before the lineages split. The lack of universally conserved miRNA genes in algae, plants and animals suggests they might have evolved independently.

The research is to appear in the May 15 issue of Genes & Development.

Mouse microRNA knockout uncovers critical roles in immune system

A role for a microRNA in the immune system has been shown by study of one of the world's first microRNA knockout mouse, reported Friday 27 April in Science. The microRNA acts as a lynchpin to balance the response of immune defences and the researchers suggest the corresponding human gene will have a similar vital role.

Cells of the immune system in the knockout mice do not work as well as normal cells and the mice develop symptoms similar to those of human autoimmune disease. They are also less able to resist infection by bacteria, such as Salmonella. The team suggest that the equivalent human microRNA will play a major role in the human immune system.

MicroRNAs are copied from DNA but do not contain code for protein. Rather, they are themselves active in controlling the activity of other genes, often by inducing destruction of protein-coding messenger RNAs or by preventing their activity in the cell.

The research team, led by the Wellcome Trust Sanger Institute, targeted a gene called Bic/microRNA-155 (or miR-155) in embryonic stem cells which they used to transfer the mutation into mice. [Correction for journalists, see bottom: iBic is a gene from which the microRNA-155 is derived from. MicroRNA-s are NOT genes - AJP]. Previous research showed that miR-155 was active in cells of the immune system and overactivity was found in lymphoma development.

"Very little is known about the function of the hundreds of microRNA genes," [genes associated with particular microRNA - AJP] said Dr Antony Rodriguez, lead author on the paper from the Wellcome Trust Sanger Institute. "Although plentiful, this class of genes had never before been knocked out in mice, the best model organism for human disease."

"But we simply did not know whether microRNA knockouts would have an effect in mice: previous knockout studies in nematode worms suggested that most microRNAs were not essential. Our findings were dramatically different."

The effects of the miR-155 knockout swept across the immune system. The team showed that, although knockout of miR-155 did not appear to affect normal growth and development of cells in the immune system, each major cell type - T-cells, B-cells and dendritic cells - performed less well.

"These findings demonstrate the importance of this level of control in the immune system and will lead immunologists to rethink how the immune system works," said Dr Martin Turner, Head of the Laboratory of Lymphocyte Signalling and Development at the Babraham Institute.

The deficits in response were significant: the knockout mice were less able to resist infection by bacteria than mice with normal miR-155, producing lower levels of antibody and a reduced response by T-cells. They also develop changes to lung tissue, with scarring that is similar to some human systemic autoimmune disorders...

"This dramatic finding reflects a large amount of work by collaborating groups," said Professor Allan Bradley, Director of the Wellcome Trust Sanger Institute. "Showing that knocking out a microRNA has such dramatic effects opens new doors to understanding this novel class of gene regulation, with consequences for human health and disease."

"Our work builds upon the sequences of the human and mouse genomes, the power of computer analysis and microarray work and exemplifies why whole-organism research can bring understanding that cannot be developed in any other way."...

MicroRNAs and BIC

MicroRNAs (also known as siRNAs - short, interfering RNAs) are short (22-25 base) sequences that do not code for protein, [that is, MicroRNA-s are "junk" DNA...according to the obsolete terminology - AJP] but can lead to destruction of other RNA molecules or can interfere with their translation. They bind to corresponding bases in the target RNA. The mature microRNAs are derived from larger precursor molecules.

Bic is a non-coding RNA, around 1600 bases in length, which was identified in 1997 as a cancer-causing gene (oncogene) in chickens. The human and mouse versions were discovered in 2001. The BIC gene is activated in cells of the human and mouse immune system and in B-cell lymphomas and some solid tumours.

miR-155 is derived from within the iBic gene and is 65 bases in length: its mature form is 22 bases long. The human equivalent of miR-155 is found on chromosome 21: the mouse and human mature forms of miR-155 differ at one position. To date, some 377 microRNAs have been found in the mouse genome and 474 in the human.

MicroRNAs are being examined as possible therapeutic agents in a range of diseases. Trials are underway for macular degeneration (eye disease), chronic myeloid leukaemia and preeclampsia.

[Stanford] Fire and Mello shared the Nobel Prize for Physiology or Medicine in 2006 for RNAi, which led to discovery of mechanism of action of miRNAs.

[MicroRNA-s are protected intellectual property. Current (average) valuation of a single 21-letter "string" is about $150,000 - but those with direct impact for "Big Pharma" skyrocket; Merck bought SiRNA company for $1.1 Billion - Comment by A. Pellionisz, 28th of April, 2007]

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Japanese Tohoku University International Innovation Forum in Silicon Valley, California

Tohoku University US Office will hold its Opening Ceremony on April 26 and the First Tohoku University International Innovation Forum on April 27 at the Marriott San Mateo at San Francisco Airport , 1770 South Amphlett Boulevard. The US Office is the international promotion center of Tohoku University. The two day event will feature over 50 world renowned experts in their fields speaking on a broad spectrum of science and technology issues to include Nobel Laureate Roger Kornberg, Stanford University Professor, speaking on The Gene Reader in Our Cells. California Governor, the Honorable Arnold Schwarzenegger, is scheduled to present the opening keynote address. The creation of Tohoku’s Silicon Valley California office demonstrates the beginning of its intention to create a portal for the facilitation of collaboration with US companies and educational institutions.

Tohoku US Deputy Director Dr. Toshihiko Nishimura said, “June 2007 will mark the 100th Anniversary of the founding of Tohoku University. It is significant to hold the Opening Ceremony and First International Innovation Forum in the centennial year of 2007. Tohoku University has established unique policies and principles that are “Research First,” “Open Door” and “Practice-Oriented Research and Education.” Our goal for this event is to introduce Tohoku University and showcase its extensive professional and educational achievements, technologies, and intellectual property which are founded on our excellent research and education programs. The goal of the Tohoku University US office is to share and transfer these resources and to contribute to the US industry and society. We want to achieve the position of a world-known university which excels in technology research. We have selected Silicon Valley as the location of our US office, the heartland of technology, from both an academic and commercial perspective.. Our slogan is : Be The Center Of Reference; COR.

More than 50 world renowned experts, in all facets of science and technology including the president, directors, vice directors, deans, and professors from Tohoku University, will attend this event. Delegates from Miyagi Prefecture and Sendai City of Japan and the Federation of Tohoku Economic World will also attend this event. Delegates from the State of California, local counties and cities including government officials and political figures are scheduled to attend this ceremony. Stanford University and University of California will send more than twenty professors to the anniversary ceremony. The Governor of California, the Honorable Arnold Schwarzenegger is scheduled to give a congratulatory speech.

On April 27, Professor Shuji Nakamura, University of California Santa Barbara will open the all-day program of the International Innovation Forum. The 2006 Chemistry Noble Laureate, Roger Kornberg, Stanford University Professor, is the luncheon keynote speaker. Eight sessions are planned for the afternoon. This forum’s philosophy is to introduce Tohoku University’s endeavors to address key current worldwide societal issues in a road show style. Sessions are: environmental issues, energy issues, international pandemic diseases (HIV, Avian Flu), population issues, and issues associated with our aging society.

Tohoku University, being a world leader in the technology fields of Materials Science and Micro Electro Mechanical Systems (MEMS), has created sessions devoted to these topics. The MEMS session will be moderated by world renowned Tohoku University Professor Masayoshi Esashi and will include local Silicon Valley MEMS luminaries including Dr. Kurt Petersen, CEO of SiTime, Roger Howe, Stanford University Professor, Al Pisano, Professor and Director of the University of California Berkeley, Berkeley Sensor and Actuator Center and Masahiko Ogirima, MEMS Core. The Materials Science session will be moderated by Tohoku University Professor Sadamichi Maekawa with panelists including Stuart Parkin of IBM, Robert Sinclair of Stanford University and Masashi Kawasaki of Tohoku University.

Additional sessions include intellectual property collaborations with Tohoku University and future universities collaborations based on the sister city relationship between Riverside and Sendai, Tohoku’s home. At the end of the forum, distinguished US. venture capitalists including Koji Osawa, Co-Founder of Global Catalyst Partners, Steve Domenic, General Partner of Sevin Rosen Funds and James Wei , Co-Founder of Worldview Technology Partners will be joined by Stanford Professor Tom Byers. They will discuss the business vision for universities.

[The RIKEN-based "Genome Network Platform" by Japanese National Institute of Genetics is to help make sure that inside Japan progress keeps abreast with the fierce global competition. Globally, Japan has just established a bridgehead in Silicon Valley, California, with emphatic participation of Stanford and associated Venture Capital groups. Pellionisz, 26th of April, 2007]

[Please welcome the 52nd Founder of IPGS, Dr. Yauchiro Takagi, for his acceptance, keynote lecture and introduction of Nobel Laurate Dr. Kornberg at the 1st Tohoku University International Innovation Forum in Silicon Valley, 27th of April, 2007]

Cure for Alzheimer's: Japanese Vaccine Works On Mice

Reuters; Japan, March 29, 2007

Japanese scientists have developed an oral vaccine for Alzheimer's disease that has proven effective and safe in mice, the director of a research institute behind the project said on Thursday.

The team is preparing to move to small-scale clinical trials in humans, possibly this year, said Takeshi Tabira, director of the National Institute for Longevity Sciences in Aichi, central Japan.

"We hope the Phase I trials go well," Tabira said. "Animals are able to recover their functions after developing symptoms, but humans are less able to do so. It may be that this only works in the early stages of the disease, when symptoms are light."

When administered to mice suffering from the disease, which causes dementia and is currently incurable, the vaccine reduced the amount of amyloid plaques in the brain and improved mental function.

Amyloid plaques are believed to be at the root of Alzheimer's -- a growing problem for ageing populations around the world. The disease affects five million in the United States alone, the Alzheimer's Association said in a report last week.

The treatment did not cause inflammation or bleeding in the brains of the mice, Tabira said. The vaccine is made by inserting amyloid-producing genes into a non-harmful virus. When taken orally, the virus stimulates the immune system to attack and break down the amyloid proteins in the brain, Tabira said.

The treatment was tested on 28 mice genetically modified to develop Alzheimer's disease. Half the animals were given a dose of the vaccine at the age of 10 months, while the control group were not treated.

Three months later, tests showed mental function in the treated mice had returned to levels close to those before they developed Alzheimer's symptoms.

U.S. drugmaker Wyeth and its Irish partner Elan Corp have an Alzheimer's vaccine called ACC-001 in early stage human trials.

The Japanese research, carried out in conjunction with scientists at Nagoya University and others, is to be published by the Federation of American Societies for Experimental Biology in July.

[Eric Mathur] named vice president of the J. Craig Venter Co. [La Jolla]
04/16/2007

Eric Mathur of Carlsbad, ... was recently appointed vice president of the J. Craig Venter Co. in La Jolla, the discoverer of the human genes sequence...

He has been a research scientist at UCR, the Scripps Institute, Stratagene Cloning System Inc. and the Diversa Corporation (as co-founder) and recently was distinguished scientific consultant and research fellow at the J. Craig Venter Institute and its Synthetic Geonomics Inc.

Most of his activities have been and are in the field of rapidly advancing genetic engineering and sciences boundaries.

He has published more than 60 scientific papers, and is named inventor on more than 50 issued U.S. and world patents, and has been invited to present more than 100 scientific lectures.

Mathur's parents immigrated to the United States in the 1940s and 1950s. His mother, a retired Redlands teacher, came from Latvia, and his father, who was a defense research and development engineer with Aerospace Corp. and TRW, came from India.

'Junk' DNA now looks like powerful regulator, Stanford researcher finds

Craig Lowe (UCSC)

STANFORD, Calif. -- Large swaths of garbled human DNA once dismissed as junk appear to contain some valuable sections, according to a new study by researchers at the Stanford University School of Medicine and the University of California-Santa Cruz. The scientists propose that this redeemed DNA plays a role in controlling when genes turn on and off.

Gill Bejerano, PhD, assistant professor of developmental biology and of computer science at Stanford, found more than 10,000 nearly identical genetic snippets dotting the human chromosomes. Many of those snippets were located in gene-free chromosomal expanses once described by geneticists as "gene deserts." These sections are, in fact, so clogged with useful DNA bits - including the ones Bejerano and his colleagues describe - that they've been renamed "regulatory jungles."

"It's funny how quickly the field is now evolving," Bejerano said. His work picking out these snippets and describing why they might exist will be published in the April 23 advance online issue of the Proceedings of the National Academy of Sciences.

It turns out that most of the segments described in the research paper cluster near genes that play a carefully orchestrated role during an animal's first few weeks after conception. [See the "Methylation prediction of FractoGene" - AJP]. Bejerano and his colleagues think that these sequences help in the intricate choreography of when and where those genes flip on as the animal lays out its body plan. [The vague notion of gene "turn on" is a "turn off" for theorists. No serious computer scientists would ever describe the role of software "to turn bits on and off" in a computer. "Intricate choreography" is better journalism, but still no substitute for hierarchical (recursive) protein synthesis where the fractality of organism is governed by the fractality of DNA - AJP]In particular, the group found the sequences to be especially abundant near genes that help cells stick together. These genes play a crucial role early in an animal's life, helping cells migrate to the correct location or form into organs and tissues of the correct shape.

The 10,402 sequences studied by Bejerano, along with David Haussler, PhD, professor of biomolecular engineering at UC-Santa Cruz, are remnants of unusual DNA pieces called transposons that duplicate themselves and hop around the genome. "We used to think they were mostly messing things up. Here is a case where they are actually useful," Bejerano said.

He suspects that when a transposon is plopped down in a region where it wasn't needed, it slowly accumulated mutations until it no longer resembled its original sequence. The genome is littered with these decaying transposons. When a transposon dropped into a location where it was useful, however, it held on to much of the original sequence, making it possible for Bejerano to pick out.

In past work, Bejerano and his co-workers had identified a handful of transposons that seemed to regulate nearby genes. However, it wasn't clear how common the phenomenon might be. "Now we've shown that transposons may be a major vehicle for evolutionary novelty," he said.

The paper's first author, Craig Lowe, a graduate student in Haussler's lab at UC-Santa Cruz, said finding the transposons was just the first step. "Now we are trying to nail down exactly what the elements are doing," he said.

Bejerano's work wouldn't have been possible without two things that became available over the past few years: the complete gene sequence of many vertebrate species, and fast computers running sophisticated new genetic analysis software. "Right now it's like being a kid in a candy warehouse," Bejerano said. Computer-savvy biologists have the tools to ask questions about how genes and chromosomes evolve and change, questions that just a few years ago were unanswerable. [Correction: they could have been answerable e.g. for human and mouse genomes since 2002 but considering 98.7% "Junk" there was no money to run with suitable software built for computers that did exist. Now even NIH - and EU - start pouring money, but private business will run away with the fat profits just as GenenTech did when "genes" became technologically approachable - AJP]

Bejerano and his colleagues aren't the first to suggest that transposons play a role in regulating nearby genes. In fact, Nobel laureate Barbara McClintock, PhD, who first discovered transposons, proposed in 1956 that they could help determine the timing for when nearby genes turn on and off.

Could US scientists get EU funding?

European Medical Research Councils to discuss allowing US citizens to apply for grants
By Stephen Pincock
[Published 19th April 2007 01:23 PM GMT]

Representatives of Europe's national medical research councils are planning to discuss next week the possibility of letting US scientists apply for European research funding, in the same way that European researchers can receive funding from the US National Institutes of Health.

Liselotte Højgaard, chair of the standing committee of the European Medical Research Councils (EMRC) told The Scientist that during the organization's annual meeting in Stockholm next week, members would discuss a potential white paper on clinical trials in Europe.

One item that might make it into that white paper is the idea of levelling the playing field for US researchers in terms of EU funding, she said. "In my personal opinion the current situation is utterly unfair. I know that I have personally applied for NIH funding [in the past] and have really appreciated it."

Under current arrangements, researchers from outside the US can apply for NIH funding. The NIH website lists 188 grants made in 2007 to researchers based outside of the US, some for close to $1 million.

Researchers based outside of Europe, however, cannot apply for EU funding. At the newly established European Research Council, for example, "funds are open to any scientists (of any nationality) based in the EU," European Commission spokesperson Antonia Mochan said in an Email.

Højgaard, head of the department of clinical physiology and nuclear medicine at Rigshospitalet, Copenhagen University Hospital, was careful to say she couldn't predict the outcome of the debate, which would involve representatives from agencies such as the UK's Medical Research Council, the Deutsche Forschungsgemeinschaft (DFG) in Germany, and INSERM in France among others.

"It's only one small item on a long agenda," she said. "I will ask my fellow medical research council representatives whether it is of their concern also." Denmark is already discussing changing its national law to allow people from outside Europe to apply for research grants, she said.

The Scientist contacted the British, French and German medical research councils for comment. Mark Palmer from the UK's MRC declined to comment until the issue had been discussed by the board; representatives of INSERM and DFG did not return calls by deadline.

Mochan said that EU research commissioner Janez Potocnik and NIH director Elias Zerhouni had discussed the matter informally, but that the European Commission had nothing further to add at this time.

The EMRC was established in 1971. Part of its role is to develop European scientific strategies and stimulate collaboration in emerging and interdisciplinary research areas.

Stephen Pincock

[It is not only a good idea for US researchers to compete for EU research funds ("levelling the field of global competition" in order to break down monopolies of "science establishments"), but it is a formal recognition of the already existing fact that "brain drain" is not as "one-sided" as it used to be. Just as Liselotte Hojgaard quoted her personal case (having applied for US funds from EU), this columnist could quote episodes from his experience, from a complementary viewpoint. Germany has long established the "Senior Distinguished American Scientist Award", in recognition of the US "Marshall Plan" and NASA's application of a paradigm-shift of Neural Networks was quickly followed by awarding the "Alexander von Humboldt Prize" (on German money) to AJP. Likewise, very recently, the "European Inaugural of International PostGenetics Society" in Hungary resulted in awarding to AJP an "European Union Visiting Professorship" - since small new member countries of the EU are unlikely to be able to compete in "Modern Genetics" with established giants such as the UK, Germany, The Netherlands, etc. thus the newly ascended member countries of the EU would like to directly plunge into the "PostModern era of Genetics" (PostGenetics). However, given their meager resources and formidable transitional challenges, they need their US-based researchers to "pitch in" with the EU for the accomplishment of full collective success in PostGenetics. This is quite similar to global cooperation in stem cell research, where notable US-based researches turned to their UK roots to accomplish difficult goals of a paradigm-shift. - A. Pellionisz, 21th of April, 2007]

Genomicists Tackle the Primate Tree

Science, Apr. 13.
Elizabeth Pennisi

Richard Gibbs, Baylor, Houston, Texas

Primates are taking center stage in genomics, with the macaque serving as an early milestone in understanding our relatives' genomes--and therefore our own

The deciphering of the human genome was a humbling experience. The promise of the project, in the words of James Watson, was "to find out what being human is." But even when most of the 3 billion bases of the human genome had been properly placed, much about the sequence defied understanding. Where in the 20,000 human genes uncovered are the ones that set Homo sapiens apart from other mammals, or other primates? To find out, genomicists have been scrambling for more data [in the sciences "data" are the sine qua non" - but without theory, data alone never yield understanding - AJP] ever since, most recently from primates. "The goal is to reconstruct the history of every gene in the human genome," [is it, really? - should it not be an understanding why some human genes may not have a "history" - AJP] says Evan Eichler, a geneticist at the University of Washington, Seattle. And that requires data from our relatives. DNA from different branches of the primate tree will allow us "to trace back the evolutionary changes that occurred at various time points, leading from the common ancestors of the primate clade to Homo sapiens," says Bruce Lahn, a human geneticist at the University of Chicago in Illinois.

In 2005, the unraveling of the chimp genome provided tantalizing hints about differences between us and our closest relative (Science, 2 September 2005, p. 1468). Now ... the third primate genome, that of the rhesus macaque, begins to put the chimp and human genomes into perspective. Macaques are Old World monkeys, which split perhaps 25 million years ago from the ape lineage that led to both chimpanzees and humans.... So when compared to apes, monkeys can help identify the more primitive genetic variants, allowing researchers to tease out the changes that evolved only in apes. Researchers want to take such analyses back to even more ancient evolutionary divergences, and so seven more primate genome sequences are under way, as is the sequencing of the DNA of two close nonprimate relatives. Together, these genomes "should teach us general principles of primate evolution," says Lahn. [They "should" but don't be surprised if "comparative genomics" may not yield clues unless and until we define *what* we are "comparing" - AJP]

A consortium of more than 100 researchers who have been unraveling the macaque genome are detecting genes that have changed faster than expected in the chimp and human lineages; such speed is usually a telltale sign of significance in evolution. They are also finding that dozens of base changes known to put humans at risk for disease also exist in the healthy macaque--but not in the chimpanzee. That suggests that some gene variants implicated in disease are relics of the ancestral primate condition. Such studies "may be the bridge between comparative genomics and evolutionary biology," says Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center in Houston, Texas, and coordinator of the rhesus macaque genome project. [Here you go! There is a specific theoretical hypothesis lurking here; that the emergence of species is hierarchical, and a lapse back into an "outgrown" phase is not only "obsolete" but may be a harmful "glitch" - AJP]

Gibbs and his colleagues are tackling evolutionary biology in reverse. They are identifying key genomic differences without yet knowing how or whether those differences translate into traits that provide survival advantages. Traditionally, researchers have first traced changes in the shapes and sizes of beaks, bodies, brains, and so on, then sought the genes behind them. The hope is that the two modes of inquiry will meet in the middle. But so far researchers have come up short in linking genomic changes to traits subjected to natural selection and other evolutionary forces, ironically because of sparse biological data on nonhuman primates, says glycobiologist Ajit Varki of the University of California, San Diego: "[Without] basic information about the chimp, its physiology, its diseases, its anatomy, you are really very impoverished about what you can say."

Beyond mouse

In 2001, the human genome sequence drove home how little we knew about our genomic selves. About one-third of our genes were complete unknowns. Researchers immediately started lining up our DNA with that of worms, fish, and rodents to see what genes matched up and to try to pin down functions. They found not just genes but also conserved regions within the "junk" DNA that played as critical a role in genome function as the genes themselves. Their finds led to an unquenchable thirst for sequence data as a way to clarify how genomes work. "Every additional species increases our ability to resolve functional from nonfunctional [DNA]," explains Ross Hardison, a molecular biologist at Pennsylvania State University in State College.

The surprise of the chimp genome, the first nonhuman primate to be sequenced, was the large number of insertions and deletions that differed between humans and our closest living cousins. There were more changes in the order and number of genes and blocks of genes than changes in single base pairs, highlighting the importance of this kind of expansion and shuffling in primate speciation.

But the chimp data proved frustrating as well, because researchers couldn't put the chimp-human comparisons into an evolutionary context. If humans had one base, say a C, at a position where chimpanzees had a G, researchers had no way of knowing which base represented the ancestral condition. [It is much worse, since we can not exclude the theoretical possibility that "neither" - AJP]. Consequently, there was no way to tell whether the change at that position had occurred only in humans--and therefore perhaps helped define Homo sapiens--or in the chimp. And so in 2005, the National Human Genome Research Institute began stuffing more primates into the sequencing pipeline and approved the $20 million rhesus macaque sequencing project. "It is great to finally have a [distant relative] that allows us to assign differences between the human and chimpanzee genomes to either the human or the chimpanzee evolutionary lineage," says Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

Sequencers aren't stopping at the macaque. Sequencing of many primates, including the orangutan, the gibbon, and a New World monkey, the marmoset, is under way, with promises that the baboon should be next. In 2006, the Wellcome Trust Sanger Institute in Hinxton, U.K., started deciphering the gorilla genome, planning coverage similar to that of the macaque. Meanwhile, genomicists have started sequencing key genes and regulatory regions from other primates, too. "To tell what is human-specific, you need this comparative context," says Anne D. Yoder, an evolutionary biologist at the Duke Lemur Center in Durham, North Carolina. [When is "enough" "enough"? Never. Venter has just collected (and is sequencing) gezillions of genomes - leading to not only "comparative genomics" but "metagenomics". Even with sequencing getting increasingly dramatically less expensive - the amount of resources going into "data collection" is certainly in the range of hundreds of millions of dollars - while the theorethical efforts, e.g. those advocated by PostGenetics are disproportionally neglected. Trends of sciences suggest that - just as in nuclear physics - quickest advances will occur where data-production (e.g. by smashing nuclear particles) will be at least accompanied, but preferably guided by, quantitative theoretical predictions that are testable by experimentation - AJP]

To know a genome

Already, the primate genomic data are revealing bits of our genetic history. For example, more than 98% of chimp and human bases agree. So researchers hoping to pick out areas with fewer base changes than expected--such as regulatory regions conserved in all apes--are awash in a tide of virtually identical DNA. But when the search is expanded to additional primates, there's more variation in the sequences, and previously undetectable conserved regions, even small regulatory sequences, begin to surface.

For example, Dario Boffelli, now at Children's Hospital Research Center in Oakland, California, and his colleagues at the Joint Genome Institute in Walnut Creek, California, wanted to understand the regulation of genes that help maintain healthy levels of cholesterol in the body. They looked at 558,000 bases covering genes involved in cholesterol processing, comparing human and six other primates: baboon, colobus monkey, dusky titi, marmoset, owl monkey, and squirrel monkey. They discovered regions with virtually the same sequence in all the primates. Subsequent experiments showed that three of the newly identified conserved regions do indeed regulate genes in the cholesterol pathway, Boffelli's team reported in January in Genome Biology.

In other cases, particularly as researchers look for differences that reflect independent evolution, data from even one additional primate can help. In one analysis, the macaque team looked at 64,000 places in the macaque genome where they knew a disease-related mutation existed. In the past, researchers have assumed that such mutations were specific to humans. A few chimp genes had hinted that some problematic bases might predate humans, but the macaque drives home how often this may be the case. Hardison and his Pennsylvania State colleague Webb Miller found more than 200 sites where the macaque had the same base at the same position as the diseased or at-risk human. In 97 instances, both the chimp and the macaque matched the aberrant human base; in 48 cases it was just the chimp. And in 84 cases the rhesus, but not the chimp, matched the diseased human sequence, possibly because chimps also independently evolved away from the ancestral condition at those sites.

For example, about 1 in 15,000 people have phenylketonuria because their gene for an enzyme needed to process the amino acid phenylalanine is defective. Untreated, the buildup of a toxic byproduct causes mental retardation. In macaques, that same defective gene is the normal condition and has no ill effects. It could be that many "disease" variants in humans are simply ancestral variants "where [a dietary or environmental] change between the human ancestor and the human has made a variant that used to be good, bad," says Miller.

In addition, the macaque genome consortium combed the macaque, chimp, and human genomes for families of genes that had expanded in one or more species. A family consists of the original gene and any subsequent copies, many of which evolve slightly different sequences and functions over time.

