News Bulletin of International HoloGenomics Society

1 in 20,000 people suffer from FSHD — what makes it different than diseases like diabetes is that inheriting the gene means the person will one day get the genetic disease.

While scientists knew genetics was to blame, they didn’t exactly know why and how it caused disease. Now they know, zombies are to blame.

The researchers published their results in Science.

There’s a certain rhythm to this madness. To cause disease, the gene needs to be repeated a number of times and has to have the right sequence. The trouble gene is found on chromosome 4 (which is a region scientists eyed for several decades).

If the zombie gene is repeated more than 10 times, the person will not develop FSHD. Researchers believe the surplus copies change the structure of the chromosome so the zombie gene can’t attack. Otherwise, the gene (DUX4) is allowed to be made and becomes toxic to the muscle cells.

This finding fundamentally changes how geneticists think about simple genetic diseases. It’s clear that even though FSHD was thought to be a simple disease because having the gene meant the person would definitely get the disease, it’s actually much more complex than that.

In the future, researchers could knock out this dead gene and develop new treatments.

Scientists believe they will discover that other diseases will have similar causes.

Geneticist Dr. Francis Collins told The New York Times, “the first law of the genome is that anything that can go wrong, will.”

Comments--

Pellionisz

08/20/10

The "Junk DNA" misnomer was put forward as a "theory" (though totally wrong, and suspect after its first utterance) by Susumu Ohno (1972), an otherwise serious scientist; see "So much 'Junk' DNA in our genome" (full text in my junkdna.com domain). He mistakenly argued that the non-genic sequences are in the genome "for the importance of doing nothing" (p. 367).

It was only later that this catastrophic misnomer became widely accepted at face value - as an excuse for the establishment to (BTW negligently) ignore 98.7% of (human) DNA - while millions if not hundreds of millions were (and still are) dying of "Junk DNA diseases".

"The Principle of Recursive Genome Function" (2008), by retiring both the "Junk DNA" and "Central Dogma" obsolete axioms became the first full genome (hologenome) theory based on sound genome informatics, sweeping away science-nonsense that retarded genomics for over half a Century (starting from Crick's notion in 1956, that he dared to call "Central Dogma", that information "never" recurses from either RNA or from
PROTEINS to DNA).

Upon conclusion of ENCODE (2007) Francis Collins was the one to issue a public call "the scientific community will have to re-think long-held beliefs". Some lucky few did not have to re-think as they never believed the two false axioms in the first place - but now we have (really, not the first...) experimental evidence as a de facto basis to discard wrong assumptions that were totally absurd from the viewpoint of genome informatics. 1.3% of human DNA (in fact, much less since "genes" may contain a big majority of non-coding introns) is simply not enough information to govern growth of as complex organisms as humans.

FractoGene (2002) clinched it in one year after it was established that the expected 140-300,000 "genes" were nowhere to be found by The Human Genome Project. Today, "recursive genome function" prevails with close to 200,000 hits in Google...

"Fractal defects" such as reported, with the recursion derailed and/or not supported with enough auxiliary information by sufficient number of recursion not only "have been expected", but theoretically predicted. - Pellionisz_at_JunkDNA.com

IMWeira

08/23/10

Dear Pellionisz; excellent post. I have not heard it put quite that way but some of us borderline science junkies have not accepted the junk dna designation nor could we understand why anyone would accept it.

I will mention your site to some of my friends and see you there.

JohnMcGrew@...

08/23/10

Interesting.

@Pellionisz, thanks for that info. Very interesting reading.

wizoddg

08/23/10

What Pellionisz said... Is far better put than I've heard before.

But it is a symptom of the way we do research on nearly everything--if it's not seen to be part of the current problem, we discard it...only later finding that it is causing other problems or preventing them.

Part of this in medicine is the practice of studying diseases (disorders) while ignoring the study of properly functioning systems.

We've spend many many decades studying disorders to find cause and cures--at the expense of ignoring the 'benign' organisms...many of which, once examined, turned out to be essential for our health--not merely not causing problems.

We finance medical research by popularity--rather than spending our time and energy where we as a society will get the most return for the effort, we routinely spend money based upon the ability to raise funding--filling the world with images of dying children and causing the public to mis-perceive the actual risk/benefit ratios.

Investing by emotion rather than analysis, while extremely human, is counter-productive.We end up spending money to treat 'horrific' problems, rather than the problems which kill or disable the most people.

The number one killer in the world today is heart disease and related circulatory issues--yet I routinely receive pleas for funding for many other conditions which affect far fewer people, and far too often those making the appeal believe that they are actually working to find a cure for something which is kills "the most."

Much unexpressed DNA is like that in the article--old ills piggyback ridding upon our genes.

Another large group are genes which are expressed only under certain circumstances

In the past couple decades we've learned that such gene expression can continue generations after the triggering circumstance has disappeared from the environment.

With the discovery of what crystallized DNA looks like decades ago, the public assumed that it meant we understood DNA. This has happened anew with each new advance.

The latest, the mapping of the genome is seen by the public as an end--that mapping means understanding.

In fact, each major step we make is merely the beginning of understanding--often forcing us to toss out our favorite theories of how things work.

In a world where understanding changes rapidly, it is every bit as valuable to be able to 'unlearn' and let go of previously loved theories as new data arises.

The one advantage that the scientific method has over the dogmatic methods of our more distant past, is the recognition that knowledge [better said, "understanding", since knowledge constantly advances, but understanding leaps with paradigm-shifts -AJP] is not static.

[It is a delight to see that the public is far ahead of some of the ossified parts of the establishment in understanding that Genetics-Genomics-HoloGenomics experiences far more profound "paradigm-shift" than previously imagined. We have to bring attention that by "What is Life?" Schroedinger questioned (1944) none of the "diseases" but the informatics-axioms of how Life is encoded (he predicted that covalent H-bindings of an aperiodical crystal encode life - later acknowledged by Crick the pioneering vision of Schroedinger, when Watson, Crick, Wilkinson and Franklin realized (1953) that the DNA crystal is aperiodical in the nucleotides, though is periodical (helical) in the physical arrangement of the aperiodical bases. Crick attempted to provide a further axiomatic basis of Life (not diseases...) by putting forward in 1956 (the unfortunately totally mistaken, and brazenly called "Central Dogma of Molecular Biology") that "information never recourses from Proteins to DNA". This wrong axiom (shored up by Ohno's "Junk DNA" second fatal axiom, 1972) set modern Genomics back by more than half a Century - which is relatively a short time comparing to the setback that the suppression of dismissal-attempt of "Geocentric" mistaken axiom inflicted upon our understanding of the surrounding universe. The Vatican admitted some 300 years after Giordano Bruno was torched to death alive and his ashes were thrown to the Tiberis, that actually his paradigm-shift was correct. No wonder that bringing a "lucid heresy on two counts"; dismissal of both mistaken axioms have proven to take such toll in the process of bringing it to the status of the presently prevailing leading paradigm. The blogger is "right on the money" that US Congress finances its Agencies based on "popularity" (meaning, votes) - and (mostly through NIH) e.g. The Human Genome Project deteriorated into a "gene discovery" - where the surprisingly few genes were (largely mistakenly) associated with particular diseases. Now, this horrendously expensive detour (yielding not much, if anything say the very leaders...) seems finally over. Mostly, not because a rigorous scientific rationale necessarily results in automatic victory (see Giordano Bruno...). Two non-scientific factors appear actually more important. One is (proven by this blog...) that the general public (who are not only voters, but actual taxpayers) realizes in massive droves that Agencies put on an auto-pilot of a mushrooming bureaucracy are heading into the void of a wrong direction, and thus look at some Agencies in a different way than before (and may cast their votes differently, how to spend their own hard-earned tax-dollars). Most important, however, it seems that postmodern Genomics is already deep into its "Industrialization" (i.e. a massive migration from government-led R&D to businesses of the Global Private Sector), where "popularity" drops into the important, but not so essential "marketing department" - while the primary drivers are the validated science, technology, performance, cost-efficacy, proper supply-chain management, etc., etc. The first segment where the transition from government R&D to Private Industry is practically complete is "Affordable Full Human DNA Sequencing". The dollar billions already invested into sequencing industry, however, will relentlessly drive postmodern Genomics away from "popularity of Sick-Care", into the direction of valid science-based predictive, participatory and personalized prevention; a new paradigm not only in Genomics, but genome-based Health Care. To maintain health, we must first understand how the healthy hologenome functions - and not in less than exact biological terms, but in terms of software-enabling algorithmic explanations, like "recursive genome function". Thus, sequencing industry will become a driver, since their only product (DNA sequences) are virtually worthless without interpreting their function by means of intrinsic algorithms, turned into potent software - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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Pacific Biosciences Denies Helicos' Infringement Claims

September 01, 2010

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Pacific Biosciences today said that it believes the patent infringement claims brought against the company last week by Helicos Biosciences are without merit and that it intends to vigorously defend against the claims.

Helicos filed the suit Friday in the US District Court for the District of Delaware. It claims that Pacific Biosciences is infringing claims in four of its US Patents: Nos. 7,645,596; 7,037,687; 7,169,560; and 7,767,400.

Those patents cover Helicos' methods for sequencing a single strand of DNA by synthesizing a complementary strand of DNA using labeled nucleotide bases. This sequencing-by-synthesis method underlies Helicos' single-molecule sequencing platform.

"Helicos' patents are directed to methods used in their second generation 'flush and scan' system, and even at that, do not represent the earliest publication of those concepts," Hugh Martin, Pacific Biosciences' chairman and CEO, said in a statement. "Our third generation SMRT technology observes single molecules in real time, a fundamentally different approach."

Menlo Park, Calif.-based PacBio is gearing up for a commercial launch in early 2012 of its RS sequencing instrument. Among customers who have placed orders for the system are Baylor College of Medicine, the Broad Institute, Cold Spring Harbor Laboratory, the US Department of Energy Joint Genome Institute, The Genome Center at Washington University, Monsanto, the National Cancer Institute, the National Center for Genome Resources, the Ontario Institute for Cancer Research, Stanford University, and the Wellcome Trust Sanger Institute.

[Molecular Sequencing Industry is thriving - IPO-positioning, major M/A, IP lawsuits are all clear signs of an Industry coming alive. The question is not if, but when, who and (most importantly) "what is in it for me?" by everyone. One important reminder: NOTHING is in mere sequencing for anybody (except patent attorneys, but what else is new?) until and after the algorithmic understanding of "recursive genome function" will have been achieved, even partially, and software-enabling algorithms, now with the escalating "cloud solutions" are properly wrapped into the game - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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Will Fractals Revolutionize Physics, Biology and Other Sciences?

[Look at Romanesca also in The Principle of Recursive Genome Function - AJP]

A new discovery, reported in the latest Nature, hints at higher universal laws of the physical world, as well as new ways to approach and understand life in general. Even though the European discovery actually dealt with superconductors, it has an interesting twist with implications for the life sciences [predicted by FractoGene by Pellionisz, 2002 - AJP].

A group of physicists from London Centre for Nanotechnology at UCL and their collaborators at Sapienza University of Rome and European Synchrotron Radiation Facility in Grenoble, France were studying properties of so-called high-transition-temperature (high-Tc) copper oxide superconductors. They were looking at the microstructures that these superconductors form as they are cooled down. To the surprise of investigators, they discovered that microstructures, exhibited by oxygen atoms, seemed to organize into self-repeating fractals. Moreover, these fractal shapes, some extending almost to the millimeter scale, were correlating to superconductivity. In fact, larger fractals correlated with higher superconductivity temps.

What does it have to do with life? We think, plenty. Fractals, known for their geometric morphologies that are made up of patterns that repeat themselves at smaller scales infinitely, were first discovered by mathematician Benoit Mandelbrot in 1960s. Since then, they took the world of natural sciences by storm. As mathematicians and physicists discovered more and more interesting properties of these unique constructs, people started to notice fractals' ubiquitous presence in nature. Whether in the living world or in inorganic one, they seem to pop up in unexpected places. Somehow, there are laws of physics that favor these structures for whatever reason.

To us, the discovery of fractal function is eerily reminiscent of polarization in pre-quantum mechanical physics. Not until Niels Bohr, Albert Einstein and others laid the foundations of quantum mechanics, polarization of light has remained a mystery. Now we have a new puzzle to answer. Fractals are ubiquitous in the physical and living world for some unknown reason, and there is a function to them.

Paper in Nature: Scale-free structural organization of oxygen interstitials in La2CuO4+y

UCL press release: Fractals make better superconductors ...

More from Wired: Inexplicable Superconductor Fractals Hint at Higher Universal Laws...

Wired

Inexplicable Superconductor Fractals Hint at Higher Universal Laws

Wired
By Brandon Keim
August 11, 2010

What seemed to be flaws in the structure of a mystery metal may have given physicists a glimpse into as-yet-undiscovered laws of the universe.

The qualities of a high-temperature superconductor — a compound in which electrons obey the spooky laws of quantum physics, and flow in perfect synchrony, without friction — appear linked to the fractal arrangements of seemingly random oxygen atoms.

...

“Everyone was looking at these materials as ordered and homogeneous,” said Bianconi. That is not the case — but neither, he found, was the position of oxygen atoms truly random. Instead, they assumed complex geometries, possessing a fractal form: A small part of the pattern resembles a larger part, which in turn resembles a larger part, and so on.

“Such fractals are ubiquitous elsewhere in nature,” wrote Leiden University theoretical physicist Jan Zaanen in an accompanying commentary, but “it comes as a complete surprise that crystal defects can accomplish this feat.”

If what Zaanen described as “surprisingly beautiful” patterns were all Bianconi found, the results would have been striking enough. But they appear to have a function.

...

However, while the arrangement of oxygen atoms appears to influence the quantum behaviors of electrons, neither Bianconi nor Zaanen have any idea how that could be. That fractal arrangements are seen in so many other systems — from leaf patterns to stock market fluctuations to the frequency of earthquakes — suggests some sort of common underlying laws, but these remain speculative.

According to Zaanen, the closest mathematical description of superconductive behavior comes from something called “Anti de Sitter space / Conformal Field Theory correspondence,” a subset of string theory that attempts to describe the physics of black holes.

That’s a dramatic connection. But as Zaanen wrote, “This fractal defect structure is astonishing, and there is nothing in the textbooks even hinting at an explanation.”

[FractoGene (Pellionisz, 2002) attributes efficacy to the fractal coding of organelles, organs and organisms by means of fractal DNA. The "frighteningly unsophisticated" (quoting Venter) "Genes and Junk" primitive notion of genome function would have you believe the idiocy that the exon-fractions of 1.3% of the non-Junk DNA (information of a stamp-sized digital picture...) would suffice to generate e.g. a human body and brain. The second decade of Genome Revolution (now with Fractal Revolution...) is to rectify that historical insult. - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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Reanimated ‘Junk’ DNA Is Found to Cause Disease

New York Times
By GINA KOLATA
August 19, 2010

The human genome is riddled with dead genes, fossils of a sort, dating back hundreds of thousands of years — the genome’s equivalent of an attic full of broken and useless junk.Some of those genes, surprised geneticists reported Thursday, can rise from the dead like zombies, waking up to cause one of the most common forms of muscular dystrophy. This is the first time, geneticists say, that they have seen a dead gene come back to life and cause a disease.

“If we were thinking of a collection of the genome’s greatest hits, this would go on the list,” said Dr. Francis Collins, a human geneticist and director of the National Institutes of Health.

The disease, facioscapulohumeral muscular dystrophy, known as FSHD, is one of the most common forms of muscular dystrophy. It was known to be inherited in a simple pattern. But before this paper, published online Thursday in Science by a group of researchers, its cause was poorly understood.

The culprit gene is part of what has been called junk DNA, regions whose function, if any, is largely unknown. In this case, the dead genes had seemed permanently disabled. But, said Dr. Collins, “the first law of the genome is that anything that can go wrong, will.” David Housman, a geneticist at M.I.T., said scientists will now be looking for other diseases with similar causes, and they expect to find them.

“As soon as you understand something that was staring you in the face and leaving you clueless, the first thing you ask is, ‘Where else is this happening?’ ” Dr. Housman said.

But, he added, in a way FSHD was the easy case — it is a disease that affects every single person who inherits the genetic defect. Other diseases are more subtle, affecting some people more than others, causing a range of symptoms. The trick, he said, is to be “astute enough to pick out the patterns that connect you to the DNA.”

FSHD affects about 1 in 20,000 people, causing a progressive weakening of muscles in the upper arms, around the shoulder blades and in the face — people who have the disease cannot smile. It is a dominant genetic disease. If a parent has the gene mutation that causes it, each child has a 50 percent chance of getting it too. And anyone who inherits the gene is absolutely certain to get the disease.

