Admission upon Resignation of Dr. Collins. The begining of a New Era

Francis Collins, in a video interview to Charlie Rose on July 29, 2008 said (at 7:40 of the clip):

"That's the "function" question. How would we figure that out? Ah - so much of the genome - after all only about 1.5% of it is coding for protein. The rest of it is probably involved in this regulatory stuff, and for a long time were were a bit dismissive about that 98.5% of it and said that a lot of it was kind of a junk. I don't think people are using the word "Junk" any more when they are talking about the genome, because the more we study, the more functions we find in that "filler" - which is not a "filler" at all."

deCODE and SGENE Consortium Discover Deletions in the Human Genome Linked to Risk of Schizophrenia

Findings may provide the foundation for a test to complement standard clinical diagnosis, potentially enabling earlier intervention and treatment

Last update: 1:25 p.m. EDT July 30, 2008

REYKJAVIK, Iceland, July 30, 2008 /PRNewswire-FirstCall via COMTEX/ -- In a major paper published today in the online edition of the journal Nature, scientists from deCODE genetics (DCGN:decode genetics inc com DCGN 1.55, +0.02, +1.3%) and the University of Iceland, along with academic colleagues from the deCODE-led European SGENE consortium, China and the United States, report the discovery of three rare deletions in the human genome that confer risk of schizophrenia. Such deletions are gaps in the normal sequence of the genome that can arise spontaneously during the recombination or reshuffling of the genome that takes place in the creation of sperm and eggs. The deletions reported in today's study are located on chromosomes 1q21, 15q11 and 15q13, and confer, respectively, 3, 15 and 12 times greater than average risk of schizophrenia. These are the first such deletions to be associated with risk of mental illness using large sample sizes and validated across many populations. The substantial increase in risk they confer make them a valuable basis upon which to develop molecular diagnostic tests to complement standard clinical diagnosis. The study, 'Large recurrent microdeletions associated with schizophrenia,' will appear online today at www.nature.com.

"Schizophrenia is a disorder affecting thoughts and emotions. It is therefore a quintessentially human disease, but one that is little understood biologically and which is difficult to diagnose. These findings are important because they shed light on its causes and provide a first component to a molecular test to aid in clinical diagnosis and intervention. These discoveries also demonstrate one way in which we can use SNP-chips to find rarer genetic factors conferring risk of disease. In many disease areas we have had great success of late in identifying what these chips are best suited to find: common variants conferring relatively modest increases in risk. But we know that individuals with certain mental disorders such as schizophrenia tend to have few children, and thus that we may have to identify a larger number of rare but high risk variants to understand the genetic contribution to susceptibility. It is encouraging that our efforts to use SNP chips to detect rarer variations such as spontaneous deletions and duplications is now bearing fruit," said Kari Stefansson, CEO of deCODE.

In the recent wave of discoveries of risk variants for common diseases, those associated with mental disorders such as schizophrenia, autism and others have been conspicuously absent. This phenomenon, and the fact that people with these disorders tend to have few children, suggest that rarer and perhaps spontaneously generated variants may account for a greater proportion of the disease burden in these conditions than in others. SNP-chips are not well suited to finding rare SNPs but can, with sufficiently large sample sizes, be used to identify deletions and duplications -- known as copy number variations, or CNVs -- which can also be carried by healthy individuals in one generation and contribute to risk of disease in the next.

In order to identify novel CNVs, deCODE first analyzed the genomes of a total of approximately 15,000 parents and offspring taking part in deCODE gene discovery programs and who had been genotyped with the more than 300,000 SNPs on the HumanHap300 chip. The deCODE team discovered 66 de novo CNVs, that is, CNVs present in the genomic DNA of the offspring but not in that of their parents. deCODE then tested these variants for association with schizophrenia in more than 1,400 schizophrenics and 33,000 control subjects. The deletions on chromosomes 1q21, 15q11 and 15q13 were suggestively associated with schizophrenia in this first phase, and then validated in 3,300 cases and 8,000 controls. The SGENE consortium is comprised of deCODE genetics, the National-University Hospital in Reykjavik, the University of Aberdeen, the Ravenscraig Hospital in Greenock, the Institute of Psychiatry at King's College London, the National Public Health Institute in Helsinki, the Ludwig Maximilians University and GlaxoSmithKline's Genetic Research Center in Munich. The SGENE affiliated groups taking part in the second phase of the project were the University of Copenhagen, the University of Oslo, the University of Heidelberg, the University of Bonn, the University Medical Center of Utrecht, Nijmegen Medical Center, the University of Verona, the Duke University Center for Population Genomics and Pharmacogenetics and the University of Sichuan, China.

deCODE and the SGENE consortium gratefully acknowledge the participation in this study of the thousands of patients, family members and control subjects from these eleven countries. This study was supported by the European Union through the SGENE consortium ( www.SGENE.eu), by grants LSHM-CT-2006-037761 and PIAP-GA-2008-218251.

About deCODE

deCODE is a biopharmaceutical company applying its discoveries in human genetics to the development of diagnostics and drugs for common diseases. deCODE is a global leader in gene discovery -- our population approach and resources have enabled us to isolate key genes contributing to major public health challenges from cardiovascular disease to cancer, genes that are providing us with drug targets rooted in the basic biology of disease. Through its CLIA-registered laboratory, deCODE is offering a growing range of DNA-based tests for gauging risk and empowering prevention of common diseases, including deCODE T2(TM) for type 2 diabetes; deCODE AF(TM) for atrial fibrillation and stroke; deCODE MI(TM) for heart attack; deCODE ProCa(TM) for prostate cancer; and deCODE Glaucoma(TM) for a major type of glaucoma. deCODE is delivering on the promise of the new genetics.(SM) Visit us on the web at www.decode.com; on our diagnostics website at www.decodediagnostics.com; and, for our pioneering personal genome analysis service, at www.decodeme.com.

Rewriting Darwin: The new non-genetic inheritance

New Scientist
Magazine issue 2664

09 July 2008
Emma Young

[When experimental evidence is show by New Scientist on YouTube, "Rewriting Darwin and Dawkins", it may be time for a holistic view of the Genome Informatics, together with the environment. Time for HoloGenomics - AJP]

HALF a century before Charles Darwin published On the Origin of Species, the French naturalist Jean-Baptiste Lamarck outlined his own theory of evolution. A cornerstone of this was the idea that characteristics acquired during an individual's lifetime can be passed on to their offspring. In its day, Lamarck's theory was generally ignored or lampooned. Then came Darwin, and Gregor Mendel's discovery of gen etics. In recent years, ideas along the lines of Richard Dawkins's concept of the "selfish gene" have come to dominate discussions about heritability, and with the exception of a brief surge of interest in the late 19th and early 20th centuries, "Lamarckism" has long been consigned to the theory junkyard.

Now all that is changing. No one is arguing that Lamarck got everything right, but over the past decade it has become increasingly clear that environmental factors, such as diet or stress, can have biological consequences that are transmitted to offspring without a single change to gene sequences taking place.... fully accepting the idea, provocatively dubbed the "new Lamarckism", would mean a radical rewrite of modern evolutionary theory. ... "It means the demise of the selfish-gene theory", says Eva Jablonka at Tel Aviv University, Israel. "The whole discourse about heredity and evolution will change"...

That's not all. The implications for public health could also be immense. Some researchers are talking about a paradigm shift in understanding the causes of disease. For example, non-genetic inheritance might help explain the current obesity epidemic, or why there are family pattern for certain cancers and other disorders, but no discernible genetic cause. "It's a whole new way of looking at the inheritance and causes of various diseases, including schizophrenia, bipolar disorder and diabetes, as well as cancer", says Robyn Ward of the cancer research centre at the University of New South Wales in Sydney, Australia.

...recent research... has a firm basis in biological mechanisms - in so-called "epigenetic" change.

... Inside the nucleus, the DNA is packaged around bundles of proteins called histones, which have tails that stick out from the core. One factor that affects gene expression is the pattern of chemical modifications to these tails, such as the presence or absence of acetyl and methyl groups. Genes can also be silenced directly via enzymes that bind methyl gropus ont the DNA. The so-called RNA interference (RNAi) system can direct this activity, via small RNA strands. As well as controlling DNA methylation and modifying histones, these RNAi molecules target messenger RNA - much longer strands that act as intermediaries between DNA sequences and the proteins they code for. By breaking mRNA down into small segments, the RNAi molecules ensure that a cerain gene cannot be translated into its protein. In short, RNAi creates the epigenetic "marks" that control the activity of genes.

We know that genes - and possibly also non-coding DNA - control RNAi and so are involved in determining in individual's epigenetic settings. It is becoming increasingly apparent, though, that environmental factors can have a direct impact too, with potentially life-changing implications. The clearest example of this comes from honebees [here the article explains the discovery of the Australian team lead by Ryszard Maleszka, Science, DOI:10.1126/science.1153069, and describes the work of Randy Jirtle in 2000 at Duke University as a groundbreaking experiment on a strain of genetically identical mice, and a diet rich in methyl groups before conception and during pregnancy made them different - AJP]...

These and other animal studies strongly suggest that a pregnant woman's diet can affect her child's epigenetic marks. So perhaps it is not surprising that the effect of certain nutrients is being called into question. Folate, for example, is a potent methyl donor. It is routinely recommended during pregnancy and added to cereal products in certain countries, including the US, because it reduces the risk of spinal tube defects if eaten around the time of conception...

The legacy of stress

Diet is not the only environmental factor that can influence the epigenetic setting of some genes. Michael Meaney at McGill University in Montreal, Canada, and colleagues have found that newsborn mice neglected by their mothers are more fearful in adulthood and that these mice show much higher than normal levels of methylation of certain genes involved in the stress response...

There is recent evidence that abnormal epigenetic patterns play a role in mental health disorders. In March, Arturas Petronis at the Centre of Addiction and Mental Health in Toronto, Canada and colleagues reported the first epigenome-wide scan of post-mortem brain tissue from 35 people who had suffered from schizophrenia. They found a distinctive pigenetic pattern, controlling the expression of roughly 40 genes (The American Journal of Human Genetics, vol 82, p. 696). Several of the genes were related to neurotransmitters, to brain development and to other processes linked to schizophrenia. These findings lay the groundwork for a new way of understanding mental illness, says Petronis, as a disease with a significant epigenetic component..... Intriguingly, ...the abnormalities in DNA methylation in Petronis' subjects were not restricted tot heir frontal cortex: they were also present in their sperm". "[This] suggests that it is possible that inherited epigenetic abnormalities may be contributing to the familial nature of schizophrenia and bipolar disorder" says the team member Jonathan Mill at the Institute of Psychiatry at King's College London...

This work is only suggestive, but when it comes to cancer, the evidence is stronger. Some colorectal cancers are known to develop when a key DNA-repairgene called MHL1 becomes coated in methyl groups, preventing it from working. In 2007, Ward and her colleagues published a study of a woman with this type of cancer and her three children, but one son had a heavily methylated, silenced gene like his mother (The New England Journal of Medicine, vol 356, p. 697)....

Some epigenetic marks may also be inherited from fathers, however. In a now classic study published in 2005, Matthew Anway at the University of Idaho in Moscow and colleagues showed that male rats exposed to the common crop fungicide vinclozolin in the womb were less fertile and had a higher than normal risk of developing cancer and kidney defects. Not only were these effects transmitted to their offspring, they were passed from father to son through the three following generations as well (Science, vol. 308, p. 1466). The team found no DNA changes, only altered DNA methylation patterns in the sperm of these rats, suggesting that epigenetic factors were to blame. ...

Nutrition does seem to have some lasting effect, according to a study by Marcus Pembrey of the Institute of Child Health at University College London and his colleagues. They analysed records from the isolated community of Overkalix in northern Sweden and found that man whose paternal grandfathers had suffered a shortage of food between the ages of 9 and 12 lived longer than their peers (European Journal of Human Genetics, vol. 14, p. 159). ...

Also in 2006, Tony Hsiu-Hsi Chen at the National Taiwan University in Taipei and colleagues reported that the offspring of men who regularly chewed betel nuts had twice the normal risk of developing metabolic syndrome during childhood. Betel nuts are also associated with several symptoms of metabolic syndrome in chewers including increased heart rate, blood pressure, waist size and body weight. ...

[BOX]

Rewriting Darwin and Dawkins?

The realisation that individuals can acquire characteristics through interaction with their environment and then pass these on to their offspring may force us to rethink evolutionary theory... [This sounds very familiar to Francis Collins' statement upon the release of ENCODE results a year ago, concluding that "the concept of genes is a myth", that "the scientific community need to re-think long-held beliefs..- AJP; see "The Principle of Recursive Genome Function" that opens up the recursive system to protein-to-DNA interaction, of course including not only proteins generated by the DNA, but also to proteins from the envirionment - most spectacularly with prions, bovine proteins causing "mad cow disease" in humans - AJP]...

"There was a trickle of findings of epigenetic inheritance in animals through the 20th century, and it is turning into a flood about now" says Russel Bonduriansky at the University of New South Wales in Sydney, Australia. ...

For Bonduriansky the accumulating evidence calls for a radical rethink of how evolution works. Jablonka, too, believes that "Lamarckian" mechanisms should now be integrated into evolutionary theory, which should focus on mechanisms, rather than units, of inheritance. "This would be very significant", she says. "It would reintroduce development, in a very direct and strong sense, into heredity and hence evolution. It would mean that pre-synthesis view of evolution, which was very diverse and very rich, can return, but with molecular mechanisms attached". ..

What does Dawkins himself think?

...He suggests, though, that the word "gene" should be replaced with "replicator". [Which is a profoundly holistic view, since "replication" is the propensity of the entire Genome - AJP]

[The heretofore restricted views, neither Darwinian evolution, nor modern Genetics permitting "feedback" (with the key of recursion from proteins to DNA), restricting our views only to 1.3% of the Genome (falsely labeling 98.7% as "Junk DNA"), and by adhering to the Central Dogma that information from proteins to DNA "never happens", thus e.g. external proteins were particularly excluded from interaction with growth and evolutionary processes, have to come together now into a new holistic approach by HoloGenomics, pellionisz_at_junkdna.com, July, 26, 2008]

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

How the Personal Genome Project Could Unlock the Mysteries of Life

WIRED MAGAZINE: 16.08
By Thomas Goetz 07.21.08

George Church is dyslexic, narcoleptic, and a vegan. He is married with one daughter, weighs about 210 pounds, and has worn a pioneer-style bushy beard for decades. He has elevated levels of creatine kinase in his blood, the consequence of a heart attack. He enjoys waterskiing, photography, rock climbing, and singing in his church choir. His mother's maiden name is Strong. He was born on August 28, 1954.

If this all seems like too much information, well, blame Church himself. As the director of the Lipper Center for Computational Genetics at Harvard Medical School, he has a thing about openness, and this information (and plenty more, down to his signature) is posted online at arep.med.harvard.edu/gmc/pers.html. By putting it out there for everyone to see, Church isn't just baiting identity thieves. He's hoping to demonstrate that all this personal information — even though we consider it private and somehow sacred — is actually fairly meaningless, little more than trivia. "The average person shouldn't be interested in this stuff," he says. "It's a philosophical exercise in what identity is and why we should care about that."

As Church sees it, the only real utility to his personal information is as data that reflects his phenotype — his physical traits and characteristics. If your genome is the blueprint of your genetic potential written across 6 billion base pairs of DNA, your phenome is the resulting edifice, how you actually turn out after the environment has had its say, influencing which genes get expressed and which traits repressed. Imagine that we could collect complete sets of data — genotype and phenotype — for a whole population. You would very quickly begin to see meaningful and powerful correlations between particular genetic sequences and particular physical characteristics, from height and hair color to disease risk and personality.

Church has done more than imagine such an undertaking; he has launched it: The Personal Genome Project, an effort to make those correlations on an unprecedented scale, began last year with 10 volunteers and will soon expand to 100,000 participants. It will generate a massive database of genomes, phenomes, and even some omes in between. The first step is to sequence 1 percent of each volunteer's genome, focusing on the so-called exome — the protein-coding regions that, Church suspects, do 90 percent of the work in our DNA. It's a long way from sequencing all 6 billion nucleotides — the As, Ts, Gs, and Cs — of the human genome, but even so, cataloging 60 million bits multiplied by 100,000 individuals is an audacious goal.

The PGP stands as the tent pole of what Church calls his "year of convergence," the moment when his 30 years as a geneticist, a technologist, and a synthetic biologist all come together. The project is a proof of concept for the Polonator G.007, the genetic-sequencing instrument developed in Church's lab that hit the market this spring. And the PGP will also put Church's expertise in synthetic biology to use, reverse engineering volunteers' skin cells into stem cells that could help diagnose and treat disease. If the convergence comes off as planned, the PGP will bring personal genomics to fruition and our genomes will unfold before us like road maps: We will peruse our DNA like we plan a trip, scanning it for possible detours (a predisposition for disease) or historical markers (a compelling ancestry).