One in particular intrigued Miller. This family, called PRAME--short for "preferentially expressed antigen of melanoma" because the genes are activated in melanoma and other types of tumors--has had a complex history in humans. It has at least 26 intact members on chromosome 1. It's one of the regions of the human genome that "are going wild," says Miller. The chimp has a similarly complex set of PRAME genes, but Miller found just eight PRAME genes in the macaque. "The cluster is very simple [and has] remained stable for millions of years," he explains. Working from this simpler, presumably ancestral set, he and his colleagues hope to unravel the timing and types of duplications that resulted in the abundance of human PRAME genes.

Elsewhere in the genome, the consortium found that the macaque has as many as 33 major histocompatibility complex (HLA) genes, more than triple the number in humans. "When you see a dramatic change, it suggests there was some evolutionary selection that favored those extra copies," says James Sikela, a computational biologist at the University of Colorado Health Sciences Center in Denver. "The tough question is, 'What favored that event?' "

While Sikela and colleagues ponder the macaque's need for HLA genes, Adam Siepel of Cornell University and his collaborators found other genes in which mutations were apparently favored by selection. Such positive selection, as it is called, typically shows up as bases that have mutated faster than would occur by chance. So Siepel's team compared 10,376 macaque genes with their equivalents in both the chimp and human genomes. They sought genes with a relative mutation rate that was higher in bases that changed the encoded amino acid than in bases that did not alter the coding. The researchers found 178 such genes, "considerably more" than previously identified in human-chimp scans, says Siepel. Some genes, such as a few involved in the formation of hair shafts, were changing rapidly in the three species, possibly because climate change or mate-selection strategies spurred rapid evolution, Siepel speculates.

Other positively selected genes detected in at least one species included those involved in cell adhesion and cell signaling, as well as genes coding for membrane proteins. "We don't really know enough at this stage to point to a case where we have a really nice story of a difference at the molecular level that we can connect to a known phenotypic difference," Siepel laments.

Siepel and others say that such stories require more primate sequences. Evidence of positive selection in the same genes in multiple species will provide more clues to what prompted such rapid evolution. Moreover, researchers can be more confident about labeling a gene as "human-specific" once they have looked in a number of our relatives and not found it. "The more primates one can compare, the better," says Sikela.

Sequencing decisions require tough choices about what species to sequence and how thoroughly, however. For his part, Boffelli thinks seven or eight primates would suffice and favors apes over prosimians, the most primitive living primates. With ape DNA, it will be easier to look for positive selection that led to humans. But Yoder thinks it's also important to understand how the whole primate branch has evolved, a point long made by researchers studying anatomy and behavior. "If you are going to understand which genes are primate-specific, you need a pretty broad phylogenetic spectrum, [with] things outside the primate clade but close to it," she notes. That argument has already brought tree shrews and flying lemurs (which are not lemurs at all) into the picture, with researchers planning a quick skim across the DNA to get a very rough draft sequence.

Others warn that the quick skim, which is also planned for the bushbaby, mouse lemur, and tarsier, might not be enough, however. With anything short of finished sequence, the computer programs may pick up differences--signs of evolution--that in reality may be sequencing errors, warns Miller. That was the lesson of the chimp genome, which initially was not a very polished draft.

Varki says the genomic work promises to be challenging in other ways, too: "At the genomic level, evolution is extremely messy, involving every conceivable mechanism, probably with lots of blind alleys and red herrings. Deciphering the significance of these molecular changes will be far, far more complicated than I imagined." ...

J. Craig Venter Institute Announces Management Team and Organizational Structure

J. Craig Venter, Ph.D., Founder, remains as President and Chairman;
Robert Strausberg, Ph.D., is named Institute Deputy Director

ROCKVILLE, MD—April 11 , 2007—The J. Craig Venter Institute (JCVI), formed in October 2006 through the merger of several affiliated organizations—The Institute for Genomic Research (TIGR), The Center for the Advancement of Genomics (TCAG), and the J. Craig Venter Science Foundation (JCVSF), today announced the new management team and organizational structure for the JCVI.

J. Craig Venter, Ph.D., founder, remains as Chairman and President of the new JCVI. Robert Strausberg, Ph.D., who had been president of the TCAG division, is now the Deputy Director. Marv Frazier, Ph.D., former Vice President for Research at TCAG is now the Executive Vice President for Research. The General Counsel for the JCVI is Julie Gross Adelson; Chief Financial Officer is Aimee Turner, who was formerly CFO at TIGR; Vice President of Human Resources is Robin Hoesch and Robert Friedman remains as Vice President for Public Policy.

The Institute will no longer be organized under the two research divisions TIGR and TCAG, but will now encompass an administrative team and the following research groups: Genomic Medicine, Infectious Disease, Synthetic Biology & Bioenergy, Plant Genomics, Microbial & Environmental Genomics, Pathogen Functional Genomics Resource Center (PFGRC), Applied Bioinformatics, Research Informatics, Software Engineering, and the Policy Center. The genomic sequencing capability remains a cornerstone of activities at the JCVI and will continue to be led by Yu-Hui Rogers. Eric Eisenstadt, former Vice President for Research of TIGR is the new Deputy Vice President for Research.

With six buildings and more than 250,000 square feet of lab space in Rockville, MD, as well as a research facility in La Jolla, CA, and combined assets of more than $200 million, JCVI is one of the largest independent research institutes in the Unites States. There are approximately 500 employees, of whom nearly 400 are dedicated to research with 124 of those having doctoral degrees. The organization also boasts one Nobel Laureate and three members of the National Academy of Sciences.

“Since the earliest days of founding TIGR in 1992 and then with the other affiliated institutes, my goal has always been to create unique and dynamic research organizations that push the boundaries of traditional science. We have long been leaders in genomics and with our newly organized Institute, I am certain we are poised to continue to blaze new trails in this field,” said Dr. Venter.

About the J. Craig Venter Institute

The J. Craig Venter Institute is a not-for-profit research institute dedicated to the advancement of the science of genomics; the understanding of its implications for society; and communication of those results to the scientific community, the public, and policymakers. Founded by J. Craig Venter, Ph.D., the JCVI is home to approximately 500 scientists and staff with expertise in human and evolutionary biology, genetics, bioinformatics/informatics, information technology, high-throughput DNA sequencing, genomic and environmental policy research, and public education in science and science policy. The legacy organizations of the JCVI are: The Institute for Genomic Research (TIGR), The Center for the Advancement of Genomics (TCAG), the Institute for Biological Energy Alternatives (IBEA), the Joint Technology Center (JTC), and the J. Craig Venter Science Foundation. The JCVI is a 501 (c)(3) organization. For additional information, please visit http://www.JCVI.org.

The University of Maryland School of Medicine in Baltimore has named preeminent genome scientist and microbiologist Claire M. Fraser-Liggett, PhD, to head the University of Maryland School of Medicine's Institute of Genome Sciences - a new research enterprise dedicated to the application of genome sciences for the advancement of human health. This new institute will be located at the University of Maryland, Baltimore (UMB) BioPark, a biomedical research park on UMB's expanding campus.

Fraser-Liggett comes to the School of Medicine from The Institute for Genomic Research (TIGR) in Rockville, MD, where she has served as president and director since 1998. During her tenure at TIGR, federal funding to the organization tripled to $60 million per year. At TIGR, Fraser-Liggett led research teams that sequenced the genomes of many microbial organisms and helped to initiate the era of comparative genomics. She has been the most highly cited scientist in the field of microbiology for the past 10 years.

"Dr. Fraser-Liggett is a true pioneer in the effort to sequence and analyze the genomes of a large number of organisms, and we are thrilled to have her world-class expertise at the University of Maryland," says E. Albert Reece, MD, PhD, MBA, vice president for medical affairs and dean of the School of Medicine. "Dr. Fraser-Liggett is expected to bring a team of scientists and staff members with her. This major recruitment initiative will fuel the expansion of genomic research at the School of Medicine."

As an expert in the field of microbial genomics, one aspect of Fraser-Liggett's current research is to understand the communities of bacteria in the human body, especially the microorganisms that reside in the digestive tract. These bacterial cells far outnumber the human cells that make up our bodies and are vital to good health.

By comparing DNA sequences from these microbes, researchers have already determined the biological function of some beneficial bacteria. The research could lead to new ways to promote health and novel vaccines to prevent disease.

"I am extremely excited about the opportunity to build a new genomics institute within the School of Medicine," says Fraser-Liggett. "The School of Medicine has a rich history in medical and graduate education and an outstanding faculty in both basic and clinical research, many of whom are current or past collaborators with TIGR."

Fraser-Liggett has overseen the genome sequencing of important human pathogens, including bacterial infections that cause cholera and anthrax, and parasitic infections responsible for malaria and other devastating diseases in the developing world. Her work also includes the study of influenza and other viruses. These studies have provided a strong foundation for the development of new diagnostics, therapeutics and vaccines.

At the University of Maryland, Fraser-Liggett will build on her impressive body of work while collaborating with physician-scientists in an environment that fosters translational medicine.

"One of the most important challenges over the next two decades will be integrating new insights from the past 10 years of genomics studies into the clinical environment to impact human health," says Fraser-Liggett. "There is no better place to be working toward these goals than in a large academic medical center like the University of Maryland School of Medicine."

"The University of Maryland School of Medicine's Institute of Genome Sciences will provide countless opportunities for multi-disciplinary collaboration," says Bruce E. Jarrell, MD, vice dean for research and academic affairs. "Institute faculty will have opportunities for clinical research and benefit from the School of Medicine's strong international programs, such as the Center for Vaccine Development, headed by Dr. Myron Levine; the Institute of Human Virology, led by Dr. Robert Gallo; and the Department of Microbiology and Immunology, chaired by Dr. James Kaper."

Fraser-Liggett has been continuously supported by federal funding, including the National Institutes of Health). She currently serves on the National Science Advisory Board for Biosecurity and the National Research Council's Committee on Metagenomics. She is a member of the editorial boards of The Journal of Biological Chemistry and The Journal of Bacteriology. She has published more than 220 articles in scientific journals and is a reviewer for nine journals.

["Boom" is defined by multiple bidders competing for the same resources - A. Pellionisz, 12th of April, 2007]

Scientists reveal structure of gateways to gene control

Scientists at Penn State University will reveal in the 29 March 2007 issue of the journal Nature the first complete high-resolution map of important structures that control how genes are packaged and regulated throughout an entire genome. "For the first time, we are seeing in very high resolution on a genome-wide scale how nucleosomes control the expression of an organism's genes," said B. Franklin Pugh, professor of biochemistry and molecular biology and the study's lead investigator.

The map pinpoints the locations of certain key gene-controlling nucleosomes -- spool-like structures that wrap short regions of DNA around a protein core. The research suggests how these nucleosomes, positioned at important transcription-promoter sites throughout the cell's DNA, control whether or not a gene's function can be turned on in a particular cell...

The study revealed that almost all genes have the same kind of structure where transcription begins, that this beginning contains a critical gateway for transcription, and that the transcription gateway of each gene almost always is located at the same place on a nucleosome. The researchers also discovered some genes whose pattern is somewhat different from this norm, and these unusual sequences also are reported in the Nature paper. "We previously had a low-resolution idea that these structures all could be roughly in the same position, but now this high-resolution map makes it very clear that they really are in exactly the same position. It's a remarkably consistent arrangement," Pugh said.

The study also revealed that the nucleosomes at the transcription-promoter control centers occupy several overlapping positions on the DNA molecule, typically 10 base pairs apart, which exactly matches the periodic rotation of the DNA double helix. "It is striking how well these positions match with the architecture of the DNA as it wraps around the nucleosome's protein core," Pugh said.

This result powerfully simplifies previous theories about the possible architecture of gene packaging. "There is a certain DNA sequence that shapes the gene's architecture in the same way, producing the same structure in every gene," Pugh said. The overall sequence of DNA building blocks is different in each gene, but the underlying architecture is the same."...

Another discovery is that transcription-control centers tend to be located on the outside edge of the nucleosome and tend to face outward on the DNA helix, allowing the cell's transcription proteins to find them more easily. "This arrangement makes sense, because when signaling proteins arrive at a control center they are well situated to help push the nucleosome out of the way so the reading of the gene can begin," Pugh said.

"Previous research had indicated that DNA sequences located upstream of a gene might be a region that controls whether that gene is read or not, but we did not know the architecture of those sequences -- whether they were exposed and therefore ready for work. Now we know that the gateway to transcription is a part of this control region and that the nucleosome keeps it locked so the gene cannot be turned on until it is needed," Pugh said. When the gene is needed, the cell's molecular machinery loosens the DNA wrapping around the nucleosome, unlocking the transcription gateway to give access to the cell's molecular transcription machinery. "We think that the function of the nucleosome is to control the gateway to transcription," Pugh said....

The knowledge that most genes are packaged basically the same way is powerful information with implications for future research and potential applications. "One implication that I think is important is that we now have a better idea about how packaging the DNA in nucleosomes controls the expression of a gene," Pugh said. "We don't yet know where all the important gene-regulation features are located on the DNA molecule, but now we know we should start looking for some of them on the edges of nucleosomes," Pugh said. "We might even discover some sites that regulate genes that we didn't even know existed."

Is Biology Reducible to the Laws of Physics? [Philosophy of PostGenetics is to come]

John Dupré

Darwinian Reductionism: Or, How to Stop Worrying and Love Molecular Biology. Alex Rosenberg. x + 263 pp. University of Chicago Press, 2006.

Alex Rosenberg is unusual among philosophers of biology in adhering to the view that everything occurs in accordance with universal laws, and that adequate explanations must appeal to the laws that brought about the thing explained. He also believes that everything is ultimately determined by what happens at the physical level—and that this entails that the mind is "nothing but" the brain. For an adherent of this brand of physicalism, it is fairly evident that if there are laws at "higher" levels—laws of biology, psychology or social science—they are either deductive consequences of the laws of physics or they are not true. Hence Rosenberg is committed to the classical reductionism that aims to explain phenomena at all levels by appeal to the physical.

It is worth mentioning that, as Rosenberg explains, these views are generally assumed by contemporary philosophers of biology to be discredited. The reductionism that they reject, he says, holds that there is a full and complete explanation of every biological fact, state, event, process, trend, or generalization, and that this explanation will cite only the interaction of macromolecules to provide this explanation.

Such views have been in decline since the 1970s, when David Hull (The Philosophy of Biological Science [1974]) pointed out that the relationship between genetic and phenotypic facts was, at best, "many/many": Genes had effects on numerous phenotypic features, and phenotypic features were affected by many genes. A number of philosophers have elaborated on such difficulties in subsequent decades. ["Neurophilosophy" as a discipline was born in realization that the causal relationship of one neuron to another, and the next (in a "reflex arc") was obsolete, and in view of the emergence of massively parallel connectionism in the new discipline of "Neural Networks" the general philosophyical underpinning had to be re-crafted. Patricia Churchland (UCSD) accomplished this in her epoch-making book. In the presently ongoing new paradigm-shift, "The Philosophy of PostGenetics" is yet to find its author - undoubtedly to be catapulted into a similar career to those of the Churchlands - AJP]

The question then is whether Rosenberg's latest book, Darwinian Reductionism: Or, How to Stop Worrying and Love Molecular Biology, constitutes a useful attack on a dogmatic orthodoxy or merely represents a failure to understand why the views of an earlier generation of philosophers of science have been abandoned. Unfortunately I fear the latter is the case. More specifically, his portrayal of the genome as a program directing development, which is the centerpiece of his reductionist account of biology, discloses a failure to appreciate the complex two-way interactions between the genome and its molecular environment that molecular biologists have been elaborating for the past several decades.

In earlier work, Rosenberg accepted the consensus among philosophers of biology that biology couldn't be reduced to chemistry or physics. But whereas most philosophers saw this as a problem for philosophy of science, and for traditional models of reduction, Rosenberg concluded that it was a problem for biology, a problem indicating that the field's purported explanations were neither fundamental nor true.

However, in his most recent book Rosenberg is more sanguine about biology. As the title suggests, the new idea is that recognition of the pervasiveness of Darwinism in biology will enable us to assert reductionism after all. Rosenberg is an admirer of Dobzhansky's famous remark that nothing in biology makes sense except in the light of evolution:

Biology is history, but unlike human history, it is history for which the "iron laws" of historical change have been found, and codified in Darwin's theory of natural selection. . . . There are no laws in biology other than Darwin's. But owing to the literal truth of Dobzhansky's dictum, these are the only laws biology needs.

The suggestion is that something Rosenberg calls "the principle of natural selection" is actually a fundamental physical law. Natural selection, according to him, is not a statistical consequence of the operation of many other physical (or perhaps higher-level) laws, as most philosophers of biology believe. Rather, it is a new and fundamental physical law to be added to those already revealed by chemistry and physics. I won't try to recount Rosenberg's arguments for this implausible position.

The largest part of the book motivates reductionism from a quite different direction by defending the view that genes literally embody a program that produces development. Rosenberg introduces this view by recounting some work on the development of insect wings. There is a rather disturbing tendency in this exegesis to suggest an imputation of agency to the genes that are implementing this program. He says that the genes fringe and serrate "form the wing margin," for example, and "wingless builds wings." He also maintains that in Drosophila, "2500 genes . . . are under direct or indirect control of eyeless." As the last two examples illustrate and Rosenberg explains, genes are frequently identified by what doesn't happen when they are deleted. But Rosenberg seems quite untroubled by the dubious inference from what doesn't happen to the conclusion that making this happen is what the genes "do" when in place. These reifications provoke a range of worries, but at a minimum, a defense of such ways of speaking will need to address another growing philosophical consensus to which Rosenberg is an exception, that the gene is a concept that no longer has an unproblematic place in contemporary biology.

Rosenberg does attempt a defense of the gene, but his arguments are unconvincing. The biggest problem is that he never says what he means by a gene. He refers uncritically to estimates of the number of genes in the human genome; although he does outline some of the difficulties with these estimates, he does not seem to appreciate their force. As a positive contribution, it appears that all he has to offer is the proposal that genes are "sculpted" out of the genome by natural selection to serve particular functions. The central point of critics of the gene concept is that functional decomposition identifies multiple overlapping and crosscutting parts of genomes. The "open reading frames" to which biologists refer when they count the genes in the human genome not only can overlap but are sometimes read in both directions. Subsequent to transcription they are broken into different lengths, edited, recombined and so on, so that one "gene" may be the ancestor of hundreds or even thousands of final protein products. Sophisticated would-be reductionists, such as Kenneth Waters, have tried to accommodate this point. Rosenberg seems just to ignore it as happily as he ignores most of the literature that has expounded the difficulties (for example, What Genes Can't Do, by Lenny Moss [2003], and The Concept of the Gene in Development and Evolution, edited by Peter Beurton, Raphael Falk and Hans-Jörg Rheinberger [2000]).

The problem might have been ameliorated if Rosenberg had paid more attention to the increasingly diverse constituents recognized in the genome apart from the genes he needs to run his programs. The lack of concern with the genome is highlighted, for example, when in the course of a single paragraph he says that sculpting of the genome by natural selection has resulted in "a division mainly into genes" and refers to 95 percent of the human DNA sequence appearing to be "mere junk" (another hypothesis that has been widely rejected). It is conceivable that Rosenberg means to define genome so as to exclude the junk, although I have never encountered such a usage before. What is clear, though, is that he sees the genome merely as a repository for the informationally conceived genes supposed to run the developmental program. Attention to the increasingly understood complexities of the genome as a material object would have made the misguided nature of the enterprise much clearer.

A further problem is that some of the biology in the book is dated. For example, Rosenberg says that "there are about 30,000 to 60,000 genes in our genome," but in fact there is a fairly stable consensus now that the number is about 23,000. More striking is his remark that alternative splicing is "uncommon but not unknown," whereas it is actually widely accepted that such splicing occurs in more than 70 percent of human genes. Although Rosenberg has researched some biological topics in detail, the book contains other lapses as well. He appears to be unaware, for instance, that methylation occurs in contexts other than sexual imprinting. And I was struck by his remark that the world is now mainly populated by sexual species; in fact, the overwhelming majority of organisms now, as ever, are prokaryotes and (relatively) simple asexual eukaryotes. It is admittedly difficult or impossible to stay fully au courant with the latest in molecular biology, but a careful reading of the manuscript by a practitioner would have been very helpful.

Because I have been involved for many years in criticism of the earlier orthodoxy that Rosenberg continues to defend, it is not surprising that I am unconvinced by his reactionary argument. And it is of course very often a good thing for philosophers to confront the orthodoxies of their discipline. But the standards for undermining orthodoxy are inevitably high, and Rosenberg does not come close to meeting them.

The subtitle invites us to learn to love molecular biology. Many of the philosophers whom Rosenberg's views contradict greatly admire the achievements of molecular biology. Love, however, is well known for being blind. I would encourage Rosenberg to settle for admiration.

Reviewer Information

John Dupré [a new Founder of International PostGenetics Society] is professor of philosophy of science in the Department of Sociology and director of the Economic and Social Research Council's Centre for Genomics in Society (Egenis). His most recent book is Darwin's Legacy: What Evolution Means Today (Oxford University Press, 2003).

Trillion-dollar prize turns dotcom into watt-com

The New York Times

Silicon Valley's best and brightest have identified the next big thing: alternative energy. Matt Richtel reports.

SILICON Valley's dotcom era might be giving way to the watt-com era.

Out of the ashes of the internet bust, many technology veterans have regrouped and found a new mission in alternative energy: developing wind power, solar panels, ethanol plants and hydrogen-powered cars.

It is no secret that venture capitalists have begun pouring billions into energy-related start-ups with names such as SunPower, Nanosolar and Lilliputian Systems.

But that interest is now spilling over to many others in Silicon Valley - lawyers, accountants, recruiters and publicists, all developing energy-oriented practices to cater to the cause.

The best and the brightest from leading business schools are pelting energy start-ups with résumés. And, of course, there are entrepreneurs from all backgrounds - but especially former dotcommers - who express a sense of wonder and purpose at the thought of transforming the $US1 trillion ($1.2 trillion) American energy market while saving the planet.

"It's like 1996," says Andrew Beebe, one of the remade internet entrepreneurs. In the boom, he ran Bigstep.com, which helped small businesses sell online. Today, he is president of Energy Innovations, which makes low-cost solar panels. "The valley has found a new hot spot."

Beebe says the valley's potential to generate change is vast. But he cautioned that a frenzy was mounting, the kind that could lead to over-investment and poorly thought-out plans.

"We've started to see some of the bad side of the bubble activity starting to brew," Beebe says.

The energy boomlet is part of a broader rebound that is benefiting all kinds of start-ups, including plenty that are focused on the web. But for many in Silicon Valley, high tech has given way to "clean tech", the shorthand term for innovations that are energy-efficient and environmentally friendly. Less fashionable is "green", a word that suggests a greater interest in the environment than in profit.

The similarities to past booms are obvious, but the valley has always run in cycles. It is a kind of renewable gold rush.

In this case, the energy sector is not so distant from other Silicon Valley specialities as it might appear, say those involved in the new wave of start-ups. The same silicon used to make computer chips converts sunlight into electricity on solar panels, while the bioscience used to make new drugs can be employed to develop better ethanol processing.

More broadly, the participants here say their whole approach to building new companies and industries is easily transferable to the energy world. But some wonder whether this is just an echo of the excessive optimism of the internet boom. And even those most involved in the trend say the size of the market opportunity in energy is matched by immense hurdles.

Starting a clean technology firm is "not like starting an online do-it-yourself legal company", says Dan Whaley, chief executive of Climos, a San Francisco company that is developing organic processes to remove carbon from the atmosphere. "Scientific credibility is the primary currency that drives the thing I'm working on."

Just what that thing is, he would not specify. For competitive reasons, Whaley declines to get into details about his company's technology. His advisory board includes prominent scientists, among them his mother, Margaret Leinen, the head of geosciences for the National Science Foundation. In the last Silicon Valley cycle, Whaley's help came from his father. In 1994, he did some of the early work from his father's living room on GetThere.com, a travel site. It went public in 1999 and was bought by Sabre for $US750 million in 2000.

This time around, entrepreneurs say they are not expecting such quick returns. In the internet boom, the mantra was to change the world and get rich quick. This time, given the size and scope of the energy market, the idea is to change the world and get even richer - but somewhat more slowly.

Those drawn to the alternative-energy industry say they need time to understand the energy technology, and to turn ideas into solid companies. After all, in contrast to the internet boom, this time the companies will need actual manufactured products and customers.

"There are real business models and real products to be sold in established markets and growing economics," says George Basile, who has a doctorate in biophysics from the University of California, Berkeley, and specialises in energy issues.

Basile has just stepped into the fray himself. In January, he became the executive adviser for energy issues at Bite Communications, a San Francisco public relations firm with scores of technology clients that is now working to attract energy start-ups.

The sudden interest of lawyers, accountants and other members of the wider valley ecosystem strikes some as opportunistic.

"There's a large amount of bandwagon-jumping right now," says Mark Hampton, chief executive of Blanc & Otus, a technology-oriented public relations firm whose clients have included TiVo, Sybase and Compaq. Still, he understands the interest of relative newcomers: "There's a huge opportunity."

They are all, plainly, following the money. In the first three quarters of 2006, venture capital firms put $US474 million into a broad range of valley start-ups in energy storage, generation and efficiency, according to Cleantech Venture Network, an industry trade group. Energy was by far the fastest-growing area, and the amount was on par with what was put into telecommunications and biotechnology.

Yet the amount of money involved is still relatively small compared with the boom years. Over all, venture funding last year was still less than a third of the nearly $US34 billion venture capitalists invested in the region in 2000, the peak of the bubble, according to the Centre for the Continuing Study of the California Economy, based in Palo Alto.

"This is not 2000. It doesn't feel like 2000 on the street," says Stephen Levy, the centre's director. But, he says, "there's no doubt there's a buzz".