About two decades ago, geneticists zeroed in on the region of the genome that seemed to be the culprit: the tip of the longer arm of chromosome 4, which was made up of a long chain of repeated copies of a dead gene. The dead gene was also repeated on chromosome 10, but that area of repeats seemed innocuous, unrelated to the disease. Only chromosome 4 was a problem.

“It was a repeated element,” said Dr. Kenneth Fischbeck, chief of the neurogenetics branch at the National Institute of Neurological Disorders and Stroke. “An ancient gene stuck on the tip of chromosome 4. It was a dead gene; there was no evidence that it was expressed.”

And the more they looked at that region of chromosome 4, the more puzzling it was. No one whose dead gene was repeated more than 10 times ever got FSHD. But only some people with fewer than 10 copies got the disease.

A group of researchers in the Netherlands and the United States had a meeting about five years ago to try to figure it out, and began collaborating. “We kept meeting here, year after year,” said Dr. Stephen J. Tapscott, a neurology professor at the University of Washington.

As they studied the repeated, but dead, gene, Dr. Tapscott and his colleagues realized that it was not completely inactive. It is always transcribed — copied by the cell as a first step to making a protein. But the transcriptions were faulty, disintegrating right away. They were missing a crucial section, called a poly (A) sequence, needed to stabilize them.

When the dead gene had this sequence, it came back to life. “It’s an if and only if,” Dr. Housman said. “You have to have 10 copies or fewer. And you have to have poly (A). Either one is not enough.”

But why would people be protected if they have more than 10 copies of the dead gene? Researchers say that those extra copies change the chromosome’s structure, shutting off the whole region so it cannot be used.

Why the reactivated gene affects only muscles of the face, shoulders and arms remains a mystery. The only clue is that the gene is similar to ones that are important in development.

In the meantime, says Dr. Housman, who was not involved in the research but is chairman of the scientific advisory board of the FSHD Society, an advocacy group led by patients, the work reveals a way to search for treatments.

“It has made it clear what the target is,” he said. “Turning off that dead gene. I am certain you can hit it.”

The bigger lesson, Dr. Collins said, is that diseases can arise in very complicated ways. Scientists used to think the genetic basis for medical disorders, like dominantly inherited diseases, would be straightforward. Only complex diseases, like diabetes, would have complex genetic origins.

“Well, my gosh,” Dr. Collins said. “Here’s a simple disease with an incredibly elaborate mechanism.”

“To come up with this sort of mechanism for a disease to arise — I don’t think we expected that,” Dr. Collins said.

[Susumu Ohno (1972), an otherwise serious scientist, put forward his (totally wrong) theory, see in junkdna.com full text free, that the non-genes are in the human genome "for the importance of doing nothing". It was only later that this catastrophic misnomer became widely accepted at face value - as an excuse such that the establishment could feel free to ignore 98.7% of (human) DNA - while millions if not hundreds of millions were (and still are) dying of "Junk DNA diseases". "The Principle of Recursive Genome Function" (2008), by retiring both the "Junk DNA" and "Central Dogma" obsolete axioms became the first full genome (hologenome) theory based on sound genome informatics, sweeping away science nonsense that retarded genomics for over half a Century (starting from Crick's notion in 1956, that he dared to call "Central Dogma" that information "never" recurses from either RNA or from PROTEINS to DNA). Upon conclusion of ENCODE (2007) Francis Collins was the one to issue a public call "the scientific community will have to re-think long-held beliefs". Some lucky few did not have to re-think as they never believed the two false axioms in the first place - but now we have (really, not the first...) factual evidence to discard wrong assumptions that were totally absurd from the viewpoint of genome informatics. 1.3% of human DNA (in fact, much less since most of the "genes" are non-coding introns) is simply not enough information to govern growth of as complex organisms as humans. FractoGene (2002) clinched it in one year after it was established that the expected 140-300 thousand "genes" were nowhere to be found by The Human Genome Project. Today, "recursive genome function" prevails with close to 200,000 hits in Google.... - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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Life Technologies inks $725M deal for Ion Torrent

August 18, 2010 — 11:23am ET | By John Carroll
FierceBiotech

Arming itself for a looming showdown with Illumina over the booming market for second-generation gene sequencing technologies, Life Technologies struck a deal to buy Ion Torrent for $375 million in cash and stock with $350 million more on the line based on a series of milestones.

The deal gives Life Technologies a shot at introducing a gene sequencing device later this year that will be sold for less than $100,000, according to the San Diego Union-Tribune. A variety of companies have been angling for the fast track in the race to market new, faster and far cheaper sequencing technologies.

"We believe Ion Torrent's technology will represent a profound change for the life sciences industry," said Gregory Lucier, chairman and chief executive of Life Technologies. "This technology will usher in a new era in science, one in which DNA sequencing can be done easier, faster and more cost effectively than ever before."

- check out the San Diego Union-Tribune story [below]
- here's the Life Technologies release [below]

SingOn San Diego

Life Technologies of Carlsbad said Tuesday it will acquire Ion Torrent, a Guilford, Conn., company that has developed a new way of sequencing genes, in a deal worth as much as $725 million.

The move is Life Technologies’ latest effort to boost its position in the increasingly competitive and potentially lucrative genomic sequencing technology business.

It also intensifies the rivalry between Life Technologies and Illumina, another San Diego genetic sequencing technology company, said Daniel MacArthur, a genetic researcher at the Wellcome Trust Sanger Institute in Cambridge, England.

“Life Technologies already owns a second-generation sequencing platform [SOLiD - AJP], but has been struggling to compete against the current market-dominating technology from Illumina [with their Genome Analyzer - AJP],” MacArthur wrote Tuesday on his blog, Genetic Future.

Life Technologies is paying $375 million in cash and stock for Ion Torrent, a privately held company created in August 2007 by high-speed DNA sequencing developer Jonathan Rothberg. The sellers will receive up to $350 million in additional cash and stock if certain milestones are reached by 2012.

“We believe Ion Torrent’s technology will represent a profound change for the life sciences industry,” said Gregory T. Lucier, chairman and chief executive of Life Technologies. “This technology will usher in a new era in science, one in which DNA sequencing can be done easier, faster and more cost effectively than ever before.”

Standard DNA sequencing devices use a chemical process to attach fluorescent tags to individual pieces of DNA, which are then illuminated by lasers and photographed with a high-tech camera. Super computers interpret the light signals and convert them into usable genetic data. The process is time consuming and costly.

With the technology developed by Ion Torrent, tiny pH meters measure the change in acidity that occurs in a solution when DNA base pairs are formed. Those pH changes are then translated into the alphabet code that identifies genetic strands.

Life Technologies will launch the Personal Genome Machine, the first commercial sequencing device to use Ion Torrent’s process, later this year at a cost of less than $100,000, the San Diego company said. [Life Technologies, with its SOLiD, may not be known as best in "on rig software" - thus, this business move opened the "Big Four" (PacBio, Complete Genomics, Oxford Nanopore and Ion Torrent) to the vulnerability of software, especially algorithmic IP, as the critical factor for users - AJP]

Life Technologies announced the purchase after stock markets closed Tuesday.

In after-hours trading, the company’s shares were up 36 cents, or nearly 1 percent, to $45.31.

[Business Wire - Company Release]

CARLSBAD, Calif. & GUILFORD, Conn., Aug 17, 2010 (BUSINESS WIRE) -- --Complements Existing Sequencing Solutions Portfolio

Life Technologies Corporation, a provider of innovative life science solutions, today announced a definitive agreement to acquire Ion Torrent for $375 million in cash and stock.

The sellers are entitled to additional consideration of $350 million in cash and stock upon the achievement of certain technical and time-based milestones through 2012. Life Technologies' Board of Directors has approved an additional share repurchase program in order to repurchase its shares associated with the stock portion of the consideration. The impact on total share count is expected to be neutral.

Formed by life sciences pioneer Dr. Jonathan Rothberg, founder of CuraGen, 454 Life Sciences and co-founder of Raindance Technologies, Ion Torrent has revolutionized DNA sequencing by enabling a direct connection between chemical and digital information through the use of proven semiconductor technology. Ion Torrent's proprietary chip-based sequencing represents a new paradigm in DNA sequencing by using PostLight(TM) sequencing technology, the first of its kind to eliminate the cost and complexity associated with the extended optical detection currently used in all other sequencing platforms.

The first product using this technology will be the Personal Genome Machine (PGM), an easy-to-use, highly-accurate benchtop instrument optimal for mid-scale sequencing projects, such as targeted and microbial sequencing. The instrument is currently available through an early access program and will be launched later this year at an entry cost of less than $100,000. Subsequent products will benefit from cutting edge semiconductor fabrication technologies that can expand throughput at an accelerated pace, thereby dramatically lowering the cost to sequence a genome.

Gregory T. Lucier, Chairman and Chief Executive Officer of Life Technologies, said, "We believe Ion Torrent's technology will represent a profound change for the life sciences industry, as fundamental as the one we saw with the introduction of qPCR. This technology will usher in a new era in science, one in which DNA sequencing can be done easier, faster and more cost effectively than ever before.

"By leveraging the cumulative $1 trillion already invested in semiconductor research and development, we believe that Ion Torrent will drive unprecedented scalability, delivering the solution required for future generations of sequencing," Lucier continued. "With a heritage of more than 25 years as a leader in sequencing, Life Technologies is perfectly suited to bring such an innovative technological breakthrough to market."

Mark Stevenson, Life Technologies' President and Chief Operating Officer, said, "This transaction enhances our strategy of providing a complete sequencing offering to our customers across the research and applied markets. Ion Torrent's technologies are highly complementary to our existing portfolio of sequencing CE and SOLiD platforms."

Dr. Rothberg said, "The entire Ion Torrent team is excited to be joining the talented people at Life Technologies. Our products and mission make this an ideal and logical strategic fit for both companies. Both Ion Torrent and Life Technologies share rich cultures of innovation and excellence, and I firmly believe that Life Technologies is the right partner to bring such revolutionary technology in the sequencing arena to market."

Dr. Rothberg will continue to lead Ion Torrent with the support of the Ion Torrent leadership team. Life Technologies intends to retain Ion Torrent's presence in Guilford, CT and South San Francisco, CA where it has established R&D centers of excellence.

Life Technologies will finance the transaction with cash on hand, available lines of credit, and stock. Including the impact of specific cost saving initiatives, the transaction is expected to be 2 cents dilutive to Life Technologies' earnings per share in 2010, neutral in 2011, and accretive in 2012 and beyond. Earnings per share guidance for 2010 remains unchanged at $3.35 to $3.50. Life Technologies expects to deliver double-digit earnings-per-share growth in 2011 including the impact of this transaction. Upon closing, Life Technologies expects to benefit from synergies created by combining Ion Torrent's proprietary technologies, product pipeline and R&D capabilities with Life Technologies' commercial channel, sample preparation, sequencing automation, informatics, and reagent expertise.

Life Technologies remains committed to a strategy of balanced capital deployment, including the execution of the previously announced $350 million share repurchase. In addition, Life Technologies reaffirms its goal of reaching 10% ROIC by 2012.

The transaction, which is expected to close in the fourth quarter, is subject to customary closing conditions, including regulatory approval.

About Life Technologies

Life Technologies is a global biotechnology tools company dedicated to improving the human condition. Our systems, consumables and services enable researchers to accelerate scientific exploration, driving to discoveries and developments that make life even better. Life Technologies customers do their work across the biological spectrum, working to advance personalized medicine, regenerative science, molecular diagnostics, agricultural and environmental research, and 21st century forensics. Life Technologies had sales of $3.3 billion in 2009, employs approximately 9,000 people, has a presence in approximately 160 countries, and possesses a rapidly growing intellectual property estate of approximately 3,900 patents and exclusive licenses. Life Technologies was created by the combination of Invitrogen Corporation and Applied Biosystems Inc., and manufactures both in-vitro diagnostic products and research use only-labeled products. For more information on how we are making a difference, please visit our website: http://www.lifetechnologies.com.

About Ion Torrent

Ion Torrent has developed a DNA sequencing system that directly translates chemical signals (A, C, G, T) into digital information (0, 1) on a semiconductor chip. The result is a sequencing system that is simpler, faster, less expensive and more scalable than any other technology available. Because Ion Torrent produces its proprietary semiconductor chips in standard CMOS factories, it leverages the $1 trillion investment that has been made in the semiconductor industry. Ion Torrent uniquely and directly benefits from four decades of exponential improvement in semiconductor technology, expressed as Moore's Law. Ion Torrent will launch the Ion Personal Genome Machine sequencer in 2010. Ion Torrent was founded in August 2007 by Dr. Jonathan M. Rothberg, who pioneered high-speed, massively parallel DNA sequencing. Ion Torrent is based in Guilford, Connecticut, with an office in South San Francisco. For more information about Ion Torrent, visit www.iontorrent.com.

[Molecular DNA sequencing is at full swing with the Life Technologies' deal with Ion Torrents (grand total $725 M). Illumina invested into Oxford Nanopore, and both Complete Genomics and Pacific Biosciences filed for IPO. Quite a foursome! The net result is that sequencing technology is in a "home run" - thus the emphasis shifted to Intellectual Property in Full DNA Analytics and Consumerism of the results (a HolGenTech profile). An interesting question is why Jonathan Rothberg "gave away" his company Ion Torrent for under a $ Billion? An answer may be "bis dat qui cito dat" - Jonathan's R&D is to be kept both in CT and in CA (San Francisco) ... instead of going through an agonizing public scrutiny of IPO (e.g. full disclosure of all their "risk factors", such as IP) he can plunge into his third major venture (actually his sixth, after 454 sold to Roche, and Ion Torrent sold to Life Technologies, and also including CuraGen, Clarifi and Raindance). Brilliant technologies, brilliant business moves ... - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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PacBio files for $200 million IPO

FierceBiotech
August 16, 2010 — 10:39am ET | By Maureen Martino

Money-raising machine Pacific Biosciences--a 2009 Fierce 15 winner--has decided to take its act public. The company has filed a $200 million IPO, the proceeds of which will help the company fund R&D of its products and SMRT technology, which uses nanofabrication, biochemistry, molecular biology, surface chemistry and optics to enable real-time analysis of biomolecules.

Just last month, PacBio closed a $109 million Series F, bringing its total haul to $370 million, and in June landed a PacBio gets $50 million investment from Gen-Probe. In addition to R&D expenses, PacBio will boost its sales and marketing in advance of commercial launch, increase its manufacturing operations, and for general corporate purposes. PacBio added in its filing that it may be in the market to acquire complementary technology or businesses that would boost its own operations, but that no acquisitions were planned at this time.

In the short term, PacBio will focus its technology on clinical, basic and agricultural research. It hopes to expand into molecular diagnostics, drug discovery and development, food safety, forensics, biosecurity and bio-fuels. "We believe that our SMRT platform represents a new paradigm in biological science...that has the potential to significantly impact a number of areas critical to humankind, including the diagnosis and treatment of disease as well as efforts to improve the world's food and energy supply," the company boasts in its SEC filing.

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PacBio's SEC filing stipulates (verbatim quote):

RISK FACTORS

Investing in our common stock involves a high degree of risk. You should consider carefully the risks and uncertainties described below, together with all of the other information in this prospectus, including our financial statements and related notes, before deciding whether to purchase shares of our common stock. If any of the following risks is realized, our business, financial condition, results of operations and prospects could be materially and adversely affected. In that event, the price of our common stock could decline, and you could lose part or all of your investment.

Risks Related to Our Business

We are a development stage company with limited operating history.

We may never achieve commercial success and have not yet commercially launched our first product. We have no historical financial data upon which we may base our projected revenue. We have limited historical financial data upon which we may base our planned operating expense or upon which you may evaluate us and our prospects. Based on our limited experience in developing and marketing new products, we may not be able to effectively:

• drive adoption of our products;

• attract and retain customers for our products;

• comply with evolving regulatory requirements applicable to our products;

• anticipate and adapt to changes in our market;

• focus our research and development efforts in areas that generate returns on these efforts;

• maintain and develop strategic relationships with vendors and manufacturers to acquire necessary materials for the production of our products;

• implement an effective marketing strategy to promote awareness of our products;

• scale our manufacturing activities to meet potential demand at a reasonable cost;

• avoid infringement and misappropriation of third-party intellectual property;

• obtain licenses on commercially reasonable terms to third-party intellectual property;

• obtain valid and enforceable patents that give us a competitive advantage;

• protect our proprietary technology;

• provide appropriate levels of customer training and support for our products;

• protect our products from any equipment or software-related system failures; and

• attract, retain and motivate qualified personnel.