Bringing the genome into the light, Church says, is the great project of our day. "We need to inspire our current youth in a way that outer space exploration inspired us in 1960," he says. "We're seeing signs that knowing about our inner space is very compelling."

To Church, who built his first computer at age 9 and taught himself three programming languages by 15, all of this is unfolding according to the same laws of exponential progress that have propelled digital technologies, from computer memory to the Internet itself, over the past 40 years: Moore's law for circuits and Metcalfe's law for networks. These principles are now at play in genetics, he argues, particularly in DNA sequencing and DNA synthesis.

Exponentials don't just happen. In Church's work, they proceed from two axioms. The first is automation, the idea that by automating human tasks, letting a computer or a machine replicate a manual process, technology becomes faster, easier to use, and more popular. The second is openness, the notion that sharing technologies by distributing them as widely as possible with minimal restrictions on use encourages both the adoption and the impact of a technology.

Inside the Personal Genome Project

The project will turn information from 100,000 subjects into a huge database thath can reveal the connections between our genes and our physical selves. Here's how. — Thomas Goetz

1. Entrance Exam

Volunteers take a quiz to show genetic literacy. One question: How many chromosomes do unfertilized human egg cells contain? a) 11, b) 22, c) 23, d) 46, or e) 92? (Answer: c.) Only those with a perfect score proceed, but retests are allowed. 2. Data Collection

Volunteers sign an "open consent" form acknowledging that their information, though anonymized, will be accessible by others. They fill out their phenotype traits, listing everything from waist size to diet habits. Suitable respondents go on to the next step. 3. Sample Collection

Volunteers hit the medical center, where they are interviewed by an MD. Then a technician draws some blood, gathers a saliva sample, and takes a punch of skin. Don't worry: It hurts about as much as a bee sting.

4. Lab Work

The tissues are sent to a biobank, where DNA is extracted from the blood. One percent of it — the exome — is sequenced. Meanwhile, bacteria DNA is extracted from the saliva and sequenced to reveal the volunteer's microbiome. 5. Research

Now the fun part: Crunching the numbers. PGP scientists and other researchers start working with the data assembled from 100,000 individuals to investigate potential links between phenotypes and genotypes. The team will look for patterns and statistically significant anomalies. 6. Sharing

The volunteers get access to not only the raw data from their genome, but anything the research team gleans from their information. Insights — a newly discovered cancer risk, for example — are posted in a volunteer's file, which they'll be free to share with other PGP participants.

"I always tell people, your biggest problem in life is not going to be hiding your stuff so nobody steals it," Church says. "It's going to be getting anybody to ever use it. Start hiding it and that decreases the probability to almost zero."

For most of his career, Church has been known as a brilliant technologist, more behind-the-scenes tinkerer than scientific visionary. Though he was part of the group that kicked off the Human Genome Project, he's far less known than scientists like Francis Collins or J. Craig Venter, who took the stage at the end. His obscurity is due partly to his style. He talks about his accomplishments with a certain detachment that one might mistake for ambivalence. "He's not without ego; it's just a different sort of ego," says entrepreneur Esther Dyson, a friend and one of the first 10 PGP volunteers. "Everything is a subject of his intellectual curiosity, including himself."

His low profile may be the result of his tendency to get too far ahead of the curve, working a decade or two ahead of his field — so far that even the experts don't always get what he's talking about. "Lots of George's work is so advanced it's not ready to become standard," says Drew Endy, a professor of bioengineering at Stanford and cofounder with Church of Codon Devices, a synthetic-biology startup. "He's perfectly happy to spin out tons of ideas and see what might stick. It's high-throughput screening for technology and science. That's not the way most people work."

But thanks to the PGP, the Polonator, and the fact that the rest of the world is finally starting to understand what he's been talking about, Church's obscurity is coming to an end. He sits on the advisory board of more than 14 biotech companies, including personal genomics startup 23andMe and genetic testing pioneer DNA Direct. He has also cofounded four companies in the past four years: Codon Devices, Knome, LS9, and Joule Biosciences, which makes biofuels from engineered algae. Newsweek recently tagged him as one of the 10 Hottest Nerds ("whatever that means," Church laughs).

For someone who has spent his whole career ahead of his time, he is suddenly very much a man of the moment.

Most historians would cite Prague or Paris or Berkeley as the intellectual hub of the 1960s, but for people interested in computers, there was no place so significant as Hanover, New Hampshire. There, at Dartmouth College, an experiment in time-share computing was flourishing. Developed by professors John Kemeny and Thomas Kurtz, the Dartmouth Time-Sharing System let students remotely access the power of a mainframe computer to do calculations for mathematics or science assignments or to play a simulated game of college football. It ran on an easy-to-learn, intuitive program that Kemeny and Kurtz called Basic.

In 1967, the DTSS transitioned to a more-powerful GE-635 machine and offered remote terminals to 33 secondary schools and colleges, including Phillips Academy, a prep school in nearby Andover, Massachusetts. The terminal — not much more than a teletype machine, really — sat in the basement of the school's math building, forgotten until the next fall, when a young George Church showed up for his freshman year and began asking whether there was a computer on campus. Someone pointed Church to the basement. "There wasn't even a chair in the room. I had used a typewriter before, but never a teletype. And so I just started pressing keys," Church recalls. "Eventually I hit Return, and it came back with 'What?' And so I started typing in stuff like crazy and hitting Return. And it kept coming back with 'What?' At that point, I was pretty convinced it wasn't a human, but it was actually talking in words. So I just hadn't asked the right question or given the right answer."

Soon, Church found a book on Basic. "I was just sailing," he says. He spent endless hours in that basement — he eventually borrowed a chair — and taught himself the intricacies of coding, learning to program in Basic, Lisp, and Fortran. Indeed, thinking in code came so naturally to Church that he stopped going to his classes (a habit that would later get him kicked out of graduate school at Duke) and taught the computer linear algebra instead.

It turns out that learning how to write code — change it, hit Return, see what it will do — was ideal training for Church's eventual career in computational biology. "That's how we reverse engineer things like E. coli — you change something, and you see how it behaves," he says. "Little did I know that 30 years later, we would use almost exactly the same operations to optimize metabolic networks."

Church first hit on the power of computation to automate biology in the mid-'70s when he was in graduate school at Harvard. At the time, he was working on recombinant DNA, a then-new technique to splice a gene from one organism into another. Identifying a sequence of 80 or so base pairs of genetic code was a slow, tedious process. "You had to literally read off the bases and write them on a piece of paper, one by one," Church says. "So I wrote a sequence-reading program that would crunch it out. When the senior graduate student heard I had automated that, he said, 'What do you want to do that for? That's the only fun part.'"

By 1980, when Church's adviser, Wally Gilbert, won the Nobel Prize for DNA sequencing techniques, the process was still slow and expensive, executing one DNA strand at a time. So Church began working on one of his earlier targets for automation. His idea was to sequence several strands together by combining them into a single sample mixture. He called it multiplexing, drawing an analogy to signal multiplexing in electronics, in which more than one signal flows through a current at the same time. Church thought most of the work could even be integrated into one device rather than numerous machines.

It was a provocative idea, not just because he was substituting several human tasks for machine-driven ones, but also because he didn't make the usual false promise that technology would simplify the process. On the contrary, multiplexing would be complicated, Church maintained. But technology was up to the task.

Four years later, Church was invited to present his work on multiplexing at a small meeting in Alta, Utah. The Department of Energy had gathered about 20 scientists to mull over one question for five days: How might recent advances in genetics be used to measure an increase in genetic mutations arising from radiation exposure, as in Hiroshima? The group quickly reached the conclusion that technology circa 1984 couldn't answer that question. Meanwhile, they still had several more days in the mountains. "There were a bunch of us there who could talk about genomics as if it were an engineering exercise. And then we said, well, as a kind of booby prize, we could think of other things you could do," Church recalls, "like, say, sequencing the human genome."

Though Church was almost entirely unknown before the meeting, his presentation on multiplex sequencing methods stole the show. When he fell into a huge snow drift during a break one afternoon, one participant worried that the future of sequencing had disappeared with him.

That Alta brainstorm would become the Human Genome Project — the effort, adopted by the National Institutes of Health, to sequence one human genome for $3 billion within 15 years. However audacious the HGP seemed, Church was disappointed by it almost from the start. "We could have said our goal was to get everybody's genome for some affordable price," he says, "and one genome would be a milestone" on the way toward that goal.

The HGP also played it safe with its choice of technology. Despite the promise of Church's multiplexing system, the HGP instead used a more established instrument manufactured by Applied Biosystems, based on a technique developed by biochemist Frederick Sanger. As Church saw it, this meant that the project had failed to put its $3 billion toward improving the state of the art. Even worse, the HGP consumed so many of the resources available to the field of genetics that it effectively locked that state of the art into 1980s technology.

The result was nearly two decades of inertia. It wasn't until 2005, when the Human Genome Project was complete and new goals were put forth, that Church finally perfected the multiplexing approach he had presented 20 years earlier at Alta. In a paper published in Science, Church demonstrated a technique that could analyze millions of sequences in one run (Sanger's method could handle just 96 strands of DNA at a time). And Church's method not only accelerated the process, it made it far cheaper, too, elegantly demonstrating the power of automation to drive exponential advances and bring down costs. Church's approach, and a competing innovation developed by 454 Life Sciences that same year, inaugurated the second generation of sequencing, now in full swing.

In the past three years, more companies have joined the marketplace with their own instruments, all of them driving toward the same goal: speeding up the process of sequencing DNA and cutting the cost. Most of the second-generation machines are priced at around $500,000. This spring, Church's lab undercut them all with the Polonator G.007 — offered at the low, low price of $150,000. The instrument, designed and fine-tuned by Church and his team, is manufactured and sold by Danaher, an $11 billion scientific-equipment company. The Polonator is already sequencing DNA from the first 10 PGP volunteers. What's more, both the software and hardware in the Polonator are open source. In other words, any competitor is free to buy a Polonator for $150,000 and copy it. The result, Church hopes, will be akin to how IBM's open-architecture approach in the early '80s fueled the PC revolution.

In the sequencing game, though, the cost of the machine is only half the equation. The more telling expense is the operating cost, particularly the cost of sequencing entire human genomes. Executives at 454 estimate that their latest machine can pull off a whole genome sequence for $200,000. Applied Biosystems claims its instrument has completed a genome for just $60,000. Church maintains that, while the Polonator isn't up to whole-genome reads, it is clocking in at about one-third the cost of Applied Biosystems' estimate. A whole sequence from Knome, the retail genomics firm cofounded by Church, goes for $350,000. (It's worth noting that these figures are only roughly comparable, since each company uses slightly different quality measures and specifications.)

As these numbers continue to drop, the mythical $1,000 genome comes ever closer. Sequencing a human genome for $1,000 is the somewhat arbitrary benchmark for true personalized genomics — when the science could become a component of standard medical care. An important catalyst in achieving that point is the Archon X Prize for Genomics, which is offering $10 million to the team that can sequence 100 complete genomes in 10 days for less than $10,000 each. As of June, seven teams, including Church's lab, had entered the competition. Church, who served for a time on the advisory board of the contest, says that the prize will drive costs down further and help publicize the potential of personalized whole-genome sequencing.

That's important because Church hopes the Polonator and other next-generation instruments will inspire a new generation of smaller labs to begin work in personal genomics, as well as other genetic sciences. Already, the onslaught of technology has jump-started new projects, like sequencing part of the Neanderthal genome, examining extremophile microbes in old California iron mines, and studying the regenerative properties of the salamander. In medicine, cheaper sequencing has enabled research into drug-resistant tuberculosis; the genetics of breast, lung, and other cancers; and the DNA architecture of schizophrenics.

But if the Polonator is going to lead that charge, it has to work — and work on a massive scale. And that means passing a major test: successfully sequencing the 100,000 exomes in the PGP.

All of us know our height, weight, and eye color. Fewer of us know our arm span or resting blood pressure. But who among us knows the direction of our hair whorls or the Gell-Coombs type of our allergies? This is the level of detail that the PGP requires the 100,000 volunteers to reveal about themselves, a list staggering in its exhaustiveness. The PGP will tally head circumferences, injuries, chin clefts and cheek dimples, whether volunteers can roll their tongues or hyperflex their joints, whether they dislike hot climates or are hot tempered, if they've often been exposed to power lines or wood dust or diesel exhaust or textile fibers. The project questionnaire asks how many meals they eat a day and whether they prefer their food fried, broiled, or barbecued. It even demands to know how much television they watch. And, of course, PGP volunteers will hand over most aspects of their medical history, from vaccines to prescriptions.

This phenotype data will be integrated with a volunteer's genomic information, then combined with statistics from all the other subjects to create a potent database ripe for interrogation. In contrast to the heavy lifting that genetic research requires now — each study starts from scratch with a new hypothesis and a fresh crop of subjects, consent forms, and tissue samples — the PGP will automate the research process. Scientists will simply choose a category of phenotype and a possible genetic correlation, and statistically significant associations should flow out of the data like honey from a hive. A genetic predisposition for colon cancer, for instance, might be found to lead to disease only in connection with a diet high in barbecued foods, or a certain form of heart disease might be associated with a particular gene and exposure to a particular virus. Genomic discovery won't be a research problem anymore. It'll be a search function. (This helps explain why Google, among others, has donated to the project).

The process began last year, and each of the first 10 volunteers has a background in medicine or genetics. They include John Halamka, CIO of Harvard Medical School and a physician; Rosalynn Gill, chief science officer at Sciona (a personalized genetics nutrition company); and Steven Pinker, the noted psychologist and author. The other 99,990 participants won't be expected to be so elite, though they will have to pass a genetics-literacy quiz to demonstrate informed consent. The general selection process, which starts with registration at personalgenomes.org, is scheduled to begin later this year.

Besides offering up their genomes, subjects will have to part with some spit and a bit of skin. The saliva contains their microbiome — the trillions of microbes that exist, mostly symbiotically, on and in our bodies. If phenotype is a combination of genotype plus environment, the microbiome is the first wash of that environment over our bodies. By measuring some fraction of it, the PGP should offer a first look at how the genome-to-microbiome-to-phenome chain plays out.

The skin sample goes into storage, creating what would be one of the world's largest biobanks. Members of Church's lab have devised a way to automate turning the skin cells into stem cells, and they hope to publish the technique later this year. (Similar work has been done at the University of Wisconsin and Kyoto University.) By reprogramming the skin cells using synthetically engineered adenoviruses, Church's team can transform the skin cells into many sorts of tissue — lungs, liver, heart. These tissues could be used as a diagnostic baseline to detect predisposition for various diseases. What's more, the reprogrammed cells could be used to treat disease, replacing damaged or failing tissue. It's an intriguing hint of how Church's work with synthetic biology complements genomic sequencing.

If the PGP were simply an exercise in breaking down 100,000 individuals into data streams, it would be ambitious enough. But the project takes one further, truly radical step: In accordance with Church's principle of openness, all the material will be accessible to any researcher (or lurker) who wants to plunder thousands of details from people's lives. Even the tissue banks will be largely accessible. After Church's lab transforms the skin into stem cells, those new cell lines — which have been in notoriously short supply despite their scientific promise — will be open to outside researchers. This is a significant divergence from most biobanks, which typically guard their materials like holy relics and severely restrict access.

For the PGP volunteers, this means they will have to sign on to a principle Church calls open consent, which acknowledges that, even though subjects' names will be removed to make the data anonymous, there's no promise of absolute confidentiality. As Church sees it, any guarantee of privacy is false; there is no way to ensure that a bad actor won't tap into a system and, once there, manage to extract bits of personal information. After all, even de-identified data is subject to misuse: Latanya Sweeney, a computer scientist at Carnegie Mellon University, demonstrated the ease of "re-identification" by cross-referencing anonymized health-insurance records with voter registration rolls. (She found former Massachusetts governor William Weld's medical files by cross-referencing his birth date, zip code, and sex.)

To Church, open consent isn't just a philosophical consideration; it's also a practical one. If the PGP were locked down, it would be far less valuable as a data source for research — and the pace of research would accordingly be much slower. By making the information open and available, Church hopes to draw curious scientists to the data to pursue their own questions and reach their own insights. The potential fields of inquiry range from medicine to genealogy, forensics, and general biology.

And the openness doesn't serve just researchers alone. PGP members will be seen as not only subjects, but as participants. So, for instance, if a researcher uses a volunteer's information to establish a link between some genetic sequence and a risk of disease, the volunteer would have that information communicated to them.