An Introduction to Synthetic Biology

66 Commercial companies - more than half in North-America, ~20% in California.

Definition: Synthetic Biology (also known as Synbio, Synthetic Genomics, Constructive Biology or Systems Biology) – the design and construction of new biological parts, devices and systems that do not exist in the natural world and also the redesign of existing biological systems to perform specific tasks. Advances in nanoscale technologies – manipulation of matter at the level of atoms and molecules – are contributing to advances in synthetic biology…

Is it biotech? Is it nanotech? Or is it an information technology? The field of synthetic biology is in fact all three – an example of “converging technologies,” the latest industrial strategy favored by OECD policymakers. Scientists predict that within 2-5 years it will be possible to synthesize any virus; the first de novo bacterium will make its debut in 2007; in 5-10 years simple bacterial genomes will be synthesized routinely and it will become no big deal to cobble together a designer genome, insert it into an empty bacterial cell and – voilà – give birth to a living, self-replicating organism. Other synthetic biologists hope to reconfigure the genetic pathways of existing organisms to perform new functions – such as manufacturing high-value drugs or chemicals…

Impact: A clutch of entrepreneurial scientists, including the gene maverick J. Craig Venter, is setting up synthetic biology companies backed by government funding and venture capital. They aim to commercialize new biological parts, devices and systems that don’t exist in the natural world – some of which are designed for environmental release…

In the 1960s an Indian- American Nobel prize winner, Har Gobind Khorana, first developed a chemical protocol for building DNA chains to order – arranging its four compounds known as the nucleotide bases (adenine, cytosine, guanine, and thymine represented by the letters A, C, G and T) into the spiraling ladder of the DNA molecule via some fairly slow and complicated chemistry. In 1970 the Nobel laureate and an army of helpers succeeded in constructing the DNA of an entirely artificial gene 207 base pairs long (although it wasn’t until 1976 that he and a team of 24 others managed to get their synthetic gene to work). Back in 1973 it would take one scientist a whole year to make a length of DNA eleven base pairs long. Today Khorana’s monumental feat would take minutes and would cost around $200. In the same year that Khorana announced his functional artificial gene (1976), California-based start-up Genentech – the world’s first commercial biotech company – invented a faster, automated method of synthesizing genes, and so the gene synthesis industry was born…

“Gene foundries” – gene synthesis companies that produce longer pieces of double-stranded DNA (including whole genes or genomes) – sell made-to-order sequences over the Internet. ETC has identified at least 66 commercial gene synthesis companies (see world map of gene synthesis companies)...

In July 2006 Codon Devices manufactured and sold a strand of DNA exceeding 35,000 base pairs – what they claim is the largest commercially produced fragment to date. It’s a record that is sure to be broken soon. Synthetic biologists predict that a million base-pair bacterial genome will be constructed within the next two years, that a yeast genome of about 12 million base pairs could be synthesised in about 18-24 months and a plant chromosome would not take much longer...

Andrew Hessel, a bioinformaticist in Toronto puts it: “DNA is getting pretty freaking cheap to make.” In mid-2006 ETC Group surveyed advertised costs and found that most gene synthesis companies currently charge between US$1-$2 dollars per base pair (around “a buck a base” as they like to say). The cheapest advertised rate was Epoch Biolabs, at $.85 per base pair. In October 2006, Codon Devices advertised $.79 per base pair. At a May 2006 synthetic biology conference gene synthesis companies were confidently predicting that the price would drop to $.50 per base pair by the end of 2007. Gene synthesis for oligos (shorter, single strands) is already at $.10 per base and a new method pioneered by geneticist George Church of Harvard University may reduce the cost ten-fold, to $.01 per base…

Our informal survey suggests that most of the synthesis companies can turn around a synthetic gene (around 1,000 base pairs known as 1 kilobase pair – Kbp) in under two weeks. At present Craig Venter holds the world’s gene-speed record for synthetically producing a 5,386 bp genome (of the virus phiX 174) in under 14 days…

Cleaning up the Code – Codons, Proteins and Pathways. Cranking out DNA is pointless unless scientists know how to arrange it into meaningful code. In the popular understanding of genetics, a gene, a length of DNA composed of base pairs, is regarded as the smallest functional unit of genetic code, instructing cellular machinery via RNA (ribonucleic acid) which proteins to manufacture. Those proteins in turn carry out the tasks and processes within organisms that we understand to be “life.” As Francis Crick, a co-discoverer of the DNA double-helix, put it: “DNA makes RNA, RNA makes proteins, and proteins make us.”… [FractoGene inserted: "DNA makes RNA, RNA makes proteins. Repeat; proteins recurse. Iterative protein synthesis makes us." - Pellionisz]

Unfortunately for would be life builders, genetic code is not as linear as computer code. [Fortunately, recursive code is nothing new to computers... - Pellionisz]. While the popular view of genetics links units of DNA (genes) to specific traits, the reality is messier. In real life, genes and parts of genes co-operate in subtle and complex networks, each producing proteins that promote or suppress the behavior of other genes. [See? Evidence is already there... Pellionisz] The result is a system of cellular regulation that controls the amount or timing by which a substance or trait is produced .... Geneticists interested in manipulating genomes have begun mapping the interactions between genes to try to determine the full set of interactions necessary to produce a desired protein…

In the mid 1990s Venter’s non-profit outfit, The Institute for Genomic Research (TIGR), pursued a Minimal Genome Project to discover the fewest number of genes necessary for a bacterium to survive. The bacterium they chose was Mycoplasma genitalium, a bug that causes urinary tract infections. It has one of the smallest known genomes of any living organism (517 genes made up of about 580,000 DNA base pairs). Clyde Hutchison of TIGR began modifying the genome of Mycoplasma genitalium, observing which genes could be disrupted without killing the organism and then disabling those genes one at a time. He guessed that the bacterium might be able to survive with almost half its genes removed. In a 2005 workshop at the US Department of Energy, Hutchison’s team announced that they had reduced the genome to about 386 essential genes. In another bacterium, Bacillus subtilis, they found that all but 271 of 4100 genes could be knocked out. Others are now trying to minimize the genome of organisms such as E-coli. For Venter’s team, the ultimate goal of creating a minimal microbe is to use it as a platform for building new, synthetic organisms whose genetic pathways are programmed to perform commercially useful tasks – such as generating alternative fuels. Hutchison, Venter and Nobel laureate Hamilton Smith are now attempting to artificially synthesize their reduced version of the Mycoplasma genitalium genome so it could be used as a stripped-down ‘chassis’ for future synthetic organisms. They will remove the DNA from an existing bacterium and insert their synthesized genome in its place. If it successfully ‘boots up,’ their synthetic organism, dubbed Mycoplasma laboratorium, would amount to an entirely new species of bacterium – the first fully synthetic living species ever created (viruses must use a host cell’s machinery in order to replicate and are therefore not considered living organisms). Venter calls Mycoplasma laboratorium a “synthetic chromosome” and his intention is to use it as a flexible biofactory into which custom-designed synthetic “gene-cassettes” of four to seven genes can be inserted, genetically programming the organism to carry out specific functions. As a first application, Venter hopes to develop a microbe that would help in the production of either ethanol or hydrogen for fuel production (see The New Synthetic Energy Agenda). He is also looking to harness the mechanisms of photosynthesis to more effectively sequester carbon dioxide, ostensibly as a means of slowing climate change…

Venter’s team should have plenty of genetic booty to exploit following its US government-funded ocean expedition on Venter’s yacht to collect and sequence microbial genetic diversity from around the globe. Exotic microbes are the raw materials for creating new life-forms and new energy sources. Venter claims that his expedition has discovered 3,995 new gene families not previously known, and 6-10 million new genes – which he describes as “design components of the future.” To harness synthetic microbes for energy production, Venter’s non-profit institutes have received over $12 million from the US Department of Energy’s Genomes to Life project. In February 2006 the former head of that government program, Aristides Patrinos, became the president of Venter’s Synthetic Genomics. Venter talks big. In 2004 he predicted that “engineered cells and life forms [will be] relatively common within a decade.” And he claims his will be the first fully synthetic life- form. The birth date of Venter’s new organism is shrouded in secrecy. In August 2004 Venter boasted to Wired magazine that there would be an announcement by the end of the year. It never came. In June 2005 Venter told the Wall Street Journal that he was two years away from completing the synthetic microbe and that the number of people working on the project was about to jump from 30 to 100. In February 2006 Venter told a Hollywood gathering that his team was just a few months away from creating an artificial organism and, once that happened, the biotech field would be blown wide open. Venter took a more somber tone at this year’s synthetic biology conference in Berkeley (SynBio 2.0), predicting that his organism would be ready within two years, admitting that it has been “a rolling two years” for some time now…

Venter’s attempt to build an artificial chromosome is among synbio’s most high-profile projects. It also has the most visible commercial backing, including corporate agriculture and energy interests. Synthetic Genomics received half its start-up capital from Alfonso Romo Garza, the Mexican billionaire who owns agribusiness giant Savia. Bloggers at the University of California- Berkeley conference known as SynBio 2.0 noted that Venter was conspicuously conversing with Silicon Valley’s top venture capital investor, Vinod Khosla – the cofounder of Sun Microsystems and a big proponent of ethanol-based fuels. Accustomed to pushing ethical envelopes, Venter expects his artificial life-form to raise eyebrows, and his institute is one of three heading a study on the ethics of synthetic biology, which will no doubt serve as a pre-emptive strike against critics. When asked by interviewers if they are playing God, Venter’s colleague Hamilton Smith gives a characteristically hubristic response: “We don’t play.”…

At the University of California at Berkeley, the synthetic biology department led by Jay Keasling is engineering the genetic pathways of cells to produce valuable drugs and industrial chemicals – a goal that is fast becoming the cause célèbre of synbio. . .Keasling’s team has synthesised about a dozen genes that work together to make the chemical processes (or ‘pathways’) behind a class of compounds known as isoprenoids – high-value compounds important in drugs and industrial chemicals. Isoprenoids are natural substances produced primarily by plants. Because of their structural complexity, chemical synthesis of most isoprenoids has not been commercially feasible, and isolation from natural sources yields only very small quantities. Synthetic biologists at Berkeley hope to overcome these limitations by designing new metabolic pathways in microbes, turning them into “living chemical factories” that produce novel or rare isoprenoids. Most notably, they are focusing on a powerful anti-malarial compound known as artemisinin. Backed by a $42.5 million grant from the Bill and Melinda Gates Foundation, the Berkeley team believes that synthetic biology is the tool that will allow unlimited and cheap production of a previously scarce drug to treat malaria in the developing world. In 2003 Keasling and colleagues founded a synbio start-up called Amyris Biotechnologies to bring the project to fruition… Amyris hopes to use the same technology platform to produce far more lucrative drugs. “A number of drugs can be produced this way, not just one,” Keasling explains. “We’ve essentially created a platform that will allow you to produce many drugs cheaper. Down the road, we will be able to modify enzymes to produce a number of different molecules, even some that don’t exist in nature.” According to the company’s website, Amyris “is now poised to commercialize pharmaceuticals and other high value, fine chemicals taken from the world’s forests and oceans by making these compounds in synthetic microbes.” There are thousands of isoprenoid compounds and many of them have industrial uses. Amyris plans to use synthetic biology to produce commercial drugs, plastics, colorants, fragrances and biofuels. The company claims that its microbially-derived chemicals could be used for remediation of radioactive materials and to neutralize dangerous toxins such as sarin… Keasling’s lab is also attempting to re-engineer the metabolic pathways that produce natural rubber (also an isoprenoid). These pathways will then be incorporated into bacteria, or in sunflowers or desert plants, to boost rubber production (see Synthetic Commodities)….

Chris Voigt, a synthetic biologist at the University of California at San Francisco announced in May 2006 that he had re-engineered a strain of salmonella to produce the precursor to spider silk – a substance as strong as Kevlar with 10 times the elasticity….

California-based Genencor has been working with chemical giant DuPont to add synthetic genetic networks to the cellular machinery of E-coli. When mixed with corn syrup in fermentation tanks, their modified bacterium produces a key component in Sorona, a spandexlike fibre. DuPont and sugar giant Tate & Lyle are building a $100-million biological factory in Tennessee, which they plan to complete in late 2006, to produce this new biomaterial. DuPont hopes that its new bio-based textile will cause as much fuss as the introduction of nylon back in the 1930s. DuPont plans to build additional Sorona production factories, probably in the global South. According to John Ranieri, Dupont’s vice-president of bio-based materials, “one thing is for sure: we need to be close to the agricultural producing centers, in Brazil, India or the USA.”…

In his 2006 State of the Union address, US President George W. Bush announced that his government would devote “additional research funds for cutting-edge methods of producing ethanol, not just from corn, but from wood chips and stalks or switch grass.” Synthetic biology is one of the “cutting- edge” methods for biofuel production alluded to by President Bush. That part of his speech was written a few days earlier by Aristides Patrinos, then-associate director of the US Department of Energy’s (DOE) Office of Biological and Environmental Research. At the DOE, Patrinos had overseen both the Human Genome Project and more recently the Genomes to Life (GTL) program – which supports research to focus synthetic biology on the production of biofuels such as ethanol and hydrogen. The GTL program also promotes research on technological fixes such as carbon sequestration to mitigate climate change.

Two months after Bush’s speech, Patrinos left the Department of Energy to take up a new post as president of Craig Venter’s new company, Synthetic Genomics, Inc. The company aims to use microbial diversity collected from seawater samples as the raw material to create a new synthetic microbe – one that is engineered to accelerate the conversion of agricultural waste to ethanol. Patrinos is one of many high-profile industrialists and senior scientists who are climbing aboard the biofuels bandwagon. Bill Gates, for example, the soon-to-be retired chairman of Microsoft, recently bought 25% of Pacific Ethanol, while his Microsoft co-founder Paul Allen has invested in Imperium Renewables, a Seattle-based company that will produce ethanol mainly from soybeans and canola oil. Richard Branson, chairman of the Virgin Group of companies, is devoting $400 million to ethanol investment while Vinod Khosla, co-founder of Sun Microsystems and partner at Kleiner Perkins, a venture capital firm that famously backed AOL, Google and Amazon,150 now has a string of investments in ethanol companies…

There’s a lot we don’t know about living organisms. Almost 55 years after the discovery of the double helix, molecular biologists are still uncovering new information about how genes work and what role they play in life functions. Only recently have scientists rejected conventional wisdom about genetic inheritance: no single gene exclusively governs the molecular processes that give rise to a particular inherited trait. Scientists have moved away from the “one gene = one trait” assumptions of earlier days. Scientists are still learning that when they introduce a foreign gene into an organism it can produce uncertainty about the gene’s function as well as the function of the DNA into which it is inserted. They have also discovered that the vast “non-coding” sequences of DNA (so-called “junk” DNA), [too] long considered irrelevant because they yield no proteins, may actually play indispensable roles in affecting an organism’s function, health and heredity. Recent scholarship on gene regulation and expression emphasizes the non-coding regions of DNA that transmit information in the form of RNA and on the importance of factors outside the DNA sequence. For all the talk about synthetic bio’s genetic circuits and off-the-shelf parts, a living organism is not a logical and predictable “machine.”

Biofuels launch biotech's 'third wave'

Reuters | Thursday, 22 March 2007

SAN FRANCISCO: Biotechnology was first applied in medicine, then farming. Today, dozens of lifesaving drugs are on the market, while many crops are genetically engineered to withstand weed killers.

Now, a 2-year-old push to develop alternative fuels is driving biotechnology's growth into the industrial sector.

Thousands of corporate executives and scientists gather this weekend in Orlando, Florida, for an industry trade show specifically aimed at touting biotechnology's so-called third wave, industrial applications. The word on everyone's lips: ethanol.

After decades of unfulfilled promise and billions in government corn subsidies, energy companies may finally be able to produce ethanol easily and inexpensively thanks to breakthroughs in biotechnology.

Most of the 19 billion litres of ethanol produced annually in the United States is still made by fermenting corn, but the crop is expensive and its use in biofuels cuts into the nation's food supply. So the Canadian biotech company Iogen Corp has developed a method for deriving ethanol from a variety of plants including wheat, oats and barley. Others are genetically engineering microbes to produce enzymes that will convert the cellulose in crop waste, wood chips and other plants into ethanol.

President George W Bush helped breathe new life into this once-sleepy biotech sector by touting the need to ramp up production of this "cellulosic ethanol" in his last two State of the Union speeches.

The president wants to reduce the country's oil consumption by 20 per cent within 10 years and he sees alternative fuels as the way to get there. Bush visited the North Carolina biotechnology company Novozymes Inc. last month to underscore the industry's vital role in accomplishing that ambitious goal.

Government agencies led by the Department of Energy are sinking millions into biotech projects aimed at making ethanol more efficiently. And startups dedicated to turning plants into fuel have captured the fancy of deep-pocketed venture capitalists like Vinod Khosla. The billionaire co-founder of Sun Microsystems Inc is investing hundreds of millions of dollars in green technology and will be a featured speaker this year at the World Congress on Industrial Biotechnology & Bioprocessing.

Other heavy hitters attending the conference include University of California scientist Jay Keasling, Discover magazine's Scientist of the Year in 2006 and a leader in the burgeoning "synthetic biology" field, which aims to create living species that will spit out drugs and fuel.

Oil companies are also investing heavily in biotechnology these days, and executives from ConocoPhillips Co, Chevron Corp and Shell Oil Corp will also be on hand at Walt Disney World for the conference, which starts Thursday.

By contrast, these annual gatherings have historically been sleepy affairs. Last year's industrial biotech meeting, sponsored by the Biotechnology Industry Organisation, drew little interest even though it was held in Hawaii in January. That state's lieutenant governor may have been the biggest draw.

Past conferences have featured discussions on topics like biotech's role in manufacturing enzymes used to help laundry detergent break down dirt and give blue jeans the stone-washed look. But this year's meeting will be focused on the industry's role in making ethanol and other alternative fuels.

The DOE has awarded up to $US385 million over four years to six companies to develop ethanol.

"We are moving into a very diversified fuel era," said Ron Pernick, who co-founded Portland, Oregon-based Clean Edge, which tracks venture capital investment. "Private investment is really taking off."

Pernick said venture capital investment in biofuels has increased from less than $US1 million in 2004 to $US20.5 million in 2005 to $US813 million last year. Much of that investment is flowing to biotechnology companies that genetically engineer microbes that produce enzymes needed to break down crops into alcohol. ...San Diego's Diversa Corp, which has lost $US329.5 million since its inception in 1994, bought the Cambridge, Massachusetts-based ethanol company Celunol in January for $US154.7 million in stock, plus debt financing. The Celunol management team will take over the new energy company once the deal is approved.

Still, even industrial biotechnology's adherents concede that commercial success in the alternative energy industry is years away – if ever.

"Taking any invention from the lab to the marketplace is a long-term process and takes a lot of patience," said Celunol spokesman John Howe, who said the company's plan to convert sugar cane into ethanol will take many years to become profitable.

Others wonder if trend to making more ethanol has created a bubble that may soon burst.

Economist Lester Brown, who launched the Washington-based think tank Earth Policy Institute, said it is easier to make automobiles more fuel efficient than it is to radically alter the country's fuel supply.

"If we were to raise fuel efficiency standards, we could save as much oil as the president wants," Brown said. "Ethanol is not a winning ticket."

Microsoft Goes Bio

By Eli Kintisch
ScienceNOW Daily News

13 March 2007

Microsoft is adding synthetic biology to its universe. Today, the software giant announced $570,000 in grants to six teams of academic researchers exploring new ways to meld biology with computer science, math, and engineering.

"The reason we're in this area is there is a lot of potential," said Microsoft official Simon Mercer earlier this year in an interview with Science. "We may never be a biotech company, but ... we want to see growth of a set of tools that support synthetic biology activities." Synthetic biology uses mathematical modeling and other computational tools to devise new biological functions...

March 14, 2007 | Microsoft Research (MSR) has announced the six winners of its inaugural grants in synthetic biology. The company issued a request for proposals a few months ago, seeking to identify outstanding research projects aimed at tackling the computational challenges in two areas of synthetic biology:

The re-engineering of natural biological pathways to produce interoperable, composed, biological parts; and

The development of tools and information repositories relating to the use of DNA in the fabrication of nanostructures and nanodevices

The company said that 49 proposals were submitted from 11 countries, including many leading researchers and labs in the field. Following external peer review, six proposals were chosen. They are as follows:

Computational Interchange Standards for Synthetic Biology -- Herbert Sauro, University of Washington

Design and Synthesis of Minimal and Persistent Protein Complexes -- David Green and Steven Skiena, Stony Brook University

BioStudio: A Collaborative Editing and Revision Control Environment for Synthetic Genomes -- Joel Bader and Jef Boeke, Johns Hopkins University School of Medicine

Identification of Standard Gene Regulatory Sequences for Synthetic Biology -- Robert Holt, University of British Columbia, Canada

Using programmable stacking bonds to combine DNA origami into larger, more complex, reconfigurable structures -- Paul Rothemund and Erik Winfree, California Institute of Technology

Noise Suppression and Next-Generation Cloning Vectors -- Johan Paulsson, Harvard University

In announcing the program in December, MSR Bioinformatics Program Manager Simon Mercer said the challenges faced by scientists today will be faced by business tomorrow and eventually by everyone. “Encouraging and participating in basic research helps us to better understand these problems and their potential solutions.” Synthetic biology is a particularly interesting field, Mercer said, because it has “the potential to provide insights into living systems, transform biotechnology and perhaps generate entirely new industries.”

A Tiny Knock Out [effect of "knock out microRNA"]

By Jennifer Couzin
ScienceNOW Daily News

23 March 2007

Geneticists often say that the way to figure out how a gene works is to delete it and see what happens. But researchers haven't widely applied the same approach to microRNAs, tiny RNA molecules that regulate genes, in deciphering their functions. Now, in the first report on the effects of erasing a single microRNA in a vertebrate, scientists describe mice with subtle but profound heart abnormalities.

Discovered in the 1990s, microRNAs control a staggering quarter or more of the human genome. They can stop the production of certain proteins and might play roles in cancer and early development. Last year, developmental biologist Eric Olson of the University of Texas Southwestern Medical School in Dallas, his postdoc Eva van Rooij, and colleagues reported that nearly a dozen microRNAs were up- or down-regulated in failing mouse and, in some cases, human, hearts (ScienceNOW, 14 November 2006). But it wasn't clear what the individual microRNAs were doing.

Olson and van Rooij began eyeing a particular microRNA whose sequence is identical to a portion of one gene. That gene, alpha-myosin heavy chain, is mainly expressed in heart muscle cells. The researchers were curious about what deleting the portion of the gene that encodes this microRNA, miR-208, would do to mice, who would then lack miR-208 altogether.

At first, the answer appeared to be not much. "We had these mice that looked healthy, so we had to try to figure out what was wrong with them," says Olson. The team did that by stressing the animals' hearts in a way that mimics atherosclerosis and by blocking thyroid signaling, which also puts pressure on the organ. A defect surfaced: The hearts failed to switch on a genetic cousin of alpha-myosin heavy chain, called beta-myosin heavy chain, which usually kicks in when the heart is under duress. Instead, protein levels of the alpha version increased, suggesting that one gene was compensating for the other's silence, the group reports online this week in Science. This suggested that miR-208 normally targets the beta version of this gene and enables its expression. It's not clear, the researchers say, how the switch affects the animals’ health, but they believe that miR-208 is helping control the heart's response to stress.

Furthermore, in heart tissue from these mice, the scientists found genes turned on that are normally seen in skeletal muscle, not heart muscle. This finding suggests that miR-208 might ensure that heart muscle cells develop properly, says van Rooij.

Scott Hammond, a molecular biologist at the University of North Carolina, Chapel Hill, says he was struck by the microRNA's precise effects: "It's only in adults; it's only under certain stress conditions" that the abnormalities appear, he notes. Hammond and others expect many more stories about microRNAs and disease to come.

MetaGenomics: Ocean Study Yields a Tidal Wave of Microbial DNA [Scientific PostDarwinism]

[Sailing towards Scientific PostDarwinism]

John Bohannon

Data glut or unprecedented science? A global hunt for marine microbial diversity turns up a vast, underexplored world of genes, proteins, and "species"...

After relishing the role of David to the Human Genome Project's Goliath, J. Craig Venter is now positioning himself as a Charles Darwin of the 21st century. ... Four years ago, Venter set sail for the same islands and returned 9 months later with his own cache of data--billions of bases of DNA sequence from the ocean's microbial communities. ...

On 13 March, Venter, head of the J. Craig Venter Institute in Rockville, Maryland, and a bevy of co-authors rolled out 7.7 million snippets of sequence, dubbed the Global Ocean Sampling, in a trio of online papers in PLoS Biology. As a first stab at mining these data, which have just become publicly available to other scientists, Venter's team has found evidence of so many new microbial species that the researchers want to redraw the tree of microbial life. They have also translated the sequences into hypothetical proteins and made some educated guesses about their possible functions.

...The diversity of microbes uncovered is "overwhelming, … tantamount to trying to understand the plot of a full-length motion picture after looking at a single frame of the movie," says Mitch Sogin, a molecular evolutionary biologist at the Marine Biological Laboratory in Woods Hole, Massachusetts. And Venter doesn't necessarily disagree. In 2004, as the data were first rolling in, Venter confidently predicted that his salty DNA survey would "provide a different view of evolution." To make that happen, however, he now says, "we need even more data." [Perhaps even more importantly than an already staggering body of data, a conceptual re-thinking might be inevitable of "the new pattern of evolution" - AJP]

...The researchers sampled at 41 locations, isolating and subsequently freezing bacterium-sized cells. They also recorded the temperature, salinity, pH, oxygen concentration, and depth.

Back at Venter's institute, technicians extracted and sequenced the DNA. Using a whole-genome shotgun approach, they shattered all the DNA in a sample into fragments of specific sizes, sequenced each one, and then assembled these sequences together by matching the ends of the DNA with a powerful overlap-hunting computer program. In principle, this approach allows the reconstruction of entire genomes of the different organisms in a sample.

Three years and 6.3 billion bases of DNA sequence later, at least one thing is clear: The DNA in a typical community of marine microbes is so diverse that nothing close to a whole genome can be assembled, even with all the sequencing that Venter has mustered. Half of his 7.7 million DNA sequence fragments are so different that they could not be linked at all.

Nonetheless, the researchers could estimate the number of species in the samples based on slowly evolving marker genes. Judging by these glimpses of genomes, Venter's team identified more than 400 microbial species new to science, and more than 100 of those are sufficiently different to define new taxonomic families, they report. "This is a great milestone event" for environmental microbiology, says Dawn Field, a molecular evolutionary biologist at the Centre for Ecology and Hydrology in Oxford, U.K., who predicts that "these papers will become among the most highly cited of all time in biology."

Diversity deep end

...Traditional ecological theory predicts that when multiple species compete for the same resources--in the case of ocean microbes, light and dissolved nutrients--then one, or a few, species should eventually outcompete the rest. If that were the case, then many of the sequences plucked from the waters by Venter's crew should map down onto a few dominant genomes.

But rather than a sharp portrait of a few different microbes, the data create a pointillist painting of a countless mob. [Pointillism: A postimpressionist school of painting exemplified by Georges Seurat and his followers in late 19th-century France, characterized by the application of paint in small dots and brush strokes - answers.com - AJP]. The vast majority of the microbes that found themselves snared in Venter's filters were genetically unique, says Scanlan: "It's a clear message that there's a tremendous gene pool in the ocean."

The diversity itself could be the solution to the paradox, according to Douglas Rusch, a computational biologist at the Venter Institute, and his colleagues. The staggering variety of genes may endow each species with sufficiently different metabolic tool kits to take advantage of slightly different combinations of resources, including the waste products of others, such that they can all coexist....