In addition, a high percentage of our expenses is and will continue to be fixed. Accordingly, if we do not generate revenue as and when anticipated, our losses may be greater than expected and our operating results will suffer. You should consider the risks and difficulties frequently encountered by companies like ours in new and rapidly evolving markets when making a decision to invest in our common stock.

[About two weeks after Complete Genomics filed for IPO, almost overnight challenged by Illumina intellectual property infringement lawsuit, PacBio decided to deny the uniqueness of Complete Genomics to capture public funds. This move will no doubt re-vamp the competitive landscape - perhaps most critically in intellectual property matters - Pellionisz_at_JunkDNA.com or Andras Pellionisz at FaceBook]

How Can the US Lead Industrialization of Global Genomics? [AJP]

[Francis Collins, Head of NIH, USA (left) and BGI co-founder Wang Jian (right) - AJP]

There is no question that a Global Industrialization of Genomics is taking place - in which the USA is hard pressed to (maintain to) lead with its somewhat antiquated and fragmented R&D system. As we recall, the shock of Soviet Satellite "Sputnik" (1957 - over half a Century ago...) triggered a successfull re-vamping of the entire US education and R&D system. Hruschev' Soviet Union was provocative and arrogant - while (as the brilliant write-up by Kevin Davis, shows below) - China deliberately underplays their cards. Nonetheless, a somewhat similar re-adjustment at every half a Century might be needed if the US is to maintain her lead - this time in the Global Industrialization of Genomics. I illustrate this thesis by a contrasting triad of write-ups . One is from Nature on NIH, the other is in Bio-IT World, and the third is my conclusion that "Industrialization of Genomics is not possible either by the brute force of government administration of orthodox Biochemistry Research or massive deployment of the shere force of Big Information Technology (their converge I predicted since 2004, and disseminated in YouTube 2008 - by now viewed over 8,500 times) - without a theoretical understanding of recursive genome function" - Pellionisz_at_JunkDNA.com or Andras Pellionisz on FaceBook.

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Francis Collins: One year at the helm [US government over the cliff in Genomics - AJP]

Nature 466, 808-810 (2010) | doi:10.1038/466808a
Published online 11 August 2010 |

Meredith Wadman

Having taken on the biggest job in biomedicine - leading the US National Institutes of Health - Francis Collins must now help his agency over a funding cliff. Meredith Wadman looks at his record so far, and his plans to cushion the fall.

There were three scans of Francis Collins's genome, and all showed the same thing: the geneticist and physician has an increased risk of developing type 2 diabetes. After Collins received the results from the genetic-testing companies in the spring of 2009, shortly before he became director of the US National Institutes of Health (NIH), he hired a personal trainer and began working out three times a week. He jettisoned his favourite junk food - honey buns and oversized muffins - in exchange for yoghurt, granola bars and broccoli. The 60-year-old now dead lifts 48 kilograms, chest presses 43, and has lost more than 11 kilograms himself. [So much for some bureaucrats who consider DTC "useless"; if it did change the lifestyle of one of the most knowledgeable man, perhaps its relatively small impact is because others are not yet at his level - AJP] "It has helped me a lot in terms of being able to take on the intensity of the job," he says.

That salubrious slimming is nothing compared with the crash diet that Collins's US$31-billion-a-year agency is about to go on. Collins took control of the NIH - the world's largest biomedical-research funder - in the middle of a feast: a $10.4-billion, two-year boon delivered in 2009 by the American Recovery and Reinvestment Act, as part of the US government's effort to revive a moribund economy. Next month, the last of that money will go out of the door, and its recipients will have spent the bulk of it by September 2011. "The Recovery Act provided an enormously timely and appropriate stimulus for the community after five years of flat funding," Collins said in an interview with Nature at the NIH's Bethesda, Maryland, campus last month. "But now we face this potential of falling off a cliff. That's the biggest challenge" of his job, he says.

Collins comes equipped for challenges, intellectually and temperamentally. From his co-discovery of the gene for cystic fibrosis 21 years ago, to his 15 years of leadership of the NIH'sNational Human Genome Research Institute - and, with it, the Human Genome Project - he has proved that he combines serious scientific know-how with a leader's vision (see 'Francis Collins: in sequence'). With his boy-scout manners and folk-guitar habit, he is also a decided contrast to his immediate predecessor, the sharp-suited Elias Zerhouni, a radiologist whom many bench investigators viewed warily for not being a scientist's scientist.

Collins's exceptional self-discipline extends well beyond dieting. By the time he started the job, he had already formulated a 'pocket list' of 22 goals for his first year in office, from hosting a visit to the NIH by President Barack Obama to hiring a new cancer-institute director. Now, he proudly hands over the list of mostly ticked-off accomplishments: Obama visited the NIH last September, and Harold Varmus, a former NIH director, took the reins of the National Cancer Institute in July. "He's in a hurry," says Susan Shurin, the acting director of the NIH's National Heart, Lung and Blood Institute (NHLBI). "He moves fast and he likes to be surrounded by people who are going to make things happen."

Collins has detractors as well as fans. When he was appointed, some scientists voiced loud scepticism that he could separate his very public Christian faith from his policy decisions. There were also fears that his roots heading the Human Genome Project would lead him to favour NIH-initiated mega-projects over proposals by individual scientists. Others scolded him - and still do - for what they call his perennial overpromising on the fruits of the genomic revolution. "He is still leading people to believe that genetics is the key to everything," says Neil Greenspan, an immunologist at the Case Western Reserve University School of Medicine in Cleveland, Ohio. If, five or ten years from now, only a handful of therapies emerge as a direct result of the genome project, "you could end up with a lot of people [in Congress] getting upset and cutting the NIH because they are not producing what they claimed".

Such concerns do not worry a lean, list-checking Collins. "My job it seems to me is not to spend my time apologizing for being optimistic. But rather to try to take that optimism and turn it into reality," he says.

Morning to night

On a sultry morning in mid-July, Collins straps on his black motorcycle helmet and rides his Harley-Davidson the 15 minutes from his suburban Maryland home to the NIH campus. Collins had grabbed his usual, abbreviated night of sleep, after recording an interview for the Charlie Rose Show, marking the tenth anniversary of the draft sequencing of the human genome, and then staying up until nearly midnight to watch the popular talk-show air. In between, he had participated in a conference call with senior government officials, discussing how to enrol 20,000 subjects in a long-term study of the health effects on workers cleaning up the Gulf of Mexico oil spill. Having risen at his usual time of 5:00 a.m. - "that is a protected time, before all hell breaks loose, when I can actually try to think and plan," he says he is now on his way to a 7:45 a.m. interview with a candidate to head the NHLBI.

Collins wasted no time on his first day as NIH director either, when he announced five 'themes' - areas of what he calls "exceptional opportunity" - that would receive special priority during his tenure (see Nature 460, 939; 2009). Collins targeted translational medicine, health-care reform, global health and "empowering and energizing the research community". And he said he wanted to apply high-throughput technologies including genomics and proteomics to answer, as he puts it, questions with 'all' in them, such as "what are all of the major pathways for signal transduction in the cell?"

He also had to deal with some of the issues left over from Zerhouni's watch. He was faced with the delicate job of making new human embryonic stem-cell lines available for federal funding fast enough to suit a community that was hankering for them after eight years of drought - without any missteps that would provide ammunition to opponents of the research. Between December and June, the agency approved 75 new stem-cell lines. (Collins points to the approvals as evidence that he "will not allow my own personal spiritual beliefs to interfere with decision-making or priority setting".) But the agency has also drawn criticism for rejecting scores of disease-specific cell lines because of the broad legal language used in patient-consent forms (see Nature 465, 852; 2010).

Collins also faced the aftermath of several scandals in which NIH-supported academics had flouted reporting rules by failing to disclose five- and six-figure sums that they had collected from drug companies. In May, the NIH published proposed changes that would tighten the rules governing financial-interest reporting by its grantees.

Still, nothing Collins has faced so far comes close to the budget straits that the agency now confronts as the government struggles to control ballooning deficits, fight two wars and deal with the detritus of a major economic crisis. As NIH director, "what happens to you is going to depend on things beyond your control", says Anthony Fauci, director of the National Institute of Allergy and Infectious Disease since 1984. "I hope that circumstances beyond his control start leaning towards helping him rather than hindering him."

Slim chances

Already, this year, success rates for scientists applying for the agency's research-project grants have dipped to an estimated 19%, down from 21% in 2009 and far lower than the comfortable 32% of a decade earlier (see 'Grant applications to the NIH'). The worsened odds partly reflect an increase of about 10% in the number of applications, many of which are recycled from failed stimulus grant proposals. In 2011 and 2012, the grant success rates are expected to fall further as stimulus funding runs out and its recipients attempt to extend support for their projects.

The NIH's baseline budget is also approaching dangerous waters. Although agency supporters were heartened last month when key subcommittees of the Senate and House of Representatives approved Obama's request for a 3.2%, $1-billion boost that would bring the budget to $32 billion in 2011, the increase is not guaranteed to survive final congressional wrangling this autumn or winter. And it does no more than match the government's predicted biomedical inflation rate. Things could be even bleaker in 2012: this June, Collins, like every other federal agency director, was asked by the White House's Office of Management and Budget, as part of its planning process for the 2012 US budget, to identify cuttable programmes amounting to 5% of the agency's budget. This is hardly a calamity compared with the deep research cuts occurring in some European countries, but still a shock to the NIH, which has faced only one absolute funding cut since 1970, and that only a 0.1% shave (see 'NIH budget'). Late last month, Collins collected from the directors of the NIH's 27 institutes and centres a list of targeted programmes, constituting 7% of their budgets - the 7% giving him some flexibility to cut less here and more there. The final list is due to the White House in mid-September.

The initial response of the institute directors to his request was "full of angst", says Collins. "But there has also been a sense of 'We need to look hard at everything we are doing at a time like this'." He remains hopeful that given Obama's emphasis on science, "when the dust all settles and they [the White House] decide exactly what to do, we will be at some level a bit protected, but we don't know that".

All or none

All this has been a growing cloud on the horizon even as Collins has been fleshing out his five themes. He has emphasized translational research, throwing his weight behind a programme aimed at speeding treatments for rare and neglected diseases towards human trials. He has embraced health reforms by overseeing the spending of $400 million in Recovery Act money earmarked for research into the 'comparative effectiveness' of medical treatments. And he has promoted his global health priority with initiatives such as a collaboration involving Britain's Wellcome Trust medical charity, in which the NIH will contribute $25 million over five years to study the genetic and environmental underpinnings of chronic diseases in sub-Saharan Africa.

Collins has also been launching high-tech assaults on the 'all' questions, committing $175 million in Recovery Act money to accelerate The Cancer Genome Atlas - a five-year-old effort to develop a detailed catalogue of all of the mutations associated with 20 common cancers. [Results of these programs will, or course, be available for the World, for free - AJP]. Collins's emphasis on these types of ambitious projects has led some to question his commitment to the individual investigator and the mainstay, multi-year 'R01' grants that fund many such scientists. But his defenders say there is no evidence that Collins is advancing the first at the expense of the second. "Francis fully gets the importance of funding some of the larger efforts that can be so transforming. But I think he's also paying very close attention to maintaining a vigorous pipeline of R01-funded research," says Levi Garraway, a cancer biologist at Harvard Medical School and Dana-Farber Cancer Institute in Boston, Massachusetts, who holds investigator-initiated NIH grants and also participates in The Cancer Genome Atlas project.

Collins says that big-team science is the only way to produce some tools that greatly benefit individual investigators. [Craig Venter, who single-handed matched at least to a tie the $3 Bn "Human Genome Project" is likely to question the rationale of this statement - AJP]. But he says that the individual lab "is where almost all of the discoveries of the present and the future are going to come from". [It is interesting that Dr. Collins uses the term "individual lab" as the source of advancement of science. Albert Einstein, who never ran any lab of physics, might question the rationale of this statement, since advancements of science have come in the past from "individual brain" of Newton, Heisenberg, Planck, Schrodinger, Einstein, etc - AJP], And these labs are at the centre of his push to "energize and empower" the research community by addressing peer review, training and other workforce issues. Anaemic success rates for research-project grant applicants have created "a terribly stressful circumstance, particularly for early-stage investigators", says Collins, noting that the average age for winning a first R01 award has now crept above 42 years old. As a partial response to this, he has been planning the launch in 2011 of an award that will allow promising young investigators to skip postdoc positions entirely, giving them five-year funding to launch independent labs.

As for the immediate concerns of thousands of NIH grantees edging towards the funding cliff, Collins says that the agency will be "sympathetic" in allowing Recovery Act-funded grantees to spend their money over more than two years, "making it more of a ramp instead of a cliff". [Does it matter if US leadership slides or falls into demise? - AJP] "We will be doing other things which may assist the ability to give new grants, but hurt the people who already have them," he adds. Those will include cutting individual grant budgets "as we have to, in order to keep as many researchers going as possible".

These measures bring cold comfort for many in postdoc purgatory with little prospect of securing independent funding. "I didn't think it would be some Glory Hallelujah moment when Collins was appointed," says one 35-year-old scientist in his second postdoc, who asked to remain anonymous. He would like Collins to make it possible for those more than five years beyond their PhDs to secure transition funding such as a coveted 'K99' award, which supports postdocs in the shift to independent positions. "To be brutally honest, I haven't noticed any difference in his tenure after the first year compared to Zerhouni," he says.

But if Collins hasn't impressed some struggling bench scientists, his skill as a public communicator may nonetheless help to improve the NIH's prospects — or at least lessen its immediate peril. William Talman, president of the Federation of American Societies for Experimental Biology, attributes the White House's request for a $1-billion boost for the NIH - even in a stark funding climate - to Collins's persuasive powers. "He has been a superb advocate for the NIH with the administration and with Congress." Collins has the rare gift of being able to translate complex concepts into simple language, leaving his audiences - including all-important congressional audiences - feeling brilliant about their grasp of his material. (In one typical analogy he describes a haplotype, a group of genetic markers that are inherited together, as being like a neighbourhood of houses that moves together - with a causative mutation residing at one street address.)

"The most important thing he has done really is his public outreach," says Shurin, who recalls as typical Collins's May guitar performance for patient advocacy groups affiliated with her institute. Set to the tune of Del Shannon's hitRunaway, his lyrics described the anxieties raised by confronting a readout of one's own genome "I'm a walking through the genes/Don't know what all this means/Oh what can the meaning be?/Behind that G and T?/And I wonder …" He received a standing ovation. [Others worked their butts off to focus not on a song but on a breakthrough theory.. - AJP]

Collins is going to need all of that support and more to help those funded by the agency over the cliff - or down the ramp - ahead. "I don't have any magic here," says Collins. "I wish I did." [For believers in God, there is always a hope for a miracle ...]

[NIH got $40 Bn "for a song" - as in 2007 when DECODE was wrapped up - Genomics confessed in science papers - as well as by public whining - "Don't know what it all means". We simply can't make it without "theory of genome function" - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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BGI Americas [and BGI Europe] Offers Sequencing the Chinese Way

By Kevin Davies
Bio-IT World
August 11, 2010

25 years ago, Shenzhen was a tiny fishing village in southwest China, just one hour north of Hong Kong. Today, [Shenzhen] is the country’s second largest port after Shanghai, a booming technology haven and since 2007, home to BGI, formerly known as the Beijing Genomics Institute.

With 3,000 employees currently rising to an expected 5,000 by the end of this year, and a fleet of more than 150 Illumina and Life Technologies next-generation sequencing instruments, most of which are being installed in a former printing press in Hong Kong, BGI is poised (if it isn’t already) to become the world’s largest genome sequencing center. And it wants to share its extraordinary resources and expertise with, well, everybody.

Last April, BGI Americas was officially incorporated in Delaware as the official interface for BGI in North America. BGI Europe followed suit the next month (see “European Union”). From a small office in an incubator space overlooking Boston’s Charles River, a stone’s throw from the Broad Institute, the husband-and-wife team of Paul Tu (president) and Julia Dan (CEO) are reaching out to potential academic and commercial partners and customers. By the end of 2010, BGI Americas will have as many as 20 sales representatives spanning the continent in search of partners who wish to avail themselves of BGI’s prodigious sequencing capacity.