This is precisely what makes the PGP controversial in genetics circles. Though Church talks about it as the logical successor to the Human Genome Project, other geneticists see it as a risky proposition, not for its privacy policy but for its presumption that the emerging science of genomics already has implications for individual cases. The National Human Genome Research Institute, for example, has cautioned that the burgeoning personal-genomics industry, which includes research-oriented projects like the PGP as well as straight-to-consumer companies like Navigenics and 23andMe and whole-genome-sequencing shops like Knome, puts the sales pitch ahead of the science. "A lot of people would like to rapidly capitalize on this science," says Gregory Feero, a senior adviser at the NHGRI. "But for an individual venturing into this now, it's a risk to start making any judgments or decisions based on current knowledge. At some point, we'll cross over into a time when that's more sensible."

Church cautions, however, that keeping clinicians and patients in the dark about specific genetic information — essentially pretending the data or the technology behind it don't exist — is a farce. Even worse, it violates the principle of openness that leads to the fastest progress. "The ground is changing right underneath them," he says of the medical establishment. "Right now, there's a wall between clinical research and clinical practice. The science isn't jumping over. The PGP is what clinical practice would be like if the research actually made it to the patient."

In the not-too-distant future, Church says, hospitals and clinics could be outfitted with a genome sequencer much the way they now have x-ray machines or microscopes. "In the old books," Church says, "almost every scientist was sitting there with a microscope on their table. Whether they're a physical scientist or a biological scientist, they've got that microscope there. And that inspires me."

Wired deputy editor Thomas Goetz (thomas@wired.com) wrote about personal genomics in issue 15.12.

What You Should Know Before You Spit Into That Test Tube

By Rick Weiss

Washington Post

Sunday, July 20, 2008; Page B01

Jeffrey Gulcher had no reason to think much about prostate cancer. He was just 48, and the disease typically strikes later in life. Even the most cautious medical groups agree that most men need not begin annual prostate screenings until age 50.

But Gulcher happens to be the chief scientific officer of deCODE Genetics -- one of several companies that, amid some controversy, have begun offering direct-to-consumer DNA tests that can help people predict which diseases they are likely to get. So in April, he spat into a test tube and, without giving the matter much thought, sent the sample in for analysis by his own company.

He was in for a shock. The test indicated that he carries a genetic variant that nearly doubles his lifetime risk of getting prostate cancer: While the average man has a 15 percent chance of being stricken, Gulcher had a 30 percent shot. That spurred his physician to order a standard blood test for prostate cancer. The result was toward the high end of the range considered normal, which, together with the DNA test, worried the doctor. He referred Gulcher to a urologist, who performed an exploratory biopsy -- and found that Gulcher's prostate gland was riddled with cancer, and a fairly aggressive version of it at that.

Gulcher is going in for surgery tomorrow, and not a moment too soon. Tests suggest that the disease has not yet spread to other parts of his body, a milestone that often portends death and that may well have been passed had he waited until he turned 50 to get a standard prostate-specific antigen (PSA) test.

Did genetic testing save Gulch er's life? I think it may have. His dramatic story seems to illustrate perfectly the claims, made by his company and others, that an open market of DNA tests is the 21st century's ticket to a healthier nation. But a closer look suggests that this fast-growing industry, with its snazzy Web-based come-ons, could benefit from some temperance and independent oversight.

The technology is undeniably impressive. For as little as $1,000, anybody who can drool into a mailing tube can now find out his or her genetic odds of getting any of 20 or more potentially debilitating diseases, including cancer, heart disease and diabetes. Most of these tests will not lead to a frank diagnosis, as happened with Gulcher. But discovering an inherited propensity toward a particular illness can motivate consumers -- or, as they used to be known, patients -- to get more frequent checkups, take preventive medicines or make lifestyle changes to try to ward off the specter of disease. At last, we seem to be on the cusp of the long-promised personalized-medicine revolution in which gene tests allow physicians to craft far more individualized and effective ways of keeping us well.

But tests that look into the fog of people's medical futures are freighted with tricky medical, economic and bioethical implications. For one thing, most genes are not determinative, so these tests can convey only odds, not destinies. Even with the doubled lifetime risk for cancer that's associated with Gulcher's prostate gene variant, two out of three men who receive a "positive" test for that gene will never get the disease. And many of those who do will get it so late in life and in such a benign form that no treatment would be justified. So that's at least two new members of the "worried well" who could be losing sleep and spending money on unnecessary follow-up tests for every person who would arguably be appropriately forewarned.

Moreover, the tests are still new and easily misinterpreted, even by professionals. Online results may be subject to security and privacy breaches. And some companies are using people's gene profiles to conduct independent research. That suggests to many ethicists and lawyers that these firms' paying clients ought to be informed that they are subjects in experiments, with full disclosure of potential risks and rights.

Most worrisome of all, at least a few companies seem to be peddling DNA-based versions of snake oil. Some firms claim to be able to identify inherited nutritional deficiencies that -- guess what? -- are treatable with pricey supplements that they just happen to sell. Some even promise to discern from your genes what kind of person you should marry to ensure a blissful sex life and healthier babies. Welcome to the Wild West of personalized genomics.

These problems are not insurmountable. But there is precious little oversight of this burgeoning new industry, in part because genetic analysis does not fit cleanly into any existing category of medical practice. And if the first wave of DNA-screening companies to hit the market gets its way, there won't be any more adult supervision in the foreseeable future. In a blatant effort to stave off regulation, top officials from all the major competing gene-test companies met early this month and quietly agreed to spend this summer hammering out a "best practices" document that they would promise to follow. This is a great idea, but it's not enough.

No state or federal agency can today assure consumers that the DNA tests they order will give accurate results -- or that the results, even if technically accurate, will have any practical value. The Food and Drug Administration says it has the authority to regulate all gene tests but has decided, at least for now, to ignore the vast majority of those developed so far. The Federal Trade Commission (FTC), which is supposed to protect consumers from fraudulent claims, has never taken an enforcement action against even the most transparently deceptive gene-test companies. And the Centers for Medicare and Medicaid Services, the division within the Department of Health and Human Services that oversees clinical laboratories, has so far opted to steer clear of the genetic-testing world, despite pleas from federal advisers to ensure a minimal standard of gene-test proficiency.

The companies say that what they do is different enough that they should not be shoehorned into the conventional medical-testing rules. "For the first year and a half of our existence, all we did was try to figure out how to fit into the regulatory environment," said Dietrich Stephan, co-founder of Navigenics, a leading California-based gene-test company, adding that the effort cost an estimated $10 million.

That's real money. Yet even with all that preparation, Navigenics and a dozen other testing companies recently received warnings from individual states accusing them of violating state rules for labs. Situations such as this cry out for the guiding hand of the federal government -- not necessarily through cumbersome regulations, which can be too rigid to keep up with quickly changing science, but through formal guidelines, at least, promulgated by HHS. These could set clear expectations about how accurate gene tests should be -- and what it means to be "accurate" in the brave new world of predictive health -- and what level of informed consent should be obtained from clients. The promulgation of such standards will take real effort from HHS Secretary Mike Leavitt, who has championed personalized medicine but who has thus far been largely AWOL on the gene-test issue and has little incentive to push hard in the final months of the Bush administration. The FTC also needs to show that it has teeth and can bite.

Genetic-testing companies need to ante up, too. The responsible ones could buy a lot of good will by offering the public easily accessible scientific details (online and elsewhere) about the specific genes or genetic markers they are testing for; citations for the published studies they use to justify their claims that those genes have real medical relevance; the privacy and security systems they have in place; and the protocols for any experiments that clients' specimens may be used in. The firms should also disclose any approvals they have sought, obtained or denied from independent scientific and ethical review boards.

I took heart that such a future is possible when, at an HHS meeting two weeks ago, I saw chiefs from the five major competing gene-test companies sitting next to one another, speaking cooperatively to federal advisers. If these executives move aggressively to do the right thing, and if federal officials help them with some smart but tough guidance, perhaps those corporate heads can avoid a future in which they are called upon to appear side by side again -- this time before Congress, looking more like those famously photographed tobacco CEOs, being asked tough questions about what exactly they have been selling, and at what cost to American health.

rweiss@americanprogress.org

Rick Weiss, a former science reporter for The Post, is a senior fellow at the Center for American Progress.

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

Principle of Recursive Genome Function Supersedes Dogmas; By Andras Pellionisz, Online Ahead of Print; (Scientific Visionary Vindicated)

[The Pri nciple of Recursion comprised in a single color Fig. (Not in the paper; see Supplementary Information)]

[Free Full Text of Journal Article, with clickable references, plus Supplementary Information is available]

A Eureka Moment concerning the fractal character of neurons led in turn to a novel picture of genomics where protein structures act back recursively upon their DNA code -- in outright contradiction to prevailing orthodoxy. A household name in neuroscience for his tensor network theory, Dr. András Pellionisz has recently had another far-reaching discovery borne out. This insight has now received striking confirmation in stunning results from the new field of epigenetics -- promising a whole raft of novel medical diagnoses and therapies.

Sunnyvale, Calif. (PRWEB) July 16, 2008 -- A landmark article on "The Principle of Recursive Genome Function" (received December 7, accepted December 18, 2007) by András J. Pellionisz appears online in Springer's e-Journal Cerebellum.

The paper marks the first anniversary of an historic event--the release of pilot results for ENCODE, the Encyclopedia of DNA Elements project. Building on the results of the Human Genome Project, the ENCODE effort revealed a far more complex DNA coding sequence than was ever previously imagined. "There's a lot more going on than we thought," said Collins, who was director of the National Human Genome Research Institute (NHGRI). Dr. Collins issued a mandate a year ago "the scientific community will need to rethink some long-held views".

A happy few did not need to rethink either the "central dogma of molecular biology" (Crick, 1956) or the misnomer of "junk" DNA (Ohno 1972), since they never believed them in the first place. The dictum claiming that a flow of information from proteins back to DNA "never happens" or the idea that 98.7% of the human genome should be disregarded as junk was never very believable.

As a direct response to Dr. Collins' call, the principle of recursive genome function (PRGF) in one stroke sweeps away two dogmas which prevailed for over 50 years concerning the function of the double helix.

Recursive genome function is a process whereby proteins iteratively access information packets of DNA to build hierarchies of more complex protein structures. Such recursive development is illustrated in the fractal growth of cerebellar Purkinje neuron:

[See all Figs. plus color versions here]

Starting from a primary information packet, a Y-shaped, fractal protein template is constructed by a "forward growth" process - in accord with the traditional picture - via transcription of DNA to RNA (where, in turn, RNA builds nucleic acids up into structural protein). In the course of constructing the Y-shaped template, the primary gene is turned on. Thus, the most primitive part of the process retains Watson's simplified scheme. The principle does not contradict the 'DNA makes RNA makes proteins' picture, but rather goes beyond it - dispensing with both the hitherto forbidden feedback mechanism as well as the entire notion of junk DNA.

On the contrary, the genetically crucial process known as methylation demonstrates just such a "backward" flow. In a stunning reversal of long-held views, it now appears that environmental influences can act directly on the genetic code. Moreover, methylation of DNA is not merely epigenetic, but HoloGenomic.

Dr. Alexandre Akoulitchev, Oxford University, UK (not involved in the study) says: "The PRGF of Pellionisz is helping not only his recursive algorithmic approach to the genome (FractoGene), but puts the various meanings of 'epigenetics' into the perspective of clearly defined novel axioms. The PostModern Age of Genomics (starting with his PostGenetics.org), synthesizes inconsistent interpretations and haphazard notions of "epigenetics" into a solid scientific foundation of HoloGenomics."

Leroy Hood (2003) and finally Richard Dawkins (2008) have suggested that genomics is now a branch of information science. With modern genomics becoming postmodern genome informatics, a natural question arises: What axioms will take the place of outmoded assumptions?

The traditional axioms could not put to a dignified rest because, as the wisdom has it, "data never kill theories, only better theory can kill less tenable theories."

The principle of recursive genome function addresses this fundamental, decisive role. The time has come to go public, after more than a decade of clandestine work - not even asking for support.

András Pellionisz is a biophysicist, formerly of New York University. Since heading up HelixoMetry in Silicon Valley, he has been busy assembling a portfolio in anticipation of the time when the imposing dogmas and their bulwarks would give way. A widely published author, Pellionisz remained largely silent for 15 years to spare him a collision with the powers that were.

His pioneering work in biological neural networks, aired in over a hundred publications, won him both NIH support and recognition by way of the Alexander von Humboldt Prize for Senior Distinguished American Scientists.

When Pellionisz also made a bold step and published his research on the fractal geometry of cellular development based on a recursive DNA paths (1989), his next NIH application was overlooked by his peers and the establishment maintained a double lock on genomics. Their ideology was: Don't look back on DNA, since recursion can "never happen" and even if you would, "there is only junk."

As a scientist with his first degree in engineering, he developed a neural net application for NASA, using the parallel computers of the time (so-called Transputers).

By 2005 fundamental problems with underlying axioms of genomics became too obvious. Meanwhile, millions, if not hundreds of millions were dying of junk DNA diseases while 98.7% of the human DNA was officially still considered untouchable.

Together with his fellow pioneers, Dr. Pellionisz launched the trial balloon of International PostGenetics Society. Indeed, almost a year ahead of disclosing the official conclusions of ENCODE that "junk" DNA is anything but, the IPGS became the first organization to officially abandon the misnomer at its European Inaugural in 2006. At that meeting, Pellionisz pioneered the approach of diagnosis (leading to therapy and eventual cure) of junk DNA diseases caused by fractal defects in genomic regulatory sequences.

In late 2006 a manuscript attempting to close the chapter on junk DNA was co-authored by 20 Founders of IPGS. Those suffering from "junk DNA diseases" probably wish that the manuscript was given the benefit of a peer-review.

Instead, the mounting pressure caused publication of ENCODE results 3 months earlier than planned. Thirty major papers shredded long-held views and printed staggering statements such as "the concept of genes is a myth." A deafening silence ensued.

Rather than heeding advice of Dr. Collins of "re-thinking long-held beliefs" research went "genome-wide" for more data, as next-generation sequencing made the entire genome of many species (including humans) available with rapidly melting price tag.

Application of brute force to turn out more data instead of revising axioms created its own problems, however. A dreaded DNA data deluge looms large. Without a combination of algorithmic reduction as well as building the proper computing architecture, the brute force approach of full genome sequencing and genome-wide analysis have already hit a compute- and data-wall.

The old bottleneck was "get info" (sequencing to obtain data). The new bottleneck is "use info" (understanding what sequenced data mean). The promise inherent in the Principle is that an algorithmic reduction delivers us an understanding of physiological and therefore pathological genome function in a new light. This clears the road for rapid advancement beyond a long-overdue breakthrough. In HoloGenomics, all, including non-genic conditions can now be focused upon. This is the direct response to consumers, including those who are not even patients. For those impatient enough to prevent some undesirable conditions, the principle opens an opportunity.

PRESS CONTACT:
Brian Flanagan
Phone: (+1) 319-338-6250

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

Intel, Others Back New DNA Sequencer

By BRIAN GORMLEY

July 14, 2008; Page B6

Investors are pumping $100 million into a start-up developing technology to propel DNA sequencing into mainstream medicine.

The infusion is expected to enable Pacific Biosciences of California Inc. to introduce in 2010 its high-speed system for reading the chemical "letters" of DNA. The technology is designed to expand the use of sequencing to develop treatments tailored to patients' genetic makeup.

In time, for example, pharmaceutical researchers may routinely use sequencing to identify people who respond well, or poorly, to a drug based on specific genetic markers.

The federally funded Human Genome Project, completed in 2003, took 13 years and cost $450 million. In five years, Pacific Biosciences will make it possible to sequence a genome in 15 minutes, Chief Executive Hugh Martin said. The initial product will facilitate genome sequencing in a matter of days, at an undisclosed cost, he said.

Corporate investors, asset managers and venture-capital firms are taking part in the latest funding round for Pacific Biosciences, of Menlo Park, Calif. They include Intel Capital, an arm of Intel Corp.; Deerfield Capital Management LLC; T. Rowe Price Group; Morgan Stanley; FMR LLC; AllianceBernstein Holding LP; Maverick Capital Ltd.; Redmile Group; Alloy Ventures; DAG Ventures; Teachers' Private Capital; Kleiner Perkins Caufield & Byers; and Mohr Davidow Ventures.

A key part of Pacific Biosciences' system is an enzyme called polymerase that human cells use to copy DNA. With the system, scientists break double-stranded DNA molecules into single strands and then fragment the strands. These fragments are fed into chambers on sequencing chips. Then, individual nucleotide letters, each linked to a fluorescent marker, are added.

Inside each chamber, the polymerase enzyme pairs these letters to their corresponding nucleotides on the DNA fragment. As letters bind, they emit flashes of light, enabling scientists to read the DNA fragment's sequence.

Other companies seeking to cut the time and cost of DNA sequencing include publicly traded Illumina Inc. and Helicos BioSciences Corp., and closely held Complete Genomics Inc.