Marine data-mining

The samples brought to port by Sorcerer II do more than shake up microbial taxonomy. Based on their best guess as to the beginning and end of each gene teased out from the DNA sequences, Venter Institute computational biologist Shibu Yooseph and his colleagues have concluded that the DNA encodes 6.12 million hypothetical proteins. That finding almost doubles the number of known proteins in a single stroke. It also shows that the end of protein diversity is not in sight, says David O'Connor, a molecular biologist at the University of Southampton, U.K. Most of the predicted proteins are of unknown function, and a quarter of them have no similarity to any known proteins. Venter expects that some of these can be exploited to develop new synthetic materials, clean up pollution, or bioengineer fuel production.

But the hypothetical proteins are already offering a new view of basic microbial biology. A team led by Venter and Gerard Manning, a computational biologist at the Salk Institute for Biological Studies in San Diego, California, says that the current picture of the proteins responsible for coordinating marine microbes' gene expression and metabolism is off the mark. By comparing predicted amino acid sequences with those of known proteins, they found a surprising abundance of signaling proteins thought to be used only by multicellular organisms. Among the hypothetical proteins from their marine samples, the researchers found 28,000 of the so-called eukaryotic protein kinases, as well as another 19,000 of a group that are highly similar to these kinases--triple the number previously known.

These analyses of Venter's metagenomic data hint at the work that lies ahead for protein researchers. "Claims by some biologists that complete catalogs of the protein universe would be attainable within a decade now look naïve," O'Connor points out.

...To help researchers deal with not just Venter's 100 gigabytes of sequence data but also other relevant information about a microbe's environment and location, Venter's team and Larry Smarr, a computer scientist at the California Institute for Telecommunications and Information Technology in San Diego, have built a metagenomics version of GenBank, the online genetic database curated by the National Center for Biotechnology Information in Bethesda, Maryland..

A more serious drawback of Venter's study, says Prosser, is that the samplings do not appear to have been carried out with any specific scientific hypotheses or aims in mind. The cynical view is that these are little more than "fishing trips," he says. "There would be greater potential for scientific advances if more focused, better designed studies were carried out." [This seems to be unfair criticism, since when Faraday discovered electricity by phenomenological experimentation did not - could not - have specific scientific hypotheses or aims - still rather quickly arrived at the electric motor. If anything, the fact that Venter embarked on his epoch-making voyage with an open mind, without biased by entrenched "axioms" (perhaps dogma) may be the one of the greatest tribute to him - AJP]

Will the voyage of the Sorcerer II live up to Venter's hopes? It took Darwin 25 years after returning from his expedition to publish his theory of evolution. With the three papers online this week, Venter, at least, has hopped on the fast track. But in terms of synthesizing the big picture of marine microbiology, he and his colleagues are still out to sea. [No. Not "he and his colleagues" - but we all are "out to sea" - but Venters sails clearly far ahead of anybody on the Earth - AJP].

Downoad entire PLOS Venter collection (high resolution 136 Mb)

Copy number linked to autism

Researchers find high rates of copy number mutations in non-heritable forms of autism

[Published 15th March 2007 05:54 PM GMT]

Copy number variation could be an important factor in autism, according to a new study published in Science today (March 15).

The largest percentage of copy number mutations occurred in families with one autistic child, the so-called sporadic, or spontaneously occurring cases -- not in families with multiple autistic children, indicating genetic inheritance.

Autism is widely recognized to be a genetic disorder, but this study focused on de novo genetic mutations (those present in the child but not the parents), rather than inherited mutations. "The majority of genetic studies to date have focused on the minority of families with multiple affected kids," study author Jonathan Sebat of Cold Spring Harbor Laboratory in New York told The Scientist. Until recently it hadn't been recognized that "the sporadic cases might be a rich source of genetic information," he said.

This study is part of a growing shift in the focus of study in genetics [towards PostGenetics - AJP], according to James R. Lupski at Baylor College of Medicine, who did not participate in the research. Instead of looking at single nucleotide mutations of single genes, advances in microarray technology are letting researchers zoom out to look at the whole genome. And what they are finding is that structural genomic mutations can cause major phenotypic changes, according to Lupski. ...

The frequency of de novo mutations in children with sporadic autism "is high," said Charles Lee of Brigham and Women's Hospital at Harvard Medical School, who did not participate in the research. Lee has surveyed CNVs in the general population and found rates of de novo mutation in the general population on the order of 0.2%.

Most of the mutations seen in the autistic children overall were deletions, whereas the two CNV cases in the control group were gene duplications. The finding isn't necessarily surprising, said Sebat, who said that human bodies are "less tolerant" of deletions. "When you're down to only your back-up copy for a gene, you're at greater risk for whatever minor defects may exist in that that gene."

Lupski noted that one of the paper's limitations is that it falls short of describing the exact gene, or set of genes, that cause autism. "But I don't care what the gene is right now," he said, "because I know that this will lead us to a better chance at finding that gene." [including the clear possibility that "Autism gene", just like (sporadic) "Alzheimer's gene" or "Parkinson's gene" will never be found, but rather, the excess repetitions occur in critical regions of "non-coding" area, just as in the documented case of Friedreich' where the "triple repeat run" well known to be intronic - AJP]

Finding the genes responsible for autism is one of the goals that Sebat and his colleagues have set for their next project. "We'll be screening at least 2,000 families over the next three years using a much higher resolution platform," Sebat said. He added that he hopes the data will provide a better estimate of the frequency of CNV in sporadic autism, as well as a view of a larger array of genes involved than when researchers restricted their studies to inherited cases. "I think this will be a study that really tips the balance in the field towards using technologies that can directly detect mutations, [and] focusing on the majority of cases that are sporadic."

[Science Abstract] We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (2%) of patients with an affected first-degree relative, and in 2 out of 196 (1.0%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

[Supporting Material] ...Hidden Markov Model program for identifying CNVs [more about HMM in "comments"]

Microarray hybridization data were analyzed using a Hidden Markov Model (HMM) that was designed to distinguish differences in DNA copy number fromother variation in probe ratios due to experimental noise and sequence polymorphisms. The HMM assumes that, in a comparison of two individuals, most intervals of the genome are equal in copy number, in the state wedesignate as “0”. Some intervals of the genome may differ in copy number by discrete constant ratios, and it is assumed that all CNV states enter and leave through state “0”. There are six experimentally distinguishable CNV states: ratiosof 3:2 and 4:3 are designated as state “+1”; ratios of 4:2 and 2:1 are designated as state “+2”; any ratios >2:1 are designated as state “+3”; and the inverse ofthese ratios are designated as states “-1”, “-2” and “-3”, respectively. The initial parameters of the HMM (means and standard deviations of states) were derived using the expectation maximization (EM) algorithm, and the transition probabilities were initialized by a non parametric clustering of outliers. In thepresent study, a CNV is defined as the interval where the most probable path defined by the HMM is a CNV state. The statistical measure of confidence givento a CNV is the probability that the interval is not in the ground state.

A [fractal] theory with the potential to unify all of biology

The Scientist

Geoffrey West, Brian Enquist and Jim Brown of the Santa Fe Institute

On the edge of Santa Fe, New Mexico, cacti, pinyon pines, and stunted junipers seem to slumber beneath the remnants of a fierce January snowstorm. As ravens circle overhead, their shadows send the desert cottontails darting about the sparse landscape.

In the frigid hush of these hills, each organism is playing its role in the high desert's idiosyncratic ecosystem. Inside the nearby Santa Fe Institute three researchers are trying to peel back life's feathers, fur, and bark to reveal the formula that makes it all tick. Could it be that the steady rhythms coursing here - from the rabbit's pounding heart [see fractal coronaries below - AJP] to the juniper's roots straining to pull water from the frozen ground - obey some immutable law?

...West and his collaborators, Jim Brown and Brian Enquist, have gathered at the Institute to put the finishing touches on their latest paper, a comprehensive test of their idea's ability to describe and predict the structure and function of forest plant communities.

They call the idea "metabolic theory," in essence a cognitive framework to describe linkages within and between living things based on commonalities in how they convert resources into energy. Melding first principles of physics, geometry, chemistry, and biology, they've built mathematical models that represent and may even predict the complexities of ecology. ... Perhaps unsurprisingly, an idea this ambitious has caused quite a stir.

A 1997 Science paper [1] introduced the group's theory and has been cited more than 700 times. While attracting a fair share of praise, it has also proved a magnet for criticism. "We've created a cottage industry for critics," says Brown, an ecologist at the University of New Mexico. "There are whole labs out there that get the vast majority of their publications from criticizing our stuff."

And as West, Brown, and Enquist bounce ideas around a glass-walled conference room, they are crafting their strategy to stave off the next round of critiques. "We absorb the criticism and move forward," Enquist says.

West, the team member most likely to voice the excitement for the potential of their theory, is less patient with the deluge of criticism. In his mellifluous British accent, he snipes, "Part of me doesn't want to be cowered by these little dogs nipping at our heels."

At 66, Geoffrey West is the elder statesman of the team. He is also the only nonbiologist. A theoretical physicist by training, West led the particle theory group at Los Alamos National Laboratory in the late 1980s and early 1990s.

...West began thinking about biology. His own mortality was partially to blame. "I was now into my fifties, and I was very conscious of aging and dying," he says. He struggled with biology's lack of theory and inability to answer key questions: "Why can I only live on the order of 100 years? Why can't I live a million years? Why is it if this piece of flesh that is me happened to have been a mouse [with 98% homologuous set of genes - AJP], it would have in fact been dead after a few years?"

So, West looked for answers as he combed the aging and gerontology literature, replete with data but devoid of fixed rules. Then West discovered the writings of Swiss-American physiologist Max Kleiber, who had taken precisely the kind of integrative approach West was looking for.

In 1932 Kleiber measured an array of animals ranging in size from rats to cattle and showed that metabolic rate was proportional to body mass raised to the power of 3/4 across the board.

This 3/4-power relationship between metabolic rate and body size, dubbed Kleiber's law, supplanted a 2/3-power relationship previously thought to describe accurately the relationship between mass and metabolic rate in animals. This early formula used Euclidean geometry - namely the ratio between surface area (length2) and volume (length3) - to explain the difference in metabolic rate for organisms of different sizes. This surface area-to-volume ratio gave the metabolic rate of a particular organism as proportional to its mass raised to the power of 2/3.

Kleiber used a more robust data set to construct a more accurate model for the scaling of metabolism with body size, but he failed to suggest an adequate physical explanation for the relationship. He simply let his data construct the model. So Kleiber's law, while supported across a broad range of animals and corroborated by his successors, remained devoid of a mechanistic underpinning for decades. It was the kind of puzzle that attracted West: "I looked at all these and said... I can't believe this isn't a central piece of biology."

Other well-established scaling laws show several characteristics of living things changing steadily with changes in body size. For instance, an animal's lifespan is proportional to the 1/4 power of its mass; the cross-sectional area of a mammal's aorta is proportional to the 3/4 power of its total mass; heart rates vary as body mass to the negative 1/4 power; and the density of individuals inhabiting an area tends to scale to body mass at the negative 3/4 power. "It obviously can't be some diabolical accident that all these things scale," West says. "That got me thinking about where all these scaling laws came from." [Ultimately, DNA coding has to do with it... AJP]

West focused on this conundrum and he reached for geometric architecture of biological transport networks, such as the mammalian vascular system that delivers resources. Then in 1995, he received a call from his friend and former Los Alamos colleague, Mike Simmons, who had become the vice president for academic affairs at the Santa Fe Institute and who knew of West's new forays into biology. Simmons told West of two ecologists from the University of New Mexico in Albuquerque who happened to be pondering similar questions about biological scaling and Kleiber's law.

The two ecologists were Brown and Enquist. Through painstaking statistical analysis of plant data in the literature, Enquist, who was Brown's graduate student at the time, had shown that Kleiber's law applied even to trees. Yet, they had arrived at the same impasse as West and many before them: explaining the fundamental physical mechanism operating at the root of this pattern.

That explanation proved elusive. Kleiber's law suggests the presence of some fourth dimension as opposed to the more familiar three-dimensionality inherent to the 2/3-power law. What extra-dimensional physical characteristic could explain the observation that, when corrections are made for body size, virtually all living things convert resources at a similar rate?

Like West, Brown and Enquist suspected that the answer to this question lay in the geometry of transport systems. The ecologists constructed theoretical networks using a branch of mathematics called graph theory, but the systems they built functioned at rates proportional to the 1/3 power or 2/3 power of their size. Enquist and his advisor realized that they needed help to solve the problem.

Brown and Enquist arranged to meet West at the Santa Fe Institute to discuss the scientific questions that had been vexing them. Though 20 years his junior, Enquist says he felt an immediate intellectual connection to West. "It was very weird meeting him for the first time because he was this long-lost brother," he remembers. "He could relate to [Jim and me] in terms of the ideas we we're thinking about." And ultimately, West would provide the key for successfully modeling an ideal biological resource-transport system.

That key was fractal geometry. In these branched structures, where each subunit is an approximation of the whole structure, was the fourth dimension that was necessary to explain the anatomic origin of Kleiber's law. "It was immediately clear that what Geoffrey was bringing to the table, which was very novel to what Jim and I had been thinking about, was the notion of self-similarity and the fractal," says Enquist. "That gave us the language to codify all of this."

This first meeting grew into a weekly event. Enquist, now an established plant ecologist at the University of Arizona, remembers the hour-long drives fondly. "I would have a time with no telephones, no interruptions, where Jim and I could just talk about things."

After a year's worth of meetings, the team had constructed a model that proposed a mechanistic explanation for Kleiber's 3/4-power law. The model described space-filling networks that, obeying established geometric and physical principles and operating under three important underlying assumptions, optimize the transport of metabolism's raw materials through living things.

The model was built on three assumptions: 1) The networks were constructed of tubes that branched in fractal-like patterns; 2) The networks minimized the amount of energy needed to transport materials through the system of tubes; and 3) The size of the terminal units at the ends of this system (i.e., capillaries) did not vary with overall body size. These provided an idealized network that is a reasonable approximation of real-world biological transport systems. For example, mammalian vascular systems are highly branched, and capillary size is relatively invariant across mammals of different size. Thus, it is conceivable that natural selection has endowed mammals with a maximally efficient vascular system.

In April 1997 West, Brown, and Enquist published their groundbreaking paper. Employing a slew of complex mathematical equations - what Enquist refers to as "pyrotechnics" - they provided mathematical justification for their theory. They also tested their model against measurements taken for several characteristics of vascular and respiratory systems in several mammalian species. The model predicted the observed values exceedingly well. West, Brown, and Enquist had built a predictive model that seemed to resolve the central role of body size in much of biology, and in doing so, provided the most robust mechanistic explanation yet for the pattern that Max Kleiber had revealed more than 65 years before. Their metabolic theory was born.

The paper would form the cornerstone for the group's subsequent work, and it was far from subtle. Writing that "quarter-power allometric scaling is perhaps the single most pervasive theme underlying all biological diversity," West, Brown, and Enquist left themselves open to criticism.

Just two months before the Science publication, Jan Kozlowski and January Weiner of Jagiellonian University in Krakow published a paper in American Naturalist. [2] The Polish biologists proposed a vastly different explanation for the prevalence of Kleiber's law.

Kozlowski and Weiner constructed a model that showed wide variation in the scaling of metabolic rate (from mass to the 2/3 power to mass to the power of 1) within species that, when plotted across different species, produces the 3/4 power seen in Kleiber's law. Their model suggests that Kleiber's law is simply a statistical artifact and not the result of some underlying structural or functional commonality between living things.

Though not a direct response to metabolic theory (the two teams claim not to have been aware of each other's work at the time), Kozlowski and Weiner's argument did illustrate a fundamental departure from the theory's foundation. Biological diversity, they say, defies encapsulation by a single, reductive model.

"For me, [West, Brown, and Enquist's] models represent oversimplification," says Kozlowski, on the phone from his Krakow office. "They want to explain, with this one simple parameter [body size], everything up to a very broad scale. I'm not so optimistic," he continues. "I believe that nature is much more complex than that."

... West, Brown, and Enquist have been adding to metabolic theory as its reach across organism types expands. And the trio, along with a growing corps of collaborators, has constructed more complex models to predict the structure and function of ever-broader swaths of nature. "Muller-Landau raises two good points," says Enquist: namely that growth rates and size distributions in natural forests might deviate from the model's predictions in real-world conditions. Nonetheless, he is adamant: These points "don't invalidate the core of the model."

In 2001, Jamie Gillooly, then a postdoc at the University of New Mexico, in collaboration with Brown and West, added temperature to the core metabolic theory model as a variable necessary to explain the 3/4 scaling of metabolic rates across organisms from microbes to mammals of varying sizes. 5 ...

As Muller-Landau, Kozlowski, and other critics circle around their metabolic theory, West, Brown, Enquist, and collaborators continue to extend the theory's reach. They have applied the fundamental principles of metabolic theory to successfully model a remarkable array of organisms, processes, and life-history characteristics. ...

The three did not anticipate the amount of criticism they would receive. "I was a little unprepared for the magnitude and amount of criticism we got," says Brown, "but if you're doing something important, that's what you'd expect." Moreover, ecology is steeped in the tradition of descriptive science. Brown says the idea of creating a predictive, "overarching theory" is bound to ruffle feathers.

... Inside the Institute on a chilly January day, the three scientists strategize over their newest publication. Much has stayed the same since those first meetings a decade ago: the collegial atmosphere, the enthusiastic exchange of ideas, and the constant search for new angles on old questions. ...

"I'm sure it will be controversial," says West. Enquist agrees and stresses that the statistical analyses in their paper must be airtight. Otherwise, he says, "a big fat torpedo will be headed our way." The attention their work has garnered has helped shape the team's collaboration over the past decade, and their interactions, now, reflect this...

References

1. G.B. West et al., "A general model for the origin of allometric scaling laws in biology," Science, 276:122-6, 1997. [PubMed]

Allometric scaling relations, including the 3/4 power law for metabolic rates, are characteristic of all organisms and are here derived from a general model that describes how essential materials are transported through space-filling fractal networks of branching tubes. The model assumes that the energy dissipated is minimized and that the terminal tubes do not vary with body size. It provides a complete analysis of scaling relations for mammalian circulatory systems that are in agreement with data. More generally, the model predicts structural and functional properties of vertebrate cardiovascular and respiratory systems, plant vascular systems, insect tracheal tubes, and other distribution networks.

2. J. Kozlowski and J. Weiner, "Interspecific allometries are by-products of body size optimization," Am Nat, 149:352-80, 1997

[in Kozlowski et al ] Our explanation of the 3/4 power law for metabolic rate is an alternative to the model by West et al. (25), which is based on several questionable assumptions. The most important one is that the standard metabolic rate depends on the structure of the supplying systems (e.g., the fractal structure of the circulatory system in vertebrates); it is more likely that the structure of the supplying system adjusts to meet the maximum metabolic demands (31, 33). Furthermore, close to 3/4 scaling of the metabolic rate has also been observed in organisms that lack a space-filling, self-similar fractal organization of internal supply systems, such as protists (26).

3. - 5 [omitted - AJP]

["Unifying (mathematical) theories" used to be the "privileged domain" of physics - until biology reached the era of geometrization. The totally empirical "Kleiber's law" (1935) had no mathematical (geometrical) explanation till 1997 when first Kozlowski and Wiener explained it at the level of statistics, and two months later West, Brown and Enquist provided a causal geometrical explanation (based on fractality of e.g. circulatory system; see fractal model of coronaries of heart below). It may be important to point out that the two mathematical theories are just as not contradictory to one-another as the Schrödinger wave-theory of light is not a contradiction to Heisenberg, although the wave-theory is fundamentally different from Heisenberg's corpuscule-theory of light. West, Brown and Enquist dig deeper in causality in the direction of the underlying fractality of structure - while Kozlowski (with Konarzewski and Gawelczyk) dig deeper (to the level of genome) in causality of the cell-size; effectively eliminating another "puzzling empirical observation", the so-called "C-value enigma". ("C-value" started as an observation by Vendrely and Vendrely in 1948 who thought that the genome size was "constant" within a species. Hewson Swift improved on the phenomenology in 1950 observing that the "C" [Constant] of the genome-size tends to be constant in one species, but with exceptions falling into different classes. Realizing that the coding contents of the genome did not correlate with the genome size, in 1971 C.A. Thomas coined the "C-value paradox". Albeit there is a general trend that the genome size increases with evolution, there are spectacular deviations, sometimes within one species (Richard Dawkins favors the example of sub-species of salamandra differing in about an order of magnitude of genome size), Ryan Gregory in 2001 sharpened phenomenology to "C-value enigma". One would add that FractoGene theory provides a causal basis of fractality of organelles, organs and organisms by the fractality of DNA that governs growth; and thus dovetails with the Metabolic Theory by West, Brown and Enquist, 1997 (with FractoGene, 2002 shedding light on fractality "dyed in the DNA") as well as the Cell Size/C-Value theory by Kozlowski et al. (2003) that cell size correlates with non-coding DNA amount; according to FractoGene growth is supported by the amount of auxiliary information in the "junk" DNA to enable iterative recursion of growth, occasionally excessively). To put a perspective on the dogged pursuit of geometrization of biology, one may mention that "by the way" FractoGene also helps carry further yet another "puzzling empirical observation", the so-called "Zipf's Law" (1949) of the "language of DNA" (demonstrating that a "whole genome" of particular interest does not follow "Zipf's " law, after all - but demonstrates fractality...) - A. Pellionisz, 12th of March, 2007]

from "FractoGene visual gallery"; Fractal model of the coronaries of the human heart. Scientific American, 1990. (262) February, p. 46. by Hans van Beek and James B. Bassingthwaighte, University of Washington

Researchers Create Bacterial DNA Memory [The "Triple Helix" of "Biotech-Nanotech-Infotech" is complete]

The latest development from Japan in the field of data storage is a technique so far beyond current-generation hard drives and optical disks it has the potential for storing limitless amounts of data for infinite periods of time.

Keio University Institute for Advanced Biosciences and Keio University Shonan Fujisawa Campus have managed to use the DNA of bacteria to store large data files organically.

The new technology uses artificial DNA strands that have the data to be stored encoded on them. This is then copied many times over before all the DNA sequences are inserted into the bacterial genome.

[See science full-text at link below]

Alignment-Based Approach for Durable Data Storage into Living Organisms

Yoshiaki Ohashi et al.

The practical realization of DNA data storage is a major scientific goal. Here we introduce a simple, flexible, and robust data storage and retrieval method based on sequence alignment of the genomic DNA of living organisms. Duplicated data encoded by different oligonucleotide sequences was inserted redundantly into multiple loci of the Bacillus subtilis genome. Multiple alignment of the bit data sequences decoded by B. subtilis genome sequences enabled the retrieval of stable and compact data without the need for template DNA, parity checks, or error-correcting algorithms. Combined with the computational simulation of data retrieval from mutated message DNA, a practical use of this alignment-based method is discussed.

Rosetta Genomics underwriters exercise green shoe option [If the genome is a goldmine, where is the gold?]

562,500 shares were sold for $3.66 million.

Gali Weinreb 8 Mar 07 14:51

Rosetta Genomics Ltd. (Nasdaq:ROSG) has closed the sale of an additional 562,500 shares for $3.66 million to the full exercise of the over-allotment (green shoe) option granted to the underwriters of its IPO.

C.E. Unterberg, Towbin LLC was the lead manager and the sole bookrunner of the offering, and Oppenheimer & Co. Inc. was co-manager. Including the green shoe option, Rosetta Genomics issued a total of 4.3 shares for total gross proceeds of $30.2 million, before commissions and expenses, and net proceeds of $26.2 million.

Little genomes for big dinosaurs
March 7, 2007

Courtesy Harvard University and World Science staff

They might be giants, but many dinosaurs apparenty had genomes no larger than that of a modern hummingbird. So say biologists who’ve gauged the genome sizes of 31 species of extinct dinosaurs and birds, their descendants.

This suggests a stripped-down genome may have been one feature that helped birds take flight, by saving them energy, according to the researchers.

They estimated genome sizes using a previously noted relationship between those, and the size of bone cells.

“We see distinct differences between two major lineages of dinosaurs,” said Chris Organ of Harvard University in Cambridge, Mass., one of the scientists, who reported the findings in the March 8 issue of the research journal Nature.

“Theropods—carnivores such as Tyrannosaurus rex and Velociraptor—have very small genomes, in the range of modern birds. Ornithischians—which include Stegosaurus and Triceratops—had more moderately sized genomes, akin to those of living lizards and crocodilians. We aren’t sure about the genomes of the long-necked sauropods yet.”

Researchers had previously reported that the sizes of various cell types tend to reflect an organism’s genome size. Organ and Edwards had found this also applies to bone cells called osteocytes. Since these lie in small pockets in bone, the size of the pockets betrays that of the cells—letting the investigators take a measure of extinct species’ genomes by studying their fossils.

Organ said the clear dichotomy in dinosaur genome sizes is likely due to different amounts of repetitive gene sequences, or sequences of a type sometimes dubbed “junk DNA” because they seem to be inactive. Those two factors largely account for variation in genome size across animal species, he noted.

The findings indicate that the spare genetic makeup of birds—which have remarkably small genomes—evolved in dinosaurs some 230 to 250 million years ago, rather than when modern birds emerged just 110 million years ago, Organ and colleagues said. They suggested that after this shrinkage, theropod genome size stabilized for hundreds of millions of years, continuing to the present in birds.

The work refutes a theory that birds’ diminutive genomes “co-evolved with flight,” said Harvard’s Scott Edwards, who with Organ led the study. “These streamlined genomes arose long before the first birds and flight, and can be added to the list of dinosaur traits previously thought to be found only in modern birds, including feathers, pulmonary innovations, and parental care and nesting.”

Alnylam and Isis Announce Allowance of First U.S. Patent Covering Human microRNAs

"We think anyone developing synthetic RNAs will need to license our intellectual property," says John Maraganore, Alnylam's president and CEO"

CAMBRIDGE, Mass. & CARLSBAD, Calif.--(BUSINESS WIRE)--Mar 1, 2007 - Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) and Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) announced today that the United States Patent and Trademark Office (USPTO) has allowed claims in a patent application that covers microRNAs (miRNAs) and therapeutic molecules that target these miRNAs. The USPTO issued a "Notice of Allowance" for patent application 10/490,955, which is derived from the "Tuschl III" patent series licensed co-exclusively to Alnylam and Isis for miRNA therapeutics on a world-wide basis through an agreement with Max-Planck-Innovation GmbH, the licensing agent for the Max Planck Society. Following a "Notice of Allowance," the companies would expect final issuance of the patent within six months.

miRNAs have been shown to regulate the expression of a large number of genes in the human genome through the RNAi pathway, and many of these miRNAs are believed to be involved in disease processes including cancer, metabolic disease, and viral infection. The Tuschl III patent series pertains to the discovery of over 120 novel mammalian miRNAs and stems from groundbreaking research performed by Alnylam founder Thomas Tuschl, Associate Professor of RNA Molecular Biology at The Rockefeller University, while at the Max Planck Society (Lagos-Quintana et al., (2001) Science 294, 853-858). The allowed claims cover a disease-associated miRNA, specifically miR-122, which is a liver-specific miRNA that has been shown to be required for hepatitis C virus (HCV) infection (Jopling et al. (2005) Science 309, 1577-81). Isis and Alnylam have demonstrated that in vivo antagonism of miR-122 with antisense drugs is associated with regulation of a discrete set of genes involved in liver metabolism (Krutzfeldt et al. (2005) Nature 438, 685-689; Esau et al. (2006) Cell Metab., 3, 87-98).