“We’re an interface representing BGI to collaborators in America and to promote the BGI brand,” says Tu. “That means finding collaborators working on different interesting projects, or fee-for-service projects, to support our operations.” He smiles: “3,000 people need to eat!” [American scientists need to eat, too - AJP]

Tu graduated from MIT’s Sloan School of Management and worked in venture capital for ten years before meeting BGI co-founder Wang Jian and “drinking the Kool-Aid”. Indeed, Tu and Dan abandoned their own start-up plans in China to sign on with BGI Americas. Tu’s wife is also his boss: Dan previously worked in corporate development for Genzyme. She lets Tu do most of the talking, but corrects him occasionally, just like any happily married couple.

Lucky Numbers

The growth and data output at BGI is nothing short of astonishing. The institute currently employees 3,000 staff in Shenzhen, including 1,500 working in bioinformatics, including programmers and IT staff. As of July 2010, BGI had 40 Illumina HiSeq 2000 instruments installed in its new facility in Hong Kong (a former printing press), growing to 100 by the end of 2010. When Illumina introduced its new state-of-the-art sequencer in January 2010, BGI immediately ordered a total of 128 machines -Tu explains that 128 is a lucky number in Chinese. (The number eight sounds like ‘wealth.’)

“God forbid it was 124,” he adds dryly. “Four would sound like ‘death!’ ” [2, 6, 8 or 9 are also "lucky numbers" in China; why do they need two orders of magnitude bigger numbers? - AJP]

The new facility in Hong Kong will greatly facilitate the shipment of samples from the rest of the world. [Yes, it is "lucky"... AJP]. “It’s a British system: one China, two systems,” says Dan about Hong Kong. “It’s the same thing with BGI.” For investigators leery of sending samples to Hong Kong, Dan hopes to give them the option of shipping to a sample receiving lab attached to BGI Americas headquarters in Boston, which will then handle the paperwork and shipment. That could be ready as early as September 2010.

By the time the Hong Kong facility is fully operational at the end of 2010, BGI will have a total sequencing output of 5 Terabytes/day—the equivalent of 1500x human genome/day. The data center now boasts 50,000 CPUs, 200 Terabytes of RAM and will reach a whopping 1,000 Petabytes—1 Exabyte—of data storage by year’s end. “It’s an awesome machine to play games on,” jokes Tu.

Such infrastructure comes at a price. BGI spends an estimated $10 million on electricity annually. “We cannot be a non-profit organization without any external support,” says Tu.

That is where BGI Americas and BGI Europe come in. “We’d love to work with [principal investigators] around the world, not just the U.S., on any interesting projects,” says Tu. Back in China, a committee of animal, plant and disease experts will select which projects BGI takes on. “BGI can be flexible—give us the samples, we can fund everything, and then we co-author the publication,” says Tu. A variant of that model would have BGI split everything—the costs, authorship and IP—with its partners.

“Not everyone can offer that. We don’t just do human, we do animals, plants, bacteria, complex diseases,” says Tu. “That’s the non-profit aspect. We want to sequence 1,000 plants and animals and have set aside $100 million for this initiative… It’s all about the science.”

But BGI is also offering a fee-for-service option. “We are a contractor,” says Tu. “Every single profit generated by the fee-for-service division will be returned to BGI to support the non-profit research agenda.” As a contractor, BGI will take any specs and deliver what the client wants. “If you want your data via FTP, or hard disk, we’ll do that. We give you a report, annotation, mapping, analysis. Not just sequencing, we also do all the back end as well,” says Tu.

Cost and Competition

Tu turns very diplomatic when asked about potential competition to BGI’s sequence service plans. “Personally, and throughout the organization, we don’t view anybody as our competitor. This field is extremely nascent. In science, what we know today may be only 2-5% of what it will be later. The science keeps advancing, we keep discovering new things.” As an example, he cites the recent UC Berkeley/BGI publication in Science that described a highly selected gene variant associated with altitude adaptation.

Dan says that, unlike a commercial service provider such as Complete Genomics, BGI’s value proposition is the flexibility to offer a pure fee-for-service as well as a collaborative model. “We don’t want to be restricted by funding for which research we can do. That’s the reason we do fee-for-service, and we love to do collaborations. We spend a lot on the collaboration side.”

Diplomacy turns to downright evasion when the subject is cost. “It depends,” says Dan not unpredictably, “on coverage, analysis, volume, and so on.”

“All these players—Complete Genomics, Broad Institute, etc.—are just collaborators for us,” says Tu. “When it comes to fee-for-service, we’re at the mercy of what Illumina charges us for reagent costs. We have gigantic overheads… We’ll eat some of the overhead, but the variables, somebody has to cover.”

“Can we compete head-to-head with Illumina and Complete Genomics, where this is all they do? They don’t even do exomes, they only do whole genome humans? They make their own machines and reagents, how can we compete with that?”

Tu marvels at the drop in sequencing prices over the past 12-24 months. “I’ve never seen such price erosion! This is like, Whoosh!... We’re a service provider, how can we compete with that? We compete with the back end, our bioinformatics. That’s where we’re good. Who else has 1,500 staff?” BGI already makes its popular software SOAP (Short Oligonucleotide Alignment Program) freely available (See http://SOAP.genomics.org.cn). Any data or tools built for the SOAP platform (using C++) are being donated to the public sector [This may not apply on everything beyond SOAP... AJP]

The average age of the BGI staff is just 24.7. [Compare this to the average age of US researchers getting their FIRST RO1 NIH grant - at the tender age of 42]. Tu calls the legions of bioinformatics workers “the young and the brightest,” drawn from the top tiers of mathematicians and scientists from the top universities around the country, supplemented with operations people who have worked abroad. “They work around the clock,” he continues. “If they come to BGI, they get to work on real projects. Plus you get to program all day, with these toys in the background! It’s like a video game, they love it!” New recruits cannot rest on their laurels however: every month for the first six months, there’s a test. Fail it, and it’s bye-bye BGI.

Tu and Dan have only been on the job a few months, but they too are working pretty much around the clock. Inquiries are already flooding in—mosquito genomes from Brazil, palm oil from Costa Rica, ancient DNA from the University of Massachusetts Medical Center. Tu was preparing to visit researchers at the Children’s Hospital of Philadelphia, and is already discussing projects with partners and clients at the Dana Farber Cancer Institute, Harvard Medical School, and the Broad Institute. He hasn’t had time to speak to all of the U.S. genome centers yet.

“We want to be a trusted scientific partner and research collaborator,” stresses Tu, speaking on behalf of 3,000 BGI scientists and counting.

European Union

BGI Europe was registered in Copenhagen, Denmark, in May 2010, and officially launched in June at the European Society of Human Genetics. The plan is to invest $10 million and to recruit 20 local staff in the organization’s first year alone. The CEO of BGI Europe is Mason Mak, who joined BGI earlier this year, although he is based primarily in Shenzhen.

Given BGI’s historic ties with Denmark, it is no surprise that BGI Europe headquarters is at the University of Copenhagen, Faculty of Life Sciences. The president of BGI, Yang Huanming, obtained his PhD from the University of Copenhagen in 1988. BGI’s director, Wang Jun, is a visiting professor at the University of Copenhagen and Aarhus University.

A new Copenhagen research institute on metabolic diseases, funded by a $170-million donation from Novo Nordisk, will strengthen an ongoing collaboration with BGI, led by diabetes researcher Oluf Pedersen. He says the alliance with BGI will create “an international powerhouse in the field of medical genetics.” (Diabetes and obesity are a growing health concern in China.) “Genomics cannot be done alone,” says BGI director Wang Jun. He says the Sino-Danish collaboration harnesses the superb medical infrastructure in Denmark with “Chinese genomics muscle” in the study of type 2 diabetes and obesity.

According to BGI Europe’s business development director, Danish-educated Wang Xuegang (he prefers to go by the name ‘Greg’), BGI Europe will offer European clients two models—collaboration or fee-for-service—just like its American counterparts. BGI Europe has six sales people already, but will be recruiting additional staff specializing in different fields such as agriculture, pharmaceutical, and biotech, spread across key regions including the UK, Germany, and Scandinavia.

As for what BGI’s key selling point is, Wang Xuegang says it is not necessarily the cost of sequencing. “Price is not what we sell on,” he says. A bigger selling point is BGI’s “very strong bioinformatics team,” with its immense experience in genome data analysis and de novo sequencing.

BGI Europe has an even more ambitious agenda than its American counterparts. The current plan is to establish a sequencing facility, probably in Copenhagen, within a couple of years, while growing the local staff to around 100 people. It would be futile for BGI Americas to set up a sequencing operation in the Broad Institute’s backyard, but BGI Europe may see an advantage to establishing a local production base in Copenhagen.

“Our vision is to make BGI Europe to be one of largest centers of sequencing services and bioinformatics,” says BGI Europe’s Xuan Min. “We’re trying to set up a sequencing lab in Copenhagen,” adds Wang Xuegang, likely in collaboration with a biotech partner or partners. The availability of a local facility might appease some potential biotech clients worried about data security and privacy. “We can set up a pipeline where everything is under control by the customer,” says Wang.

[Hope that this masterful interview by Kevin Davies will ring some bells - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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Junk DNA: Does it Hold More than what Appears?

Junk DNA: The secret key

What is the mystery behind so called “junk DNA” afterall? Is it really “junk” just because pretty little has been done to reveal its’ exact function? But, their codons have in them all! This particular variety of the “junk DNA” regulates the behavior of the normal coding genes. Presently, researchers [except the FractoGene explanation of Recursive Genome Function by Pellionisz] are unable to say anything with certainty about the supposed functions of these “non-coding” genes.

It is the same reason why scientists abhor from the usual practice of inserting foreign genes in the normal gene sequence. They fear that it could start the production of hitherto unknown proteins due to its uncontrollable spread. But, numerous possibilities exist due to the striking resemblance of these to the normal genes. [That is, synthetic genomics will not really take off, until regulation of recursive genome function is mathematically understood - AJP]

The future

The possibilities are endless. In fact, scientists do speculate that these genes could contain some kind of coded information for the future. Even if they ascribe the reasons of dreaded diseases like cancer to the “junk DNA”, others like Haig H. Kazazian, chairman of the University of Pennsylvania, has linked them evolution of the new species.

A June 2004 Harvard Medical School report while working on a “junk DNA” gene in the yeast, quotes an evidence regarding a new find, gene SRG1. It is believed that it physically blocks the transcription of the adjacent normal “coding” gene, SER3. Studies done elsewhere say that the non-functional DNA, aids in the gene expression regulation during development.

Over 700 studies done in this arena prove the role of “junk DNA” as an enhancer for the transcription of proximal genes. While around 60 studies in the same, have again proved that the non-coding DNA acts as a silencer during the suppression of transcription of “proximal” genes. Apart from that yet others talk about the function of the non-coding DNA in the regulation of the translation of proteins.

The twist in the tale

Russian researchers like Gariaev suggest the possible mediation of the non-coding genes at the quantum level. The studies done by the above and group confirm about the chromosomal ability “to gyrate the polarization plane of its own radiated and occluded photons”.

The very idea that about 98% of the DNA belongs to the junk category is a misnomer now. Biologists have long since ignored the fact that majority of the biological species — complete energy entities in themselves – function on the principle of minimal energy expenditure. This therefore, means that it is completely against the norm of energy saving feature of these organisms to include in their biological mechanism, the “non-coding DNA”.

It is but a reality that the unused DNA does have a function according to the researchers now. But, what that is can be anybody’s hard guess as of now.

The mathematical link

What is appearing now is the new branch of genomics itself supported by the likes of Andras Pellionisz, a biophysicist [formerly] at the New York University. He has some done ground-breaking work in the field of biological neural networks, based on the fractal geometry of cellular development addressing the decisive role of recursive genome function [both at the level of peer-reviewed science publication and having secured IP, widely distributed the concept of "Recursive Genome Function" in Google Tech Youtube (presently fetching 181,000 hits on a regular day, see below, with occasional peaks close to a million). The FractoGene concept was also embraced in the Churchill Club YouTube, as well as upon inviation of George Church (a BoA of holgentech.com), in Cold Spring Harbor, 2009] According to him, protein structures act back upon their genetic code, which is supported by many an observation and analysis of the genome sequences.

This, in fact, is undoubtedly a vast subject. But, amazing strides made in the recent times have left everyone dumbfounded as one upon another, information unlocks itself. The above principles could find their usage in the customization of the foods, drugs, cosmetics, chemicals; materials etc. which could then be matched with our genome. Of course, this will prevent the diseases from occurring, or maybe even halt the adverse conditions from developing further in their lethality.

[Algorithmic approach by A. Pellionisz, HolGenTech, Inc.]

[Cloud-solutions (this is by DNAnexus - in addition to the slew of such services) rushing to the market created by the "Dreaded DNA Data Deluge" need algorithms, e.g. for targetable structural variants (fractal defects) - AJP]

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Biotech is back [in Korea - AJP]

JoonAng Daily
Korea
August 11, 2010

The [Korean - AJP] nation’s biotechnology and life sciences industries are hitting one milestone after another. Many of the biological and genetic experiments undertaken in laboratories more than a decade ago are finally ready to see daylight and hit drug store shelves.

According to the Korea Food and Drug Administration, a local biotechnology enterprise has completed clinical safety testing of a drug aimed at treating acute myocardial infarction - or heart attacks - and has filed for approval with health authorities. If it passes the screening, the company will be able to release the world’s first legitimate drug derived from stem cell technology.

Other biotechnology companies are also actively involved in developing disease-specific stem cells into drugs to treat and repair knee cartilage and spinal cord injuries. These companies may open the door to entirely new medical treatments and prop up the health care industry by releasing blockbuster drugs using human embryonic stem cells.

News of breakthroughs in the local bioengineering industry is coming from many areas. Single-gene malady treatment using an individual’s DNA genome is ready for commercialization. Thanks to advances in genome analysis and technology, the cost of having a hospital study your gene sequence is expected to fall to $1,000 within two to three years. We may not be far away from the days when we’ll commonly receive accurate diagnosis of ailments and individually tailored treatments based on our genetic makeup.

Competition in the area of low-cost generic products marketed after the expiration of patents is also getting fierce. Large business groups like Samsung, LG, Hanwha and CJ are jumping into the fray to sell drugs with similar properties to biotech drugs whose patents are about to expire.

The local biotechnology industry has groped its way through a dark tunnel over the last 10 years. The gold hunt in the Kosdaq market and controversy over scientist Hwang Woo-suk’s fabrication of his stem-cell research also scarred and crippled the industry.

But news of technological headway is triggering excessive competition and reckless scouting of scientists and bioengineers. Authorities must now step in to redefine the industry and revisit the nation’s strategy for biotechnology.

The industry is a high-end market that can fuel the country’s future growth. The government should administer state projects in key areas and promote strategic alliances among companies. A new business model can be created by fostering partnerships between large corporate giants and upstart biotech companies.

[Wishing for some specifics - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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CLC bio [of Denmark] and PSSC Labs [California] Deliver Turnkey Solution for Full-Genome Data Analysis

Business Wire
Aug 12, 2010

AARHUS, Denmark, Aug 12, 2010 (BUSINESS WIRE) -- Today, CLC bio and PSSC Labs announced a new turnkey solution, CLC Genomics Factory, for assembly, read mapping, and subsequent downstream analysis of very large amounts of high-throughput DNA and RNA sequencing data. Built as a high-performance bioinformatics appliance, CLC Genomics Factory comes in three different sizes with varying numbers of compute nodes, capable of processing the data output from up to 10 Illumina HiSeq2000 or 7 Life Technologies SOLiD 4 systems.

Vice President Bioinformatics Solutions at PSSC Labs, Alex Lesser, states, "As we're already working with the leading instrument providers such as Roche 454, Life Technologies, and Illumina, it was a natural step for us to partner with the leading software provider within high-throughput sequencing data analysis, CLC bio. Based around their enterprise platform, we have tailored an extremely powerful turnkey solution for analyzing the vast amounts of data coming off all the different high-throughput sequencing instruments, including upcoming technologies such as Ion Torrent and Pacific Biosciences."

CEO at CLC bio, Thomas Knudsen, continues, "It was obvious for us to combine our expertise on high-performance bioinformatics algorithms and user-friendly software, with PSSC Labs' extensive experience in cluster solutions for the life science industry. We now provide the first and only turnkey solution for full-genome analysis of data from all types of high-throughput sequencing instruments. Our customers don't have to invest in a new cluster for each technology they wish to adopt: CLC Genomics Factory handles them all - now and in the future!"

CLC Genomics Factory is built around CLC bio's enterprise platform, including the award-winning CLC Genomics Server, as well as all of CLC bio's accelerated algorithms for full-genome assembly and analysis. Multiple licenses for CLC Genomics Workbench enable users to interface with the server software through either a user-friendly graphical user interface or, optionally, a command line interface. CLC Genomics Factory includes also support for CLC bio's Software Developer Kit, for those wishing to integrate 3rd party systems and software.