Write to Brian Gormley at brian.gormley@dowjones.com

New Targets For RNAs That Regulate Genes Identified

[IPGS Founders Drs. Bethany Janowski and David Corey shake the foundations of "Modern Genetics" - AJP]

ScienceDaily (July 6, 2008) — Tiny strands of genetic material called RNA -- a chemical cousin of DNA -- are emerging as major players in gene regulation, the process inside cells that drives all biology and that scientists seek to control in order to fight disease.

The idea that RNA (ribonucleic acid) is involved in activating and inhibiting genes is relatively new, and it has been unclear how RNA strands might regulate the process.

In a new study available online today and in a future issue of Nature Structural and Molecular Biology, RNA experts at UT Southwestern Medical Center found that, contrary to established theories, RNA can interact with a non-gene region of DNA called a promoter region, a sequence of DNA occurring spatially in front of an actual gene. This promoter must be activated before a gene can be turned on.

"Our findings about the underlying mechanisms of RNA-activated gene expression reveal a new and unexpected target for potential drug development," said Dr. David Corey, professor of pharmacology and biochemistry at UT Southwestern and one of the senior authors of the study.

Genes are segments of DNA housed in the nucleus of every cell, and they carry instructions for making proteins. Faulty or mutated genes lead to malfunctioning, missing or overabundant proteins, and any of those conditions can result in disease. Scientists seek to understand the mechanisms by which genes are activated, or expressed, and turned off in order to get a clearer picture of basic cell biology and also to develop medical therapies that affect gene expression.

In previous studies, Dr. Corey and Dr. Bethany Janowski, assistant professor of pharmacology at UT Southwestern and a senior author of the current study, have shown that tiny strands of RNA can be used to activate certain genes in cultured cancer cells. Using strands of RNA that they manufactured in the lab, the researchers showed that the strands regulate gene expression by somehow perturbing a delicate mixture of proteins that surround DNA and control whether or not genes are activated.

Until now, however, it was not clear exactly how the synthetic RNA strands affected that mix of regulating proteins.

In the current study, also carried out in cancer cell cultures, the UT Southwestern research team discovered an unexpected target for the manufactured RNA. The RNA did not home in on the gene itself, but rather on another type of RNA produced by the cell, a so-called noncoding RNA transcript. This type of RNA is found in association with the promoter regions that occur in front of the gene. Promoter regions, when activated, act essentially as a "start" command for turning on genes.

The researchers found that their man-made RNA strand bound to the RNA transcript, which then recruited certain proteins to form an RNA-protein complex. The whole complex then bound to the promoter region, an action that could then either activate or inhibit gene expression.

"Involvement of RNA at a gene promoter is a new concept, potentially a big new concept," Dr. Janowski said. "Interactions at gene promoters are critical for understanding disease, and our results bring a new dimension to understanding how genes can be regulated."

Until recently, many scientists believed that proteins alone control gene expression at promoters, but Drs. Corey and Janowski's results suggest that this assumption is not necessarily true.

"By demonstrating how small RNAs can be used to recruit proteins to gene promoters, we have provided further evidence that this phenomenon should be in the mainstream of science," Dr. Corey said.

Although using synthetic RNA to regulate gene expression and possibly treat disease in humans is still in the future, Dr. Corey noted that the type of man-made RNA molecules employed by the UT Southwestern team are already being used in human clinical trials, so progress toward the development of gene-regulating drugs could move quickly.

Other researchers from UT Southwestern involved in the research were lead author and student research assistant Jacob Schwartz; student research assistant Scott Younger; and research associate Ngoc-Bich Nguyen. Researchers from the University of Western Ontario and ISIS Pharmaceuticals also participated.

Science is being held back by outdated laws

From The Times

July 5, 2008

The question "who owns science?" is now crucial

Sir, It is now widely recognised that the system of law and practice that has regulated science and protected the rights of those who make scientific discoveries and turn them into products and therapies in a process known as “innovation” is unfit to serve the needs of the contemporary world.

Science and the innovation it generates is a vast enterprise: commercial and pro-bono, public and private, industrial and educational, amateur and professional. It permeates our lives and shapes the world. Some would say it is the defining characteristic of modern society, stimulating and harnessing our innate curiosity and, more than any other endeavour, shaping our world and, increasingly, ourselves.

An important component of the innovation process is the idea of ownership of science and technology and its products, enabling profits to be made from research and development. The question of “Who owns science?” is therefore a crucial one, the answer to which will have broad-reaching implications for scientific progress and for the way in which the benefits of science are distributed, fairly or otherwise. Two of the most pressing issues concern equity of access to scientific knowledge and the useful products that arise from that knowledge.

The current system of managing research and innovation incorporates a complex body of law governing the ownership of “intellectual property” — copyright and patents being the most familiar. Intellectual property rights are intended to provide incentives that encourage the advancement of science, enhance the pace of innovation, increase the derived economic benefits and provide a fair way of regulating access to these benefits. But does it really achieve these purposes? There is increasing concern that, to the contrary, it may, under some circumstances, impede innovation, lead to monopolisation, and unduly restrict access to the benefits of knowledge.

We believe it is time to reassess the effect of the present regime of intellectual property rights, especially with respect to the area of patent law, on science, innovation and access to technologies and determine whether it is liberating — or crushing; whether it operates to promote scientific progress and human welfare – or to frustrate it.

The second issue we wish to highlight is that of access to science itself. The ideal shared by almost all scientists is that science should be open and transparent, not just in its practices and procedures, but so that the results and the knowledge generated through research should be freely accessible to all. There is a broad consensus in the scientific community that such openness and transparency promotes the advancement of science and enhances the likelihood that the benefits of science are enjoyed by all. For more than a hundred years, these principles have been the bedrock of academia and the scientific community.

We call upon all interested in the future of science to join with us in an active and open-ended search for answers.

John Sulston

Chair, Institute for Science, Ethics and Innovation, University of Manchester

Joseph Stiglitz

Chair, Brooks World Poverty Institute, University of Manchester

When's a Gene Test Not a Gene Test?

Jun 25 2008 3:11PM EDT
Wired

Genetic-testing company Navigenics has responded to the state of California's cease-and-desist letter with a novel defense: It doesn't actually test patients' genomes, it just analyzes 'em.

In a letter sent to the Health Department obtained by Wired.com, the company argues that it does not actually perform genetic tests, and therefore should not be regulated as a clinical laboratory under California state law.

Instead, Navigenics argues it merely applies algorithms to DNA data it receives from tests performed by a third-party, a licensed laboratory.

As we noted Monday, this regulatory battle hinges on the definition of a clinical laboratory test.

"Nothing in the definition of a clinical laboratory test supports a conclusion that the interpretation of the data resulting from such a test is itself a test," Navigenics wrote in its response.

Though abstruse, these definitions could shape the long-term future of genetic testing. The arguments boil down to whether or not the information contained in your DNA should be treated like blood or like data.

Navigenics is arguing that once the state-licensed lab turns a biological sample into digital data, DNA is no longer within the purview of health department laboratory regulation. Navigenics is just an information service, combining scientifically-published genetic disease correlation data with personal genotype data.

Whether or not the health department (or eventually the courts) will buy this argument remains to be seen. The state is reviewing responses from the thirteen companies it served with cease-and-desist letters.

According to Navigenics, it contracts the actual biological work to a Federally-certified and California-licensed lab run by Affymetrix, so it never touches the spit-containing DNA that forms the basis of genetic testing. What Navigenics receives from Affymetrix is merely digital data about a person's genetic variations.

In that way, it argues, the company merely interprets clinical lab tests, much like a physician would, and physicians are not regulated as clinical labs.

The state, on the other hand, holds that because Navigenics obtains the biological data, it is essentially doing the test.

Navigenics' also proposes a second line of defense relating to the necessity of including a physician in ordering a genetic test.

Navigenics has argued all along that it has a California physician who actually orders and receives the tests, but it is not clear whether any physician can order a test, or whether it had to be "your doctor" (whatever that means in today's health care system).

The letter to the health department makes a strong argument that Navigenics' on-staff doctor can order a test even if the test is initiated by a consumer. It quotes from a 2003 communication between the health department and Quest Diagnostics, in which the agency recognizes the difference between ordering a prescription drug and a clinical test.

"Until and unless the law is changed, it would appear that any licensed physician in California may order laboratory tests on persons of whom they have no knowledge," the health department wrote.

With these two trenches dug, Navigenics also extended an olive branch to the health department in the form of a three-page letter from the company's CEO Mari Baker.

"I look forward to the opportunity to meet with you and your team as soon as possible, and preferably within the next two weeks, to fully brief you on our company's approach and operational practices," Baker wrote.

The genetic testing industry, led by Navigenics and 23andMe, are eager to come up with a regulatory framework that would allow their businesses to run smoothly and get the health department out of their hair, said Rick Weiss, a senior fellow at the Center for American Progress.

"The companies' responses have been quite cordial. It's been, 'OK, let's talk,'" Weiss said. "They clearly want to hammer out a system that will allow this industry to grow."

Still, both companies have told the state of California that they plan to remain in business without substantive changes to the business practices that earned them sent cease-and-desist letters in the first place.

Weiss sees that as a sign that the two sides need to acknowledge that genetic testing is something new that falls outside the existing regulatory paradigm.

"[Genetic testing companies] are offering something new that doesn't fit into the landscape of clinical laboratory regulation," he said. "There needs to be some sort of dialogue between regulators and the industry."

by Alexis Madrigal for Wired.com

First Anniversary of ENCODE: The Principle of Recursive Genome Function

[The full paper is available here with more clickable references than in the Online publication by Springer, Heidelberg & New York]

"Upon publication of the results of project Encyclopedia of DNA Elements (ENCODE), a 4-year research effort let by the US Government, its architect issued a mandate: 'The scientific community will need to rethink some long-held views [Francis Collins, June 2007].

What views require our revision? The sequencing of the human genome engendered the idea of genomics as information science [Leroy Hood, 2003]. New avenues must be explored that are opening up to scientific research once breakthroughs from decades-old theoretical cul-de-sac lead to theoretical and experimental advances...This paper reviews the dichotomy of genomics regarding historical conflicts regarding gene and gene regulation and offers a guiding principle of their synthesis. Introduction of this principle is made possible by a long-delayed but now respectful removal of two pragmatic dogmas, replacing them by a sound information-theoretical axiom..."

[This "re-thinking" was submitted within half a year of Francis Collins' call on December 7, 2007, accepted on December 18, 2007 and published online by The Cerebellum, a Springer New York peer-reviewed science journal to commemorate the First Anniversary of ENCODE, on the 20th of June, 2008.]

Colleagues - not involved in the study - comment:

"Epigenetics is rapidly revising Darwin and opening whole new realms in medical science and technology. Dr. Andras Pellionisz, who is Director of Genome Informatics at Mitrionics in Silicon Valley, saw it all coming decades ago.

A scientific visionary, Pellionisz has made a career of being ahead of his time. His profoundly influential work on the mathematics of brain function inspired generations of leaders in neuroscience, including the Churchlands.

This time around, his far-sighted work on fractal mechanisms in genetics has recently been vindicated.

Pellionisz drew attention early on to the fractal character of dendritic trees. He then moved on to genetics, where he argued that gene expression is not, as was dogmatically asserted, a one-way street from DNA to organism, but rather a recursive process akin to the generation of fractals.

Today, in groundbreaking work on 'nanotrees,' scientists have produced a spiral shape akin to the helical structure of DNA -- an aperiodic crystal. Nanotrees are microscopic structures which result from crystalline 'defects' in nanowires.

Although these developments are fast-breaking and the implications have yet to be worked out, it seems clear enough that we have here a direct path from the atomic symmetries of quantum theory thru simple fractal crystals thru DNA and on up the ladder to fractal neurons.

What's also clear is that these developments open entire new vistas for R&D on medical diagnosis, therapy and up to cure for a host of diseases and hologenomic risk factors and disorders."

[Brian Flanagan, USA]

---

"PRGF of Pellionisz is helping not only his algorithmic recursive approach to the genome (FractoGene), but puts ‘epigenetics’ into the perspective of clearly defined novel axioms.

The PostModern Age of Genomics (starting with his PostGenetics), embraces many interpretations and examples of ‘epigenetics’ and is synthesizing haphazard notions into a solid scientific foundation of our era of HoloGenomics".

[Alexandre Akoulitchev, Fellow of the Royal Society of Medicine, Oxford University, UK]

---

“Based on Pellionisz' 'Principle of Recursive Genome Function' the puzzling history becomes understandable why the first wave of suspecting fractality of DNA in the late 1980-s and early 1990-s by his own fractal Purkinje neuron model (1989), and efforts by Drs. Buldyrev, Stanley et al (1993), Flam 1994, Mantegna (1994) could not break through.

They violated not one, but two prevailing dogmas - and could not provide a replacement for the dogmas of "junk DNA” and “No feedback recursion".

Now, with Pellionisz’ Principle, such unifying synthesis is available to greatly facilitate progress. Therefore, an avalanche of recursive algorithms is likely to ensue his breakthrough.

Fractals, however, are very computation-intensive, though both an algorithmic approach, and especially the data-compression by fractals are likely to significantly ease the burden of a brute-force approach to cope with the dreaded DNA data-deluge."

[Jules Ruis, Director of EU Center of Excellence of Fractal Design, THE NETHERLANDS]

---

“The Principle accounts for and smoothly puts together hitherto ill-fitting pieces in the old puzzle. The different picture, with a new meaning, calls for a new name.

With PRGF, the unresolved relationship between mathematical information and biological formation is explained by the repetitive action and consequent feedback of the genome where any incremental DNA information refines a formative protein growth, governed e.g. the algorithmic guidance of fractals.

Reading The Principle, Eugene Wigner’s reminder in the year of discovery of Operon regulation (1961) rings loudly in our ears:

‘There is a contradiction between the model of reproduction proposed by Crick and Watson, in which a determined mechanism is transferring the characteristics to the descendants. This model is also based on classic and not quantal concepts ... the particulars of this model are not completely worked out (Eugene Wigner; The Probability of the Existence of a Self-Reproducing Unit, In: The Logic of Personal Knowledge, Routledge and Kenan Paul Ltd, London 1961 p. 231)’”

Another early giant, John von Neumann , architect of both serial and parallel computers in the 1940s-1950s would probably look upon this progress with interest as well, since genome computing is likely to bring about a synthesis of both architectures.

[The Michael Conrad Group for Bioinformation and Biocomputation Research; E. Perjes, E. Pataki and I. Szentesi, HUNGARY]

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

Genetics Became Information Science - The Holistic View of Genome Structure and Function

See video Richard Dawkins actually saying so at the 2008 DLD conference with Craig Venter (below):

Neither of them were the first to say so, at the least in 2003 Leroy Hood already came to the same realization. So did Francis Collins ("God's language [DNA and mathematics]). Dr. Dawkins' admission of the handover from molecular biology to informatics is paramount, because he is "neutral" - neither a molecular biologist nor a genome informatics specialist. As the arguably most influential science communicator he does not have a vested interest (like Leroy Hood or Eric Lander) in declaring genome informatics holding the torch.

Indeed, it has become common knowledge: "At this point, the old sort of science is almost entirely irrelevant. 'It now has come out of the labs and into the domain of informatics,' Butcher says" (Basically, the DNA is a computing problem).

So, what are we waiting for? Isn't it time for Genome Informatics to come forward with a Holistic perspective where not only the outmoded "Genes" thesis and "Junk DNA" antithesis become a Genomewide synthesis, but molecular biology and genome informatics is unified into HoloGenomics?

[A. Pellionisz, commemorating the First Anniversary of the ENCODE release, June 14, 2008 - pellionisz_at_junkdna.com]

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

BIOCOM 2008: Turning personalized medicine into reality

By Terri Somers

UNION-TRIBUNE STAFF WRITER

June 18, 2008

[Collins in Genomics led the chase of genes. In the new Post-ENCODE era of HoloGenomics, there is a new role - AJP]

It's been a hot couple of years for genomics, the study of the long chain of chemicals that determines all the hereditary information in a person's DNA, from hair and eye color to propensity for disease.

First, the Human Genome Project mapped the entire human genome, a chain of 3 billion chemicals, giving scientists a template for comparing the genetic makeup of all individuals to spot differences and their possible relationship with disease.

Subsequent advances in technology have led to machines that quickly and efficiently read samples of genes, allowing scientists to uncover more than 100 genetic links to disease. Ultimately, their goal is personalized medicine – finding specific therapies that work for each individual.

Some of the world's top genetic experts, including Francis Collins and Craig Venter – two scientists who played key roles in mapping the human genome – are in San Diego this week for the BIO International Convention, discussing the technologies that might help them reach that goal.

The Human Genome Project allowed scientists a glimpse of diseases caused by a single gene, which were few, Collins said during a panel discussion yesterday on innovation in genomics. The information from the project was not helpful in unraveling complex genetic diseases such as diabetes, hypertension, cancer and Alzheimer's, Collins said.