"The recent discovery that over 250 human genes encode miRNAs that may control gene expression for as much as one-third of the genome suggests that these small, non-coding RNAs play a major role in human physiology and disease," said C. Frank Bennett, Ph.D., Senior Vice President, Research for Isis. "Scientists at Isis and Alnylam have been performing an exciting line of research to identify novel, antisense-based therapeutic approaches for targeting miRNAs, and our collaborative efforts point to significant opportunities for the future."

"As part of our 2004 agreement with Isis, we have been engaged in consolidating intellectual property in the miRNA field," said Robert Millman, Ph.D., Chief Intellectual Property Counsel for Alnylam. "We believe that, in addition to this first allowed U.S. patent covering isolated miRNAs and molecules that are complementary to the miRNA, several other patents will likely result from the Tuschl III patent series because similar claims to each of the over 120 miRNAs are disclosed in the patent application as well as methods of altering the level of the miRNA in a cell."

About microRNA (miRNA)

RNAi can also be induced by microRNAs, or miRNAs, that occur naturally within all mammalian cells. The miRNA molecules are encoded by the cell's own genes, giving rise to small RNA molecules that are similar in structure to siRNAs. There are believed to be over 250 confirmed miRNA genes in the human genome and there are many other predicted miRNAs. miRNAs are thought to work through RNAi to regulate the activity of an estimated one-third of genes in the genome. The inappropriate absence or presence of specific miRNA molecules in various cells has been shown to be associated with specific human diseases, including cancer and viral infections.

Netherlands Genomics Initiative: Strategic Plan 2008 - 2012: additional € 298 million public investment

Genome Centers in The Netherlands

In 2001, the Dutch government decided to invest € 200 million – later extended to € 300 million – in genomics.

Although Dutch research groups were international leaders in various areas, the field as a whole was highly fragmented.

A joint approach to necessary technological development was clearly missing. By this time, genomics was broadly recognised as an absolutely vital element in the further development of the life sciences. Moreover, the cabinet saw the opportunities offered by genomics to strengthen the economic structure and the quality of life (food, health, the environment). A large-scale investment in genomics was necessary in order to strengthen the leading position of the Netherlands and to make this country a more attractive location for scientific talent and innovative companies.

To create cohesion, based on targeted choices, the Netherlands Genomics Initiative (NGI) was established in 2002. Existing activities and programmes in the field of genomics, which were being conducted under the auspices of NWO and SenterNovem,were incorporated in NGI.

NGI's goal is to make the Netherlands an international leader in genomics and to build a structure that links high scientific quality to economic and social returns.

[2007] NGI aims for additional € 298 million to strengthen Dutch genomics infrastructure. Central elements of the plan are continuation of the national approach to genomics, increased emphasis on social and economic returns, and further strengthening of the knowledge base (research, technology and education).

NGI believes that further investment in genomics is needed in order to meet the challenges faced by society, both in the Netherlands and abroad, now and in the future. Genomics is indispensable for realising true innovation in key fields such as health, food, agricultural and industrial production, environment, safety and sustainable growth. According to NGI, a public investment of € 298 million is required to optimally develop and utilise the potential of genomics in the form of tangible contributions to improving the quality of life and strengthening the economic structure.

Non-coding RNAs: lessons from the small nuclear and small nucleolar RNAs

(Fig. 2 of the cited paper) [The emerging Brave New World of PostGenetics; [fractal] self-similar short repetitive sequences and protein synthesis by recursive iteration coming together [a concept going back to the first FractoGene application; 2002 Aug. 1. - AJP]

[Article at a glance] We now understand that genomes in all three domains of life produce functional RNAs that do not encode proteins (non-coding (nc)RNAs), but do exert important influences on diverse cellular processes.

Most ncRNAs function with essential partner proteins (that is, as non-coding ribonucleoproteins; ncRNPs) and use cognate antisense elements to interact with target molecules. The small nuclear (sn)RNAs and small nucleolar (sno)RNAs are founding members of the family of ncRNAs that helped to establish these common paradigms.

Recent studies of the snRNPs and snoRNPs have revealed unexpectedly elaborate biogenesis pathways that will probably also be travelled by other ncRNPs.

snRNAs and snoRNAs can be transcribed from independent promoters (similar to mRNAs) or can be encoded within intronic sequences.

RNA function can require multiple partner proteins with roles that might include modulating RNA structure or securing an enzyme, as well as catalysing the reaction.

Assembling a functional complex seems to involve a series of non-functional intermediate states that are matured by a series of cellular factors along a defined physical pathway in the cell. These transport and assembly steps might serve as control points for the regulation of the activity of a given ncRNP.

---

[preamble of full article]

Less than 2% of the human genome is translated into protein, yet more than 40% of the genome is thought to be transcribed into RNA1. The vast, untranslated fraction of the human transcriptome includes a truly remarkable number of functional non-coding (nc)RNAs2. Indeed, the ongoing discovery of new classes of ncRNA (for example, microRNAs, short interfering (si)RNAs, repeat-associated RNAs and germline-specific RNAs) and of new members of existing classes (for example, small nucleolar (sno)RNAs) underscores the breadth and depth of ncRNA function. Importantly, ncRNAs have emerged as key trans-acting regulators of diverse cellular activities in all three domains of life3, 4, 5, 6, 7 (Table 1). Among the known activities of ncRNAs are: endonucleolytic RNA cleavage and ligation, site-specific RNA modification, DNA methylation, DNA (telomere) synthesis and modulation of protein function. These activities are important (at many levels) for gene expression and also for genome stability (Table 1).

[Table 1. of article]

Study moves chimp-human split to 4 million years ago

Fri Feb 23, 2007 10:05pm ET
By Maggie Fox, Health and Science Editor

WASHINGTON (Reuters) - Chimpanzees and humans split from a common ancestor just 4 million years ago -- a much shorter time than current estimates of 5 million to 7 million years ago, according to a study published on Friday.

The researchers compared the DNA of chimpanzees, humans and our next-closest ancestor, the gorilla, as well as orangutans.

They used a well-known type of calculation that had not been previously applied to genetics [? - AJP] to come up with their own "molecular clock" estimate of when humans became uniquely human.

"Assuming orangutan divergence 18 million years ago, speciation time of human and chimpanzee is consistently around 4 million years ago," they wrote in their study, published in the Public Library of Science journal PLoS Genetics, available online at [ full text ] .

"Primate evolution is a central topic in biology and much information can be obtained from DNA sequence data," Dr. Asger Hobolth of North Carolina State University said in a statement.

The theory of a molecular clock is based on the premise that all DNA mutates at a certain rate. It is not always a steady rate but it evens out over the millennia and can be used to track evolution.

Experts agree that humans split off from a common ancestor with chimpanzees several million years ago and that gorillas and orangutans split off much earlier. But it is difficult to date precisely when, although most recent studies have put the date at somewhere around 5 million to 7 million years ago.

Hobolth and colleagues from the University of Aarhus in Denmark and the University of Oxford in Britain looked at four regions of the human, chimpanzee, and gorilla genomes.

QUICK SPLIT

They used a statistical technique called the hidden Markov model, developed in the 1960s and originally applied to speech recognition.

What they found may contradict some other recent research. They found evidence that it took only 400,000 years for humans to become a separate species from the common chimp-human ancestor.

Just last May, David Reich of the Broad Institute at the Massachusetts Institute of Technology and Harvard Medical School's Department of Genetics found evidence that the split probably took 4 million years to occur, although his team put the final divergence at just 5.4 million years ago.

"I don't think it really contradicts our paper," Reich said in an e-mail exchange.

"We were focusing on a maximum time for the common ancestor of humans and chimpanzees, while they were focusing on a best estimate," added Reich, who revieved Hobolth's paper before it [w]as published. [? - Oops, reviewers must remain anonymous for proper peer-review process... - AJP]

Experts have long known that humans and chimpanzees share much DNA, and are in fact 96 percent identical on the genetic level.

And one year ago, Soojin Yi and colleagues at the Georgia Institute of Technology said they found genetic evidence that chimpanzees may be more closely related to humans than to gorillas and orangutans.

Their look at the molecular clock showed humans evolved one unique trait just a million years ago -- our longer life span and our long childhood that means humans reach sexual maturity very late in life compared to other animals.

Biotech specialist hits near-record $570m
Mark Cobley
21 Feb 2007

SV Life Sciences, the biotechnology specialist venture capital firm [in Silicon Valley, California], has raised the second-biggest venture fund to date in the sector amid a flurry of venture interest in life sciences.

The fund, which the company said was significantly oversubscribed, was closed at $572m (€439m).

It is surpassed in Europe only by UK venture firm Abingworth's fifth biotech fund, which closed at £300m ($590m) at the end of January, although there are a few US-only funds of similar size.

Donald Nelson, a partner at SV Life Sciences, said he was not disappointed to have been pipped to the largest European fund.

He said: "It is a good achievement for everyone who works here. It is not so much the numbers as the quality of the names we have investing, some very large institutions and family offices."

Among other funds, Wellington Partners recently held a €50m first close on its third life sciences fund, which it expects to grow to €120m by the summer, and San Francisco-based Sofinnova Ventures closed its seventh fund in November at $375m, $75m over target.

SV Life Science's fund is the fourth raised by the firm since 1994, when it was part of Schroder Ventures Group, the private equity business of London fund manager Schroders that went on to become Permira.

SV Life Sciences manages or advises on funds worth $1.6bn, invested in Europe and the US, and focuses on biotechnology, pharmaceuticals, healthcare services and healthcare IT.

James Garvey, chief executive of SV Life Sciences, said the firm had benefited from M&A activity in the biotech sector. The company made $2bn from sales of portfolio companies in 2006, he said.

Killing The Messenger RNA -- But Which One?

2/23/2007

Small gene-silencing molecules subject to redirection by editing

Tiny molecules called microRNAs, only 19 to 21 nucleotides in length, are able to effectively silence sometimes large sets of genes. They do this by specifically binding to and neutralizing another form of RNA called messenger RNA, responsible for conveying the information from genes to the cellular machinery that uses that information to create proteins, the building blocks of the body. Several hundred species of microRNAs have been identified to date, and increasingly they are being seen as vitally important players in regulating the genome.

Now, a new study led by researchers at The Wistar Institute shows that these microRNAs can undergo a kind of molecular editing with significant physiological consequences. A single substitution in their sequence can redirect these microRNAs to target and silence entirely different sets of genes from their unedited counterparts. Further, errors in the editing can lead to serious health problems. The team’s findings appear in the February 23 issue of Science. [See Abstract below- AJP]

"What we found was that, in certain cases, edited versions of these microRNAs are being produced that differ from the unedited versions by only a single nucleotide change," says Kazuko Nishikura, Ph.D., a professor in the Gene Expression and Regulation Program at Wistar and senior author on the study. "These edited microRNAs are not encoded in the DNA, which means that at least two versions can being produced by one gene. This was not anticipated – it was something really new.

"Looking more closely, we realized that the substitution we’d identified occurred in a particularly critical region of the molecule, the first 7 or 8 nucleotides – out of a total of only 19 or 21 – that define the molecule’s target specificity. This suggested that the change might well redirect these edited microRNAs to silence entirely different sets of genes from the unedited versions."

Using bioinformatics tools to compare the unedited and edited versions of only one species of microRNA against data banks of known gene sequences, the scientists identified two different groups of about 80 genes each likely to be targeted by the two versions of the molecule. They then selected three genes from each group for a closer look, testing to see whether their expression was in fact altered, up or down, by the microRNAs. It was.

Then they chose one potentially affected gene at random to explore the ramifications of microRNA editing in depth. As it turned out, the gene they selected, known as PRPS1, codes for an essential enzyme involved in synthesizing uric acid. If levels of the enzyme are poorly regulated, a number of health problems can arise. For example, too-high levels of the enzyme can cause uric acid levels to rise in the blood, triggering painful episodes of gout. Similarly, in the brain, excess uric acid can damage sensory neurons and cause deafness.

Working with a strain of transgenic mice unable to perform RNA editing and normal control mice, the researchers found that a complete lack of the edited version of the microRNA in question had the effect of driving production of the PRPS1 enzyme to about double its normal levels. This, in turn, drove levels of uric acid up to about two times what they should be.

"This confirmed that our original computer prediction of differential targeting by unedited and edited microRNAs of different sets of genes is likely to be correct," Nishikura says. "And in at least the case of the one gene we investigated, this differential has physiological consequences seen in the elevated uric acid levels."

Given the fact that the PRPS1 gene was randomly selected for investigation by the researchers, the findings suggest that a number of other as-yet unidentified disorders may also have their roots in this newly identified microRNA editing process.

Redirection of Silencing Targets by Adenosine-to-Inosine Editing of miRNAs

Yukio Kawahara, Boris Zinshteyn, Praveen Sethupathy, Hisashi Iizasa, Artemis G. Hatzigeorgiou, Kazuko Nishikura

Science 23 February 2007:
Vol. 315. no. 5815, pp. 1137 - 1140

 Kazuko Nishikura

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.

Primary transcripts of certain microRNA (miRNA) genes are subject to RNA editing that converts adenosine to inosine. However, the importance of miRNA editing remains largely undetermined. Here we report that tissue-specific adenosine-to-inosine editing of miR-376 cluster transcripts leads to predominant expression of edited miR-376 isoform RNAs. One highly edited site is positioned in the middle of the 5'-proximal half "seed" region critical for the hybridization of miRNAs to targets. We provide evidence that the edited miR-376 RNA silences specifically a different set of genes. Repression of phosphoribosyl pyrophosphate synthetase 1, a target of the edited miR-376 RNA and an enzyme involved in the uric-acid synthesis pathway, contributes to tight and tissue-specific regulation of uric-acid levels, revealing a previously unknown role for RNA editing in miRNA-mediated gene silencing.

[Supporting material]

LS9 Launched to Create Renewable Petroleum(TM) Biofuels [Khosla and MIT-Harvard-Stanford into Synthetic Biology]

GENetic Engineering and Biotechnology News
Feb 14 2007, 3:30 AM EST

SAN CARLOS, Calif., Feb. 14 /PRNewswire/ -- LS9 Inc., the Renewable Petroleum Company(TM), announced its launch today. Founded in 2005, the company is pursuing industrial applications of synthetic biology to produce proprietary biofuels. LS9's products, currently under development, are designed to closely resemble petroleum derived fuels, but be renewable, clean, domestically produced, and cost competitive. In addition to biofuels, LS9 will also develop industrial biochemicals for specialty applications.

LS9 Inc. is developing Renewable Petroleum(TM) biofuels through work pioneered by scientific founders Chris Somerville, Director of the Carnegie Institution and Professor of Plant Biology at Stanford University, and George Church, Director of the MIT-Harvard US-Dept. of Energy GTL Center and Professor of Genetics at Harvard along with venture founders Flagship Ventures and Khosla Ventures. In addition, the company relies upon a distinguished scientific advisory board including leaders in the fields of synthetic biology, metabolic engineering, microbiology, enzymology, genomics, bioinformatics, and chemical engineering.

"Thanks to rapid advances in industrial biotechnology and synthetic biology along with the strength and talent of our scientific team, LS9 is uniquely suited to design, develop, and commercialize the next generation of biofuels," said Dr. Somerville. "We have looked to nature to identify the required biological tools, redesigned them to function under industrial conditions, and are optimizing their performance to meet our economic objectives," added Dr. Church.

"Novel solutions are required to address the energy crisis. LS9 represents a new frontier in our venture creation activities, combining breakthrough scientific work with a strong market orientation," said Noubar Afeyan, Managing Partner and CEO of Flagship Ventures.

Since 2005, the company has quietly but aggressively pursued a highly focused research and development plan and amassed an extensive technology and intellectual property portfolio for the production of Renewable Petroleum(TM) biofuels.

Doug Cameron, former head of biotechnology research at Cargill and acting Chief Executive Officer of LS9 Inc., said the advances stand to change the dynamics of the fuel market.

"LS9 is pursuing a disruptive technology in a large established market," Dr. Cameron said. "Our rate of scientific progress is a testament to the quality of the team we have assembled at LS9."

About LS9

LS9, Inc., the Renewable Petroleum Company(TM), is a privately-held biotechnology company. LS9 is pursuing industrial applications of synthetic biology to produce biofuels that are compatible with existing fuel distribution and consumer infrastructure. Based on an enabling technology portfolio, LS9 was founded in 2005 by leading scientists along with venture capital firms Flagship Ventures and Khosla Ventures. LS9 is headquartered in San Carlos, California, in the heart of Silicon Valley.

News Analysis: UC’s Biotech Benefactors [Biofuels or "H2 Economy"?]

By Miguel A. Altieri and Eric Holt-Gimenez

6 February, 2006

With royal fanfare, British Petroleum just donated $500 million in research funds for UC Berkeley, Lawrence Berkeley National Laboratory and the University of Illinois to develop new sources of energy—primarily biotechnology to produce biofuel crops. This comes on the anniversary of Berkeley’s hapless research deal with seed giant Novartis ten years ago. However, at half a billion dollars, the BP grant dwarfs Novartis’ investment by a factor of 10. The graphics of the announcement were unmistakable: BP’s corporate logo is perfectly aligned with the flags of the Nation, the State, and the University.

CEO/Chairman Robert A. Malone proclaimed BP was “joining some of the world’s best science and engineering talent to meet the demand for low carbon energy … we will be working to improve and expand the production of clean, renewable energy through the development of better crops…” This partnership reflects the rapid, unchecked and unprecedented global corporate alignment of the world’s largest agribusiness (ADM, Cargill and Bunge), biotech (Monsanto, Syngenta, Bayer, Dupont), petroleum (BP, TOTAL, Shell), and automotive industries (Volkswagen, Peugeot, Citroen, Renault, SAAB). With what for them is a relatively small investment, these industries will appropriate academic expertise built over decades of public support, translating into billions in revenues for these global partners.

Could this be a “win-win” agenda for the university, the public, the environment and industry? Hardly. In addition to overwhelming the university’s research agenda, what scientists behind this blatantly private business venture fail to mention is that the apparent free lunch of crop-based fuel can’t satisfy our energy appetite, and it will not be free or environmentally sound.

Dedicating all present U.S. corn and soybean production to biofuels would meet only 12 percent of our gasoline demand and 6 percent of diesel demand. Total U.S. cropland reaches 625,000 square miles. To replace U.S. oil consumption with biofuels, we would need 1.4 million sq.mi. of corn for ethanol and 8.8 million square miles of soybean for biodiesel. Biofuels are expected to turn Iowa and South Dakota into corn-importers by 2008.

The biofuel energy balance—the amount of fossil energy put into producing crop biomass compared to that coming out—is anything but promising. Researchers Patzek and Pimentel see serious negative energy balances with biofuels. Other researchers see only 1.2 to 1.8 returns, for ethanol at best, with the jury still lukewarm on cellulosic biofuels.

Industrial methods of corn and soybean production depend on large-scale monocultures. Industrial corn requires high levels of chemical nitrogen fertilizer (largely responsible for the dead zone in Gulf of Mexico) and the herbicide atrazine an endocrine disruptor. Soybeans require massive amounts of non-selective, Roundup herbicide that upsets soil ecology and produce “superweeds.” Both monocultures produce massive topsoil erosion and surface and groundwater pollution from pesticides and fertilizer runoff. Each gallon of ethanol sucks up three to four gallons of water in the production of biomass. The expansion of irrigated “fuel on the cob” into drier areas in the Midwest will draw down the already suffering Ogallala aquifer.

One of the more surreptitious industrial motives of the biofuels agenda—and the reason Monsanto and company are key players—is the opportunity to irreversibly convert agriculture to genetically engineered crops (GMOs). Presently, 52 percent of corn, 89 percent of soy, and 50 percent of canola in the United States is GMO. The expansion of biofuels with “designer corn” genetically tailored for special ethanol processing plants will remove all practical barriers to the permanent contamination of all non-GMO crops.

Obviously the United States can’t satisfy its energy appetite with biofuels. Instead, fuel crops will be grown in the developing world on large-scale plantations of sugarcane, oil palm and soybean already replacing primary and secondary tropical forests and grasslands in Argentina, Brasil, Colombia, Ecuador and Malaysia. Soybeans have already caused the destruction of over 91 million acres of forests and grasslands in Brazil, Argentina, Paraguay and Bolivia. To satisfy world market demands, Brasil alone will need to clear 148 million additional acres of forest. Reduction of greenhouse gases is lost when carbon-capturing forests are felled to make way for biofuel crops.

Meanwhile, hundreds of thousands of small-scale peasant farmers are being displaced by soybeans expansion. Many more stand to lose their land under the biofuels stampede. Already, the expanding cropland planted to yellow corn for ethanol has reduced the supply of white corn for tortillas in Mexico, sending prices up 400 percent. This led peasant leaders at the recent World Social Forum in Nairobi to demand, “No full tanks when there are still empty bellies!”

By promoting large-scale mechanized monocultures which require agrochemical inputs and machinery, and as carbon-capturing forests are felled to make way for biofuel crops, CO2 emissions will increase not decrease. The only way to stop global warming is to promote small-scale organic agriculture and decrease the use of all fuels, which requires major reductions in consumption patterns and development of massive public transportation systems, areas that the University of California should be actively researching and that BP and the other biofuel partners will never invest one penny towards.

The potential consequences for the environment and society of BP’s funding are deeply disturbing. In the wake of the report of the external review of the UCB-Novartis agreement that recommended that the university not enter into such agreements in the future, how could such a major deal be announced without wide consultation of the UC faculty? The university has been recruited into a corporate partnership that may irreversibly transform the plant’s food and fuel systems and concentrating tremendous power in the hands of a few corporate partners.

It is up to the citizens of California to hold the university accountable to research that supports truly sustainable alternatives to the energy crisis. A serious public debate on this new program is long overdue.

Miguel A. Altieri is a professor at UC Berkeley and Eric Holt-Gimenez is executive director of Oakland’s Food First.

What is the purpose of noncoding DNA? [Wired beats Scientific American - Open letter to Sydney Brenner]

Wired, February, 2007 - Steve Olson

A typical human cell contains more than 6 feet of tightly cornrowed DNA. But only about an inch of that carries the codes needed to make proteins, the day laborers of biology. What's the other 71 inches?

Sydney Brenner, 2002 [Now it is time to take "Junk" DNA back "from the attic" and formally close a chapter towards "Genomics beyond Genes" - AJP]

It's junk, Nobelist Sydney Brenner said after it was discovered back in the 1970. The name stuck, but biologists have known for a while that the junk DNA must contain treasures. If noncoding DNA were just along for a ride, it would rapidly incorporate mutations. But long stretches of noncoding DNA have remained basically the same for many millions of years - they must be doing something.

Now scientists starting to speculate that proteins, and the regular DNA that creates them, are just the nuts and bolts of the system. "They are like the parts for a 757 jet sitting on the floor of a factory", says University of Queensland geneticist John Mattick. The noncoding DNA is likely "the assembly plans and control systems". Unfortunately, he concludes, because we've spent 30 years thinking of it as junk, we're just now learning how to read it.

[The "trivial" conclusion is that a brilliant journalist at a high-tech evangelist journal (Wired) can beat "hands down" a "research expert" moonlighting for a science journal with a venerable reputation (SciAm - see next newspiece). Not that this pearl is without its defect (the term "Junk" DNA originated not from Sydney Brenner* but from Susumu Ohno, 1972). However, the journalist uses an easy-to-grasp metaphor to convey a very "non-trivial" concept (genes making parts, and non-coding DNA providing a blueprint). This time, John Mattick was quoted on this metaphor. Metaphors are to help with communication gaps.

FractoGene, conceived 5 years ago, to the day, and yielding patent applications since, was heralded in San Francisco Chronicle: "Another way to describe the idea: The genes we know about today, Pellionisz says, can be thought of as something similar to machines that make bricks (proteins, in the case of genes), with certain junk-DNA sections providing a blueprint for the different ways those proteins are assembled" (2002). The FractoGene approach more than metaphorically specifies the "blueprint": "Rather than being useless evolutionary debris, he says, the mysteriously repetitive but not identical strands of genetic material are in reality building instructions organized in a special type of pattern known as a fractal. It's this pattern of fractal instructions, he says, that tells genes what they must do in order to form living tissue, everything from the wings of a fly to the entire body of a full-grown human".

* An open letter - five years after Nobel lecture of Sydney Brenner (2002)

Dear Dr. Brenner,

In your "Nobel lecture" almost five years ago, for the record you pointed out the difference between "trash" (discarded forever) and "junk" that is not thrown away (since it is expected to be useful at a later time):

"In 1985, when the first suggestions were made to sequence the human genome, I thought that the sequencing techniques, even with incremental improvements, would not be equal to the task, and would require a factory scale operation to do it. I had also come to the conclusion that most of the human genome was junk, a form of rubbish which, unlike garbage, is not thrown away. My view at the time was that we should treat the human genome like income tax and find every legitimate way of avoiding sequencing it. It could therefore be asked whether a genome existed in Nature which perhaps had very much less junk but nevertheless had the full repertoire of vertebrate genes? It is easy to ask the question if one already has the answer. Towards the end of the 1960’s I spent time in Woods Hole and took advantage of the library where I first discovered the papers of Hinegardner (10). At the time, I was puzzled by the enormous variations in the amounts of DNA in different organisms. Indeed, whereas most physicists thought that organisms did not have enough DNA to specify their complexity, it was clear to me that many organisms had too much. I discovered from Hinegardner that one group of fish, the Tetraodontidae, which included the Japanese pufferfish, Fugu, had very small genomes, with a haploid content of about 400 megabases as opposed to the 3000 megabases of mammalian genomes. Although teleost fish are distant from humans they are still vertebrates, with the same body plans, development and physiological systems as ourselves. Because of these basic similarities it seemed unlikely that Fugu, with a haploid DNA content one eighth that of mammals would have eight times fewer genes, making it much more probable that what was missing in Fugu was junk DNA. If Fugu had the same gene repertoire as humans, then its genome would be more compact giving us the human gene inventory for eight times less work and expense. We proved that this was indeed the case and proposed the genome of Fugu as the ideal model vertebrate genome (11), with a DNA content only 4 times that of C.elegans. I failed to persuade any of the official genome organizations ..."