CLC Genomics Factory includes a master node, multiple job nodes, as well as varying amount of storage. Read more about CLC Genomics Factory including full technical specifications at http://www.clcfactory.com [The specs reveal that in complete configuration the system can analyze 32 full human genomes per week ~ 5 hours per individual genome - about an order of magnitude more than will be required in biopsy-sequencing AND analysis - AJP]

CLC Genomics Factory is sold by CLC bio and CLC bio resellers. The computer hardware is assembled, tested, distributed, and supported by PSSC Labs who have great experience in delivering complex computer setups, with more than 1000 running installations of their clusters across 35 countries around the world. CLC bio handles the support on the software.

[The California-based hardware manufacturer, because of competitive funding requirement, is again forced to be quite specific, but we don't learn a lot here about the software created in Denmark - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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GenomeQuest and SGI Announce Whole-Genome Analysis Architecture

PRWeb
August 4, 2010

Immediate Availability of World's First Whole Genome Analysis Services for Researchers

Westborough, MA and Fremont, CA (Vocus) August 4, 2010

GenomeQuest and SGI (NASDAQ: SGI) today announced the immediate availability of the world’s first whole-genome analysis (WGA) services for researchers. As a result, pharmaceutical companies, core labs, biotechs, government agencies, and clinics now have direct access to whole-genome processing previously found only inside genome centers combined with comprehensive, self-serve analysis.

The WGA services allow whole-genome/exome research teams to:

Store, manage, and compare their sequences and annotations

Assemble and align sequences from any instrument

Interactively query and analyze their runs and projects

Merge and re-analyze with findings from colleagues and public studies

Use standard workflows, including Variant Detection, RNA-Seq, and ChIP-Seq

Build and query enterprise-wide variant archives

"Data analysis is recognized as the bottleneck of whole-genome research. Traditionally, researchers receive static reports for their sequence runs which, at today's volumes, are impossible to analyze and increasingly siloed,” said Jean-Jacques Codani, GenomeQuest Chief Scientific Officer. “From its inception, the GQ Engine has provided researchers with rich, interactive reports and the ability to integrate and re-analyze with other work. Now, with SGI's longstanding experience in high-performance computing, we have found the bow that best fits our arrow for WGA-scale services.”

GenomeQuest and SGI co-developed a software and hardware architecture that is optimized for next generation sequencing and enables whole-genome scale and performance. Based on this architecture, the WGA services are available through the just-upgraded GenomeQuest data center or deployed directly into a customer data center, as may be required by larger accounts, core labs, and clinics.

“Clearly, the storage and computational needs of WGA are massive and unique,” said Dr. Eng Lim Goh, senior vice president and chief technology officer at SGI. “Given the complexity of the algorithms and the scale of the data, success in this area requires a careful factoring then optimization across four key parts of the system -- software, computational and I/O capabilities, and burstability. We are very excited about the new GenomeQuest center, and applying this enabling blueprint for life science organizations.”

The GenomeQuest center was upgraded on May 18, 2010. A major investment, it radically improved the user experience and performance for over 2000 existing commercial and academic users.

“We have observed a radical change in the use of GenomeQuest since the opening of the new center,” comments Ron Ranauro, GenomeQuest CEO. "Our personalized medicine research application is processing thousands of exomes per month and will soon scale to over 1000 full-human genomes at deep-coverage.”

The SGI-based upgrade includes:

Multiple, load-balanced head nodes to service high-volume user requests and interactions

Rackable XE, server stack of high-performance compute nodes to service highly-parallelized, sequence database comparisons

Storage solution featuring high-performance I/O subsystem scalable to Petabytes

Housed in a Type II SAS 70 compliant data center with fully redundant hardware and software for 24/7 availability

In related recent news at BIO-IT WORLD, GenomeQuest also announced GQ-PMR, the world’s first genomic reference system for personalized medicine-based research. With GQ-PMR, pharmaceutical companies can integrate raw data from public whole genome studies, such as the 1000 Genome Project, directly into their private research. The combination allows research organizations to massively expand sample sizes at virtually no cost and accelerate their transition to molecular-based personalized medicine.

As background, in a July 8, 2010, feature story in USA Today titled "The human genome: Big advances, many questions", Vivien Bonazzi, head of computational biology for National Human Genome Research Institute at the National Institutes of Health, comments, "We're really crying out for the ability to analyze this (output of genome sequencing machines) efficiently and effectively."

[By this illustration of a US (MA-based) software company (Genomequest), working with the Silicon Valley based company SGI (California), the point is to contrast the transparency of USA technologies (also applying to HolGenTech' "Genome Computing Architecture" that - having filed for IP protection - has even been broadcast on YouTube-s). Such dangerous transparency is necessitated in the USA because of competitive funding pressures - and is contrasted by the largely elusive (at times evasive) nature of certain Asian comparable efforts - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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Pacific Biosciences Expands into European Union

Pacific Biosciences - release
August 3, 2010

Terry Pizzie Appointed Vice President, Europe

UK-based Wellcome Trust Sanger Institute Becomes Early Access Customer Menlo Park, Calif. – August 3, 2010

Pacific Biosciences, a private company developing a disruptive technology platform for real-time detection of biological events at single molecule resolution, today announced it has expanded its operations into the European Union with the appointment of Terry Pizzie as Vice President, Europe and with its first European customer, the Wellcome Trust Sanger Institute. Mr. Pizzie has more than 20 years experience in a broad range of international commercial life sciences industry management positions. Previous to joining Pacific Biosciences he was Director of Global Commercial Operations (a board position) for Genetix (now part of the Leica Division of Danaher Corp.) Prior to joining Genetix in 2007 he was Senior Vice President of Commercial Operations from 2005-2007 at Biacore (now part of GE Healthcare), a market leader in protein interaction analysis in research, drug discovery development and manufacturing. Before joining Biacore, he was Vice President Europe of Applied Biosystems (now part of Life Technologies Corp.) from 2002-2004 with responsibility for all European commercial operations including strategy, performance and operational efficiency. He joined Applied Biosystems in 1988 as a sales engineer and advanced through the organization in increasingly responsible positions including Vice President of Sales and Marketing for Europe from 2000-2002. Mr. Pizzie holds a degree in Physiology and Biochemistry from the University of Reading. “Terry has an exceptional track record of strategically managing the commercial success of leading life science organizations in Europe, and we are delighted that he will lead the establishment of our European operations,”said Hugh Martin, Chairman and Chief Executive Officer of Pacific Biosciences.

Pacific Biosciences also announced that the Wellcome Trust Sanger Institute has purchased a PacBio RS 3rd generation sequencing system as part of the company’s early access program. Earlier this year, Pacific Biosciences announced the first 10 customers as part of its North American early access program. These sites, which represent genome centers, cancer research institutions, commercial organizations, and universities, have begun receiving their instruments.

Today’s announcement reflects the company’s expansion of its early access program to a limited number of sites outside of North America.

[While PacBio already made Full DNA Genome Analytics GLOBAL by establishing Partnership with Canadian and Danish developers (see DevNet below) - the actual physical delivery of the now "lead-technology" nanosequencer equipment (by PacBio) into foreign land, starting with the UK, completes the globalization of the spread of sequencing machines (and, therefore, puts the produced full human DNA sequences outside the jurisdiction of the USA). For the previous generation of machines (Illumina Genome Analyzer, Roche/454 and Life Technologies' SOLiD the global spread, especially to China, has alredy been a fact for quite a while - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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Pacific Biosciences launches PacBio DevNet at ISMB 2010

9. July 2010 08:29
The Medical News

As part of its commitment to introducing third generation DNA sequencing technology to the market, Pacific Biosciences today announced the launch of a software developer's network - the PacBio DevNet - at the Eighteenth International Conference on Intelligent Systems for Molecular Biology (ISMB 2010).

“We look forward to contributing to a robust analytical ecosystem that allows more scientists to exploit the new possibilities enabled by this technology.”

Throughout the development of the company's Single Molecule Real Time (SMRT™) technology platform, Pacific Biosciences has been working closely with members of the informatics community to develop and define standards for working with single molecule sequence data. Now, as the company prepares for the commercial launch of the PacBio RS, it is launching a more formal program to support the needs of the informatics community.

The PacBio DevNet was created to support the ecosystem of academic informatics developers, life scientists, and independent software vendors interested in creating tools to work with PacBio's third generation sequencing data. Interested parties can sign up for the PacBio DevNet at www.pacbiodevnet.com, a hub for data sets, source code for algorithms, application programming interfaces (APIs), conversion tools to industry standard formats, and documentation related to SMRT sequencing.

Eric Schadt, Ph.D., Chief Scientific Officer for Pacific Biosciences commented: "Single Molecule Real Time sequencing introduces entirely new dimensions to data, such as a time component, that are unlike anything the bioinformatics community has encountered to this point. Therefore, in addition to a strong internal focus on informatics development, we are committed to supporting third-party software development and facilitating the rapid adoption of this new data type into the scientific community where the really exciting 'big science' can begin [already begun in 2002 - AJP] to happen."

At the ISMB conference, PacBio scientists and collaborators will present results from some of their informatics development efforts to date, including new algorithms tailored to the unique characteristics of the SMRT data such as its long reads. Pacific Biosciences has also developed a suite of data management and analysis software tools that mimic the granularity, scalability and functionality of the PacBio RS. These informatics solutions are designed to efficiently integrate with the user's LIMS system, making them accessible not only to high-end informatics researchers, but also to biologists and clinical researchers.

"The release of PacBio's tools under an open source license and the launch of its Developer's Network will foster the creation of tools that maximize the value of SMRT sequencing," said Reece Hart, Chief Scientist, Genome Commons. "We look forward to contributing to a robust analytical ecosystem that allows more scientists to exploit the new possibilities enabled by this technology."

[The key to "industrialization of genome analytics" is precisely how some "open source license" system could be brought into a productive synthesis with "professional (and for profit) private entrepreneurs". Our "Internet Boom" in Silicon Valley provided some very important lessons; e.g. the Internet browser started with Jim Clark founding Netscape - but having failed to develop a secured business model around it, reverted into Mozilla (open source) - while Microsoft and now Google ran away with the software profit. (With Cisco to be mentioned as the winner in Internet hardware). PacBio' DevNet requires registration, accepting their terms & conditions, but even the public interface reveals their "Partnership" with Amazon Web Services, BioTeam, CLCbio, GenoLogics, GenomeQuest and Geospiza - yet none of them are the Silicon Valley HQ-d "genome informatics pure-play" with proprietary algorithmic approach to Recursive Genome Function, like HolGenTech, Inc. - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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Illumina Inc. et al. v. Complete Genomics Inc.

1:10-cv-00649; filed August 3, 2010 in the District Court of Delaware

• Plaintiffs: Illumina Inc.; Solexa Inc.

• Defendant: Complete Genomics Inc.

Infringement of U.S. Patent Nos. 6,306,597 ("DNA Sequencing by Parallel Oligonucleotide Extensions," issued October 23, 2001), 7,232,656 ("Arrayed Biomolecules and Their Use in Sequencing," issued June 19, 2007), and 7,598,035 ("Method and Compositions for Ordering Restriction Fragments," issued October 6, 2009) based on defendant's manufacture and sale of its Complete Genomics Analysis Platform products and services. View the complaint here.

[This lawsuit, aimed at core technologies, is an obvious setback not only to Complete Genomics, but the entire "Full DNA sequencing" industry. Immediately, it may adversely affect Complete Genomics' determination to go public at this time, since in some investors' eye a relatively novel company that is sued by one of the leading and well-established companies (Illumina) at the least would lessen the financial success of a Complete Genomics IPO. A quick settlement looks unlikely as Complete Genomics is capital hungry, and Illumina by demanding "jury trial" looms large, possibly inflicting a multi-year and expensive process. This three-pronged lawsuit is also a set-back to the entire "Full Human DNA Sequencing" industry - and given that Complete Genomics altered twice the expectations (first as quoted in my YouTube 2008 October, promising a "Google-type Data Analytics Center", and secondly the service seems to be open to batches of 100-s of sequences, in a whole-sale mode to R&D, rather than to the public) - Illumina (and Life Science) may stay longer as an established provider with their "pre-nanosequencing technology" (the Genome Analyzer by Illumina and SOLiD by Life Science). This altered dynamics is likely to trigger a ripple of business decisions - Andras Pellionisz (FaceBook) / Pellionisz_at_JunkDNA.com]

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I was wrong ...

At the Churchill Club event "Personal Genome Computing: Breakthroughs, Risks and Opportunities on January 22, 2009 in the Q&A period the question was asked when would the first genome computer game appear. I said "In Two Years". I was wrong. In exactly One Year (January 22, 2010, that is precisely half the time predicted) the following paper was submitted to Nature (accepted June 30, 2010):

Predicting protein structures with a multiplayer online game

Seth Cooper, Firas Khatib, Adrien Treuille, Janos Barbero, Jeehyung Lee, Michael Beenen, Andrew Leaver-Fay, David Baker, Zoran Popović & Foldit players

Nature 466, 756–760 (05 August 2010) doi:10.1038/nature09304

Received 22 January 2010 Accepted 30 June 2010

People exert large amounts of problem-solving effort playing computer games. Simple image- and text-recognition tasks have been successfully ‘crowd-sourced’ through games1, 2, 3, but it is not clear if more complex scientific problems can be solved with human-directed computing. Protein structure prediction is one such problem: locating the biologically relevant native conformation of a protein is a formidable computational challenge given the very large size of the search space. Here we describe Foldit, a multiplayer online game that engages non-scientists in solving hard prediction problems. Foldit players interact with protein structures using direct manipulation tools and user-friendly versions of algorithms from the Rosetta structure prediction methodology4, while they compete and collaborate to optimize the computed energy. We show that top-ranked Foldit players excel at solving challenging structure refinement problems in which substantial backbone rearrangements are necessary to achieve the burial of hydrophobic residues. Players working collaboratively develop a rich assortment of new strategies and algorithms; unlike computational approaches, they explore not only the conformational space but also the space of possible search strategies. The integration of human visual problem-solving and strategy development capabilities with traditional computational algorithms through interactive multiplayer games is a powerful new approach to solving computationally-limited scientific problems.

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"Recursive Genome Function" - winner takes it all

[Screenshots of Google, Aug.4, 2010 - AJP]

The astonishing fact overnight is not that "Recursive Genome Function" inched forward from 160,000 by two thousand hits.

"The Winner Takes It All" is shown by the obsolete axioms dropped overnight by almost thirty thousand hits (combined). An almost 10% daily drop of the stock market index halts trading. A more common example: You never want to take away toys, even old ones, from those (not scientists) playing in a sandwalk. They scream from the top of their lungs. The thing to do is to offer a new (and better) toy. The obsolete ones are quietly dropped by those grabbing the novelty, while those who drop the old but fail to grasp the new show all the signs of hard times - FaceBook: Andras Pellionisz, or email Pellionisz_at_JunkDNA.com

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Pellionisz' "Recursive Genome Function" supersedes both obsolete axioms of "Central Dogma" AND "Junk DNA"

[Screenshots of Google, Aug.3, 2010 - AJP]

At the tenth Anniversary of The Human Genome Project, there is a unanimous agreement of scientists worldwide that there is tremendous intellectual void between our ability of reading the Full Human DNA (all 6.2 Bn A,C,T,G-s of a diploid human genome) on one hand, and our (limited) ability of writing new sequences, on the other hand. It is not the greatest problem that both our reading (e.g. precision) and synthesis (size) needs improvements. E.g. synthetic sequences presently must be small enough in size and in difference from existing forms of life to remain "stealth" to Genome Regulation, such that they can be synthesized and even started to function (nobody knows through how many generations, since they have been put into a freezer...).

By far the most critical void is the present almost complete lack of professional theoretical foundation of genome informatics. This coming intellectual void was actually predicted by Francis Crick when he attempted to temporarily shore up his collapsing "Central Dogma" (upheld since his promulgation in 1956 till his passing in 2004); "If it were shown that information could flow from proteins to nucleic acids, he said, then such a finding would 'shake the whole intellectual basis of molecular biology' "(Crick, 1970). Although Ohno (1972) rushed to save the establishment with his misnomer that even if there were such recursion, it would only find "Junk DNA" in the 98.7% non-genic part of the genome, which is there, he falsely claimed, for "the importance of doing nothing" (p.367), by now the "genes-Junk" primitive and obsolete school is what Venter calls flatly: "we have a frighteningly unsophisticated view of genome function". What happened to Dr. Collins' call upon concluding ENCODE in 2007 that "the scientific community has to re-think long-held beliefs"?