But innovation since then has led to a dramatic change, Collins said. Government-funded programs such as the 1,000 Genome Project, which will collect information on the genomes of 1,000 people from various ethnic backgrounds and store it in a public database, will give scientists an even more detailed catalog of human genetic variation, Collins said.

“Genomics is a necessary step,” said Charles Cantor, chief science officer at San Diego-based Sequenom, which is developing a noninvasive genetic test for pregnant women and their fetuses.

“Now we know what the genes are, but we still have to figure out which are important to which traits and disease,” said Cantor, who was director of the Human Genome Center Project at the Lawrence Berkeley National Laboratory. “It's like having a list of parts to your automobile but not knowing how to build it, or how it works, but knowing that the tires play a very important role.”

One technology pushing the science forward is gene sequencing, which is determining the order of the genes on a genome and identifying mutations.

Illumina, another San Diego company, has played a role in the field with its Solexa sequencing technology. And it has benefited from the boom, with its revenue jumping from $184.6 million in 2006 to $366.8 million for 2007.

Last week, Carlsbad's Invitrogen spent $6.4 billion to become a bigger competitor in the field, acquiring Applied Biosystems and its system for genetic testing. Applied is best known for supplying genetic-analysis machines to the Human Genome Project.

Only a few years ago, mapping a genome cost millions of dollars and took years to complete. Now the process is faster and costs just thousands of dollars.

“People have generated more data about the human genome with our next-generation sequencing (tools) than in all of history,” Illumina Chief Executive Jay Flatley said. “We've sequenced three human genomes since December. In the history of the world, only seven or eight genomes had been sequenced previously.”

Last June, Elaine Mardis' lab at Washington University in St. Louis began mapping the genome of a leukemia patient. The task was finished in six months, said Mardis, who heads the university's Genome Sequencing Center.

The cost of mapping an individual human genome is now flirting with $100,000, said Mardis, who will be at the BIO conference discussing questions that may be answered using this improved technology.

Collins, who heads the National Human Genome Research Institute, is pushing for the cost to drop to $1,000.

And the X-Prize Foundation, an educational nonprofit organization that seeks to solve scientific challenges, is offering a $10 million prize to whoever can develop technology for the $1,000 human genome test. Venter, who sequenced his complete genome as part of the Human Genome Project, is a member of the board's foundation.

Faster and cheaper means that sequences can be done of more people, providing information on what mutations are rare and appear to be linked to disease. As the database of genomic information grows, the more statistically significant it is for scientists, Mardis said.

This could be very important for understanding diseases such as cancer, which are thought to be connected to structural changes in the genome.

At the J. Craig Venter Institute in La Jolla, scientists are testing genomics-sequencing technologies to determine which is most accurate, Venter said. Since his genome is one of only two that are completely sequenced and known, Venter and his co-workers can use it as a standard for comparison.

A broader database of human genome information will help prioritize drug development, such as work being done on cancer because a single drug probably cannot be developed to work on all the genes that play a role in the disease, said Dr. Lynda Chin of Harvard's Dana-Farber Cancer Institute.

Genetic information will give researchers and physicians a blueprint on how to use drugs, Chin said.

Chin, who is speaking at BIO, is chairwoman of Harvard's Cancer Genome Atlas, a three-year pilot project of the National Cancer Institute and the National Human Genome Research Institute that seeks to understand the genomic changes that occur in cancer.

All the experts agree: The Human Genome Project, and the research conducted during the ongoing genomics boom, showed scientists that they still have much more to learn about genetics and disease. But the growing body of knowledge is helping them to ask better questions.

For instance, researchers once thought an individual's genome, which is essentially a chemical chain, remained unchanged. They now know that environmental factors can cause alterations, Cantor said.

As a result, the study of epigenetics, environmentally fueled changes in DNA, is beginning to take off, he said.

“Just because you have a certain set of genes linked to a disease like cancer doesn't necessarily mean that's going to happen,” Cantor said. “You have to look at genetic/environment interaction.”

Products that allow researchers to determine whether a specific gene has been turned on or off are just coming onto the market, Illumina's Flatley said.

Genomics has also revved up research into biomarkers – traces of chemicals that can be found in blood, urine, skin and other cells that indicate whether a specific gene is performing a function that can be linked to disease.

Sequenom, for instance, is developing a diagnostic test that would look for certain biomarkers from an unborn child. Those biomarkers would be traces of chemicals from the fetus, such as proteins, that show whether specific genes in the unborn baby are functioning in a way that is linked to disease.

Meanwhile, there are obvious signs we are moving closer toward personalized medicine and away from the concept of “the normal dose for an average white male,” Flatley said.

There is some ability now to determine whether a drug, such as the expensive cancer therapy Herceptin, will work on a specific individual. And Genoptix, a Carlsbad company, tests blood samples of people with cancer to help oncologists determine which drugs and what dosages would be the best course of treatment.

Some companies are working on cancer vaccines, drugs derived from a cancer antigen on a patient's tumor. An antigen is a protein on the surface of a tumor cell that varies from patient to patient.

In theory, such a cancer vaccine is designed to teach the body's immune system to recognize and kill the tumor cells.

“My projection is that five years from now we are going to be genotyping everyone when they are born, so we have the basic knowledge of an individual's genetics as part of their medical record,” Flatley said. “It will be essential for doctors to determine the right dose of the right drug at the right time.”

First Anniversary of ENCODE - video interviews with leading Genomics experts in Cold Springs Harbor

LEIF ANDERSSON

KELLY FRAZER

MICHAEL ASHBURNER

RICHARD GIBBS

LEENA PELTONEN

DAVID BENTLEY

DAVID HAUSSLER

DAVID SCHWARTZ

LEO BRIZUELA

THOMAS HUDSON

KARI STEFANSSON

CARLOS BUSTAMANTE

MICHAEL LEVINE

DIETRICH STEPHAN

MICHELE CLAMP

JOSEPH MCINERNEY

HILLARY SUSSMAN

JOSEPH ECKER

ELAINE MARDIS

GEORGE WEINSTOCK

XAVIER ESTIVILL

RICK MYERS

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

Calif. cracks down on 13 genetic testing startups

By MARCUS WOHLSEN – 42 minutes ago

SAN FRANCISCO (AP) — California health regulators have demanded that 13 direct-to-consumer genetic testing startups halt sales in the state until they prove they meet state standards.

The state Department of Public Health sent the cease-and-desist letters last week following an investigation spurred by consumer complaints about the tests' accuracy and cost, a department spokeswoman said Monday.

Two of the most visible companies to offer consumer genetic tests — Redwood Shores-based Navigenics Inc. and Mountain View-based 23andMe Inc. — confirmed receiving the letters.

Health officials would not identify the companies involved until confirming they had received the letters but said all the targeted companies advertise on the Internet.

All the companies have two weeks to demonstrate to regulators that their laboratories are certified by the state and federal governments, said department spokeswoman Lea Brooks. The startups also must show the tests they are selling California residents have been ordered by a doctor as required by state law.

"There's either concern they don't have a license, there isn't a physician's order, or both," Brooks said. "That's what's under investigation."

Companies face fines of up to $3,000 a day.

The New York State Department of Health issued similar notices to nearly two dozen testing companies in April.

The crackdowns follow the launch of a batch of new DNA analysis services spawned by recent genetic discoveries. The mostly Web-based services will scan customers' genes to spot potential health risks, from cancer to lower back pain.

State and federal public health officials have urged consumers to be skeptical, pointing out that related research is in its earliest stages and doctors have little training in interpreting the results.

The federal Food and Drug Administration does not evaluate the tests for accuracy, though a federal panel recently recommended stepped-up oversight to ensure their validity.

A spokeswoman for 23andMe, which has financial backing from Google Inc. and Genentech Inc., described the company as an "informational service."

"What we do is offer people information about their genetic makeup, including ancestry and applicable scientific research," spokeswoman Rachel Cohen said. The company scans customers' DNA for about $1,000. Cohen declined to say Monday whether 23andMe had halted sales in California.

Navigenics charges $2,500 to screen nearly 2 million genetic markers in a DNA sample — typically a swab of saliva — for potential health risks.

In a statement released Monday, Navigenics said it believed it was in full compliance with California law. The company said it would submit details to regulators showing its labs were certified and its tests are ordered and reviewed by California-licensed physicians.

First ENCODE Anniversary

Today (June 14, 2008) marks the First Anniversary of the ENCODE Pilot-result release.

It is time to take stock if Francis Collins' call for the science community to "re-think long-held views" was appropriately answered in a single year.

An announcement in a few days will provide a definite answer. [UPDATE: See announcement of The Principle of Recursive Genome Function, Online by Springer, New York]

[More info at pellionisz_at_junkdna.com June 14, 2008]

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

Applied Biosystems Joins 1000 Genomes Project

June 13, 2008

Foster City, CA - Leaders of the 1000 Genomes Project announced recently that three firms that have pioneered development of new sequencing technologies have joined the international effort to build the most detailed map to date of human genetic variation as a tool for medical research. The new participants are: Applied Biosystems, an Applera Corporation business in Foster City, Calif.; 454 Life Sciences, a Roche company in Branford, Conn.; and Illumina Inc. in San Diego.

The 1000 Genomes Project, which was announced in January 2008, is an international research consortium that is creating a new map of the human genome that will provide a view of biomedically relevant DNA variations at a resolution unmatched by current resources. Organizations that have already committed major support to the project are: the Beijing Genomics Institute, Shenzhen, China; the Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K.; and the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. The NHGRI-supported work is being done by the institute's Large-Scale Sequencing Network, which includes the Human Genome Sequencing Center at Baylor College of Medicine, Houston; the Broad Institute of MIT and Harvard, Cambridge, Mass.; and the Washington University Genome Sequencing Center at Washington University School of Medicine, St. Louis.

"The additional sequencing capacity and expertise provided by the three companies in the pilot phase will enable us to explore the human genome with even greater depth and speed than we had originally envisioned, and will help us to optimize the design of the full study to follow," said Richard Durbin, Ph.D., of the Wellcome Trust Sanger Institute, who is co-chair of the consortium. "It is a win-win arrangement for all involved. The companies will gain an exciting opportunity to test their technologies on hundreds of samples of human DNA, and the project will obtain data and insight to achieve its goals in a more efficient and cost-effective manner than we could without their help."

The genetic blueprints, or genomes, of any two humans are more than 99 percent the same. Still, the small fraction of genetic material that varies among people holds valuable clues to individual differences in susceptibility to disease, response to drugs and sensitivity to environmental factors.

The 1000 Genomes Project builds upon the International HapMap Project, which produced a comprehensive catalog of human genetic variation – variation that is organized into neighborhoods called haplotypes. The HapMap catalog laid the foundation for the recent explosion of genome-wide association studies that have identified more than 130 genetic variants linked to a wide range of common diseases, including type 2 diabetes, coronary artery disease, prostate and breast cancers, rheumatoid arthritis, inflammatory bowel disease and a number of mental illnesses.

The HapMap catalog, however, only identifies genetic variants that are present at a frequency of 5 percent or greater. The catalog produced by the 1000 Genomes Project will map many more details of the human genome and how it varies among individuals, identifying genetic variants that are present at a frequency of 1 percent across most of the genome and down to 0.5 percent or lower within genes. The 1000 Genomes Project's high-resolution catalog will serve to accelerate many future studies of people with specific illnesses.

"In some ways, this application of the new sequencing technologies is like building bigger telescopes," said NHGRI Director Francis S. Collins, M.D., Ph.D. "Just as astronomers see farther and more clearly into the universe with bigger telescopes, the results of the 1000 Genomes Project will give us greater resolution as we view our own genetic blueprint. We'll be able to see more things more clearly than ever before and that will be important for understanding the genetic contributions to health and illness."

The HapMap was based mainly on genotyping technology, in which genetic markers were used to broadly scan the genome. In contrast, the 1000 Genomes Project catalog will be built on sequencing technology, in which the genome is examined at the level of individual DNA letters, or bases. The increased resolution will enable the 1000 Genomes' map to provide researchers with far more genomic context than the HapMap, including more precise information about the genetic variants that might directly contribute to disease.

To enhance the production of the 1000 Genomes map, each of the three biotech companies, including Applied Biosystems, has agreed to sequence the equivalent of 75 billion DNA bases as part of the pilot phase. The human genome contains about 3 billion bases. Consequently, each company will contribute the equivalent of 25 human genomes over the next year, and additional sequence data over the project's expected three-year timeline. In addition, Applied Biosystems is expected to contribute an additional 200 billion bases of human sequence through its collaboration with Baylor.

"This project is clearly the most ambitious and comprehensive study to date of the human genome," said Francisco de la Vega, distinguished scientific fellow and vice president for SOLiD System applications and bioinformatics at Applied Biosystems. "Our participation continues our commitment to partner with the scientific community to explore the genetic factors involved in human disease."

In its first phase, expected to last about a year, the 1000 Genomes Project is conducting three pilots that will be used to decide the best strategies for achieving the goals of the full-scale effort. The first pilot involves sequencing the genomes of six people (two nuclear families) at high resolution; the second involves sequencing the genomes of 180 people at lower resolution; and the third involves sequencing the coding regions of 1,000 genes in about 1,000 people.

The full-scale project will involve sequencing the genomes of at least 1,000 people, drawn from several populations around the world. The project will use samples from donors who have given informed consent for their DNA to be analyzed and placed in public databases. Most of these samples have already been collected, and any additional samples will come from specific populations. The data will contain no medical or personal identifying information about the donors.

Given the rapid pace of sequencing technology development, the cost of the entire effort is difficult to estimate, but is expected to be about $60M. The sequence data provided by the three companies are estimated to be worth approximately $700,000 for the pilot phase, and the firms are expected to contribute much more sequencing to the full project.

Already, the 1000 Genomes Project has generated such vast quantities of data that the information is taxing the current capacity of public research databases. Since the first phase was begun in late January, project participants have produced and deposited some 240 billion bases of genetic information with the European Bioinformatics Institute and the National Center for Biotechnology Information, a part of the U.S. National Library of Medicine. Data generated by the 1000 Genomes Project also will be distributed from a mirror site at BGI Shenzhen.

Along with their contributions of sequencing capacity, Applied Biosystems, like all other project participants, have agreed to comply with the policies established by the 1000 Genomes Project Steering Committee. Those policies include rapid public release of the data, including project participants having no early access to the data; an intellectual property policy that precludes any participants from controlling the information produced by the project; regular progress reporting; and coordination of scientific publications with the rest of the consortium.

Additional information about the project can be found at http://www.1000genomes.org/.

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

Apple in Parallel: Turning the PC World Upside Down?

Steve Job's Parappler Computer [ AJP]

June 10, 2008, 9:50 am
By John Markoff

At the outset of his presentation at the opening session of Apple’s Worldwide Developers Conference, Steve Jobs showed a slide of a stool with three legs to describe the company’s businesses: Macintosh, music and the iPhone.

The company is making another bet on parallelism, and the implications may be more profound than anyone yet realizes.

In describing the next version of the Mac OS X operating system, dubbed Snow Leopard, Mr. Jobs said Apple would focus principally on technology for the next generation of the industry’s increasingly parallel computer processors.

Today the personal computer industry is going through a wrenching change in trying to find a way to keep up with the speed increases that were the hallmark of the PC business until about five years ago. At that point, companies like Intel, I.B.M. and A.M.D. had simply lived off their continual ability to increase the clock speeds of their microprocessors. But the industry hit a wall as chips reached the melting point.

As a consequence, the industry shifted gears and began making lower-power processors that added multiple C.P.U.’s. The idea was to gain speed by breaking up problems into multiple pieces and computing the parts simultaneously.

The problem is that, having headed down that path, the industry is now admitting that it doesn’t know how to program the new parallel chips efficiently when the number of cores goes above a handful.

On Monday, Mr. Jobs asserted that Apple was coming to the rescue.

“We’ve added over a thousand features to Mac OS X in the last five years,” he said Monday in an interview after his presentation. “We’re going to hit the pause button on new features.”

Instead, the company is going to focus on what he called “foundational features” that will be the basis for a future version of the operating system.

“The way the processor industry is going is to add more and more cores, but nobody knows how to program those things,” he said. “I mean, two, yeah; four, not really; eight, forget it.”

Apple, he asserted, has made a parallel-programming breakthrough.

It is all about the software, he said. Apple purchased a chip company, PA Semi, in April, but the heart of Snow Leopard will be about a parallel-programming technology that the company has code-named Grand Central.

“PA Semi is going to do system-on-chips for iPhones and iPods,” he said.

Grand Central will be at the heart of Snow Leopard, he said, and the shift in technology direction raises lots of fascinating questions, including what will happen to Apple’s partnership with Intel.

ADDED: Snow Leopard will also tap the computing power inherent in the graphics processors that are now used in tandem with microprocessors in almost all personal and mobile computers. Mr. Jobs described a new processing standard that Apple is proposing called OpenCL (Open Compute LibraryComputing Language) which is intended to refocus graphics processors on standard computing functions.