Dear Dr. Brenner, while realizing that the experimental impracticality at that time dictated the temporary "shelving" of "junk DNA" to the attic, I was another (bio)physicist convinced by my mathematical and computer modeling evidence of Purkinje brain cells that "organisms did not have enough DNA to specify their complexity". As early as in 1989, however, I forwarded evidence that the algorithmic (fractal) "blueprint" of these Purkinje cells requires an enormously compressed amount of information; instead of elaborating complexity determining it by much simpler set of recursive instructions. Five years ago today, I conceived the "FractoGene approach" - establishing the cause-and-effect relationship of the fractality of DNA resulting in the fractality of organelles, organs and organisms. Another key consideration you put forward in your Nobel lecture (that the 1/8 of the genome of fugu compared to human DNA - yet still vertebrates with cerebellar Purkinje neurons - might provide insights to the "non-coding DNA") led to quantitative predictions of FractoGene e.g. for the morphology of the fugu Purkinje neuron - and the prediction received experimental support.

You may agree that the grotesque depiction in Scientific American (see below) as "clochards" of some who undisturbed by the mundane "practicalities" carried on with pioneering research of the 98.7% of human DNA may be due some adjustment of their image to be optimally effective.

This might need to be done for social as well as science reasons. International PostGenetics Society (for Genomics to go "beyond genes") was established based on the realization that marginalized individuals ("clochards"), unless united, are no match for one of the biggest paradigm-shifts (from 1.3% of DNA to "genome wide"). Science reasons for the "PostModern era of Genetics" don't need to be belabored to you, either. Especially, since your latest results show that e.g. sequences of such "non-coding DNA" have been preserved with astounding strictness over half a billion years. Your seminal work with Robert Horovitz and John Sulston paved the way for the development of Caenorhabditis elegans as a model organism for studying development and behavior, for which you received the Nobel Prize for Medicine in 2002. C. elegans is the same organism in which the RNA interference was first demonstrated. The term “RNA interference” (RNAi) was coined by Andrew Fire and Craig Mello to describe a sequence-specific gene silencing phenomenon in C. elegans.

The present-day environment of "the microRNA revolution", that your oeuvre made possible, can be well-characterized by the statement: “If the RNAi technology can be made to work, there’s a long list of diseases it can be applied to.” – Phillip A. Sharp, Nobel laureate. While for some of the hundreds of millions suffering from "Junk DNA diseases" our efforts may already be to late, there are so many hopefuls whom we should not disappoint. With a strong collective effort, we can avoid that could even happened to you "I failed to persuade any of the official genome organizations".

Since five years ago (for good practical reason, at that time), you reserved "non-coding DNA" for later use, I respectfully ask you and all pioneers named and/or inferred above to please consider in these dramatically changed times joining International PostGenetics Society in your appropriate role(s) in order to implement the needed social/scientific changes that your "Noblesse oblige":

postgenetics_at_junkdna.com

What is junk DNA, and what is it worth?

Scientific American
A. Khajavinia

Wojciech Makalowski, a Pennsylvania State University biology professor and researcher in computational evolutionary genomics, answers this query.

Our genetic blueprint consists of 3.42 billion nucleotides packaged in 23 pairs of linear chromosomes. Most mammalian genomes are of comparable size—the mouse script is 3.45 billion nucleotides, the rat's is 2.90 billion, the cow's is 3.65 billion—and code for a similar number of genes: about 35,000. Of course, extremes exist: the bent-winged bat (Miniopterus schreibersi) has a relatively small 1.69-billion-nucleotide genome; the red viscacha rat (Tympanoctomys barrerae) has a genome that is 8.21 billion nucleotides long. Among vertebrates, the highest variability in genome size exists in fish: the green puffer fish (Chelonodon fluviatilis) genome contains only 0.34 billion nucleotides, while the marbled lungfish (Protopterus aethiopicus) genome is gigantic, with almost 130 billion. Interestingly, all animals have a large excess of DNA that does not code for the proteins used to build bodies and catalyze chemical reactions within cells. In humans, for example, only about 2 percent of DNA actually codes for proteins.

For decades, scientists were puzzled by this phenomenon. With no obvious function, the noncoding portion of a genome was declared useless or sometimes called "selfish DNA," existing only for itself without contributing to an organism's fitness. In 1972 the late geneticist Susumu Ohno coined the term "junk DNA" to describe all noncoding sections of a genome, most of which consist of repeated segments scattered randomly throughout the genome. [If by "random" the author would mean the common misunderstanding that "random" is equivalent to "chaotic" (it is *not*), he would be half-right - since the actual distribution is fractal; fractals and chaos are the two sides of a coin. To say that repeated segments are scattered "randomly" has been known to be false since 1987 - AJP]

Typically these sections of junk DNA come about through transposition, or movement of sections of DNA to different positions in the genome. As a result, most of these regions contain multiple copies of transposons, which are sequences that literally copy or cut themselves out of one part of the genome and reinsert themselves somewhere else.

Elements that use copying mechanisms to move around the genome increase the amount of genetic material. In the case of "cut and paste" elements, the process is slower and more complicated, and involves DNA repair machinery. Nevertheless, if transposon activity happens in cells that give rise to either eggs or sperm, these genes have a good chance of integrating into a population and increasing the size of the host genome.

Although very catchy, the term "junk DNA" repelled mainstream researchers from studying noncoding genetic material for many years. After all, who would like to dig through genomic garbage? Thankfully, though, there are some clochards who, at the risk of being ridiculed, explore unpopular territories. And it is because of them that in the early 1990s, the view of junk DNA, especially repetitive elements, began to change. In fact, more and more biologists now regard repetitive elements as genomic treasures. It appears that these transposable elements are not useless DNA. Instead, they interact with the surrounding genomic environment and increase the ability of the organism to evolve by serving as hot spots for genetic recombination and by providing new and important signals for regulating gene expression.

Genomes are dynamic entities: new functional elements appear and old ones become extinct. And so, junk DNA can evolve into functional DNA. The late evolutionary biologist Stephen Jay Gould and paleontologist Elisabeth Vrba, now at Yale University, employed the term "exaptation" to explain how different genomic entities may take on new roles regardless of their original function—even if they originally served no purpose at all. With the wealth of genomic sequence information at our disposal, we are slowly uncovering the importance of non-protein-coding DNA.

In fact, new genomic elements are being discovered even in the human genome, five years after the deciphering of the full sequence. Last summer developmental biologist Gill Bejerano, then a postdoctoral fellow at the University of California, Santa Cruz, and now a professor at Stanford University, and his colleagues discovered that during vertebrate evolution, a novel retroposon—a DNA fragment, reverse-transcribed from RNA, that can insert itself anywhere in the genome—was exapted as an enhancer, a signal that increases a gene's transcription. On the other hand, anonymous sequences that are nonfunctional in one species may, in another organism, become an exon—a section of DNA that is eventually transcribed to messenger RNA. Izabela Makalowska of Pennsylvania State University recently showed that this mechanism quite often leads to another interesting feature in the vertebrate genomes, namely overlapping genes—that is, genes that share some of their nucleotides.

These and countless other examples demonstrate that repetitive elements are hardly "junk" but rather are important, integral components of eukaryotic genomes. Risking the personification of biological processes, we can say that evolution is too wise to waste this valuable information.

Stratagene Acquires Rights To microRNA Sequences

2/6/2007

Exclusive License Provides Access to More Than 150 microRNA Sequences for the Development, Manufacture and Sale of Molecular Diagnostic Kits

La Jolla, CA - Stratagene Corporation, a developer, manufacturer and marketer of specialized life science research and diagnostic products, today announced that it has obtained the last of the four co-exclusive licenses to more than 150 microRNA sequences available from Max Planck Innovation, the technology transfer agency of the Max Planck Society. Under the terms of the agreement, Stratagene will have the right to use the microRNA sequences for the development, manufacture and sale of molecular diagnostic kits.

MicroRNAs are naturally occurring, small RNAs that act to regulate messenger RNA, or mRNA, expression in humans. Currently there are in excess of 300 microRNA’s identified and research in this field is likely to push this number much higher. MicroRNAs are believed to regulate many genes, and thus are thought to be good indicators for biomarkers that are associated with many diseases. Of particular interest to Stratagene is the association of microRNAs with cancer.

"We are very excited to move into the microRNA area. The potential of these sequences, when paired with our proprietary FullVelocity technology, should allow us to develop important detection tests for the molecular diagnostics marketplace," said Joseph A. Sorge, MD, Chairman and CEO of Stratagene. “This relationship with Max Planck Innovation supports our initiatives to develop molecular detection technologies, diagnostics tests and instruments for the molecular diagnostics market.”
[The "hottest" business model in PostGenetics is the "in silico" prediction of microRNA (and target), and licensing in vivo validated IP to Pharma - Comment on the 11th of February, 2007 by A. J. Pellionisz]

Pharma giants grab piece of RNAi pie
By Mike Nagle

[SR Pharma illustration]

05/02/2007 - As SR Pharma and Quark Biotech start clinical trials of a drug that uses a Nobel Prize winning technique to 'silence' disease-causing genes, the largest pharma firms are keen to grab a piece of the action.

SR Pharma subsidiary Atugen developed RTP-801i and later licensed it to Quark Biotech. The drug utilises a natural phenomenon called RNA interference (RNAi) to prevent a specific disease-related gene from functioning. The gene in question here is REDD-1 and is linked to the progression of wet Age-related Macular Degeneration (AMD) where aberrant blood vessels beneath the retina leak blood and fluid into the eye causing loss of vision.

RNAi is a process in which short strands of RNA, called small interfering RNA (siRNA), block signals from a particular gene. This gene silencing prevents it from producing a protein and so doing its job. Since its discovery, many companies have started to develop siRNA therapies and now the world's largest pharma companies are beginning to take an interest.

RTP-801i is licensed by Pfizer with Quark Biotech the main beneficiary. SR Pharma specialises in developing siRNA anti-cancer drugs and SR Pharma chairman Iain Ross, told DrugResearcher.com that he sees large license deals as a first step to vindication of siRNA.

He said: "If RNAi can be shown to be delivered systemically, we will see a new drug class."

He explained that, being based on natural molecules, RNAi drugs hold a number of advantages over traditional drugs, both small molecules and biopharmaceuticals.

"RNAi drugs can remove years of screening and the drug candidates can get into the clinic very quickly," he continued.

Not only does this save money, but it could also extend the patent life of the drug while it's actually on the market. The drugs also don't need to be stabilised like many other therapies based on RNA molecules.

The interest from large pharma not only increases the incentive for new research but it also generates interest from other large companies that are keen not to miss out.

"We are excited about the AMD clinical trial commencing as it marks the first clinical study with one of our AtuRNAi molecules," said Ross.

"The fact that this is only the fourth clinical programme with siRNA therapeutics worldwide confirms SR Pharma's leading position in this young Nobel Prize winning technology."

There are no marketed siRNA drugs as yet - indeed, RTP-801i is only the fourth to enter clinical trials. Sirna Therapeutics was the first company to take a siRNA drug into trials. It had two drug candidates in clinical development - one that also treated AMD - when Merck & Co recently bought it in a deal worth $1.1bn (€850m). Merck & Co has also, in the past, signed collaboration deals with SR Pharma and Alnylam Pharma.

A third large pharmaceutical company that has taken an interest in siRNA drugs is Novartis. It owns a stake in Alnylam Pharma whose siRNA drug, ALN-RSV01, to treat respiratory syncytial virus is currently in Phase I trials.

AMD is the leading cause of blindness in the developed world affecting about 15m Americans over the age of 50 alone. Current treatments only work in early AMD and include destroying the blood vessels using a laser or using drugs that prevent blood vessel growth.

One such drug is Genentech's Lucentis (ranibizumab). The antibody fragment was approved in June 2006 and is administered via an injection directly into the eye. It works by inhibiting VEGF proteins, which play an important role in blood vessel growth and is also a target for several treatments designed to prevent cancer tumours from growing and spreading.

Andrew Fire and Craig Mello first discovered that RNA could knockdown genes in 1998 and were recently [2006] awarded the Nobel Prize in Physiology or Medicine for their research.

Ross also revealed that SR Pharma is "talking to a number of very large companies at the moment and I wouldn't be surprised if we are announcing our own license deal sometime this year."

He also pointed out that it was interesting that the larger companies are showing interest in siRNA compounds that are still quite early in clinical development rather than wait for later, Phase II and III compounds.

Which genome variants matter? [What really matters may be the algorithm...]

Global survey of the consequences of small and large DNA variants in our genome

Findings published today in Science will accelerate the search for genes involved in human disease. The report provides a first genome-wide view of how the unique composition of genetic variation within each of us leads to unique patterns of gene activity.

By defining those genetic variants with a biological effect, the results will help prioritise regions of the genome that are investigated for association with disease. This is an important step to understanding links between genes and disease for individuals, and across populations.

The Human Genome Project gave us the instruction manual for building a human. The HapMap and Copy Number Variation (CNV) Projects developed indices of where to find differences in the manuals of different people. One of the challenges for research into variation and disease is that most variants have no consequence for our wellbeing.

The new study gives a global view of the consequences of those differences for gene activity. The work shows that activity of more than 1000 genes is affected by sequence variation and is the first map of human populations that identifies the most important fraction of DNA variation, that which directly affects gene activity.

The research was led by scientists from the Wellcome Trust Sanger Institute, together with colleagues from the University of Cambridge, Hospital for Sick Children/University of Toronto and Harvard Medical School/Brigham and Women's Hospital.

Using the HapMap series of cell samples from four populations, they measured the activity of more than 14,000 genes in cells grown in culture. The cell samples provide a snapshot of genetic activity in one cell type. The activity of each gene was then correlated with genetic variation nearby, as defined by the HapMap, an index of single-base changes (single nucleotide polymorphisms, or SNPs) and the new index of copy number variants (CNVs).

"We've been able to look back into our history and find changes that are older and likely to be shared among populations," explained Dr Manolis Dermitzakis, senior author and Project Leader at the Wellcome Trust Sanger Institute. "But we also find many that are newer and less widespread.

"These are part of our recent evolution and a step along the way to understanding the origin and personal consequences of genetic change, not least for our wellbeing. This is a first generation map of biologically important DNA sequence variation" [There is no claim that with another and more complete measures no more divergence will be found... AJP]

The understanding of the genetic basis of gene activity will help medical research to provide individuals with information about their personal predisposition to disease.

The study was a massive undertaking: it included HapMap genotype data on 700,000 SNPs located close to genes, as well as 25,000 sites interrogated for potential structural variation to examine copy-number differences, looking at the activity of 14,000 genes in 210 unrelated individuals.

SNP and CNV variation correlated with altered activity in almost 900 and 240 genes, respectively. The HapMap has been invaluable in detecting variants involved in many diseases and these results suggest that the CNV index will prove similarly useful.

"The remarkable finding was that there is such little overlap in the genes found by using the two indices," commented Dr Matthew Hurles, also a leader of the project at the Wellcome Trust Sanger Institute. "Only about 10% of the activity variants associated with a CNV were also associated with a SNP.

"This suggests that we must include CNV studies in our searches for genetic variation associated with disease or we will be missing a lot of the important genetic effects."

The results show that at least 10-20% of heritable variation in gene activity is due to CNVs. The team found associations that included previously known examples, such as UGT2B17, which has been associated with prostate cancer, proving that the new approach works well.

They also showed for the first time that activity of other genes, located close to UGT2B17, was affected. Finding other effects in this way will enhance the search for critical genes within a region of genetic possibilities.

Some associations were not found in all four populations, two-thirds (CNVs or SNPs) being found in only one population. A gene implicated in Spinal Muscular Atrophy showed an association in three populations, but not in Yoruba from Ibadan, Nigeria. Understanding population differences can help us understand our history.

Variation in copy number can affect gene activity by altering the 'dose' of a gene, by disrupting the active parts of a gene that contain the code for protein, or by disrupting the regulatory regions of the genome that control gene activity - the on/off and dimmer switches in our genome.

"Although the simplest model for a CNV affecting gene activity is where the variant is a deletion of a gene or part of a gene, we found examples where activity is affected from a distance," commented Barbara Stranger, first author and post-doctoral fellow at the Wellcome Trust Sanger Institute. "This may occur when the CNV reduces the effectiveness of a region that works to switch the genes on or off."

The survey gives the first global view of the effects of SNPs and CNVs on gene activity. The methods and resources developed will help researchers better understand the link between differences - large and small - in our genome and our health.

Science 9 February 2007:
Vol. 315. no. 5813, pp. 848 - 853

Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes

Barbara E. Stranger,1 Matthew S. Forrest,1 Mark Dunning,2 Catherine E. Ingle,1 Claude Beazley,1 Natalie Thorne,2 Richard Redon,1 Christine P. Bird,1 Anna de Grassi,3 Charles Lee,4,5 Chris Tyler-Smith,1 Nigel Carter,1 Stephen W. Scherer,6,7 Simon Tavaré,2,8 Panagiotis Deloukas,1 Matthew E. Hurles,1* Emmanouil T. Dermitzakis1*

Extensive studies are currently being performed to associate disease susceptibility with one form of genetic variation, namely, single-nucleotide polymorphisms (SNPs). In recent years, another type of common genetic variation has been characterized, namely, structural variation, including copy number variants (CNVs). To determine the overall contribution of CNVs to complex phenotypes, we have performed association analyses of expression levels of 14,925 transcripts with SNPs and CNVs in individuals who are part of the International HapMap project. SNPs and CNVs captured 83.6% and 17.7% of the total detected genetic variation in gene expression, respectively, but the signals from the two types of variation had little overlap. Interrogation of the genome for both types of variants may be an effective way to elucidate the causes of complex phenotypes and disease in humans.

[Fig. from Science]

Abingworth co-drives £9m Dutch fundraising
By Business Weekly, 07 February 2007

Cambridge-based Abingworth has co-led an $18 million (£9m) fundraising round into Prosensa, a Netherlands based biotech firm focused on RNA interference therapeutics using exon skipping technology.

The investment was announced just days after Abingworth revealed it had raised £300 million to close Europe’s largest ever Life Sciences venture fund, Abingworth Bioventures V LP. The fund is Abingworth’s eighth in the Life Sciences and originally targeted £250m, but was significantly oversubscribed, which led Abingworth to limit the fund size at £300m. ABV V LP will invest in biotechnology and medical companies, both in Europe and the US. The fund will invest broadly across the life sciences field in technologies, therapeutics and medical devices at all stages of development from early-stage private deals to quoted companies. Investment size will generally range from £7.5m up to £20m per investment after all private rounds of financing. It is planned to make more than 20 venture investments.

Abingworth also has a history of investing in the Cambridge biocluster; between 1998 and present it has funded ventures such as Lorantis, Solexa, Astex and Akubio. Global placement agent, MVision Private Equity Advisers, acted as advisers and fund raising took two months to get to the first close of £222m on 21 December 2006. The second and final closing was on 26 January 2007.

“This has been a tremendous response and we are delighted with the quality of investors we have been able to attract,” said Dr Stephen Bunting, Abingworth managing director. “We believe the fund raising was helped by several factors including Abingworth’s lengthy track record, the strength of the team and our transatlantic presence with offices in London, Cambridge, UK, Menlo Park, California, and Boston.”

Abingworth was joined on the Prosensa deal by LSP on the Series A round and Medsci-ences Capital, an existing shareholder, also participated. The funds will be used to develop its two lead programs, in the field of Duchenne Muscular Dystrophy (DMD).

China Planning Major Investment in Biotech R&D
Posted on Feb 7th, 2007

After 35 existing, this will be 1 of 16

China declared its strong financial support in R&D when Xu Guanhua, the Minister of Science and Technology, recently announced the Chinese science goals for 2020 at a national conference in Beijing. China’s R&D expenditures were already at a record high of $38.5 billion in 2006, and rising quickly at 22% over 2005.

As part of the rapidly expanding program to bring China technology R&D into a position of global leadership, 16 national-level projects will be launched, including several in biology and health. Ten new national laboratories will be built, two of them for drug development and protein engineering.

While China is still lagging other world powers in relation to the portion of its GDP allocated to scientific research and development, it is rapidly gaining ground. What makes China different than other countries, including the U.S., is that it has established very aggressive and broad programs to develop and commercialize its technology, and it is supporting those programs from the top down – from national government down to the local levels.

On a trip to Shanghai in late January to focus on biotech investment opportunities there, I witnessed the government’s strong commitment to commercialize its biotechnology in action. Nestled in the 12 square mile Hi-tech Park in the Pudong New Area of Shanghai (see China Generates New Opportunities for Biomedical Companies) are two rather nondescript buildings called the “Pharma Engine,” housing forty-five (yes, 45) start-up biotechs, all funded or supported by the government. Scattered elsewhere in the park are another 150 biotech startups.

While China’s incubator model is similar to incubators in the U.S. (although significantly larger), many of the companies already have revenue while others have drugs in early and mid-stage clinical development with China’s SFDA. The SFDA has a drug approval process that closely parallels the U.S. but trial results are not usually transferable to the U.S. – at least not yet.

China loves to say that it is “number one” at things and this time it truly is. Assuming a five-year program from incubation to independence, 200 startups will result in 40 new biotechs launched each year. It would take 20 or more U.S. incubators to accomplish the same thing, and I’m not sure there even are 20 biotech incubators in the U.S., yet China is doing this with one. And there are several similar parks and incubators in other parts of China.

China is also working hard to attract foreign investment, and that extends even more so to biotech. Nestled between the drab incubator buildings in Pudong is a striking, curved building with flags from many nations flying in front. This houses the “VC Plaza” and all government offices supporting biotechnology and pharma companies in the park. The VC Plaza currently houses close to 20 VC and investment firms with plans to expand to as many as 60. There are also several major law firms, investment banks, and VCs there including Perkins Coie and Burrill and Co. These firms receive government support in exchange for their intention to invest in the incubator companies.

On my visit there, I met with four officials of the park and incubator, and it was obvious they are incredibly excited about their jobs, and I understand why. The energy here is at an extreme high and can’t help but be contagious. So much so, that we now have plans to open a Shanghai bureau.

Abingworth raises Europe’s largest ever life sciences venture fund

ABV V closes on £300 million

London, UK, 29 January 2007 - Abingworth, the international life sciences investment group, today announced the final closing of its £300 million ($587 million) life sciences fund, Abingworth Bioventures V LP (ABV V). This is Abingworth’s 8th life sciences fund and the largest venture fund dedicated to life sciences raised by a firm based in Europe. The fund’s target of £250 million was significantly oversubscribed but Abingworth decided to limit the fund size to £300 million.

ABV V will invest in biotechnology and medical companies, both in Europe and the US. The fund will invest broadly across the life sciences field in technologies, therapeutics and medical devices at all stages of development from early-stage private deals to quoted companies. Investment size will generally range from £7.5 million up to £20 million per investment after all private rounds of financing. It is planned to make more than 20 venture investments.

Global placement agent, MVision Private Equity Advisers, acted as advisers and fund raising took two months to get to the first close of £222 million on 21st December 2006. The second and final closing was on 26th January 2007.

“This has been a tremendous response and we are delighted with the quality of investors we have been able to attract,” said Dr Stephen Bunting, Managing Director. “We believe the fund raising was helped by several factors including Abingworth’s lengthy track record, the strength of the team and our transatlantic presence with offices in London, Cambridge (UK), Menlo Park (California) and Boston.”

SJ Berwin acted as UK legal advisers and Proskauer Rose acted as US legal advisers.

Abingworth is a long-established venture capital firm dedicated to the life sciences sector on both sides of the Atlantic. The company invests across all stages of development, including early-stage as well as public companies. Abingworth has funds under management of over $1.25 billion. Founded in 1973, Abingworth has offices in London, Cambridge (UK), Menlo Park (California) and Boston.

Existing Funds

To date, Abingworth has raised seven venture funds dedicated to investment in life sciences as well as Abingworth Bioequities, an open-ended fund and Abingworth’s first fund dedicated solely to investments in public companies.

Successful investments have included Alnylam Pharmaceuticals, Aurora Biosciences, Aviron, GelTex Pharmaceuticals, Gilead Sciences, Healtheon, IDEC Pharmaceuticals, Pharmion, PowderMed and Solexa. For a full list of Abingworth’s portfolio companies please visit the website.

High-density tiling array reveals introns and extensive regulation of splicing

Ronald W. Davis, Stanford

Knowing gene structure is vital to understanding gene function, and accurate genome annotation is essential for understanding cellular function. To this end, we have developed a genome-wide assay for mapping introns in Saccharomyces cerevisiae. Using high-density tiling arrays, we compared wild-type yeast to a mutant deficient for intron degradation. Our method identified 76% of the known introns, confirmed 18 previously predicted introns, and revealed 9 formerly undiscovered introns. Furthermore, we discovered that all 13 meiosis-specific intronic yeast genes undergo regulated splicing, which provides posttranscriptional regulation of the genes involved in yeast cell differentiation. Moreover, we found that 16% of intronic genes in yeast are incompletely spliced during exponential growth in rich medium, which suggests that meiosis is not the only biological process regulated by splicing. Our tiling-array assay provides a snapshot of the spliced transcriptome in yeast. This robust methodology can be used to explore environmentally distinct splicing responses and should be readily adaptable to the study of other organisms, including humans.

[full text]

New Life for "Junk" DNA

By Ilene Raymond Rush
Editor-in-Chief

February 1, 2007

[Illustration to the SHPress News Headlines article; named workers. See Founders of IPGS]

Genetic material called 'junk' DNA because it did not seem to contain instructions for protein coding genes and appeared to have little or no function may actually play an important role in evolution and an array of dreaded diseases.

Although this non-coding DNA comprises 98.7 percent of human DNA -- compared with the 1.3 percent of genes that make up the human genome -- researchers so far have a limited, though tantalizing, understanding of its functions.

To accelerate interdisciplinary research and funding in this area, a new International PostGenetics Society (IPGS, http://www.postgenetics.org) has been announced. Headed by Dr. Andras Pellionisz, a longtime advocate for genome-wide understanding, and signed by over 20 international scientists, the group has outlined plans to launch "PostGenetics Study Programs" and to promulgate the emergence of "PostGenetics Centers" along with a scientific journal and Congress.

In addition, the announcement builds the case for abandoning the 'junk' DNA label and replacing it with "Post-Genetics" to reflect an interest in exploring the complete genetic package.

Pellionisz is a long time advocate for the investigation and critical importance of non-coding DNA. Using his mathematical approach called "FractoGene", Pellionisz was among the first researchers to interpret patterns in this DNA, recently scaled to capabilities by the IBM Watson Center. These observations lead him to believe that this 'junk' DNA had functional importance despite its non-coding properties in the classical sense.

"With hundreds of millions dying of diseases originating from non-coding DNA, no effort should be spared to promote the long overdue agenda of PostGenetics, leading towards the emergence of PostGenetic Centers," says Pellionisz in an e-mail exchange. Among the diseases that may have tentative links to this DNA are Alzheimer's, Parkinson's, psoriasis, asthma, muscular dystrophy, HIV-AIDS and a variety of cancers.

So far, some of the most intriguing explanations of the role of this genetic material have arisen in the area of evolutionary biology. In 2005, for example, Dr. Peter Andolfatto, an assistant professor of biology at University of California, San Diego, showed that non-coding regions play an important role in maintaining an organism's genetic integrity.