A lucky few did not have to re-think "Central Dogma" and "Junk DNA" - since they never believed them in the first place. Thus I had a decade-long lead to build The Principle of Recursive Genome Function (2008) - that elaborates my FractoGene concept (2002). Nobody seems to raise "no, the genome function is not recursive" - that would be pretty foolish. If some think "yes, it is recursive, but not fractal", one would recommend the recent Science cover issue (Oct. 9, 2009) "Mr. President, the Genome is Fractal!" (Lander et al., 2009) Though Pellionisz Principle was quoted by a dozen or so authors within 6 months of its publication in a peer-reviewed science paper, totally independent authors are joining the fray (Jean-Claude Perez, France, 2010, Borros M. Arneth, Germany, 2010) - before it will (soon) be everywhere "that we have all been saying that the genome function was recursive, and in fact was based on my thoughts of fractal recursive iteration...". People might forget that it was my double "lucid heresy" to put to rest the two ruling false axioms that hidered genome informatics over half a Century - by discovering and publishing (now applying...) the more advanced Principle of "Recursive Genome Function".

Some may ask why do I make such a strong point about theoretical foundation of full (holo)genome function (including the epigenomic pathway through which extrinsic proteins make the hologenome "an open loop" - The Circle of Hope).

The primary of the two strong reasons is, that most of the general public (and unfortunately, even some scientists) maintain that "our genome is our destiny"; there is nothing we can do about it, and it deterministically defines our future. Clearly, this totally mistaken attitude stems from Crick's "Central Dogma", that sees a "straightforward, DNA>RNA>PROTEIN genome function that "dead end"-s with proteins, and the genome is assumed to lack even the possibility of a PROTEIN>DNA recursion. The deterministic philosophy also has deep roots in natural sciences, since e.g. in physics it was only a mere 83 years ago (a footnote in the over 2,000 years of physics) that the Heisenberg Uncertainty Principle was put forward. Physics of today is probabilistic (rather than deterministic), but such a profound change of attitude (in fact, philosophy) certainly does not happen overnight in postmodern genomics - or even biology. Most unfortunately, the old and gloomy (and false) legacy often prevails, e.g. in discouraging people of taking advantage of genomic tests; "why should I know if nothing can be done". Once I published The Principle of Recursive Genome Function (2008) I rushed to disseminate "the Circle of Hope" widely over Google Tech Talk YouTube - such that the public picks up a new wave of positive motivation based on rock-solid new science.

Unfortunately, the public's view greatly affects both the government R&D programs, as well as the sustainability of private domain R&D and applications. Those who paid $3 Billion by their taxes for sequencing a single Full Human DNA, and a decade after the same scientists openly declare that they don't have the slightest how to understand it, could significantly tone done government funding enthusiasm. Even with today's "point of inflection" when the Private Sector is taking over, the stakes are enormous if the Genome Informatics Industry gears up for "Brute Force Approaches" (that can always be done, albeit with horrific expense) - or processing of experimental data is guided (actually, predicted) by the best theories. No sane person (or Country...) would build enormous accelerators if nuclear physics would not be available to interpret the trajectories. However, there are $Billions invested into "DNA sequencing technologies" - and theories of doing away with half-a-Century dogmas often go overlooked in anywhere - but on the Google search engine "Recursive Genome Function" beating (at some peaks by close to a million hits...) both stone-age unsophistication of "Central Dogma" and "Junk DNA" - Pellionisz_at_JunkDNA.com

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Mountain View's Complete Genomics to make Wall Street debut

Silicon Valley Mercury News
By Scott Duke Harris

Posted: 07/30/2010 07:39:49 PM PDT
Updated: 07/30/2010 09:03:44 PM PDT

A Mountain View startup that aims to drive the cost of sequencing a human genome to below $1,000 in hopes of advancing health care is preparing for a Wall Street debut and staking its claim to the ticker symbol GNOM.

In documents filed Friday with the Securities and Exchange Commission, Complete Genomics signaled its intent to make an initial public stock offering on the Nasdaq, hoping to sell more than $86 million in stock.

Startups that register for Wall Street debuts often postpone or withdraw such plans. Given the uncertain market for IPOs and excitement surrounding the commercial potential of DNA research, Complete Genomics' effort figures to attract considerable attention.

All life-forms carry a genome, a strand of chromosomes that is a full reflection of its hereditary traits. Complete Genomics is among a group of Silicon Valley startups at the cutting edge of DNA research — an endeavor that promises to advance human health while also playing a role in agriculture and biofuel development.

Complete Genomics' proprietary, assembly-line-like laboratory operation began sequencing human genomes about a year ago. The company has focused on doing large studies on human genomes for customers such as Genentech, the pharmaceutical giant Pfizer and major research institutions.

Sequencing the human genome was pioneered a decade ago at a cost of about $500 million for one genome. The expense has been an obstacle for researchers who are trying to decode patterns that correspond to maladies known to have genetic roots. Driving down the cost — the central mission of Complete Genomics' technology and business model — has been critical to performing large studies.

"It's all about scale. Sequencing one human genome is a scientific curiosity," Clifford Reid, co-founder and CEO of Complete Genomics, said in an interview with the Mercury News in September. That month, when the company announced it had sequenced a batch of 14 genomes, "we probably doubled the number of known genomes in the world," Reid said.

Last May, when Complete Genomics started commercial operations and after medical researchers published a report in the journal Science based on genomes it had sequenced, Reid was quoted as saying that his company was processing 500 genomes a month and had dropped the cost to $4,000.

In its filing with the SEC, Complete Genomics asserted that it has "optimized" its technology platform and is "able to achieve accuracy levels of 99.999% at a total cost that is significantly less than the total cost of purchasing and using commercially available DNA sequencing instruments."

It also touted "significant competitive advantages" as an independent lab: "Because our technology resides only in our centralized facilities, we can quickly and easily implement enhancements and provide their benefits to our entire customer base. We believe that we will be the first company to sequence and analyze high-quality complete human genomes, at scale, for a total cost of under $1,000 per genome."

[Assuming that the uncertain economic conditions will allow the successful IPO to happen, this is wonderful news - both for Complete Genomics and the rest of the world. While there are public companies that do DNA sequencing (best known are Illumina, Life Sciences), Complete Genomics aptly celebrates the 10th Anniversary of The Human Genome Project by becoming the first "pure play" human DNA sequencer company, using "assembly-line" mass-production by molecular nanosequencing. The planned IPO seems to be timed to pre-empt the company's main rival, Pacific Biosciences (of Menlo Park, CA) flooding the market with their sequencing machines. Watching carefully the market, if it will validate Craig Venter (see below) that full human DNA sequences provide "useless information" (without Analytics), or with the ramping up of full human DNA interpretation (also by HolGenTech, Inc. stealth-mode breakthrough) will contribute to a successful IPO is critical e.g. for Silicon Valley jobs. - "Andras Pellionisz" (FaceBook), Pellionisz_at_JunkDNA.com]

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SPIEGEL Interview with Craig Venter: 'We Have Learned Nothing from the Genome'
Spiegel
07/29/2010

[This interview deserves to be amply commented, especially since Dr. Venter (not Mr. Venter...) made this recent statement: We’re at a frighteningly unsophisticated level of genome interpretation.” . I will make my comments as my personal opinion of Dr. Venter's statements below, based on my overall assessment that I expressed for some time that "Venter is the Tesla of PostModern Genomics" - Comments on my remarks can be posted at my FaceBook ("Andras Pellionisz") or email Pellionisz_at_JunkDNA.com]

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Ten years ago, Craig Venter had plenty of reason to feel triumphant. Standing at the White House together with his rival Francis Collins of the National Institutes of Health as well as then-President Bill Clinton and former British Prime Minister Tony Blair, he announced the successful sequencing of the human genome. The historic press conference marked the end of a bitter race between Venter's firm Celera and the Human Genome Project, a government-sponsored consortium of around 1,000 scientists from around the world. Both groups had technically mapped the genome, but Venter's team had done it faster and cheaper. Since then, multimillionaire Venter, 63, has established a reputation within the scientific community for being a rebel. It's an image he appears to relish, and he stuns the world again and again with one brash victory after another. He is currently sailing around the world in his Sorcerer II research yacht documenting the genetic diversity of the world's oceans. He recently departed Valencia, Spain, to begin an expedition in the Mediterranean Sea. In May, he announced that his team had produced the world's first bacteria with a synthetic genome.

[Dr. Venter's perspective from sailing around the Globe might be motivated by the famous saying: "Be careful what you wish, since it might become true" ... Craig might feel that glorious emptiness, now for the second time, that he has accomplished the unthinkable, and "there is nothing simpler than a problem solved" (Faraday). Ten years ago he successfully competed in a single-handed manner (except computers...) with a world-wide consortium in full DNA sequencing of a human. Now he succeeded, after 15 years of effort, much longer than he anticipated, in synthesizing a functioning genome that was not the exact duplication, but slight modification, of a tiny DNA - and could implant it in a cell that accepted the "newcomer" DNA. Success is, like arriving at the mountain-top, a funny feeling. Glorious, yes, "mission accomplished" - but from the hilltop the next mountain presents a perhaps even more mounting challenge. Accomplishing the unthinkable can thus also is disappointing; a problem solved may reveal that the questions that it opened are even more formidable than what has just been answered. Venter said recently; "Were at a frighteningly unsophisticated level of genome interpretation". He acquired the entire set of character-sequence of the "big Russian novel" (quote from Esther Dyson) but realizes much more keenly than most, that "our 100-word dictionary" (which may be Chinese-English...) is a miserable failure to understand, let alone enjoy, the meaning of the Russian novel that myriads of characters tell us in an unknown language.

Craig is undoubtedly very aware of what's missing; actually both in making sense of the sequences, as well as synthesizing new, complex and big synthetic genomes. We can not go from "reading" to "writing" - without "understanding". Booting the modified and synthesized tiniest free-living organism could not succeed since the basic principles of genome function regulation were "frighteningly unsophisticated" for most. Since Craig is not (yet?) frontally attacking the "next big problem" (of analytics of genome regulation), some of his comments perhaps unduly play down the significance of what has actually been achieved - and his self-contradiction at times can be easily spotted. Maybe the journalistic title "we have learned nothing from the genome" picked up on a temporary disappointment, a "let down" after yet another major accomplishment. Venter says below, that (a truly frighteningly unsophisticated "genome function theory") expected maybe up to 300,000 "genes" in the human genome. We absolutely did learn from his (and the Consortium's) results, that the primitive assumption was totally wrong, didn't we?

In a year after the human DNA was sequenced, the mouse DNA showed that 98% of the (mere 20,000 or so) "genes" are functionally identical in human or mouse (and by now we realize that the "basic building materials" are astonishingly similar in practically all species; from the ringworm to human). For a biophysicist who devoted his oeuvre to the intrinsic mathematics of biology (and explained brain function for cerebellar neural nets by tensor geometry), the 98.7% of "Junk DNA" misnomer was dead on arrival of 2002. With sequencing techniques becoming widespread and available, we did absolutely learn, too, that the genome DNA>RNA>PROTEIN "forward model" is just absurdly incorrect, didn't we? Genomics and Epigenomics, therefore (particularly by experimental investigation of methylation) is almost universally accepted as the two sides of the same coin. Thus, the "Central Dogma" (having died a thousand deaths) was put to rest, along with JunkDNA - leading to The Principle of Recursive Genome Function - explaining e.g. the fractal growth of cerebellar Purkinje neurons as governed by the fractal DNA - through the epigenomic channels methylating auxiliary information in the "non-coding DNA" upon perusal in fractal iterative recursion. Perhaps we should have listened to Crick, that if his "Central Dogma" were shown to be untrue, "If it were shown that information could flow from proteins to nucleic acids, he said, then such a finding would 'shake the whole intellectual basis of molecular biology' "(Crick, 1970). What happened to the earth shake? What happened to Dr. Collins' call (wearing his scientist' hat upon concluding ENCODE in 2007 that he put together wearing his administrator's hat) that "the scientific community has to re-think long-held beliefs"? We did learn from the genome, did we not, that the genome itself (because of the epigenomic "open loop" - the "Circle of Hope") provides us with "probabilities", rather than certainties - but who says that "probability theory" equals to "useless information"? When will the philosophy sink in (like it did with the Heisenberg Uncertainty Principle) that sophisticated science at times must proceed in a way that the whole intellectual basis is shaken?

In the afterglow following a second accomplishment of the unthinkable one may be overly pessimistic on particular details. A good example is the statement that knowing his genome, Dr. Venter could not use it for anything. He is on record, however, that as early as during the process of his full DNA sequencing (since he was one of the five DNA donors) he started to take statins as the genomic signature of the sample in which he was dominant warranted controlling his cholesterol. The "close to zero" medical benefit from genomic knowledge is demonstrably untrue for individuals who showed elevated probability of e.g. colon cancer, followed up with colonoscopy and small, pre-cancerous polyps were removed.

Because of his double towering accomplishments, Dr. Venter is entitled to vocalize that "the more we know, the more we realize what we don't know". Those with lesser achievements can not afford to be less than optimistic. - You can comment at my FaceBook wall "Andras Pellionisz" or email Pellionisz_at_JunkDNA.com]
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The world's first bacteria with a synthetic genome was even coded with an e-mail address. [Is SPAM-ing a genome a brand new epigenomic effect, or what? - AJP]

In a SPIEGEL interview, genetic scientist Craig Venter discusses the 10 years he spent sequencing the human genome, why we have learned so little from it a decade on and the potential for mass production of artificial life forms that could be used to produce fuels and other resources.

SPIEGEL: Mr. Venter, when the elite among gene researchers undertook the decoding of the human genome, you were their greatest enemy. They called you "Frankenstein," "blood sucker," "Darth Venter" and even "asshole." Why do you attract so much hostility?

Venter: Well, nobody likes to be beaten -- by superior intelligence, planning and technology. That gets people upset.

SPIEGEL: Every area of science is competitive. But it doesn't lead to that kind of hostility in all areas.

Venter: The human genome project was completely different, it was supposed to be the biggest thing in the history of biological sciences. Billions in government funding for a single project -- we had never seen anything like that before in biology. And then a single person comes along and beats scientists who have been working on it for years. It is no wonder they didn't like that.

SPIEGEL: Wasn't it more the case that your opponents were afraid that you, as a profit-oriented entrepreneur, would make the human genome your own private property?

Venter: That is totally absurd; and you know it. Initially, Francis Collins and the other people on the Human Genome Project claimed that my methods would never work. When they started to realize that they were wrong, they began personal attacks against me and made up these things about the ownership of the genome. It was all absurd.

SPIEGEL: So it was all just propaganda?

Venter: At the end of the day, it is an argument over nothing. But this battle between common good and commerce -- that is the kind of story that sells newspapers.

SPIEGEL: Was the importance of gene patents, which fueled the dispute, exaggerated?

Venter: First of all, nobody has made any serious money off patents on human genes except patent attorneys. Second, I do not hold any patents on human genes. You can do a patent search. Then you can convince yourself.

SPIEGEL: On June 26, 2000, you had a major event -- you met with Francis Collins at the White House …

Venter: … yeah, it was obviously a big historic event. It was pretty stunning, making an announcement at the White House to the entire world. It was a big triumph for me and my team because it proved that we had won.

SPIEGEL: At the time, none of you had won. Nobel Prize recipient John Sulston, one of the researchers of the government-funded genome project wrote …

Venter: … What was his quote? That he and his people were a bunch of phonies who had nothing?

SPIEGEL: In essence, he wrote that you both had nothing.

Venter: He had no idea what we had. Sulston has proven he is not the most credible source on anything other than his own data. He said they were a bunch of phonies, we have to take him at his word on that.

SPIEGEL: It seems to have been the only time in history that a new scientific discovery was announced officially by the government. How did that unusual agreement in the White House take shape?

Venter: It was a political compromise because the people at the public Human Genome Project were afraid we would announce what we had. And we were afraid they would use the White House to make it look like they had won.

SPIEGEL: It appeared at the time that you had agreed to be undecided. Do you now view yourself as the winner of the race?

Venter: I don't think it really matters.

SPIEGEL: The New York Times later declared the public Human Genome Project to be the victor. Can you really claim that you don't care?

Venter: Oh, the New York Times! How do you define the "winner" in this case? What is decisive is that it is our data that is in the databases -- not the data the consortium put together back then.

SPIEGEL: The genome project has been called the Manhattan Project or Moon Landing of its era. It has also been said that knowledge of the genes will change the future of humanity and become a "main driver of the world economy."