“Basically it lets you use graphics processors to do computation,” he said. “It’s way beyond what Nvidia or anyone else has, and it’s really simple.”

Since Intel trails both Nvidia and A.M.D.’s ATI graphics processor division, it may mean that future Apple computers will look very different in terms of hardware.

Just this week, for example, a Los Alamos National Laboratory set the world supercomputer processing speed record. The machine was based largely on a fleet of more than 12,000 I.B.M. Cell processors, originally designed for the Sony PS3 video-game machine.

If Apple can use similar chips to power its future computers, it will change the computer industry.

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

Third Wave to Acquire Stratagene's Full Velocity Patents for $3.9M

[May 30, 2008]

This article has been updated to include the purchase price as disclosed in a regulatory filing.[Contratulation to GenomeWeb staff writer! - AJP]

NEW YORK (GenomeWeb News) – Third Wave Technologies said today that it has agreed to acquire Stratagene’s Full Velocity patents from Agilent Technologies.

In a filing with the US Securities and Exchange Commission, Third Wave said that it would pay Agilent $3.9 million, to be paid in quarterly installments over a period of three years with simple interest at an annual rate of 4.75 percent.

The Full Velocity technology provided the basis for Stratagene’s PCR and RT-PCR-based reagents and assays and is a competitor to Third Wave’s Invader technology. Stratagene’s technology was at the center of a patent suit that Third Wave brought against the firm and won in a US District Court in Wisconsin in December 2005.

Stratagene had also filed a countersuit against Third Wave alleging patent infringement. But the firms settled all litigation in January 2007, which resulted in Stratagene paying Third Wave $10.75 million.

Stratagene was subsequently acquired by Agilent nearly a year ago for $250 million. In acquiring Stratagene, Agilent gained a number of molecular diagnostic partnerships, including one with Bayer Diagnostics. The products developed under those collaborations are based on the Full Velocity technology.

Third Wave said that the acquisition of the Full Velocity patents strengthens its intellectual property position for its Invader Plus products, which combine Invader chemistry with PCR.

“Third Wave’s strategic acquisition of the Full Velocity patents cements an integral part of our clinical menu expansion plans and provides us valuable options in the research market,” Third Wave President and CEO Kevin Conroy said in a statement.

The Madison, Wis.-based firm said it is developing the next generation of Invader chemistries, which will amplify and detect DNA, RNA, and microRNA on real-time PCR instruments. It said that the new chemistries would enable it to reach new research markets including the $500 million quantitative PCR market.

Financial details of the patent acquisition were not released by the firms.

Genome 'trailblazer' Francis Collins departing research institute

Francis Collins, the guitar-playing geneticist who mingled a belief in Christianity with a defense of evolution, said Wednesday that he would step down as director of the National Human Genome Research Institute, where he led the historic effort to decode the human genome.

Collins, author of three books, said he would leave the institute, part of the National Institutes of Health, on Aug. 1. He said he planned to write a book on personalized medicine and would explore other endeavors. "It's been a marvelous ride," he told reporters Wednesday. "My time at NHGRI has been the most remarkable in my life."

"Francis has provided 15 years of outstanding leadership to NHGRI and has been a trailblazer in the scientific community," NIH director Elias Zerhouni said in a statement. Collins' deputy, Alan Guttmacher, will serve as acting director during the search for a successor.

Collins, 58, said he chose to leave before he has found a new role because conflict-of-interest rules make negotiating his next position "awkward." He added that President Bush's signing last week of the Genetic Information Nondiscrimination Act of 2008, which Collins championed, played a role in the timing.

He said he planned to consider a variety of options and added without mentioning names, that he would consider advising a presidential candidate. "If there's some way I can help in that regard, of course I'd be interested in doing so."

Collins has been the institute's director since April 1993. He succeeded James Watson, who, with Francis Crick, in 1953 identified the double helix as the structure of DNA. In 2001, Collins appeared with President Clinton and rival biologist J. Craig Venter of Celera Genomics to announce that their teams had produced a rough draft of the human genetic code. Collins announced the project's completion in 2003.

Venter said he "wishes Francis well" and noted that the J. Craig Venter Institute gets significant funding through NHGRI, "so we look forward to continuing to work with the new leadership."

The Human Genome Project led to other milestones, including the International HapMap Project, an effort to map genetic features that might shed light on common diseases; the Mammalian Gene Collection; and the Cancer Genome Atlas.

Collins also has played a key role in using gentics to understand the risk factors for diabetes, heart disease, cancer and mental illness. He and his co-workers have racked up impressive discoveries, including identifying genes for cystic fibrosis and Huntington's disease.

Collins' books include The Language of God: A Scientist Presents Evidence for Belief, published in 2006, which asserts that genetics and evolution reflect God's creativity. "Watching our own DNA instruction book emerge letter by letter … provided a profound sense of awe unlike anything I could've imagined. It was, after all, reading the language of God," Collins told Bob Abernethy, host of PBS' Religion and Ethics News Weekly.

Government's gene guru to resign

By LAURAN NEERGAARD – 48 minutes ago

WASHINGTON (AP) — Dr. Francis Collins, who became the public face for a watershed science project — unraveling the human genetic code — is resigning as the government's gene guru.

Collins, arguably the nation's most influential geneticist, announced Wednesday that he will leave the National Institutes of Health this summer to explore other opportunities.

The folksy geneticist helped translate the complexities of DNA into everyday vernacular, once famously calling the human genome or genetic code the "book of human life." He became a leading advocate for the privacy of genetic information.

But Collins may be better known to laymen for his 2007 best-selling book about his belief in both God and science.

Dutch scientists first to unravel a woman’s DNA

Monday 26 May 2008

A red-haired, 34-year-old Dutch woman has become the first woman in the world to have her compete DNA sequenced, scientists at Leiden University Medical Centre announced on Monday.

The entire genome of Marjolein Kriek, a clinical genetic scientist at the university, will be made public in the near future, minus a few sensitive details, professor Gert-Jan van Ommen told a press conference.

Male sequencing data has already been unraveled for four men, including Jim Watson, co-discoverer of the double helix structure of DNA. ‘It was time to balance the genders a bit,’ news agency AP reported Van Ommen as saying.

Kriek said she considered it an enormous honour to have her DNA unraveled and hoped it would help break through taboos surrounding DNA research. ‘It is not as if I know when I am going to die, just as I don’t know if I will win the lottery,’ she told reporters.

Kriek does now know that some 10,000 years ago her ancestors came from Ireland, Poland or eastern Turkey. The research also shows that Kriek’s DNA deviates from the norm on 18 points. ‘If the research shows that I have a greater risk of cancer, that is something I will keep private,’ she said.

But, she said, having more information about any health risks associated with her genetic make-up means she can take action to minimise them.

President Bush Signs Genetic Nondiscrimination Legislation Into Law

[May 22, 2008]

President Bush on Wednesday signed into law a bill (HR 493), the Genetic Information Nondiscrimination Act, that prohibits discrimination based on the results of genetic tests, the AP/San Francisco Chronicle reports (Feller, AP/San Francisco Chronicle, 5/22). Under the bill, employers cannot make decisions about whether to hire potential employees or fire or promote employees based on the results of genetic tests.

In addition, health insurers cannot deny coverage to potential members or charge higher premiums to members because of genetic test results. The House this month voted 414-1 to approve the bill, while the Senate last month approved the legislation 95-0 (Kaiser Daily Health Policy Report, 5/2).

Bush said the bill "protects our citizens from having genetic information misused ... without undermining the basic premise of the insurance industry" (Ward, Washington Times, 5/22).

After signing the legislation, Bush thanked Rep. Louise Slaughter (D-N.Y.), who waged a "13-year battle" to get genetic nondiscrimination legislation passed, and other congressional members instrumental in passage of the bill, the Rochester Democrat and Chronicle reports. According to the Democrat and Chronicle, in order to pass the bill, legislators had to overcome opposition from the U.S. Chamber of Commerce and other business groups, who said that the legislation could lead to frivolous lawsuits against employers (Kelly, Rochester Democrat and Chronicle, 5/22).

Reaction

Supporters called the bill the "first major civil rights act of the 21st century" and said they hope it will encourage more people to participate in clinical research for treatments of specific genetic sequences, according to the Chicago Sun-Times (Thomas, Chicago Sun-Times, 5/22).

Agilent Technologies Announces Licensing Agreement with Broad Institute to Develop Genome-Partitioning Kits to Streamline Next-Generation Sequencing [Back to "Junk DNA"? - No, a different "partitioning" of the whole genome - AJP]

SANTA CLARA, Calif., May 13, 2008

Agilent Technologies Inc. today announced that it has acquired a license to commercialize a method developed at the Broad Institute for genome partitioning using Agilent's Oligo Library Synthesis (OLS) technology. Financial terms were not disclosed.

Recent advances in DNA-sequencing technology have increased the speed of data acquisition. However, without accompanying improvements in the ability to select relevant portions of the genome, the technology cannot achieve its full potential in studying the relationships between genes and diseases. The Agilent genome-partitioning portfolio, which is currently in development, holds great potential for eliminating this bottleneck by enabling users to efficiently design and acquire ready-to-use, custom mixtures of biotinylated long RNA probes in a single tube.

Chad Nusbaum, Ph.D., co-director of the Genome Sequencing and Analysis Program at the Broad Institute, described the improved method at an Agilent customer event recently at the American Association of Cancer Research meeting in San Diego, Calif.

"We're working on a simple, highly multiplexed, cost-effective way to enable investigators to remove the sample-preparation bottleneck in sequencing targeted regions of mammalian genomes, using relatively small amounts of input DNA," Nusbaum said. "Agilent's expertise in custom oligo synthesis and our expertise in production-scale sequencing are a natural match-up to overcome these challenges."

"The Broad is part of our early-access program, in which we made oligo library synthesis capability available to a select number of luminaries to find out how these creative scientists could use custom complex mixtures of long oligonucleotides," said Yvonne Linney, Ph.D., Agilent vice president and general manager, Genomics. "This work to eliminate the sample preparation bottleneck of next-generation sequencing will greatly accelerate our understanding of how genes operate."

Agilent plans to offer kits containing custom mixtures of long biotinylated RNA molecules that can efficiently capture 5-10 megabases of genomic DNA sample in a single tube. The method is based on the combination of the Agilent SurePrint platform, capable of synthesizing high-quality oligo mixtures, and the protocols developed by the Broad Institute to transform these into RNA probes.

These RNA probes can, in turn, be used to capture genomic regions of interest in a simple, scalable and highly multiplexed manner, greatly simplifying the process for targeted re-sequencing.

"The ability to perform the capture reaction in a small volume solution enables a significant increase in the kinetic efficiency and enables users to scale from tens to thousands of samples without adding significant personnel," said Emily LeProust, Ph.D., Agilent R&D Chemistry and Genome Partitioning program manager.

In February, a researcher from Nusbaum's group presented a paper at the Advances in Genome and Biology Technology conference, describing the use of Agilent Oligo Libraries, the basis of the genome partitioning capability and next-generation sequencing to correctly identify several previously known mutations and several new ones in certain tumor types.

Linney said that this is also an example of how Agilent is leveraging the reagent manufacturing expertise of Stratagene, which joined Agilent in June 2007, to provide high-quality, cost-effective solutions.

The Broad Institute is a research collaboration of the Massachusetts Institute of Technology and Harvard University.

About Agilent Technologies

Agilent Technologies Inc. is the world's premier measurement company and a technology leader in communications, electronics, life sciences and chemical analysis. The company's 19,000 employees serve customers in more than 110 countries. Agilent had net revenues of $5.4 billion in fiscal 2007. Information about Agilent is available on the Web at www.agilent.com.

Merck's Informatics Mission [What should be the result of long-predicted Genomics-IT confluence? -AJP]

By Kevin Davies
Bio-IT World

May 12, 2009 | After five years at the helm of Merck's basic research IT group, Ingrid Akerblom calls her move to the clinical side "quite an eye opening experience." Akerblom has a Ph.D. in biology from University of California, San Diego and the Salk Institute, and later joined Incyte Pharmaceuticals as its 50th employee and "annotation guru," eventually leading informatics. She was then recruited by Merck - ironically the only pharma not to buy the Incyte database. She joined Merck in November 2002 - just over a year after the acquisition of Rosetta Inpharmatics. [For $620 M - AJP]. Akerblom worked extensively with the Rosetta IT leaders, helping to integrate systems around target identification and chemistry systems.

Assuming her former role is Martin Leach, a Brit who spent nine years leading IT and informatics at Curagen, spanning corporate IT, basic, pre-clinical, and regulatory informatics. But he also brings experience in regulatory and clinical IT areas gained during a two-year stint at Booz Allen prior to joining Merck last year. That clinical insight could prove useful even as he refocuses on basic research, and complements Akerblom's background in basic research as she transitions to the clinical side.

Kevin Davies spoke to Akerblom and Leach about their complementary roles and mutual understanding of the needs of both basic research and clinical teams, which could pay big dividends for Merck.

Bio•IT World: Ingrid, how did your move to clinical IT come about?

Ingrid: After five years in [research IT], with the last few years including leadership of Merck's Biomarker IT, it made sense to bring some of this expertise into the Clinical IT areas in order to meet the growing need to marry up clinical and discovery research information. In terms of how we operate, there has also been a significant evolution of the IT teams and operating model. At that time it was fully vertical, integrated. I had all the developers on my team; we had all the support on my team. Now, Martin and I really lead more of a client services team, where we have account managers, program managers, and business analysts, people with business expertise and technology expertise. Most of the delivery is done through shared services in the corporate area. And even within the Merck research labs IT, for some of the more innovative types of things that go on in research that aren't found in the other divisions like manufacturing and marketing. But we're evolving to a fully shared services model, which has its benefits, especially in clinical, with large projects.

Martin: For my groups, I have scientific computing, which is predominantly in the bio space, some cheminformatics, biomarker IT, of which there's a lot of collaboration with Ingrid. And drug discovery services, focused on lab automation, capture and management of biologic and chemical data and information, all of the things that make the basic research lab tick.

How useful will your mutual cross training prove, do you think?

Martin: One thing important to note is the new head at [Merck subsidiary] Rosetta. Kathleen Metters, the worldwide head of basic research, recently appointed Rupert Vessey to be the new head of Rosetta ... Rupert is a former clinical therapeutic area head, [so] basically we have a clinical leader heading up Rosetta, which is predominantly working on genomics, proteomics, genetics, and causal networks. So it's not just the IT with that cross-pollination - we've got two people from IT, from a clinical point of view and a basic research point of view, interacting with a former clinical person who is heading up the genomics space.

Ingrid: We've invested a lot in some core platforms; we need to start translating that into results in the clinic at some point. And so having people who have an understanding of what does that really take to help inform the earlier research directions, the platform directions, is a key theme...

When I was in Martin's position, it was very difficult to get the clinical IT teams to focus on longer term strategic projects, even short-term partnerships that weren't about a late-stage trial. Because at the end of the day, that's what they work for, right? They've got to get those trials filed. But when we think about the future, we want to have our data more integrated, and we weren't really getting a lot of traction. So one of the attractions for me moving to this position was someone who has that background will keep their eye on that ball and it won't be all about late stage. That's already proving true - there were a couple of times this year where there were scheduling conflicts between critical projects on both sides. And in the past, I know which one would have gotten dropped - it would have been the basic research project.

How is Rosetta working at Merck today?

Martin: There's Rosetta Inpharmatics, which is the part of Merck that's doing molecular profiling and genetics research, and then we have Rosetta Biosoftware, that is part of Rosetta Inpharmatics that makes and sells software products such as Resolver, Elucidator, and Syllego, which we also use internally at Merck.

At Rosetta Inpharmatics, I work closely with scientists working in the bioinformatics and the pathways space, who have taken a biological point of view to integrate information. One approach is trying to integrate as much information that is accessible, assay data and so on, for when scientists pull up a gene or target. They have developed a target gene index (TGI)... With a given gene, you can see all the relevant information. I think most pharmas have attempted that. I'd say it's the depth of the information and integration with some of the chemical space that is different than what I have seen at other pharmas. This depth of integration within TGI is still growing... We do data integration and data management within basic research IT, and we provide some of the core services needed to do it from a research point of view.

How do you interact on a more day to day level?

Martin: We have some very high level, strategic, long-term projects that we're working on. We have a large number of folks from my camp working with a large number from Ingrid's camp around the IT needs and implications with all the different clinical data, as well as sample data, and access to this information that's needed to enable translational research. So we have joint projects, very strategic, they have visibility all the way up to the MRL leadership.

In terms of some of the things being done at Rosetta, again, it crosses into the basic and clinical space, and we work together on making sure the right people are engaged in either basic or clinical IT. [Between the basic and clinical IT teams] we are very collaborative in terms of key strategic hires.