Early this year, a team of scientists has shown that a particular type of non-coding RNA, a chemical found in cell nuclei, plays a key role in regulating a gene implicated in control of tumor growth. The research done at the University of Oxford, U.K., and published in the journal Nature, shows that a form of RNA switches off a gene involved in cell division, which may have implications for preventing the growth of tumor cells.

"There's been a quiet revolution taking place in biology during the past few years over the role of RNA," says Dr. Alexandre Akoulitchev, a Senior Research Fellow at the University of Oxford. "Scientists have begun to see 'junk' DNA as having a very important function. The variety of RNA types produced from this 'junk' is staggering and the functional implications are huge."

The importance of an interdisciplinary approach to PostGenetics is underlined by its importance to not only biotechnology, but in both information technology and nanotechnology, says Pellionisz. He points to the work of Craig Venter, co-founder of Synthetic Genomics, a firm dedicated to using modified microorganisms to produce ethanol and hydrogen and alternative fuels.

"Venter has set out to modify the genome of the bacterium with the smallest genome of all - a self-supporting organism to produce H2 for a global hydrogen-based economy," notes Pellionisz. "Yet, 8% of the DNA of even this organism is "non-coding", thus Ventner's goal may not be attainable without going "beyond genes".

"At the dawn of the postmodern era of Genetics, we simply don't know enough about this part of genetic material," says Antonio Giordano, M.D., PhD., director of the Sbarro Institute of Cancer Research and Molecular Medicine at Temple University in Philadelphia and one of the founding members of IPGS. "With funding opening up for PostGenetics we can begin to uncover the answers to far too long overlooked questions."

^ back to table of contents ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

[Antigene RNA] Novel laboratory technique nudges genes into activity

IPGS Founder Dr. Corey, Ram and IPGS Founder Dr. Janowski

A new technique that employs RNA, a tiny chemical cousin of DNA, to turn on genes could lead to therapeutics for conditions in which nudging a gene awake would help alleviate disease, researchers at UT Southwestern Medical Center say.

The gene-activating method, which is being developed by UT Southwestern scientists, also is providing researchers with a novel research tool to investigate the role that genes play in human health.

In a paper appearing online at Nature Chemical Biology and in an upcoming edition of the journal, lead author Dr. Bethany Janowski, assistant professor of pharmacology at UT Southwestern, and her colleagues describe how they activated certain genes in cultured cells using strands of RNA to perturb the delicately balanced mixture of proteins that surround chromosomal DNA, proteins that control whether genes are turned on or off.

Dr. David Corey, professor of pharmacology and the paper’s senior author, said the results are significant because they demonstrate the most effective and consistent method to date for coaxing genes into making the proteins that carry out all of life’s functions – a process formally called gene expression.

In any medical specialty, Dr. Janowski said, there are conditions where increased gene expression would prove beneficial.

"In some disease states, it’s not that gene expression is completely turned off, but rather, the levels of expression are lower than they should be," she said. As a result, there is an inadequate amount of a particular protein in the body. "If we can bring the level up a few notches, we might actually treat or cure the disease," Dr. Janowski said.

For example, some genes are natural tumor suppressors, and using this method to selectively activate those genes might help the body fend off cancer, Dr. Janowski said.

Genes are segments of DNA housed in chromosomes in the nucleus of every cell and they carry instructions for making proteins. Faulty or mutated genes lead to malfunctioning, missing or over-abundant proteins, and any of those conditions can result in disease.

Surrounding the chromosome is a cloud of proteins that helps determine whether or not a particular gene’s instructions are "read" and "copied" to strands of messenger RNA, which then ferry the plans to protein-making "factories" in the cell.

In its experiments, the UT Southwestern team used strands of RNA that were tailor-made to complement the DNA sequence of a specific gene in isolated breast cancer cells. Once the RNA was introduced into the protein mix, the gene was activated, ultimately resulting in a reduced rate of growth in the cancer cells.

Dr. Corey said that while it’s clear the activating effects of the new technique are occurring at the chromosome level, and not at the messenger RNA level, more research is needed to understand the exact mechanism.

Although the RNA strands the researchers introduced – dubbed antigene RNA – were manufactured, Dr. Corey said the process by which they interact with the chromosome appears to mimic what naturally happens in the body.

"One of the reasons why these synthetic strands work so well is that we’re just adapting a natural mechanism to help deliver a man-made molecule," Dr. Corey said. "We’re working with nature, rather than against it."

Drs. Corey’s and Janowski’s current results are built on previous work, published in 2005 in Nature Chemical Biology, in which they found that RNA strands could turn off gene expression at the chromosome level.

The new UT Southwestern research, coupled with that from 2005 [full text, free], demonstrates a shift away from conventional thinking about how gene expression is naturally controlled, as well as how scientists might be able to exploit the process to develop new drug targets, Dr. Corey said.

For example, current methods to block gene expression, such as RNA interference, rely on using RNA strands to intercept and bind with messenger RNA. While RNA interference is an effective tool for studying gene expression, Dr. Janowski said, it’s more efficient to use RNA to control both activation and de-activation at the level of the chromosome.

"It goes right to the source, right to the faucet to turn the genes on or off," she said.

Dr. Corey said many researchers have the ingrained idea that RNA only targets other RNA – such as what occurs when messenger RNA is targeted during RNA interference. "That’s what everyone is familiar with," he said. "But the idea of RNA being used as a sort of nucleic acid modulator of chromosomes, at the level of the chromosome itself, is novel and unexpected, and it’s going to take some getting used to."

[Abstract] [Supplementary information]

BIG PHARMA consolidates for PostGenetics; PFIZER, GLAXOSMITHKLINE, BRISTOL-MYERS SQUIBB
Drug Discovery News, January, 2007

[With the anti-cancer and non-coding DNA diseases revolution, unmistakable signs show a major ripple-effect of Pharma Consolidation. The following excerpts are from a single issue of "Drug Discovery News". This is in addition to recent news about MERCK, MITSUBISHI PHARMA, etc. - AJP]

SCRIPPS receives unrestricted $100 Million from PFIZER

La Jolla, California - The Scripps Research Institute has entered into a five-year research collaboration with Pfizer Global Research and Development to advance scientific knowledge of uncured diseases and novel ways to treat them. They will jointly study and evaluate therapeutic approaches for diseases such as cancer, diabetes and mental illnesses. Under the terms of the agreement, Pfizer will pay Scripps Research $100 million over a five-year period, during which scientists from Pfizer and the Institute will work together to identify and perform as yet unidentified projects of mutual interest. ...Pfizer will also pay the Institute milestones and royalties on therapeutic compounds created through the collaboration but the specifics of these arrangements have not been finalized. In addition, based on an NIH formula, Pfizer will have the first right to license up to 47% of the discoveries made at Scripps Research during the term of the agreement.. ... "It may also speed up the timeframe for translating breakthrough discoveries in the lab into treatments for currently disabling, even fatal diseases".

GLAXOSMITHKLINE  and EPIX Pharma enter collaboration

Lexington, Massachussetts - In mid-December, GSK and EPIX Pharmaceuticals announced a worldwide multi-target strategic collaboration to discover, develop and market novel medicines targeting four G-protein coupled receptors (GPCRs) for the treatment of a variety of diseases. ... EPIX will receive total initial payments of $35 million through GSK' purchase of ...shares. In addition, EPIX will be eligible to earn potential milestones and opt-in fees of up to $1.2 billion based on the achievement of certain discovery, development, regulatory and commercial milestones... EPIX will also receive tiered double-digit royalties on sales by GSK of all collaboration-developed products.

BRISTOL-MYERS SQUIBB, EXELIXIS to discover and develop cancer compounds

South San Francisco - Exelixis Inc. and Bristol-Myers Squibb Co. have announced a worldwide collaboration to discover, develp and commercialize novel targeted therapies for the treatment of cancer. ... Under the terms of the agreement, Bristol-Myers Squibb will pay Elixis an upfront payment of $60 million for each of up to three different drug candidates selected by Bristol Myers Squibb at IND. ... Exelixis may opt out of the co-development or co-promotion in the United States, in which case Exelixis would receive milestones and royalties in lieu of a U.S. profit share.

Mapping the human genome wasn't enough. Venter is trying to create a microbe to free us from additiction to oil.

Energy_in_Venter

Atlantic Monthly, 2007 Jan/Feb
State of the Union - the Innovators
Ross Douthat [excerpts from pp. 121-125]

...Venter is out to build new genomes, not just to analyze existing ones. He's not jut trying to understand how life works; he's trying to make it work for him, and us. The race to map the human genome, in its headier moments, promised cures for Parkinson's, Alzheimer's cancer. Venter's current undertaking shows promise for something no less ambitious: a cure for our dependence on oil.

...a host of high-profile investors, from Richard Branson to Bill Gates, are jumping into the alternative-energy market as well...

...Genomic research, after all, doesn't just offer scientists an opportunity to take apart the genome of a human being, a mouse, or a bacterium to see how it works and what it does. It offers them a chance - if they're sufficiently ambitious, or hubristic - to change what a genome does, and to make the organism do what we want it to do. And one of the obvious things we might want organisms to do for us - they already do it for their own purposes - is produce energy...

... In 1995, his team published the decoded genetic script ... Later that year, a team led by Fraser published the genome for the parasite Mycoplasma genitalium, a far simpler organism, with only about 500 genes... "We immediately began to ask obvious questions," Venter says. "Is there a minimal operating system for a cell? ... Was [M. Genitalium] the minimum, or could we eliminate genes from that species and get smaller?" So began the quest for the "minimal genome", the barebones genetic material necessary for life to sustain itself and reproduce. This required dismantling M. genitalium, which suggested another possibility: If you could take a genome apart bit by bit, why not put one together in the same way, creating "life from scratch", as Venter puts it, with a genome of your choice?...

...He had money, ..."Having sequenced the human genome" he says with a laught, "gives you a few options". Using $100 million of his own funds, he started three not-for-profit research centers, which are now consolidated under the J. Craig Venter Institute... One of the new centers, the Institute for Biological Energy Alternatives, took up the challenge of creating the minimal genome. ... that could serve as "biofactories", carrying out energy-generating functions that had been written into their genetic code.

In 2003 the IBEA team, led by Hamilton "Ham" Smith, Venter's longtime research colleague and the winner of a 1978 Nobel Prize in Medicine, took just fourteen days to reconstruct the 5,386 nucleotide base pairs of a virus called phi-X174... this achievement prompted Venter to step back into the for-profit world, and in the summer of 2005 he founded Synthetic Genomics, a company that would build on the minimal genome research. ...

...Hiring [Aristides] Patrinos [for Synthetic Genomics' president, Venter is the CEO] was a coup for Venter and a sign that Synthetic Genomics intended to be a major player. Patrinos had been one of the government's point men for alternative energy... Synthetic Genomics is still getting off the ground: when I visited Patrinos, in October, the movers were bringing furniture to its Rockville offices, two parking lots over from Venter's main campus, and half the space was empty, awaiting new hires. .. using the capital raised so far to support minimal-genome research at the Venter Institute, and it has laboratories in La Jolla, California, where most of its scientists will be based. Meanwhile, through the institute, Venter has teamed up with the University of California, San Diego, and Iowa State University to compete for $500 million in funding from BP... Venter and the two universities have also joined forces to compete for one of the $125 million grants that the U.S. Department of Energy will award to each of two winning proposals for bioenergy research centers.

... and hydrogen, the cleanest fuel of all, from sunlight. We're working on modifying photosynthesis to go directly from sunlight into hydrogen production. All of this is speculative, or course. "Sometime in the future, Venter says, " ... "When is 'sometime in the future"? He doesn't say, but he is willing to venture that we should expect biological research to spark large-scale changes in the energy scene within the next ten years. The prediction comes with a touch of disarmingly frank self-centeredness: Ham is in his mid-seventies. I am turning sixty. We don't want something with a fifty year time line. We're egocentric, we want to see it take place, so we're determined to have it take place in the next decade."

... I am hoping our research teams come up with the breakthroughs, he says. "but I think as a society, we need those breakthroughs, and there's no guarantee we'll make them. So... I'd be almost as happy if somebody else makes those breakthroughs".

Almost.

AVEO [USA] acquires rights to novel anti-cancer compound from Mitsubishi Pharma Corporation [JAPAN] [The anti-cancer revolution marches on]

AVEO Pharmaceuticals has acquired from Mitsubishi Pharma Corporation an exclusive license to develop and commercialize Mitsubishi's novel multiple kinase inhibitor, MP-412, in all territories outside of Asia.

The company expects to file an IND and commence clinical studies for MP-412 by mid-2006. It initially plans to develop MP-412 for the treatment of solid tumors and will apply its Human Response Prediction platform to identify patient populations likely to be responsive to MP-412.

Financial terms of the agreement were not disclosed.

Said Tuan Ha-Ngoc, President and CEO of AVEO, “MP-412 has the potential to address large unmet medical needs in cancer, and it represents the first results from our in-licensing initiative designed to leverage our novel platform, which enables us to determine the genetic profiles of potentially responsive populations.”

“This platform provides us and our partners, with a unique advantage and has the potential to increase the efficiency and probability of success of clinical programs by bringing the right drugs to the right patients.”

[The terse business communique, without further public domain information, may not reveal the depth of the re-structuring ripping through "Pharma" - AJP]

AVEO's Human Response Prediction platform is based on AVEO's proprietary, genetically-defined mouse models of human cancer. Each of these models is engineered to contain signature genetic mutations that are present in human disease. Beyond these cancer-initiating, engineered mutations, the resultant tumors acquire common and distinct spontaneous mutations during tumor progression, providing additional natural genetic variation akin to the range of genetic heterogeneity encountered across different primary human tumors.

The tumor-to-tumor genetic variation in the system provides the opportunity to identify genetic correlations between responding and non-responding tumor populations, and to apply such genetic profiles in clinical development.

Consequently, compared with traditional xenograft models that have proven to be non-predictive of efficacy, often leading to expensive and time-consuming hit or miss outcomes in clinical trials, AVEO's cancer models are improved predictors of human response.

'Quiet revolution' may herald new RNA therapeutics

IPGS Founder Alexandre Akoulitchev

Scientists at the University of Oxford have identified a surprising way of switching off a gene involved in cell division. The mechanism involves a form of RNA, a chemical found in cell nuclei, whose role was previously unknown, and could have implications for preventing the growth of tumour cells.

RNA plays an important and direct role in the synthesis of proteins, the building blocks of our bodies. However, scientists have known for some time that not all types of RNA are directly involved in protein synthesis. Now, in research funded by the Wellcome Trust and the Medical Research Council, a team of scientists has shown that one particular type of RNA plays a key role in regulating the gene implicated in control of tumour growth. The research is published online today in Nature.

The Human Genome Project identified about 34,000 genes responsible for producing proteins. The remaining part – in fact, most of the genome – constituted what was considered to be "junk" DNA with no function. However, latest estimates show that this "junk" DNA produces around half a million varieties of RNA of unknown functions.

"There's been a quiet revolution taking place in biology during the past few years over the role of RNA," says Dr Alexandre Akoulitchev, a Senior Research Fellow at the University of Oxford. "Scientists have begun to see 'junk' DNA as having a very important function. The variety of RNA types produced from this "junk" is staggering and the functional implications are huge."

The particular form of RNA that has been of interest to Dr Akoulitchev's team is involved in regulation of the dihydrofolate reductase gene (DHFR), determining whether the gene is "on" or "off". The DHFR gene produces an enzyme that controls thymine production, necessary in rapidly dividing cells.

"Inhibiting the DHFR gene could help prevent the growth of neoplastic cancerous cells, ordinary cells which develop into tumour cells, such as in prostate cancer cells," explains Dr Akoulitchev. "In fact, the first anti-cancer drug, Methotrexate, acts by binding and inhibiting the enzyme produced by this gene."

Dr Akoulitchev believes that understanding how we can use the RNA to switch off or inhibit DHFR and other genes may have important therapeutic implications for developing new anti-cancer treatments.

[Supplementary info] [Abstract] [Figures and tables]

Google-funded genetic start-up?

VentureBeat
Matt Marshall

Anne Wojcicki, the biotech analyst who is reportedly engaged to Google co-founder Sergey Brin, has co-founded a Mountain View personal genetics startup, 23andMe, according to ValleyWag. According to the company's site, it develops "tools and producing content to help people make sense of their genetic information. Our goal is to take advantage of new genotyping technologies and help consumers explore their genetics, informed by cutting edge science...."

[Now the news is out about a potential Google-Genomics connection that has been anticipated, albeit not in this specific manifestation, over the years in this column. Now some outstanding tactical issues in the IT/Genomics theater seem to be, when/how "Venter Ventures" will join the fray from the "high end" of leading-edge Genomics, and when/how the "populist force" of Apple will re-position itself. The strategic issue, of course, is if in the paradigm-shift of a disruption "the establishment" will win the game (as it seemed for personal computers a duel of IBM/Apple) - or a tiny aggressor will spring to life (as it was when Microsoft emerged from nothing and became the winner) - comment on the 19th of January, 2007 by A. J. Pellionisz]

BioDiscovery Joins Microsoft BioIT Alliance
[Communicated by IPGS Honorary Chairman Malcolm J. Simons]

[January 17, 2007]

NEW YORK (GenomeWeb News) — BioDiscovery has joined the BioIT Alliance, the company reported yesterday.

BioDiscovery President Soheil Shams said involvement in the Alliance will “strengthen our competence in providing cross-platform, integrated software solutions.”

The BioIT Alliance is a diverse group of IT and biotech companies working with Microsoft to advance biomedical information technology through partnerships and shared knowledge on a range of issues.

Other BioIT Alliance members include Applied Biosystems, Affymetrix, Agilent, and Accelrys.

[The "Big One" earthquake when the "IT tectonic plate" will pile up on the "Genome tectonic plate" was predicted by A.Pellionisz and M.Simons by June 2004. Formation of BioIT Alliance was also duly reported in this column. With MicroSoft having pitted a tent, there is one obvious question: "What's in Genomics to GOOGLE"? To the extent of public information this column is on record with reporting what can be revealed - comment on the 17th of January, 2007 by A. J. Pellionisz]

Micro[RNA] Molecules Can Identify Pancreatic Cancer

A pattern of micro molecules can distinguish pancreatic cancer from normal and benign pancreatic tissue, new research suggests.

The study examined human pancreatic tumor tissue and compared it to nearby normal tissue and control tissue for levels of microRNA (miRNA). It identified about 100 different miRNAs that are present usually at very high levels in the tumor tissue compared with their levels in normal pancreatic tissue.

The findings suggest that miRNAs form a signature, or expression pattern, that may offer new clues about how pancreatic cancer develops, and they could lead to new molecular markers that might improve doctors' ability to diagnose and treat the disease.

Pancreatic cancer is expected to strike 33,700 Americans and to kill 32,300 others this year, making it the fourth leading cause of cancer death. The high mortality rate - the number of new cases nearly equals the number of deaths - exists because the disease is difficult to diagnosis early and treatment advances have been few.

The study, led by cancer researchers at the Ohio State University Comprehensive Cancer Center, was published online in the International Journal of Cancer.

"Our findings show that a number of miRNAs are present at very different levels in pancreatic cancer compared with benign tissue from the same patient or with normal pancreatic tissue," says principal investigator Thomas D. Schmittgen, associate professor of pharmacy and a researcher with the Ohio State's Comprehensive Cancer Center.

"Most are present at much higher levels, which suggests that developing drugs to inhibit them might offer a new way to treat pancreatic cancer. It also means that a test based on miRNA levels might help diagnose pancreatic cancer."

miRNAs are extremely short molecules that were discovered about a dozen years ago and found to be important for controlling how proteins are made. Scientists have now identified more than 470 different miRNAs in humans. More recent research has shown that miRNAs also play an important role in cancer.

"A big problem we face with pancreatic cancer is an inability to detect tumors early," says Russell Postier, chairman of surgery at the University of Oklahoma Health Science Center and a co-author of the study.

"The exciting findings in our work indicate that there is a microRNA gene-expression pattern that is unique to pancreatic tumors, and this might be useful in diagnosing pancreatic cancer in the future."

For this study, the researchers used a technique developed by Schmittgen and a group of colleagues in 2004 to measure miRNA in small tissue samples. The method is based on a technology called real-time PCR profiling, which is highly sensitive and requires very small amounts of tissue, Schmittgen says.

The researchers used the method to compare the levels of 225 miRNAs in samples of pancreatic tumors from patients with adjacent normal tissue, normal pancreatic tissue and nine pancreatic cancer cell lines.

Computer analysis of the data identified a pattern of miRNAs that were present at increased or decreased levels in pancreatic tumor tissue compared with normal tissue. The analysis correctly identified 28 out of 28 pancreatic tumors, 11 of 15 adjacent benign tissues and six of six normal tissues.

Levels of some miRNAs were increased by more than 30- and 50-fold, with a few showing decreased levels of eight- to 15-fold.

Schmittgen and his colleagues are now working to learn which of the miRNAs they identified are most important for pancreatic cancer development, and if some are found only in pancreatic cancer and not in other types of cancer.

Asuragen Licenses Yale miRNA Inventions with Potential in Lung Cancer

Jan 10 2007, 12:30 PM EST

GEN News Highlights

Asuragen gained exclusive access to Yale University’s inventions developed by Frank Slack, Ph.D., for the regulation of oncogenes by microRNA's.

"By taking this license, Asuragen continues to strengthen its position as the leader in the application of miRNAs for diagnostics and therapeutics", states Matt Winkler, CEO/CSO of Asuragen. "We believe that recent advances in the application of siRNAs and the acquisition of Sirna Therapeutics by Merck & Co., confirms that RNA chemistries are overcoming previous clinical hurdles and sets the stage for potential miRNA therapeutic applications."

Dr. Slack discovered that among the genes regulated by the microRNA let-7 in the nematode C. elegans, there are several genes related to cancer, including the homolog of the human oncogene ras. A collaboration between scientists in the Slack laboratory and at Asuragen revealed that human let-7 regulates the expression of ras and that mis-regulation of let-7 in human lung cells likely contributes to the development of lung cancer via altered expression of ras.

"Our hope is that we can use let-7 as a potential diagnostic tool to diagnose lung cancers in patients," Dr. Slack explains. "And secondly, potentially use let-7 as a way to knock out activated ras in those lung cancers."

In addition to this license agreement, Asuragen will also fund Dr. Slack’s miRNA research.

[MicroRNA-s are in the Pharma biz to stay. Pharma will "mop up" the outstanding Intellectual Property. Though financial details (of course) are not disclosed, one assumes that Dr. Slack, for having his research funded by Pharma, had to sign assignment of his IP to Asuragen - comment on the 11th of January, 2007 by A. J. Pellionisz]

NMC Group to set up facility at DuBiotech [put Dubai on the map of PostGenetics]

By Saifur Rahman, Business News Editor

Dubai: Abu Dhabi-based New Medical Centre (NMC) Group will set up a multi-billion dollar bio-technology plant at the Dubai Biotechnology and Research Park (DuBio-tech), the region's biotech hub currently being developed.

"This will be a multi-billion dollar project and the first of its kind in the region," Dr BR Shetty, vice-chairman of NMC Group, told Gulf News yesterday. "We have sought land at DuBiotech for the project, which is still in early stage of development. Once we are given the land, we will be able to start working." Announced in February 2005, DuBiotech is a science and business park dedicated to the biotech industry, set within a free zone infrastructure. DuBiotech has two main areas of interest.

US-based project managers Parsons and CUH2A, the world's largest professional services firm dedicated to planning and design of science and technology facilities, are currently carrying out the master plan of DuBiotech. Dr Shetty's pharmaceutical plant, Neopharma recently signed an agreement with leading biotechnology major, Biocon, to produce biomedicine in Abu Dhabi.

Through this joint venture, the two companies will leverage on each other's strengths to manufacture and market biopharmaceutical products for the GCC region. The joint venture will bring out life saving drugs in the field of oncology, diabetes, auto-immune disorders and cardiology. The product mix will also include anti-obesity drugs and new generation immunosuppressant drugs.

"The agreement will allow us to produce Biocon's patented bio-medicine in the UAE - the first such attempt," he said.

Biocon is India's leading biotechnology enterprise. Over the past 28 years, they have evolved from an enzyme manufacturing company to a fully integrated biopharmaceutical enterprise. They apply proprietary fermentation technologies to develop innovative biomolecules.

Dr Kiran Mazumdar-Shaw, Chairman and Managing Director of Biocon, said, "I believe that Biocon through its partnership with Neopharma, will contribute to the growth and development of this country in the field of biotechnology."

Dr Shetty said Neopharma has reached a break-even point after 18 months of operations.

Renegade RNA: Clues To Cancer And Normal Growth

Science Daily — Researchers at Johns Hopkins have discovered that a tiny piece of genetic code apparently goes where no bit of it has gone before, and it gets there under its own internal code.

A report on the renegade ribonucleic acid, and the code that directs its movement, will be published Jan. 5 in Science.

MicroRNAs, already implicated in cancer and normal development, latch on to and gum up larger strands of RNA that carry instructions for making the proteins that do all the cell's work. They are, says Joshua Mendell, M.D., Ph.D., an assistant professor in the McKusick-Nathans Institute of Genetic Medicine at Hopkins, like "molecular rheostats that fine-tune how much protein is being made from each gene."

That's why normally microRNAs always have appeared to stick close to the cell's protein-making machinery.

But during a survey of more than 200 of the 500 known microRNAs found in human cells, Mendell's team discovered one lone microRNA "miles away" --- in cellular terms --- from all the others.

"It was so clearly in the wrong place at the wrong time for what we thought it was supposed to be doing that we just had to figure out why," says Hun-Way Hwang, a graduate student in human genetics and contributor to the study.

Consisting of only 20 to 25 nucleotide building blocks (compared to other types of RNA that can be thousands of nucleotides long), each microRNA has a different combination of blocks. Mendell's team realized that six building blocks at the end of the wayward miR-29b microRNA were noticeably different from the ends of other microRNAs.

Suspicious that the six-block end might have something to do with miR-29b's location, the researchers chopped them off and stuck them on the end of another microRNA. When put into cells, the new microRNA behaved just like miR-29b, wandering far away from the cell's protein-making machinery and into the nucleus, where the cell's genetic material is kept.

The researchers then stuck the same six-block end onto another type of small RNA, a small-interfering RNA or siRNA that turns off genes. This also forced the siRNA into the nucleus.

According to Mendell, these results demonstrate for the first time that despite their tiny size, microRNAs contain elements consisting of short stretches of nucleotide building blocks that can control their behavior in a cell. Mendell hopes to take advantage of the built-in "cellular zip code" discovered in miR-29b as an experimental tool. For example, he plans to force other microRNAs and siRNAs into the nucleus to turn off specific sets of genes.

Mendell's team is actively hunting for additional hidden microRNA elements that control other aspects of their behavior in cells. They also are curious to figure out what miR-29b is doing in the nucleus. Because microRNAs have been implicated in cancer as well as normal development, Mendell hopes that further study of miR-29b will reveal other, hidden functions of microRNAs.