Venter: Who said that? I didn't. That was the people at the consortium.

SPIEGEL: You're wrong. You made all those statements in an interview with DER SPIEGEL in 1998.

Venter: Really? Those are Francis Collins' lines. So I may have said that that's how he describes it. I, on the other hand, have always said, "This is a race from the starting line to the finish."

SPIEGEL: The genome project hasn't just raised hopes -- but also worries. Do you understand those concerns?

Venter: Yes. There are two groups of people. People either want to know the information or they prefer to live like an ostrich with their head in the sand, not knowing anything. The fear is based on the ill-founded belief that those who know the DNA sequence also know every aspect of life. This nonsense has been spread by the same geneticists who were afraid of the commercialization of this stuff. From the time of the first few discoveries of gene defects -- Huntington's disease, for example, everybody thought that if you knew your genome, you would know when you would die and what you would die from. That is nonsense.

SPIEGEL: So the significance of the genome isn't so great after all?

Venter: Not at all. I can tell you from my own experience. I put my own genome on the Internet. People had the notion this was the scariest thing out there. But what happened? Nothing.

SPIEGEL: Nevertheless, Jim Watson, the co-discoverer of the DNA double helix, has said he doesn't want to know which variant of the so-called ApoE gene he has -- it could say something about his risk for developing Alzheimer's, and he's afraid of that …

Venter: That was silliness. At that age? Watson is over 80.

SPIEGEL: Are you interested in finding out what ApoE variant you have?

Venter: I know it. And according to it, I have a slightly increased risk for Alzheimer's disease. But it impresses me little because I could have dozens of other genes that counteract it. Because we do not know that, this information is meaningless.

Part 2: 'We Couldn't Even Be Certain from my Genome What My Eye Color Was'

SPIEGEL: And what about the fears about the abuse of gene data through insurers or employers, for example? Do you see that as sheer hysteria?

Venter: Abuse is not a question of whether the data is available. It is an issue of laws. You can't do anything to change the availability of genetic data. Look at this bottle that you have touched -- that's all I need to obtain your entire genetic information.

SPIEGEL: How much would you be able to learn about us by doing so?

Venter: If anything, we don't really know how to read the genome and it can't tell us very much right now. So what's the ethical debate about?

SPIEGEL: The decoding of your personal genome has so far revealed little more than the fact that your ear wax tends to be moist.

Venter: That's what you say. And what else have I learned from my genome? Very little. We couldn't even be certain from my genome what my eye color was. Isn't that sad? Everyone was looking for miracle 'yes/no' answers in the genome. "Yes, you'll have cancer." Or "No, you won't have cancer." But that's just not the way it is.

SPIEGEL: So the Human Genome Project has had very little medical benefits so far?

Venter: Close to zero to put it precisely.

SPIEGEL: Did it at least provide us with some new knowledge?

Venter: It certainly has. Eleven years ago, we didn't even know how many genes humans have. Many estimated that number at 100,000, and some went as high as 300,000. We made a lot of enemies when we claimed that there appeared to be considerably fewer -- probably closer to the neighborhood of 40,000! And then we found out that there are only half as many. I was just in Stockholm for the 200th anniversary of the Karolinska Institute. The first presentation was about the many achievements the decoding of the genome has brought. Then I spoke and said that this century will be remembered for how little, and not how much, happened in this field.

SPIEGEL: Why is it taking so long for the results of genome research to be applied in medicine?

Venter: Because we have, in truth, learned nothing from the genome other than probabilities. How does a 1 or 3 percent increased risk for something translate into the clinic? It is useless information.

SPIEGEL: There are hundreds of hereditary diseases that can be traced to defects in individual genes. You can determine a lot more than just probabilities through them. But that still hasn't led to a flood of new treatments.

Venter: There were false expectations. Take Ataxia telangiectasia, for example, a horrible disease. The nervous system degenerates, and people who have it often die in their early teens. The cause is a defect in a single gene, but it is a developmental gene. If your body is built in the wrong way, then you can't just take a magic pill to rebuild it. If your brain is wired wrong, then it is wired wrong.

SPIEGEL: Who is to blame for those false expectations?

Venter: We were simply always looking at single genes because they were the only genes we had. When people lose their keys at night, they look under the lamp post. Why? Because that's where you can still see something.

SPIEGEL: But the keys are really located in the dark?

Venter: Exactly. Why did people think there were so many human genes? It's because they thought there was going to be one gene for each human trait. And if you want to cure greed, you change the greed gene, right? Or the envy gene, which is probably far more dangerous. But it turns out that we're pretty complex. If you want to find out why someone gets Alzheimer's or cancer, then it is not enough to look at one gene. To do so, we have to have the whole picture. It's like saying you want to explore Valencia and the only thing you can see is this table. You see a little rust, but that tells you nothing about Valencia other than that the air is maybe salty. That's where we are with the genome. We know nothing.

SPIEGEL: Do you think there will be a time when you can extract all this information to yield real medical results?

Venter: For that to happen we need a lot more information: Information about your body's chemistry, your physiology, your complete medical history, your brain and your entire life. We would need to do that a million times on different people and correlate that data with their genetic information.

SPIEGEL: Will that lead in the end to the kind of personalized medicine that genetic researchers have always touted? Each person would get his or her own personal treatment that is tailored precisely to that person's genetic make-up?

Venter: That was another one of these silly naïve notions that was out there. It's not, 'Oh, we know your genome, we're going to make this drug for you.' That will never happen. It is more important that you use the information in the genome about your personal risks and reduce them through intelligent behavior.

SPIEGEL: You have complained about how naïve genome researchers were in the beginning. Will future generations eventually make fun of us in the same way for how naïve we still are today?

Venter: Only time will tell. Nevertheless, we now have what is going to be one of the most important tools for interpreting the human genome: the first synthetic cell. It will enable us to ask questions that would have been inaccessible before.

SPIEGEL: When no progress was made through the reading of the genome, you shifted to rewriting it. You sequenced the entire genome of a bacteria and used it in another cell. How is the microbe you created doing today?

Venter: It's sitting in a freezer, doing extremely well. We'll keep it for the historians.

SPIEGEL: You stored a code in the genome of this cell. Has anyone decoded it?

Venter: Yes, it is the first genome in the world to include an e-mail address. So far, 50 scientists have cracked the code and answered us.

Part 3: 'We Don't Need Any More Neanderthals on the Planet'

SPIEGEL: Many fear what might happen if humans craft new life forms. They repeatedly say that you are playing God …

Venter: Yes, and I find them frightening. I can read your genome, you know? Nobody's been able to do that in history before. But that is not about God-like powers, it's about scientific power. The real problem is that the understanding of science in our society is so shallow. In the future, if we want to have enough water, enough food and enough energy without totally destroying our planet, then we will have to be dependent on good science.

SPIEGEL: Some scientist don't rule out a belief in God. Francis Collins, for example …

Venter: … That's his issue to reconcile, not mine. For me, it's either faith or science - you can't have both.

SPIEGEL: So you don't consider Collins to be a true scientist?

Venter: Let's just say he's a government administrator.

SPIEGEL: When can we anticipate seeing the next tailor-made microbes from your laboratory?

Venter: Well, the goal is multifold. We have to start by creating minimal cells. A human cell is too complex -- we have no idea how any human cell works. We don't even know how the simplest bacterial cell works. We want to learn what the minimum cellular components are, so we're going to be taking out all the non-essential genes. But we're also trying to design new life forms for energy production, capturing carbon dioxide or to produce chemicals.

SPIEGEL: Wouldn't it be easier to modify existing bacteria using the established methods of biotechnology?

Venter: It isn't that simple. For example, there is no other way of creating a minimal cell. You can only add or take out genes at will if you have built the genome from scratch.

SPIEGEL: How long does it take to create such new forms of cells?

Venter: Right now we have the technology to make several a day, and the goal is to make a million a day.

SPIEGEL: How long will it be until the life forms you have created start producing fuel for our cars?

Venter: Not only gasoline. Plastic, asphalt, heating oil: Everything that we make from oil will at some point be made by bacteria or other cells. Whether that is in five, 10 or 20 years is unclear. Why don't we have fuel now other than alcohol from microbes? It's because nothing evolved that can produce great amounts of biofuel out of CO2. That's why we have to make it.

SPIEGEL: ExxonMobile, at the very least, appears to be convinced by your vision …

Venter: … yes, they are investing $600 million in the project, with half going to our partnership. It's a good round number. It's the same money that PerkinElmer gave me to decode the human genome. With it, we sequenced the human genome in nine months instead of many, many years. The public money that flowed into the Human Genome Project, above all, created an enormous, inflexible bureaucracy. And it is only because of private money that we can now sail across the ocean with this sailboat and discover 40 million genes -- there are only 41 million genes known to all of science. All you need are a few innovative ideas and independent funding to allow you to do things that other people can only dream about.

SPIEGEL: It took eight years from the time the first bacterial genome was decoded until the human genome was completed. How much time will elapse between the creation of the first synthetic bacteria and the creation of the first synthetic human?

Venter: There is currently no reason for us to synthesize human cells. I am, for example, a fan of the work that was done a short time ago that led to the decoding of the Neanderthal genome. But we don't need any more Neanderthals on the planet, right? We already have enough of them.

SPIEGEL: Mr. Venter, we thank you for this interview.

Interview conducted by Rafaela von Bredow and Johann Grolle

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GenePlanet in Europe makes Genome Testing Global

GenePlanet.com
Headquarters:
Gene Planet Limited
Upper Pembroke Street 28
Dublin
Ireland

Logistics centre and research:
GenePlanet d.o.o.
Technology park Ljubljana
Teslova 30
Slovenia

GenePlanet genetic testing service starts with us sending you a saliva collector by mail. In the laboratory we extract your genetic material which is used to perform the analysis. As a result you will find out to which diseases you are susceptible, what effect do certain medications have on you, what are your talents and special abilities, as well as who are your ancestors.

Your personal genetic testing is now available at 549$ / 399€.

A list of diseases, talents and medications, tested by GenePlanet

Genetic testing for disease susceptibility

ARMD
Alzheimer`s disease
Ankylosing spondylitis
Asthma
Coronary artery disease
Atrial fibrillation
Bipolar disorder
Breast cancer
Celiac disease
Crohn`s disease
Depression
Dyslexia
Endometrial cancer
Gallstones
Hypertension
Long QT interval
Lung cancer
Multiple sclerosis
Peripheral arterial disease
Prostate cancer
Psoriasis
Restless leg syndrom
Rheumatoid arthritis
Type 1 diabetes
Type 2 diabetes

Genetic testing for medicament response

Beta blockers and heart
Beta blockers and tension
Efficacy of Aspirin
Headache and triptans
Statins against heart attack
The effect of antidepressants
The secret of Viagra

Genetic testing for traits and talents

Alcohol flush reaction
Avoidance of errors
Birth weight
Bitter taste perception
Earwax type
Effect of breastfeeding on IQ
Episodic memory performance
Eye colour
Fat intake and BMI
Freckles
HDL cholesterol level
Lactose intolerance
Malaria resistance
Measures of intelligence
Memory of older people
Muscle explosiveness
Norovirus resistance
Odour detection
Pain sensitivity
Skin colour
Nicotine dependence

With Geneplanet genetic testing, you can reveal what is written in your genes, it helps you understand the effect of genes on your life and advises how to make the most of your genetic advantages.

[GenePlanet released the Genome Testing genie completely out of the bottle. Silicon Valley is losing jobs left and right. Meanwhile, the Seoul (Korea) DTC picked up the Asian market. Now, after DeCodeMe in Iceland, GenePlanet metastased Genome Testing business on the Planet to Europe, with its Headquarters in Ireland, and labs in Slovenia - that some politicians can't even distinguish from Slovakia. Independent if US inventors (etc) like it or not, Genome Testing DTC is beyond control of US - Pellionisz_at_JunkDNA.com]

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Pfizer to Study Liver Cancer in Korean Patients with Samsung Medical Center

GEN
Jul 14 2010

Pfizer formed a research partnership with Samsung Medical Center to generate gene-expression profiles of tumors from Koreans with liver cancer. The hope is that the findings will lead to targeted therapeutics that can be used not just in Korea but also in the rest of Asia.

A research team led by Samsung Medical Center scientists including Prof. Park Cheol-Guen, Prof. Im Ho-Young, and Prof. Paik Soon-Myung, director of the cancer research center, will conduct research in Seoul. Neil Gibson, Ph.D., vp of oncology research, will be responsible for the joint research program at Pfizer.

Samsung Medical Center has built a base of specimens in the liver cancer area. “This partnership will serve as a great opportunity to combine Pfizer's know-how in drug development and Samsung Medical Center's extensive genome information and technology in the liver cancer area,” says Dr. Gibson. “We further plan to share the ownership of collected and analyzed data with Samsung Medical Center.”

Pfizer signed a memorandum of understanding with the Ministry of Health and Welfare in 2007, agreeing to invest $300 million in R&D in Korea. As part of its commitment, the company also formed a strategic partnership with the Korea Research Institute of Bioscience and Biotechnology and has been leading joint research since then.

In February Pfizer linked up with Eli Lilly and Merck & Co. to set up the Asian Cancer Research Group (ACRG) to concentrate on drug R&D for the most common cancers in Asia. The nonprofit company will initially focus on lung and gastric cancers, which are two of the most common cancers in Asia.

The aim for ACRG is to generate a pharmacogenomic cancer database comprising data from about 2,000 lung and gastric cancer tissue samples. The resulting data will be made publicly available to researchers and expanded through the addition of clinical data from a longitudinal analysis of patients.

The ACRG will initially establish collaborative relationships throughout the Asian region to collect tissue samples and data. “The ACRG is about sharing information for the common good,” stresses Kerry Blanchard, M.D., Ph.D., vp and leader of drug development in China for Lilly.

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Lee Min-joo donates 3 billion won to genome project

2010-07-26 16:45

Lee Min-joo, 62, chairman of Atinum Partners, a Seoul-based privately held investment company, donated 3 billion won ($2.5 million) Friday to the Asian Genome Road Project being conducted by the Genomic Medicine Institute at Seoul National University.

The Asian Genome Road Project aims to establish an Asian-specific genome database by sequencing individuals from across Asia, including South Koreans, Mongolians and Turks. Genome analysis will make it possible to individually tailor medical treatment.

The donation pledge was a result of year-long discussions between Seo Jeong-sun, director of GMI-SNU, and Lee about the significance of the project.

Deputies of Atinum Investment Chairman Lee Min-joo deliver his donation to Genomic Medicine Institute, Seoul National University on Friday. From left are GNI-SNU director Seo Jeong-sun; SNU College of Medicine assistant dean for academic affairs Choi Jin-ho; Atinum Partners President Chung Kyung-soo and Atinum Investment President Shin Ki-chun.

GNI-SNU

Lee has shown keen interest in the health care business. The Yonsei University graduate who majored in applied statistics started up a toy company in 1975, and grew it remarkably. Around the 1997 financial crisis, he began a regional cable television business. In March, 2008, he sold C&M, one of the largest cable TV networks in the Seoul area, to a group of investors led by Macquarie, an Australian financial company, for about 1.45 trillion won.

Lee then began to invest more boldly. For the first time as a private businessman in Korea, he acquired Sterling Energy plc, a U.S. oil company, for $90 million in December, 2009. Along with an increase in investment, he reportedly has donated about 30 billion won to Yonsei, KAIST, Myongji University and Seoul Women’s University. Atinum Partners has assets under management of over $1.5 billion.

Lee is known to have a business philosophy that investment and donation should be based on a vision of a future society and the changing needs of people.

The low-profile businessman, who refrains from public appearances, did not attend the donation ceremony held at a meeting room of the College of Medicine, Seoul National University. Instead, he sent his deputies to the event.

Seo is a pioneer in Asian genome study; his research group recently published his work on Korean whole genome analysis, being the fourth group in the world to publish a whole genome study in Nature utilizing next-generation sequencing technology. His group also completed the whole genome analysis of a Korean female, which will be the first Asian female whole genome sequence published.