Ingrid: We're getting much closer to actually using genetics in our trials, based on the technology set up by our Seattle genetics group and the whole genome analysis group (See, "Merck Ties Gene Networks to Obesity"). We have a project team meeting with Martin, our business and information architects, and Rosetta Biosoftware together with clinical franchise and regulatory leaders, to talk about what is the actual proposed data flow and architecture for moving genetics data from research systems into the clinical systems. Having formerly been in basic [research], it's a lot easier to really see how that all fits together and how to move this data into the clinical systems now.

The Rosetta Biosoftware Syllego system that is being used by the FDA, is something we're looking at - How does that fit into the clinical architecture? We have a clinical warehouse, where should the genetic data go? Should it be Syllego for raw data and CDR for metadata? Again, it's moving into reality now, so understanding what that means and being on the clinical side I think is going to make it a lot easier to easily assimilate that type of data into the mainstream clinical systems.

My Basic IT team worked with the Imaging Research team to put in place an imaging platform with IBM, and Martin's team is continuing this work, that's working well in the early development and research space. Now I want to say look, we could save a tremendous amount of money if we move that into the late stage. But how to do that where every investigator now has to learn that system?... Do we show it through our portal or does it come in through EDC or on its own? So there are all these support issues once you start thinking about really getting out into the clinic with some of these newer things.

How are you handling the surge of data, especially related to genomics?

Martin: Where we are doing work on pharmacogenomics and genetics in the clinical space, there is so much data. For example, one of my team had to secure an additional 100 terabytes (TB) on the East Coast to just accommodate one experiment they were doing! Soon, I'm going to be playing around in the petabytes... At the moment, we need to keep the raw data because there's no clear guidance from the FDA as to what you need to keep. It's going to literally swamp us working in this space until we get better guidance around what data we need to keep versus could keep. One of my [team's] projects is basically a storage strategy this year because if it's 100 TB this year, it's probably going to be a couple of hundred TB next year...

We all [in the industry] have data and document retention policies, but what tools do we have to really monitor and manage that? If I've got a couple of hundred TB that's going to come around in the next couple of years, how do I know what to purge five years from now? Where are the tools to do that really large data management and purging? In the current file sharing landscape we have millions of files that normally have to be managed through retention policies. That's a challenge in itself. What is developing is managing a fewer number of files but with a large overall volume.

How do you view translational medicine?

Martin: In two parts. The first part is increasing the clinical context of basic research experiments, using clinically relevant samples with their clinical information, allowing you to "translate" additional research measurements on the samples with a clinical context. So that enables the research, but then as you get into the pharmacogenomics space, where you're looking at genetic information to segregate populations for responders and non-responders, that's then taking basic research discoveries and really applying them into the clinical space. So I sort of see translational medicine as that mix of pharmacogenomics and biomarkers and everything rolled into one.

Ingrid: I agree. One of the key areas is clearly samples, whether you're doing proteomics, gene expression, genetics, or potentially looking at what populations eventually could respond to your drug. Samples are at the center of that and so we have been actively pursuing better informatics around that in order to make it clear what samples are available from what trials, which are consented, and what can we use them for. We already have siloed platforms to show that data, we need to integrate it more than it is... We have a new standards-based clinical warehouse that went into production last year, where we're really planning to have all the patient data - whether it's through collaborations or Merck trials - in one place so that it's more available for our future data mining and understanding what types of patients and associated samples we have.

Martin: We have a major strategic collaboration with the H. Lee Moffitt Cancer Center [Tampa, FL] (See "Cancer Center Builds Gene Biobank," Bio•IT World, June 2007.) We get different types of cancer samples and those samples go to Rosetta [for] expression profiling. Moffitt uses that expression data internally for their research, and we get clinical data associated with the samples, as well as the expression profiling data, and we get to use that at Merck... This is a major collaboration driven by Stephen Friend [senior VP of Oncology] and the Oncology franchise. I think it's a landmark in how we approach translational medicine at Merck... Data from this collaboration was the first clinical data from oncology that made its way into Merck's clinical data repository (CDR).

So we have clinical data securely flowing directly from Moffitt through the firewalls, etc., into Merck's CDR meeting all compliance needs. And that data through web services is then shared to Rosetta and other places so that it can be integrated with expression profiling data. We've really embraced industry standards to make that happen. This really has been breaking down silos - it's very hard to find a clinical group that opens up web services where that information is then accessible to basic research. I think that in itself was groundbreaking at Merck. We've tried looking around to other pharmas, like are you guys doing this sort of thing? Everyone is talking to the standards boards, but I think we've really [made] an investment by implementing some of this work in a real active strategic collaboration...

Ingrid: The other important piece in that project that addresses the translational medicine question is that there are joint project teams between Merck and Moffitt clinical and basic researchers, all trying to mine and look at field experiments, build trials, identify new mechanisms, think about the future together. It's a very powerful collaboration, and IT has a seat at that table and is an active participant in those conversations. So I think it's a great area of translation where we really are leveraging clinical data to drive research.

How has informatics evolved at Merck? With budget tightening everywhere, does that impact the build-buy decision?

Ingrid: Ever since I joined, we've been primarily a buy shop, even in basic research. We mostly buy and we try not to customize too much, but you still end up in that space. The clinical systems have been primarily internally built, and now they are mostly purchased, with the exception of the data warehouse, which is based on the Janus data model, but it was still built inside with outsourcing. Where we're trying to find cost savings is in sharing services, particularly around support, maintenance of applications, infrastructure - trying to drive down cost on the maintenance and operations side in order to continue to invest in the new development of strategic applications.

There are innovative areas with many of them in the emerging research technologies where you're doing things that you just can't buy, where faster iterative in-house development is needed, for example we developed MouseTrap to support the management and display of animal phenotypic data. Generally speaking, it's quite a challenge. You've got to really be focused and the business has to partner with you to prioritize... it's critical to have a strong partnership and governance with scientific leaders to assure we are focusing IT resources on the right projects. The other thing is they're also feeling the money pressure. So it's not just IT, it's not just the services anymore, it's everybody really looking at how are we going to contribute to optimizing the bottom line, and how are we going to grow the top line, and let's all prioritize those initiatives together.

What are some projects where you think you're really going to be able to expedite or make better decisions? And what outstanding challenges remain?

Martin: We're in a position now where we know how to generate information for biomarkers, and we know how to collect clinical information. So at least one project this year is, "What is that killer application that you need to integrate the clinical information with biomarker information, so that we really do enable our scientists in their biomarker discovery or validation experiments?" At the moment, we've got bits of the puzzle - genetics being managed in Syllego, expression managed in Resolver, proteomics managed in Elucidator, these all being separate applications and repositories. But what is that killer application that brings it all together and integrates it with clinical, so that you can do some meaningful mining and analysis? That's one of my goals, and I've got some exciting challenges to work through there.

Ingrid: I think that's a shared one, because in the clinical sample area, combining the results data from clinical samples with the associated patient data, what's that platform? I know there are new commercially available things coming out like Azyxxi from Microsoft. So we need to be looking at what's out there, what's the gap, and do we put something together ourselves? We did a pilot last year with an EII platform collaborating with IBM. There was enough productivity gain from that to justify taking EII to the next level which our Innovation IT team is doing in 2008. The whole integration space and then the actual viewing of integrated data in a meaningful way continues to be a major focus.

We're embarking on an electronic medical records (EMR) strategy looking for signal detection among other uses. We're redoing our pharmacovigilance system and approaches. Those are things that are just starting to be reinvested in, figuring out how do we leverage that information, how do we get that connected? There's also appetite for clinical trial simulations across a number of dimensions including enrollment and operations optimization. We just overhauled our entire late-stage development systems in 18 months, so right now we're focused on ensuring that that gets optimized and the value from that investment gets realized.

Martin: Who is going to be the health partner with Merck? Where do we place our bet in key strategic partnerships thinking around EMR data or personal medical record data, and how do we find the best partners to enable translational research? From there it's doing the analysis of who will be the best partner and when will they be mature enough or Merck mature enough to interact with them.

Another exciting challenge is working with the external basic research team, [Catherine Strader, former head of research at Schering-Plough]. I'm working with her so that we really leverage information from our collaborations. In the past, how information flows in a collaboration has been managed ad hoc. Moving forward we really want to leverage and integrate this information more strategically.

What roles do the senior executives such as Peter Kim and Stephen Friend play?

Ingrid: Peter has a vision. He focuses us all on recognizing that the vast majority of information and innovation is happening outside the walls of Merck. We need to leverage it more by providing platforms that allow deep collaboration with external partners; there also is a focus on combining our own data with publicly generated data for competitive advantage - but holding the line to work pre-competitively where it makes sense. You get that vision through the research strategy meetings.

I think Stephen Friend is clearly a visionary who inspires many individuals at Merck both on the science side and the IT side, a very forward thinker pushing all the teams, Rosetta as well as myself and Martin, to think out of the box.

Research firm bases FPGA on Fractal-like Structure

Amir Ben-Artzi

EE Times Europe

(04/29/2008 4:00 DE EDT)

NETANYA, Israel — Cellot Ltd. (Netanya, Israel) is developing a programmable logic and memory architecture dubbed Field Programmable Cell Logic (FPCL), which is based on a recursive, fractal-like, structure. Ofer Meged, Cellot's founder, president and CTO, told EE Times that the company's chip will be primarily targeted at fabs, ASIC developers and hardware developers in various areas, including space applications. "FPLC technology has been validated and tested both on the theoretical and the implementation level," said Meged, who added that the company is currently in the process of raising initial funding of $5 million.

The FPCL architecture is optimized for complex and real-time applications where the approach usually an SOC or a collection of DSPs or FPGAs, said Meged. "In my opinion, we have created a new category in the worlds of programmable devices and structured ASICs." Meged argued that FPCL represents a small-sized programmable solution which offers a short time to market and an attractive price, and therefore the company will initially aim to serve developers, foundries and fabs.

Although some implementation work has been done the the core FPCL chip design is described as being in a pre-fab state. "We have patented our technology in Europe, the U.S and Japan, but we need the funding before we are able to go forward," said Meged. Cellot's FPCL architecture is a collection of registered memory cells interconnected via a programmable matrix that creates a recursive hierarchical (fractal-like) structure. That means that all of the cells are similar and any number of cells may be combined to create similar larger cells. Each cell can be used for logic when memory is used as a look-up table, or as storage, or both. The matrix can route the output of each cell to the input of each cell and each I/O with a fixed and predictable delay, according to Cellot.

Cellot said its PC-based development system enables the use of a high level language such as C++, Verilog, and schematic capture in the design process.

The architecture can be used to create any application, the company claimed. Cellot argued that FPLC technology is particularly applicable to fields such as evolvable hardware applications, supercomputers and neural networks.

"Every part of our component is 100 percent replaceable," claimed Meged. "In certain configurations, it can correct itself, and this is useful for space applications." The company said it plans to offer a family of FPCL chips, plus a library of intellectual property cores for useful functions that can be re-used as design building blocks. These will be accompanied by design and debugging tools including simulation and testing tools, in addition to logic analyzers, signal generators, synthesis tools, and a PCI acceleration board.

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

Unlocking the human genome: Pioneering researcher joins Buck Institute

Richard Halstead

Article Launched: 05/03/2008 10:50:34 PM PDT

VICTORIA LUNYAK, a groundbreaking genetic researcher who has just joined the Buck Institute for Age Research in Novato, credits her father for launching her career in science.

"My father, he was a physicist," Lunyak said. "He pushed me to become a scientist. Otherwise, I would have become probably a ballerina, because my mother wanted me to become a ballerina."

Lunyak, 41, earned her doctorate in molecular biology at the St. Petersburg Nuclear Physics Institute in Russia before coming to the United States 12 years ago to do research at the Department of Molecular Biology at Brown University. More recently, she was an assistant research scientist at the University of California at San Diego.

This spring, Lunyak arrived at the Buck Institute, where she will establish a program in epigenetics, a promising new field of biological research with far-reaching implications for the understanding of cancer and aging. While at UC San Diego, Lunyak led several studies describing the role of epigenetics in neurobiology and organ development.

Epigenetics, a field that is only about a decade old, [actually, more than seven decades old; The word "epigenetics" (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 - AJP] as revolutionized science's understanding of biological inheritance. Prior to the mapping of the human genome in 2003, it was believed that DNA carried all heritable information and that nothing people did during their lifetime would be biologically passed to their children.

Scientists working in the field of epigenetics have since discovered switches that can turn genes on or off.

These switches can be activated by things people experience, such as nutrition and stress. Epigenetic theory has explained how identical twins become distinct as they age. It also explains why different types of cells - brain cells and skin cells, for example - are different even though they contain the same DNA. And epigenetics explains how patterns of gene expression are passed from one cell to its descendants as cells age.

"Epigenetic changes can be acquired during life, but can also be inherited, and appear to be important in the aging process, in certain diseases of aging, and in stem cell development," said David Greenberg, vice president of special research at the Buck Institute.

At UC San Diego, Lunyak focused her research on the boundaries that separate areas of activated genes from areas of genes that have been deactivated by the epigenetic switches. These boundaries in the genome are made up of DNA that was previously regarded as "junk" because its function was mysterious.

But research by Lunyak, detailed in the July 2007 issue of Science, revealed that these boundaries act as epigenetic punctuation marks - commas and periods that help orchestrate waves of transcriptional programs in the coding portion of the genome.

Not long ago, it was believed that cancer resulted solely because of genetic changes. Now, however, scientists think that cancer is caused by a mixture of genetic and epigenetic changes. One explanation for cancer is that "something is happening in the ability of cells to properly place those bookmarks between active domains and repressed domains," Lunyak said.

That is good news because, unlike genetic damage, epigenetic changes can sometimes be reversed. Scientists have found a few drugs that can alter epigenetic patterns. Epigenetic therapy has shown promise in treating people with a form of cancer that causes overproduction of blood cells in the bone marrow.

The problem, Lunyak said, is that these drugs use a shotgun approach to altering epigenetic patterns. It is unknown what unintended effects they may be having on the genome's normal epigenetic functioning.

"It is very dangerous," she said.

That is why Lunyak intends to focus her work at the Buck Institute on mapping epigenetic blueprints for healthy cells and cells that are diseased. The hope is that such blueprints will allow doctors to target drugs so they alter only that section of the epigenetic program that is causing a problem.

It will be a big job. Different types of cells - skin, eyes, teeth, hair - will all have unique epigenetic blueprints. Epigenetic mapping efforts are also proceeding at Baylor College of Medicine in Houston, Texas and at UCLA. Lunyak will start with stem cells due to their unique ability to transform into many different cell types in the body. She estimates the project could take five years.

"It's not a quick-fix project," Lunyak said.

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

Slaughter's Anti-Genetic Discrimination Bill Becomes Law

Rachel Ward

ROCHESTER, NY (2008-05-03) Legislation slated for President Bush's signature will make much genetic discrimination illegal. The president has indicated that he will sign the Genetic Information Nondiscrimination Act, or GINA, which was first proposed by Fairport congresswoman Louise Slaughter 13 years ago...

The bill would bar health insurance companies from using genetic information to set premiums or determine enrollment eligibility. Similarly, employers could not use genetic information in hiring, firing or promotion decisions.

The bill passed the Senate unanimously last week and had only one dissenting vote in the House earlier on Thursday.

Slaughter is a microbiologist. She says that she was delighted by the scientific possibilities that could stem from the mapping of the human genome, but unnerved by the potential abuses. Slaughter says that having a faulty gene is only a prediction -- not a certainty -- of having future health problems. She says that's not sufficient cause to be denied or terminated from a job

Slaughter says when people don't have to fear genetic discrimination, a whole new type of health care is possible in which therapies can be tailored to each patients' needs.

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

Mitrionics FPGA-Accelerated Computing Platform for Bio and Genome Informatics Demonstrated at Bio-IT World Conference

Monday April 28, 11:42 am ET

BOSTON, M -- Bio-IT World Conference & Expo -- Mitrionics(TM), Inc., developer of the Mitrion(TM) Software Acceleration Platform and the Mitrion Virtual Processor, today announced it will be presenting and promoting its latest advancements in accelerated computing at the Bio-IT World Conference this April 28-30, 2008 in Boston, Massachusetts. Mitrionics released an upgrade to its SDK, including the Mitrion SDK Personal Edition, a free, downloadable, software development kit (SDK) designed to promote the development of accelerated applications with researchers in life science industries such as bioinformatics, genome informatics and high throughput sequencing. Mitrion-accelerated applications running on the Mitrion Virtual Processor (MVP) provide a dual customer benefit by increasing application performance 20x to 60x or greater when used with Intel and AMD processors while using ninety percent less power consumption than traditional systems. Mitrionics will be located in booth #306/308 with its partner SGI.