A Hexanucleotide Element Directs MicroRNA Nuclear Import

Hun-Way Hwang,1 Erik A. Wentzel,2 Joshua T. Mendell1,2*

MicroRNAs (miRNAs) negatively regulate partially complementary target messenger RNAs. Target selection in animals is dictated primarily by sequences at the miRNA 5' end. We demonstrated that despite their small size, specific miRNAs contain additional sequence elements that control their posttranscriptional behavior, including their subcellular localization. We showed that human miR-29b, in contrast to other studied animal miRNAs, is predominantly localized to the nucleus. The distinctive hexanucleotide terminal motif of miR-29b acts as a transferable nuclear localization element that directs nuclear enrichment of miRNAs or small interfering RNAs to which it is attached. Our results indicate that miRNAs sharing common 5' sequences, considered to be largely redundant, might have distinct functions because of the influence of cis-acting regulatory motifs.

Improved Quarter for Biotech on Capital Markets ... and Financings and Partnering Deals Remain Red Hot

Genomics Back in Favor in Q4

"Illumina led the resurgence in the technology, tools and genomics companies in 2006. Millennium Pharmaceuticals, Human Genome Sciences, Curagen and Celera Genomics all posted high double digit gains in their share prices for the year," added Burrill.

"The transition to a more personalized medicine world is creating the need for molecular diagnostics, biomarkers, genotyping assays, etc. and so companies specializing in these areas have received positive investor attention," he continued. "Sequenom, for example, a provider of fine mapping genotyping, methylation and gene expression analysis solutions, saw its share price rocket and closed the year up 588%."

The Burrill Genomics Index surged 14% in Q4 06 and although this gain failed to bring the Index back into positive territory, closing the year down 13%, there is every reason to believe that companies in the genomics space will have a successful 2007 driven by the industry's need for faster and more expansive genotyping technology to scan genes that will reveal clues to curing diseases.

Investors Still Positive on Biotech

"While biotech's performance in the capital markets waxed and waned throughout the year, at the mercy of prevailing macro-economic forces, concern for Iraq, elections/politics, and about healthcare cost increases, it was a big year for biotech/life sciences fund raising. Financings and partnering deals brought in a record $47 billion for US companies with over $27 billion through financings and $20 billion in partnering capital."

In total biotech raised $6.2 billion in 4Q 06, picking up the pace again after Q3 06, which saw only $2.4 billion collectively raised by the industry. Leading the way were follow-ons and debt financings. The $1.7 billion debt financings in Q4 06 put an exclamation mark on what has been a remarkable year. With almost $14 billion raised in 2006, the total debt capital generated by the industry represents what was raised in the whole of 2004 and 2005 combined. [This puts a perspective on the news that Korea WILL invest in 10 years $14 billion. The USA has invested already that much in a single year. As predicted by Juan Enriquez, the global competition will wipe out those regions that fail to meet "the genomics challenge" - AJP]

Leading the pack of over 20 deals in the quarter was Celgene, which grossed $1,032 billion from a public offering of 20 million shares of its common stock at $51.60 per share.

Selected Secondaries during Q4 06:

Company Amount ($M)

Celgene 1032

Arena Pharmaceuticals 175

Regeneron Pharmaceuticals 175

Alexion Pharmaceuticals 149

Ariad Pharmaceuticals 145

Advanced Magnetics 130

Alnylam Pharmaceuticals 101

Exelixis 84

Positive quarter for biotech IPOs

In the fourth quarter biotech IPO activity picked up with six deals getting out of the gate. The $350 million raised from these transactions was up a whopping 614% over the Q3 06 total. In fact, the Q4 06 total was the most accumulated since Q2 04, when $580 million was generated from IPOs. Financings from IPOs in 2006 were up 12% over the 2005 amount. Even more welcome news was the highly successful IPO debut of Affymax. Not only did the company price its opening day share price above its expected offering range late in December, but its share price jumped 36% in the final few trading days before the end of the month. The company's lead product, Hematide, is poised for Phase III trials. It is an erythropoiesis-stimulating agent that, if proven safe and effective, may improve the management of anemia and offer patients and physicians an alternative therapy to recombinant erythropoietin products currently on the market.

US IPOs during 2006:

Company Ticker Offer IPO Issue Price % Amount

Range date Price 12/29/06 Change Raised

($M)

Altus ALTU $14-16 Jan $15 $18.85 25.67% $121

Pharmaceuticals

Iomai Corp. IOMI $11-13 Jan $7 $4.98 -28.86% $35

SGX SGXP $11-13 Jan $6 $3.50 -41.67% $25

Pharmaceuticals

Acordia ACOR $11-13 Feb $6 $15.84 164.00% $36

Therapeutics

Valera VLRX $10-12 Feb $9 $8.10 -10.00% $35

Pharmaceuticals

Alexza ALXA $10-12 Mar $8 $11.39 42.38% $44

Pharmaceuticals

Omrix OMRI $15-17 Apr $10 $30.26 202.60% $39

BioPharmaceuticals

Targacept TRGT $11-13 Apr $9 $9.05 0.56% $45

Vanda VNDA $12-14 Apr $10 $24.65 146.50% $58

Pharmaceuticals

BioMimetic BMTI $11-13 May $8 $13.19 64.88% $36.8

Therapeutics

Novacea NOVC $11-13 May $6.50 $5.66 -12.92% $45

Replidyne RDYN $14-16 Jun $10 $5.74 -42.60% $45

Osiris OSIR $11-13 Aug $11 $25.32 130.18% $38.5

Therapeutics

Achillon ACHN $14-16 Oct $11.50 $16.11 40.09% $59.5

Pharmaceuticals

Cadence CADX $11-13 Oct $9 $12.32 36.89% $54

Pharmaceuticals

Trubion TRBN $13-15 Oct $13 $18.01 38.54% $52

Pharmaceuticals

Catalyst CPRX $11-13 Nov $6 $4.83 -19.50% $20

Pharmaceutical

Emergent EBS $14-16 Nov $12.50 $11.16 -10.72% $57.8

Biosolutions

Affymax AFFY $22-24 Dec $25 $34.04 36.16% $106

AVERAGE

(19 companies) $12-14 $10.13 $14.37 40.11% $50.14

Venture Capital: Deal Flow Continues Its Healthy Pace

The amount of venture capital generated by biotechs remained steady in Q4 06 when compared to the Q3 06 period. Although there were two fewer reported deals in the quarter, for the 45 that got done -- the average deal size of $22 million was $2 million higher per investment. Year-over-year, the $4.1 billion raised in 2006 was up 18% on the $3.5 billion generated in 2005.

Selected venture financings during Q4 06:

Company Amount ($M)

Kalypsys 100

Solstice Neurosciences 85

Cerenis Therapeutics 53.5

Magellan Biosciences 50

Concert Pharmaceuticals 48.5

Elixir Pharma 46

Xenocor 45

Chiasma 44

Morphotek 40

VaxInnate 40

Neurotech Pharma 35

Orexigen Therapeutics 30

Achaogen 26

Xanthus Pharma 25

Tetraphase 25

San Diego based Kalypsys Inc. raised $100 million in a Series C financing. It plans to use the proceeds to fund a broad range of preclinical and clinical programs in the areas of cardiovascular/metabolic diseases, pain/inflammation and oncology. Solstice Neurosciences, Inc., received a combined $85 million in Series B equity funding and debt financing. The funds will support the company's ongoing initiatives related to movement disorders and treatment for cervical dystonia using Myobloc (Botulinum Toxin Type B) Injectable Solution.

Deal Making Remains Red Hot...

However, the bigger story -- and one that has been unfolding for the past two years, is the amount the industry has generated through partnering. The $20 billion raised is an all time record amount for partnering in biotech's 30+-year history, surpassing the then record setting $17 billion total in 2005.

"Partnering deals set a new mark in biotech's comparatively short history and is a continuing testimony that big pharma's enthusiasm for doing deals with biotechs is not slowing down," said Burrill. Financings garnered in partnering deals during Q4 2006 were up a whopping 74% compared with Q3 06 and the amount raised fell just short of the record-setting $7.7 billion that was recorded in the comparable Q4 05 period.

Grabbing the deal making headlines in the quarter was GlaxoSmithKline, signing a deal, worth potentially $2.1 billion, with Genmab A/S to co-develop and commercialize HuMax- CD20 (ofatumumab), a fully human monoclonal antibody in late stage development for CD20 positive B-cell chronic lymphocytic leukemia and follicular non-Hodgkin's lymphoma and in Phase II for rheumatoid arthritis. Epix Pharmaceuticals also signed a lucrative worldwide multi-target strategic collaboration with GlaxoSmithKline to discover, develop and market novel medicines targeting four G-protein coupled receptors for the treatment of a variety of diseases, including Epix's 5-HT4 partial agonist program, PRX-03140, in early-stage clinical development for the treatment of Alzheimer's disease. Epix will receive total initial payments of $35 million and be eligible to earn potential milestones of up to $1.2 billion.

Roche was also active...Halozyme Therapeutics, Inc. and Roche entered into an agreement to apply Halozyme's Enhanze drug delivery technology based on recombinant human hyaluronidase (rHuPH20) to Roche's biological therapeutic compounds. InterMune, Inc. closed an exclusive license agreement with Roche for the worldwide development and commercialization of InterMune's hepatitis C virus (HCV) protease inhibitor program. InterMune received an upfront payment of $60 million and Roche will fund 67% of the development costs associated with ITMN-191, InterMune's lead HCV protease inhibitor drug candidate. Assuming the successful development and commercialization of ITMN-191 in the US and other countries, InterMune could receive up to $470 million in milestones.

...And So Were M&As

Multi-billion dollar acquisitions were the order of the day for big pharma and large cap biotechs during the final quarter of the year. This was biotech's second active year in a row in terms of buyouts, as large biotechnology and pharmaceutical companies went beyond licensing agreements to fill out development and product pipelines.

"We haven't seen this many deals in any year between pharma/ biotech and biotech/biotech in the industry's history," noted Burrill. "The huge premiums that big pharma is willing to pay for biotech innovation reflects their pipeline problems. Compared to the daunting $1.2 -- $1.8 billion that is needed to bring a new drug to market and the long 10-15 years development cycle, paying big premiums, even for drugs that are not even in the clinic, is both a cheap and efficient way of reducing development costs and shortening commercialization timelines for the pharma acquirers," said Burrill."

Abbott broadened its portfolio of products for lipid management with a $3.7 billion acquisition of specialty pharmaceutical company Kos Pharmaceuticals. Gilead Sciences Inc. bought Myogen for $2.5 billion and Genentech, Inc. acquired Tanox Inc., a biotechnology company specializing in the discovery and development of biotherapeutics based on monoclonal antibody technology, for approximately $919 million. The companies have been working together in collaboration with Novartis since 1996 to develop and commercialize Xolair(R), an anti-IgE monoclonal antibody approved by the FDA in 2003 as a treatment for patients with moderate-to-severe allergic asthma. The deal also helped Genentech improve its pipeline in the areas of asthma, HIV, and age-related macular degeneration.

Illumina, Inc., was also in deal-making mood mode picking up gene sequencing platform company Solexa, Inc. in a stock-for-stock merger valued at around $600 million.

"The M&A trends, that have been hot in 2005 and 2006 in biotech land, will not slow down with pharma still desperate to access pipeline and innovation, " commented Burrill. "Both big pharma and big biotech will be competing for companies with advanced product pipelines, as well as important land grabs of technology such as the $1.1B acquisition of Sirna by Merck announced in November."There will also be no slow down in partnering deals and a significant portion of the $20 billion that we project that will be raised in 2007 will be directed at gaining access to technology at an earlier stage in its development as companies strengthen their product indication franchises."

Selected M&A transactions announced during Q4 06:

Acquirer Acquired Value ($M)

Abbott Kos Pharmaceuticals 3700

Eli Lilly Icos 3200

Gilead Myogen 2500

Merck Sirna Therapeutics 1100

Genentech Tanox 919

Illumina Solexa 660

Genzyme AnorMED 584

Sirna's Shaky Shareholder Settlement Sheds Light on Merck Acquisition
[January 4, 2007]

NEW YORK (GenomeWeb News) — Merck last week closed its $1.1 billion acquisition of Sirna Therapeutics, but not before the RNAi shop managed to tentatively muzzle a trio of shareholder-led lawsuits accusing its brass of double-dealing in their negotiations with Merck, according to a filing with the Securities and Exchange Commission.

The resulting settlement-in-principle, which Sirna said can fall apart at any time, compelled Sirna to disclose information about how it negotiated the deal, which showed that it had been in negotiations with another company about a possible buyout.

According to the SEC filing, Sirna said it would reduce to $38 million from $42.1 million the termination fee it would have been required to pay Merck if the deal fell through.

The settlement-in-principle also requires Sirna to make additional disclosures to its investors to address the issue of whether its management sought the best price possible for the company when it negotiated the acquisition.

According to Sirna, after the company had received an initial offer from Merck late last year, it received a written offer from another, undisclosed, company proposing to acquire Sirna for between $10 and $12 a share, which was higher than Merck’s original offer.

Merck later sweetened its offer to $13 a share, which was “higher than the highest range of any third-party offer,” Sirna noted in the SEC filing. Additionally, “no other interested party submitted a proposal after Merck’s final proposal was received,” the company said.

The settlement-in-principle also calls for Sirna to pay $500,000 to the plaintiffs’ legal counsel to cover fees and expenses.

“We and the other defendants vigorously deny all liability with respect to the facts and claims alleged in the lawsuits,” Sirna said in the SEC filing, dated Dec. 20, 2006. “However, to avoid the risk of delaying or otherwise imperiling the merger, and to provide information to our stockholders at a time and in a manner that would not cause any delay of the merger, we and our directors agreed to the settlement.

As originally reported by GenomeWeb News sister publication RNAi News, three shareholders filed separate lawsuits last year attempting to block the sale and accused Sirna’s management of negotiating the deal for their own financial benefit.

The suits allege that Merck’s purchase of Sirna “is wrongful, unfair, and harmful to Sirna’s public stockholders, and represents an effort by [Sirna’s directors] to aggrandize their own financial position and interests” at the expense of ordinary shareholders.

The lawsuits specifically charge that Sirna’s President and CEO Howard Robin and the firm’s board members violated their fiduciary duties “insofar as they stood on both sides of the transaction and engaged in self-dealing and obtained for themselves personal benefits, including personal financial benefits.”

Sirna’s directors “are unwilling to share the lion’s share of [the company’s potential success] with the company’s shareholders, choosing instead to sell the company to Merck … and cash out Sirna shareholders for inadequate consideration,” the lawsuits charge

"Ultraconserved elements [UE]" - "Disease Gene Conserved Sequence Tags" [DG-CST]" - "Transposon-free regions [TFR]" - "FractoGene BrowserBook" [FractoGene] - "PostGene Diseases" [PGD]

[Three representative major contributions are cited below (in chronological order) for the apparent - but hitherto largely unexplained - "conservation" of DNA sequences spanning an astounding array of species, for just one example, from the mouse to human. It became evident, that - as (not publicly) predicted by the FractoGene approach - an overwhelming majority of the rushed draft of listed "PostGene Diseases [PGD]" - formerly "JunkDNA diseases" do, in fact, show up when one looks up the DG-CST database (see the Italian data-base URL below). An explanation by FractoGene of the observed facts of "conservation" and connection to specific diseases, as well as the avenues that open up by the FractoGene explanation for further and further methods of "PostGene Discovery", while disclosure is not possible here and now for a variety of reasons, will appear in the forthcoming "FractoGene ... decoding JunkDNA in PostGenetics" Browserbook - comment by A. Pellionisz on 7th of January, 2006]

DG-CST (Disease Gene Conserved Sequence Tags), a database of human–mouse conserved elements associated to disease genes

Angelo Boccia, Mauro Petrillo, Diego di Bernardo, Alessandro Guffanti, Flavio Mignone, Stefano Confalonieri, Lucilla Luzi, Graziano Pesole, Giovanni Paolella, Andrea Ballabio and Sandro Banfi [all in Italy]

The identification and study of evolutionarily conserved genomic sequences that surround disease-related genes is a valuable tool to gain insight into the functional role of these genes and to better elucidate the pathogenetic mechanisms of disease. We created the DG-CST (Disease Gene Conserved Sequence Tags) database for the identification and detailed annotation of human-mouse conserved genomic sequences that are localized within or in the vicinity of human disease-related genes. CSTs are defined as sequences that show at least 70% identity between human and mouse over a length of at least 100 bp. The database contains CST data relative to over 1088 genes responsible for monogenetic human genetic diseases or involved in the susceptibility to multifactorial/polygenic diseases. DG-CST is accessible via the internet at http://dgcst.ceinge.unina.it/ and may be searched using both simple and complex queries. A graphic browser allows direct visualization of the CSTs and related annotations within the context of the relative gene and its transcripts.

[It may be noteworthy that no evident explanation was offered for the rather astounding experimental evidence for UE - nor connection to "JunkDNA diseases" was made apparent by the first paper quoted, jointly authored by J. Mattick and D. Haussler. On the other hand, David Haussler was quoted by the December 2005 issue of "Forbes" (see below) that "You look in the closet full of junk and find out you have a Picasso."... "This will revolutionize human genetics over the next few decades," says David Haussler, a Howard Hughes investigator at UC, Santa Cruz who was on the government team that decoded the human genome. He predicts that most disease-causing genetic flaws will be found lurking in our junk DNA." In the same Forbes article MIT Nobel laureate Phillip Sharp is also quoted: "It's a revolution in how we understand the genome and how the cell functions. There's a whole new frontier there." The DG-CST paper maps out an all-important association between diseases and their full-genomic ("PostGenetic") backdrop. - AJP]

^ back to table of contents ^

Where 'Jumping Genes' Fear To Tread [TFR]

Scientists from the University of Queensland report in the journal Genome Research that large segments of the human genome are conspicuously devoid of ubiquitous mobile DNA elements called transposons. The locations of these regions are highly conserved among mammalian species and are enriched in genes crucial for the regulation of developmental processes.

Transposons, often called "jumping genes," are DNA sequences that have the capacity to move from one chromosomal site to another. More than three million copies of transposons have accumulated in humans throughout the course of evolution and now comprise an estimated 45% of the total DNA content in the human genome.

These mobile genetic elements are scattered throughout the human genome -- separated, on average, by only 500 base pairs. But Dr. John Mattick's laboratory at the University of Queensland, Australia, identified long tracks of genomic segments (greater than 10 kilobases in length) that lack transposable elements. His team identified 860 such sequences in humans, 993 in mice, and 559 in opossums. They named these segments TFRs, or transposon-free regions.

"Strikingly," says Mattick, "many TFRs in the human genome occur in the same position in the mouse and opossum genomes, despite the fact that transposons entered each lineage independently, after each species diverged from a common ancestor. It appears that many TFRs are evolutionarily conserved features that existed prior to -- and have been largely maintained since -- the divergence of eutherian mammals and marsupials approximately 170 million years ago."

The opossum was chosen for inclusion in the analysis because it is a marsupial that has a similar load of transposable elements compared to mice and humans but is evolutionarily distant from the two species. In contrast, the genomes of chicken and fish, which diverged from humans more than 300 million years ago, do not have a significant density of transposons.

Given the strong evolutionary conservation of the TFRs, Mattick's group hypothesized that they are regions of significant biological importance. Upon further characterizing the TFRs, they discovered that many (85%) overlapped at least one annotated gene and that almost all (94%) overlapped at least one known RNA transcript. In addition, the TFRs were enriched in microRNAs, in genes that encode proteins with putative DNA-binding activity, and in genes that are involved in developmental processes. Another striking feature of TFRs was that they are associated with ultra-conserved regions, or genomic segments longer than 200 base pairs with 100% identity between human, mouse, and rat. All of these observations strongly support an important role for TFRs in critical biological processes.

"The majority of the TFRs lie outside of protein-coding sequences, so they presumably represent regions of regulatory information or RNA transcripts that cannot be disrupted. However, it's difficult to explain mechanistically the requirement of 10 or more kilobases of uninterrupted sequence in terms of the current paradigms of transcriptional regulation," explains Mattick. "It appears that TFRs might be the passive signatures of one or more poorly understood mechanisms of gene regulation that operate in higher organisms, suggesting a wider role for noncoding sequences than has hitherto been appreciated." [More specifically? - The FractoGene book will provide a theoretical framework "to connect the dots". Publicly, "nothing further" - AJP]

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Evo-devo next big thing, not intelligent design

Jan. 7, 2006. 01:00 AM

JAY INGRAM

It seems that scientists are taking the offensive in the controversial issue of evolution versus intelligent design. And it's none too soon.

Intelligent design (ID), the creationism of the 21st century, has grabbed headlines, as school boards across the United States considered adding it to high school science courses or textbooks, on the pretext that it represents an alternative to the Darwinian theory of evolution.

But the ideas are not alternatives. Of all the coverage of intelligent design, very little actually explored the differences between ID and science. Now, those crucial differences are being highlighted in recent articles in Science, Natural History and Skeptical Inquirer. [With the New Year craze behind us we may need more decorum."Skeptical Inquirer"? Even "British journal Medical Hypotheses" might be better - see next "detour" - AJP]?

It really all comes down to evidence. A scientific theory, like evolution, stands or falls on the basis of the evidence gathered for or against it. [Not really. Evidence is a necessary but not satisfactory condition. Just that a theory does not contradict to evidence does not make it "scientific". A crucial further component is needed; the theory must not be contradicted by evidence AND must provide prediction(s) by which the theory can be experimentally supported OR refuted - AJP]. ID claims to have collected evidence against evolution, but those claims — how can something as complex as this have evolved by random mutations? — are mere words. [Again, not entirely correct - even if scientists don't think ID/ET is scientific, we must be fair. ID/ET did not "collect evidence against evolution". ID/ET only struggled to be an "alternative scientific theory" - never really claimed to "kill" Evolution. "Facts don't kill theories" - anyway. Only "better theory" (of the alternatives) leads to fading away of the less satisfactory - e.g. not sufficiently scientific - theory. - AJP]. The proponents offer no detailed scenarios for the creation of complex living systems, except that some unidentified "designer" must have had a hand in it. But, there are no artist's initials, no trademark of creation, just the excuse that evolution couldn't have generated it. [Come on. Requiring "initials" is an "overkill" that is really hurting Evolution-theorists, such "criticism" backfires! - AJP]

Some of the flaws inherent in ID have already been exposed. [Again, this is not the precise track scientists must follow. There are plenty of "imperfections" in *any* theory - including that of Evolution, see below. One should win not by badmouthing the other, but point of the positive - AJP]. If the designer was intelligent, then why do imperfections abound? As philosopher Daniel Dennett has pointed out, the human eye is built backwards, with the light-gathering retina positioned behind a meshwork of nerves and blood vessels. It's like watching your TV from behind. That awkwardness is perfectly understandable in terms of the gradual evolution of the eye of today from a simple patch of light-sensitive tissue, but by design? It seems not. [What a relief to read "it seems". Scientists - some I know very well - are still desperately struggling to "to build an artificial retina" - and they would be the first to admit that they are presently not winning at all over Mother Nature... - AJP]

The fact is that nothing ID has suggested can be disproved, and by definition, that makes it unscientific. [Bingo - this is the ONLY argument science must stick to. "Don't negotiate past the deal" - flimsy added arguments may look funny, but can only hurt the case - AJP]

But at the same time as ID stirs the same pot over and over, the science of evolution moves on. Science magazine selected dramatic evolutionary advances as its annual "breakthrough of the year." One such advance was a variety of studies showing just how easily a single species, anything from a bird to a fruit fly, can split into two, based on subtle signals that promote or inhibit mating.

Another was the sequencing of the chimp genome, an achievement that revealed that even though we only differ by about 2 per cent of our DNA, there are substantial differences in the way that DNA is arranged. The evolutionary history of our divergence from those chimps, about 6 million years ago, is written in these genomes, and will be read. [Bingo, again, but backwards. The little word "WILL" reveals that there WAS no "Evolution Breakthrough of 2005". There WAS one 147 years ago - and there WILL be one more when the full genome - including "junkDNA" WILL be read. In 2005 Evolution did not have any "breakthrough" - that Science reported - but ID/ET failed to pass the test "scientific". When (perhaps in 2006?) Science will report on predictive AND experimentally supported theory on "JunkDNA", that will be a "breakthrough" for Evolution scientists - since presently still some are without a firm stand for any scientific theories of "junkDNA" function - AJP]

There is a new area of science that is shedding completely new light on evolution. It is "evo-devo," evolutionary-developmental biology. [Cute - perhaps too cheesy - name, but where is the breakthrough explaining ontogenesis AND philogenesis by the same theoretical conceptual framework? FractoGene does... - AJP]

Its combination of embryology and genetics has revealed the common ground between the shape and form of organisms as diverse as humans and fruit flies. As unbelievable as it might sound, the same tool kit of genes that directs the development of the fruit fly is used throughout the living world. [Fine, we might all agree that whatever theory explains this in a predictive fashion, qualifies for the "breakthrough".. AJP]

These are not the genes that dictate the structures of things, from the wings of the fly to the arms of a human, but are rather controller genes, which determine when and where in the embryo developmental events will take place. [This is also arguable, but let it pass -AJP]

The seven vertebrae in the backbone of a chick and the hundreds in a snake are controlled by the same set of genes. [Implicit in this factual statement is that all the rest is up the widely differing sets of "JunkDNA" - AJP]. There was no need for someone to create a special set of snake-backbone genes. [So, where is the "breakthrough explanation" for this?? Hint-hint, there is at least one theory that explains (in a predictive AND experimentally supported fashion, In Press by peer-reviewed journal, that e.g. the fugu Purkinje neuron and the P-cells of higher-and-higher order mammals may differ only in the number of "fractal iterative reverberations, yielding a higher level of hierarchy" - AJP]

The most remarkable thing is that most of these bodybuilding genes were in place long before the modern organisms that make use of them evolved. [See again the Fugu fish... Four hundred million years ago - give or take a couple of millions - AJP]

The fact that the minute changes in the genomes of organisms can, over unimaginably long times, lead to the emergence of new species is difficult to grasp. [Difficult, but not impossible. Once an algorithm is understood, it may be amazingly simple to tell e.g. if it is robust and converges fast, or extremely slowly converging (if at all) .. and what algorithmic changes result in exactly what consequence.  As physicist Faraday put it "there is nothing simpler than a problem solved" - AJP]

That doesn't make it wrong.

Evolution is moving ahead. Intelligent design is not.

One is science. The other is not.

Jay Ingram hosts Daily Planet on the Discovery Channel.

[Suggestion: since Science is moving, let's abandon a very wasteful and socially disruptive pseudo-debate between moving science and static non-science, and let's just move on diligently with the literature what scientists *already can* tell about "junkDNA". - Comment by AJP on 7th of 2006]