"The genomics industry is at the forefront for the adoption, development, and implementation of accelerated computing technologies and applications," said Anders Dellson, CEO of Mitrionics, "Our free, Mitrion SDK Personal Edition is designed to help build a healthy bio-centric ecosystem for FPGA-based Accelerated Computing and Green Computing."

Mitrionics has achieved a number of milestones in the accelerated computing industry over the past 18 months including: running its open source Mitrion-accelerated BLASTn on a 70 FPGA cluster, achieving up to 900x performance increase versus commodity clusters, the establisment of the Mitrion Open Bio Project, and selection by a number of leading global research organizations customers for its accelerated BLASTn software.

In the past year, numerous accelerated computing hardware platforms have been introduced into the market but a problem existed in fully utilizing them. Mitrionics fills the gap with broad accessibility to a development platform enabling software acceleration that researchers and software developers can use immediately.

"Our customers are pleased to see processor companies Intel and AMD, and system vendors SGI and HP increase their support for FPGA-accelerated computers. Mitrionics solves the previous problem with programming FPGAs," said Mike Calise, executive vice president of Mitrionics, Inc.

Mitrion SDK PE

The Mitrion SDK Personal Edition (PE) will allow researchers, scientists, developers, institutions, and independent software vendors (ISVs) to develop and accelerate a wide range of high performance computing applications to run on the Mitrion Virtual Processor (MVP) configured on FPGA-based computer systems. The software-centric Mitrion SDK is the fastest and easiest way to accelerate an application's performance by programming the computationally intensive part of the application to run on an FPGA. The Mitrion SDK is different from other FPGA programming solutions because it requires absolutely no hardware design skills or experience.

The Mitrion Software Development Kit Personal Edition is a free version of the Mitrion SDK that allows the developer to start developing accelerated applications for the MVP ahead of FPGA hardware. The Mitrion SDK PE is a complete development environment for Mitrion-C applications. It includes an IDE, a Mitrion-C compiler and a graphical debugger. It does not, however, include the capability to generate Mitrion Virtual Processors that will run in FPGA hardware. To do this, the commercial version Mitrion SDK is required. The Mitrion SDK PE can be downloaded for free at www.mitrionics.com.

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

Baylor College of Medicine to Use Applied Biosystems Genetic Analysis Technology as Part of 1000 Genomes Project

SOLiD™ System to Help Researchers Decide Best Approach for Sequencing Complete Human Genomes

HOUSTON & FOSTER CITY, Calif.--(BUSINESS WIRE)--Scientists at the Baylor College of Medicine Human Genome Sequencing Center (HGSC) will use high-throughput sequencing systems from Applied Biosystems (NYSE:ABI), an Applera Corporation business, for a significant part of their contribution to the first pilot phases of the 1000 Genomes Project, sponsored by the National Human Genome Research Institute (NHGRI), the Wellcome Trust and the Beijing Genome Institute. This project is a worldwide research effort that will involve the sequencing of 1,000 genomes from people from around the world to create the most detailed and medically useful picture to date of human genetic variation. The HGSC will acquire six SOLiD™ Systems in order to complete the work.

The data generated as part of the 1000 Genomes Project is expected to reveal clues about how variant DNA sequences contribute to conditions such as cancer, diabetes and heart disease. The HGSC is utilizing the SOLiD System to expand its contribution of the first phases of the project and help researchers to determine the best methods for sequencing these 1,000 human genomes.

The first phases of the project began earlier this month. When the pilot phase of this project is complete, the HGSC will have used the SOLiD System to generate approximately 200 billion bases of sequence data over a span of four months. This sequence data will consist of significant sequence coverage of 24 human genome samples; and much deeper coverage of a single human genome sample. This amount of data is equivalent to the entire contents of GenBank, the largest public repository of DNA sequence data.

In the analysis of human genetic variation, the depth of coverage refers to the number of times each of the approximately 3 billion base-pairs of DNA from one genome is read by a genetic analysis system. Deeper coverage of a genome increases the confidence researchers have in characterizing the bases that exist at each position within a genome. As a result, researchers are better able to recognize the occurrence of variants in the genome. According to the HGSC, one goal of the pilot phase of the 1000 Genomes Project will be to determine the depth of sequence coverage from different data types that are needed in order to fully understand how sequences of DNA in the genome vary significantly between individuals.

One reason why the HGSC chose to use the SOLiD System for this project is because of its extremely high throughput capability. The SOLiD System has now demonstrated that it can produce greater than 10 gigabases per run, which is more than 3x genome coverage. The throughput of the SOLiD System establishes it as the highest throughput genetic analysis system available today. An ultra-high-throughput genetic analysis system will help enable scientists at the HGSC to complete this project in an efficient and cost-effective manner.

“There is clearly a role for very high density data from platforms that generate read lengths in the 25-50 base range,” said Dr. Richard Gibbs, director of the HGSC at Baylor College of Medicine. “We believe that the SOLiD System will dominate in this arena. The production and pooling of data from multiple sources and platforms on the same samples in the 1000 Genomes Project will help researchers ultimately determine the genetic analysis platform of choice.”

Although most human genetic information is the same in all people, researchers are generally more interested in studying the small percentage of genetic material that varies among individuals. Researchers characterize genetic variation as either single-base changes – single nucleotide polymorphisms – or as a series of larger stretches of sequence variation known as structural variants. To effectively characterize SNPs in the genome for the 1000 Genomes Project, researchers must be able to distinguish real genetic variants from sequencing errors, which requires a highly accurate genetic analysis system. A combination of depth of coverage and a highly accurate genetic analysis system helps researchers identify the genetic differences that exist between individuals.

Use of higher accuracy genetic analysis systems will require lower depth of coverage to confidently characterize variants in genome samples. HGSC’s decision to use the SOLiD System for the 1000 Genomes Project was in part based on a comparative study of microbial and mammalian genomes sequenced by the SOLiD System and competing short-read platforms.

“Accuracy is vital, not just for the 1000 Genomes Project, but for all other applications, too,” said Donna Muzny director of operations at the HGSC. “The internal error-checking strategy for the SOLiD System makes it superior for the read lengths that are produced.”

In deciphering the human genome, researchers strive to both accurately identify and locate genetic variants in the genome. Mate pair analysis, or the ability of a genetic analysis system to analyze pairs of sequences separated by a known distance between them – known as the insert size – allows researchers to determine the precise location of structural variants in the genome. Structural variants consist of gene copy number variations, single base duplications, inversions, translocations, insertions and deletions. For instance, by analyzing insert sizes up to 10,000 base pairs, the SOLiD System can cover sequences that span large regions of repeated patterns within the genome. Mate pair analysis also enables accurate placement of sequence reads in and around repeat regions, which can vary greatly among individuals. This capability of the SOLiD System will help researchers to accurately piece together large numbers of DNA sequence fragments as they assemble these sequences into entire human genomes.

Once researchers determine the depth of coverage necessary to confidently characterize SNPs and structural variants in human genome samples, they will be able to make better use of genomic information. For instance, researchers will be able to more effectively use this information to understand how these variations are related to an individual’s susceptibility to disease and response to treatment for disease, which is the promise of personalized medicine.

“The HGSC’s decision to scale up on the SOLiD System for a large population resequencing project further validates the benefits of the platform for these types of studies,” said Shaf Yousaf president for Applied Biosystems’ molecular and cell biology genomic analysis division. “The successful completion of this project should enable broader applications of genomic analysis and open the door for a host of personalized medicine, and disease association studies. We believe this project will move life-science researchers a step closer to defining the precise relationship between human genetic variation and disease.”

About the SOLiD System

The SOLiD System is an end-to-end next-generation genetic analysis solution comprised of the sequencing unit, chemistry, a computing cluster and data storage. The platform is based on sequencing by oligonucleotide ligation and detection. Unlike polymerase sequencing approaches, the SOLiD System utilizes a proprietary technology called stepwise ligation, which generates high-quality data for applications including: whole genome sequencing, chromatin immunoprecipitation (ChIP), microbial sequencing, digital karyotyping, medical sequencing, genotyping, gene expression, and small RNA discovery, among others.

Unparalleled throughput and scalability distinguish the SOLiD System from other genetic analysis sequencing platforms. The system can be scaled to support a higher density of sequence per slide through bead enrichment. Beads are an integral part of the SOLiD System’s open-slide format architecture, which enables the system to generate greater than 6 gigabases of sequence data per run. The SOLiD System has demonstrated runs greater than 10 gigabases per run at customer locations. The combination of the open-slide format, bead enrichment, and software algorithms provide the infrastructure for allowing it to scale to even higher throughput, without significant changes to the platform’s current hardware or software.

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

Beijing Genomics Institute Signs Multi-Million Dollar Order for 11 Additional Illumina Genome Analyzers

Illumina, Inc. ILMN today announced that in early March Beijing Genomics Institute (BGI) purchased 11 Genome Analyzers, increasing the organization's total number of the Illumina sequencing systems to 17. BGI is the fourth genome center to expand its Genome Analyzer install base to double digits. As a result of recent enhancements to the Genome Analyzer, BGI researchers will have the capacity to sequence more than two human genomes to 25x coverage per week. This significant increase in throughput will expand BGI's capacity for sequencing services to the local genetic research labs, as well as broaden the range and pace of sequencing projects undertaken by the organization, such as the YangHuang 99 project, the 1000 Genomes Project, the Giant Panda Project, the tree of life project, and numerous other large-scale initiatives.

"BGI is focused on accelerating the rate of scientific discovery, and expanding our understanding of genetic variation and diversity across human genomes. We have worked closely with Illumina to determine ways to dramatically increase our sequencing capacity in order to efficiently and quickly complete several new large sequencing projects," stated Xiuqing Zhang, Director of the Sequencing Division of the Beijing Genomics Institute. "After rigorously testing this sequencing platform, we opted to purchase the additional Genome Analyzers because of the machine's enhanced level of performance, price, and ease of use. Combined with the longer 500bp reads from other platforms, Illumina is the most suitable high throughput sequencing platform for accurate de novo genome sequencing. The collaborative relationship that we established with Illumina this past year also played a significant role in our decision to scale up to 17 Genome Analyzers."

BGI is among the world's leading scientific organizations, and aims to advance the understanding of biology and medicine through the use of large-scale sequencing and bioinformatics analysis. The institute also offers sequencing services to the international community. BGI promotes the use of genome-scale scientific approaches and strongly supports collaborative efforts in order to achieve this goal.

"BGI's decision to acquire 11 additional Genome Analyzers is further validation that our sequencing platform is delivering leading performance, and becoming the sequencing platform of choice," said Christian Henry, Acting General Manager of Illumina's Sequencing Business. "With its unmatched rate of daily output, ease of use, and proven paired-end sequencing capability, the Genome Analyzer will continue to provide the scalable solution researchers need to complete projects that were not possible one year ago."

Designed for facilities of all sizes, the Genome Analyzer has experienced rapid adoption across genome centers worldwide, including individual research labs, core and service facilities, and biotechnology and pharmaceutical companies. Specified to generate more than three gigabases of high-quality data over a five-day paired-end read run, the Genome Analyzer offers the highest rate of daily output and the simplest and most user friendly workflow. The Genome Analyzer also offers the broadest set of supported applications, including those used to profile and discover novel miRNA, to create a high-resolution genome-wide map of DNA-protein binding sites, or to sequence a whole-human genome to greater than 30x coverage. The system's groundbreaking capabilities are further validated by the continuing stream of customer peer-reviewed publications, now numbering more than 50.

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

Genetic Discrimination Law Passes Senate with Compromises

[April 24, 2008]

By Matt Jones

a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – The US Senate today unanimously passed the Genetic Information Nondiscrimination Act after senators agreed to compromises that had held up the bill since last summer.

After over a decade of failed attempts to pass the law, which has passed both houses of congress more than once with wide margins, only never in the same session, GINA also is expected to pass in the US House of Representatives as early as next week and be signed into law “in short order,” Kurt Bardella, press secretary for GINA sponsor Olympia Snowe (R – Maine), told GenomeWeb Daily News today.

GINA “passed the house twice with considerable support,” Bardella said.

The bill, which would protect Americans from discrimination based on information from genetic tests, sailed through the House a year ago by a vote of 420 to 3, but never made its way to a Senate vote after it was placed on hold by Senator Tom Coburn (R – Okla.).

Coburn has since raised concerns about the bill focused primarily on the potential for lawsuits and employers’ rights. In March of this year, he and ten other senators signed a letter to the White House listing their complaints, signaling a new threat to GINA’s passage.

“We believe the final draft of GINA should provide clarity to the health insurance industry, maintain the integrity of the underwriting process, and ensure accurate premium assessments,” the senators stated in the letter.

Now, the lawmakers have agreed to a key compromise that would salve Coburn’s concerns by adding language to create a "firewall" between the parts of the bill dealing with insurers and employers, an adjustment Coburn and the White House said was needed to protect them from some lawsuits, a source on Capitol Hill told GWDN today.

The agreement included other "minor" changes having to do with phrasing, according to the source, who asked to remain anonymous.

Senator Coburn’s office was not immediately available for comment to explain further its stance on the compromises.

As GWDN reported in March, when GINA passed the house as an amendment to another unrelated bill, the Paul Wellstone Mental Health Act, Coburn had other concerns with GINA, and it was not immediately clear how many of these have been agreed upon.

According to Bardella, the Senate will call up the House version of the bill and then insert the changes into the new Senate bill before voting on it and sending it back to the House.

“The passage of GINA today represents the culmination of an effort that began more than ten years ago to put in place landmark protections to safeguard Americans against genetic discrimination,” Snowe said today in a statement.

"Utilizing genetic testing can improve health, reduce spending, and lower health care costs. Yet our laws have not kept pace with emerging technology, and doubts about the misuse of genetic information are preventing Americans from getting tested," she said.

Snowe’s office said it expects the House to pass the bill with unanimous consent and expects President Bush to put his name on it. “We expect the White House will be pleased to sign the bill into law,” Bardella said.

While the passage of the bill was the product of “thirteen years of work,” Genetic Alliance director Sharon Terry told GWDN today, the recent consensus was the result of “constant meetings between the White House, republicans and democrats.”

Terry described the effort for the compromise as a product of a “great conversation” between all parties involved and the engagement of the genetics community. The sudden advancement of consumer genomics businesses over the past year and greater discussion about the uses and ethics of genetic tests in the media could have helped push the bipartisan effort.

“Thirteen years ago,’ Terry said, “we were talking about only a few tests, and now we’re talking about mainstream medicine.”

“Our challenge now is to make sure that doctors and patients are aware of these new protections so that fear of discrimination never again stands in the way of a decision to take a genetic test that could save a life," Kathy Hudson, director of the Genetics and Public Policy Center at Johns Hopkins University.

The pending passage of the bill also was lauded by the Personalized Medicine Coalition, a collection of industry, academic, payor, and other partners who advocate for the advancement of personalized healthcare.

“The guarantees provided by this legislation will encourage millions of Americans to use their genetic information to improve their healthcare, and to help prevent and treat cancer and other diseases,” Edward Abrahams, executive director of the PMC, said in a statement.

Mari Baker, president and CEO of consumer genomics services firm Navigenics, also applauded the Senate’s passage of the bill. “This is fundamental, foundational legislation that’s critical for the long-term ability of using genetic information to improve healthcare in this country,” Baker told GWDN today.

“With GINA passing, people can now have confidence that this information will not be used to discriminate against them, and this industry can move forward.”

[The scariest (or most beautiful?) aspect of the oncoming "Dreaded DNA Data Deluge" is, that the above article outlines mostly the first wave of the Tsunami - and the behind it the second looming wave is orders of magnitude bigger. There is just one line above to advise that there are actually three challenges (storage bandwidth, computational analysis, and data retention/migration policies. "The architecture must be of robust enough design to solve all three bottlenecks). While this article focuses on storage, why bother to store anything if we don't intend to actually use the genomic information? Here comes the second whammy; "computational analysis"; to come to some conclusions, e.g. for just a single human DNA sequence sample. There is already a lucrative market in Personal Genomics for analysis of just 0.5 M (of the 3200 M) data-points of e.g. "microarray" probes. One single array takes 4 hours of "wetwork" followed by TWO DAYS of computational analysis. If the computational analysis would require linearly more time for just one human "full genome", this would amount to 35 years of computing time... (and the function is not linear...). So why is the challenge "beautiful" rather than "depressing"? Because the "state of art" is presently "brute force" performed on old computing architecture. With Algorithmic Approaches implemented on Next-Generation Architecture Computing it should not take a generation to wait for computational analysis results of a Personal Genome...

[Does information improve the quality of life? In general, the answer is a resounding YES. With the fledging industry of DTC Personal Genomics the ways and means HOW the information will help people is emerging and to some seems controversial, the cornerstone of medicine is "informed consent". People certainly have the right for the information about their bodies, and as long as they are willing to pay for it, there will always be business to take it as an opportunity to satisfy customers.

.... - pellionisz_at_junkdna.com April, 9, 2008]
^ back to table of contents ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^