[The two articles above (shipping potential US jobs to Asia, according to economics of global business) and the two articles below (shipping potential US jobs to Asia, if an overzelous "regulation" in the US would happen) could be viewed through the looking glass of Andy Grove (former CEO of Intel and a major donor to Parkinson's research). Andy Grove argues in Bloomberg BusinessNews that unless the USA finds ways to create jobs, we face a grim picture. It is known that some venture philanthropists set as a requirement that jobs must be created on their money. Suppose those who donated so generously to Parkinson's research, and e.g. an other industry giant who might contemplate donating new funds to liver cancer research would unite, and seed a "Full DNA Analytics Center" in Silicon Valley, where two of the leading sequencer companies are about to deluge genomics with sequences, yet it is questionable if "is IT ready for the dreaded DNA data deluge" - with the requirement that a certain percentage of their funds must create Silicon Valley jobs? - Pellionisz_at_JunkDNA.com]

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Working with regulators—the road ahead

July 27, 2010
Navigenics,

Validity. Accuracy and quality. Clinical relevance. Security and privacy. These were among the top themes highlighted over and over when federal officials convened a series of meetings and hearings last week in the Washington D.C. area to discuss the prospects for personal genomics services and other innovative types of health-related tests.

For long-time readers of this blog, these ideas are nothing new. When Navigenics launched its personal genome service more two years ago, we issued a 10-point proposal for a set of industry standards to ensure the integrity of this new field of science and health and safeguard consumers. We reiterated the need for these principles again early last year, when we helped the Personalized Medicine Coalition convene a meeting on standards for personal genomics services.

So when last week’s events kicked off with a two-day meeting called by the U.S. Food and Drug Administration, we were pleased that the need for industry standards has been acknowledged at a high level. At the gathering of experts in health, genetics, science, and the law, many good points were raised and excellent ideas exchanged. Navigenics was among a group of leading personal genetics companies that presented a company overview to the gathering, and our CEO, Vance Vanier, M.D., was the only executive from a personal genomics service given the opportunity to speak on a panel. In its inclusiveness, broad discussion, and scientific rigor, the FDA meeting reflected the type of approach and expertise that will be required to develop effective standards for personal genomics.

The next day, however, saw a very different – and less productive – atmosphere come to light. On Capitol Hill, a subcommittee of the House of Representatives’ Committee on Energy and Commerce held a hearing on “Direct-To-Consumer Genetic Testing and the Consequences to the Public Health.” A key part of this hearing was a report by the Government Accountability Office, or GAO, on 15 personal genetic testing companies.

The ultimate aim of the GAO report was to inform and protect consumers. At its best, the report sheds further light on an important and well known issue in the personal genomics field – how the current lack of regulatory standards can lead to very different approaches between personal genetics companies. But as the writers of the report acknowledged, they “did not conduct a rigorous scientific study.” As a result, many of the report’s findings are anecdotal, partially informed, or incomplete.

We would have been happy to work with the authors of the report to answer any questions or provide further information along the way. Our CEO testified at the hearing, and we filed thousands of pages of informational documents with the committee before the hearing. But Navigenics was not permitted to see the report before its release. Nor were our company’s representatives even allowed to see a copy at the hearing itself. As a result, we could not always fully address questions from Congressional representatives during the hearing, and regret not having been given the opportunity to prepare all the answers that were sought.

Furthermore, the report makes assertions using incomplete information. We have made a formal request to the GAO for the detailed information behind these assertions. Should that detailed information be forthcoming, we are confident we can address any issue arising from the report. We are also appreciative of the fact that Congressional representatives, realizing the many questions left open by the report, extended the period of time to submit additional information for another 10 days. We look forward to submitting additional input to provide a more complete, more accurate picture of our company and our industry.

In the meantime, we will continue to pursue the path we started on more than two years ago. Our discussions with the FDA began even before our service first launched, and we most recently met with FDA officials in May of this year. We look forward to working further with the FDA to develop regulations for our industry at our next meeting with the agency next month. We also look forward to upcoming scientific studies of personal genomics services conducted by researchers at institutions such the Scripps Translational Science Institute, the Mayo Clinic, and Johns Hopkins. These studies, conducted with scientific rigor and involving participants whose only agenda was better understanding of themselves through their personal genetics, will provide useful, informative insights into how consumers interact with genetic information.

As plans for regulation unfold, we stand by our science, our service, and the standards we first proposed in 2008. The FDA, along with other federal officials, is making productive steps towards a new framework for our industry. We look forward to continuing to be part of the discussion.

[The question is not, if GAO will provide an answer - bureaucrats are paid (by our tax dollars) to produce papers. More interesting is the question if Dr. James P. Evans, M.D. will continue lending his reputation to "certify the uncertifiable"; i.e. make an admittedly "non-scientific" set of assertation of the GAO insinuation of "collective guilt", by his standards,"scientific". Prediction is clearly "NO". In some sense the outcome of the Congressional Subcommittee's investigation was predictable, once it became evident that Chairmanship was assigned to a "lame duck" politician, who had announced his retirement from politics weeks before this (inconsequential to him) "final act" - and thus will not be available to rectify a historical insult to a class of pioneer scientists, e.g. by his careless sound bite "From Gulf Oil to Snake Oil". In a larger sense, it has increasingly became evident that a multi-agency expert panel would have to propose new legislation to bring the 1976 mandate of FDA up-to-date - but the political will is simply not there to see through many years (or decades...) while Congressional Legislation would entangle itself in an exercise of futility of trailing an escalating Genome Revolution that they simply don't even pretend to understand even today. Thus, the Congress "won a battle" - but the FDA "lost the war". The extremely blunt Congressional "final act" now forces the FDA to come up with some solution, it will have to go out on a limb by resorting to "out-of-the-box solution" - without the kind of legislative background that forced them to inaction thus far, in the first place. It seems logical, therefore, that FDA will seek some sort of a "consensus" that practically makes a lot of sense - except that FDA would either take the heat of legal challenges (forcing the Judiciary to become Experts in Genomics, a very unlikely scenario, or -much more likely-) make FDA conclusions just watered-down "recommendations" for a largely self-regulated industry. It is worthy of mentioning that e.g. software industry is "self-regulated" as the market screens out inferior software without any need (or possibility) of regulators plunging into source-codes. It is important to emphasize the difference between "regulation" and "punishment of criminal actions"; e.g. if a largely unregulated software is "pirated" or "falsely advertised", certainly such inadmissible act could and should be penalized. Careful observer may note that most conspicuous allegations by GAO of unnamed SNP-DTC may fall into the across-the-board category of "false advertisement" (by some marketing and sales people), and not at all pertaining to the underlying science- AJP]

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GAO Studies Science Non-Scientifically

July 23, 2010
Published by 23andMe at 11:53 am

As we posted here on the Spittoon yesterday, the Subcommittee on Oversight and Investigations of the House of Representatives Committee on Energy and Commerce held a hearing on “Direct-To-Consumer Genetic Testing and the Consequences to the Public Health.”

Central to this hearing was an investigation by the Government Accountability Office (GAO) into 15 DTC genetic testing companies.

The GAO refused to discuss its concerns or its report with 23andMe, and now that the report is public and we have had a chance to review it, we are troubled and find the report is deeply flawed. We note that while such an exercise as conducted by GAO has the potential to raise questions, it does not provide the answers that a more rigorous scientific study would provide. This report raises questions, but leads to few conclusions because of its unscientific nature. The GAO itself recognizes this, writing, “It is important to emphasize that we did not conduct a rigorous scientific study.…"

...We are confident in our service’s accuracy and reliability. It is widely accepted that the technology we are using is sound. We understand that GAO did not find any problem with the underlying data that we provide – the As, Cs, Ts and Gs. What is at question is whether or not one part of the information about that data that we provide is of value, and we believe strongly that it is.

The GAO report focused only on disease risk probabilities. It did not focus on ancestry or the trait reports we offer. It also failed to address that we also provide information about carrier status for single gene diseases such as cystic fibrosis and Tay-Sachs disease, as well as the fact that we provide information about a customer’s likely response to certain prescription medications that have been shown in clinical trials to have differing effects and side effects depending on a person’s genetic make-up. This suggests that GAO found no problems with these parts of our service.

Carrier status and drug response information are clearly useful. In fact, Dr. James Evans, the Director of Adult Genetics Services at the University of North Carolina and the Editor-in-Chief of Genetics in Medicine, admitted during the Congressional hearing that drug response information would be of great interest to him as a physician. (He was specifically referring to results pertaining to a patient’s sensitivity to the anti-viral medication abacavir.) It should be noted that during the hearing it was not clear that Dr. Evans had been the primary consultant to GAO regarding the scientific and medical relevance of the results provided by DTC genetics testing companies.

The remarks made by 23andMe Co-Founder Anne Wojcicki and General Counsel Ashley Gould at the FDA public meeting on July 20, 2010 about laboratory developed tests demonstrate the importance of the work we are doing and our commitment to ensuring that members of the public are provided unfettered access to their DNA information in a responsible manner. We embrace the ideas that the FDA offered today about stepping in to provide a regulatory framework and help set scientific and transparency standards across the industry. We look forward to helping with this process.

Read on for discussion of some of the problems with the GAO report.

One of the most unfortunate parts of the GAO report is that it unfairly lumps together reputable and well known companies such as 23andMe with un-named companies making verifiably untrue endorsement claims, spurious scientific claims, and also selling potentially fraudulent supplements in addition to genetic testing services. Some of the most troubling of these interactions between the GAO and genetic testing companies can be found in a table on pages 15-16 of the GAO report, and in a Youtube video the Office has posted.

It must be noted however, that although the companies are not identified in the video or the report, at the hearing it was revealed that 23andMe is Company 1. Other than saying that we believe customers should consult with their physician or other healthcare professional when they have questions about their data, 23andMe/Company 1 is not implicated in any wrongdoing.

GAO seems to believe that directing consumers with questions about their genetic information to their health care professionals (a stance we continue to stand behind) is “misleading” because of a pronouncement by the Department of Health and Human Services’ Secretary’s Advisory Committee on Genetics, Health and Society that physicians “cannot keep up with the pace of genetic tests and are not adequately prepared to use test information to treat patients appropriately.”...

We agree with the idea that consumers should be able to compare the risk predictions they might receive from different test providers. This is an issue that deserves serious attention and one that we believe can be solved by the implementation of broad standards throughout the industry. We have approached both the NIH and FDA for assistance in this matter (see this letter sent to the heads of both agencies and posted on our blog, The Spittoon). Instead of constructively adding to these efforts, GAO has instead implied that because results differ between companies, they are simply wrong. Their report fails to provide all relevant information, and perpetuates the misunderstandings of genetics in particular and science in general that 23andMe has since the very beginning been dedicated to changing....

In conclusion, 23andMe is extremely disappointed that we did not have the opportunity to address all of these concerns at the Congressional hearing, or sooner, due to our lack of access to the report. These are serious issues that deserve serious and thoughtful discussion. Standards are needed in the genetic testing industry. We have been working towards these since the inception of our company, and we were pleased to hear FDA say that they are interested in developing a new type of regulatory framework that can deal with the many special aspects of direct-to-consumer genetic testing while still providing consumers with the protections they need and deserve. 23andMe is meeting with the FDA today and looks forward to fruitful discussion.

[Politics, while at face value won the "battle of SNP-DTC", by its glaring inability lost the war of suffocating US-political control over the emerging global genome industry. It is already leaked out that a "completely out-of-the-box" (legal?) "solution" is emerging, to save FDA from having to rely on non-scientific studies of science (see below).

The huge question therefore is, for SNP-DTC industry, how to mitigate the sizable political damage inflicted in the public's eye (made much worse by sensationalist parts of the media further distorting reality - since most of the public might not have the time/expertise to sort out the complex science issues). Since the SNP-DTC industry is unanimously committed to advance to include analytics of full human DNA sequences anyway, an acceleration might be an answer, to make SNP-DTC transitory to full DNA analytics, made interoperable with digitalized health-records, and all overridden by personal decisions. The damaged market-appeal of "SNP-DTC alone" could thus regain ground and even spectacularly increase market-demand by a "genome computing architecture" as featured on solid scientific ground of "recursive genome function" as early as in 2008, embraced by a panel in 2009, developed for the PMWC2010 this January, and in stealth-mode breaking through just at this time when SNP-DTC just suffered a major public relation set-back. - Pellionisz_at_JunkDNA.com]

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FDA's 'Out-of-The-Box' Plans

...Some lawmakers, including Committee Chairman Bart Stupak (D- Mich.), asked Shuren if FDA decided it wanted to regulate DTC genetics companies how it would go about doing so.

Shuren said that, currently, FDA is considering taking "a completely out-of-the-box approach on genetic testing" that would carve out a unique space in its regulatory tableau. This approach could involve looking at subsets of validation data on genetic variants that would enable regulators to make assumptions to trust the industry partners about some of the others.

"What we're thinking about is FDA, along with [the National Institutes of Health], pulling in from the healthcare community, pulling in from patient groups, and actually sitting there and going through the science," Shuren said.

He explained that such a regulatory council could set standards based on the available science and on the breadth and scope and veracity of the claims that the company is making in its marketing.

"And when we set the standards of what's good enough and when it's ready, then [we would] allow those claims. Those companies then would not have to come back in the door with a new application. We'd say, 'You already have a validated test, you can now make this claim,'" he said.

Shuren said that such a regulatory approach would "allow for a lot of tests to be out there" and that it "would actually be a much less expensive way of doing it for these companies as well."...

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DTC Genome Testing of SNP-s “Ready for Prime Time”?

Of course not. “What is the practical value of a baby?” Francis Collins quoted on his interview by Charlie Rose the “inventor of electricity” (Faraday) when he was naively asked by the British Prime Minister visiting his laboratories “is there any practical value of electricity?” Should Faraday have today’s hyper-hyped salesmanship and marketing-frenzy around, he could have (rightly) answered “the practical value of electricity can not be overestimated”. Instead, he gave the disarmingly smiley answer about the utility of a newborn baby…

As I commented in this column on the original assessment by Boonsri Dickinson, tested years ago by the three leading DTC genome testing SNP interrogation companies (DeCodeMe, 23andMe, Navigenics), her summary (that “they were not ready for Prime Time”) was absolutely correct.

Interrogation of up to about one million single nucleotide polymorphisms (SNP-s, out of 6.2 Bn nucleotides in the diploid full human DNA) ab ovo can not be “Prime Time News”, perhaps just the “First News of the Day at 5 A.M.” As HolGenTech, Inc. presents in the 7:44 minutes short YouTube, “Prime Time” will be a show for a future “Boonsri Dickinson” where “SNP interrogation” (presently done by DTC, using microarray technology) is interoperative with personal “full DNA sequences” (already in production at $5k per full genome, whole-sale by Complete Genomics, and PacBio is about to deluge the world with full DNA sequences with 6.2 Bn bases for about the price of “1 million bases in present DTC”), as well as with “digitalized health data” (on servers like Microsoft HealthVault and/or Google Health), all overriden by “personal preferences” (on Personal Genome Computers).

We’ll need some time/money to get there. PacBio alone absorbed about $350 M in funding, full digitalization of health data will cost billions of dollars, and Genome Computing will need substantial resources (HolGenTech already accomplished a major – stealth - breakthrough with its solution even since the YouTube was taken half a year ago).

Maybe it is 7’ Clock News in the Morning?

Sorry to say, we've just been set back. Those watching the Congressional Investigation of current DTC had to witness today, however, an ugly “wet blanket” thrown in the face of some testifying DTC company officials, dampening their smiles by an embargoed surprise-report by undercover agents of the Government Accountability Office (GAO).

Back to 5:30 A.M.?

Not really. The report admits (the obvious) in its opening “Highlights” that “GAO did not conduct a scientific study”. Normally, since the topic is the utility of genomics as a science in a nascent stage, a judge would through out right away such glaringly and admittedly “inadmissible evidence”. However, the Congressional Subcommittee is neither a Forum of Science, nor is part of the Judiciary. It can do politics (easy job) or create new legislation to update e.g. the FDA mandate (1976; hard job). Clearly, the entire set-up by GAO to frame DTC verbally as “not ready for prime time” (though this – copyrighted? -coinage, "borrowed" from Boonsri Dickinson's remark made years ago nowhere appears in the written Report) was not at all about science, but about (also well known) deficiencies of marketing and sales. It may be sobering to Congress to realize that their laws are also often misrepresented by “marketing and sales” forces (in their profession called “the press”) for political purposes.

The community of researchers may wonder if hard-working pioneer scientists deserve better; e.g. the use of (available, see below) peer review instead of questionable practices of non-scientist undercover agents of “Big Brother”, who not only admit but brag about their using fictitious profiles of users (and thus getting confusing answers; a well known effect in science; “garbage in – garbage out”). Are you surprised that a Caucasian (non-scientist) customer giving the deliberately false profile that she is "Asian" is getting "off the chart" results? I am not surprised. Nor is anyone who knows how different are the genomes of Chinese (at least 9 main tribes) and various European genomes (dozens).

It is too bad, that the general media, in their rush-reporting (not always scientist-checked) further distorts the misimpression: Bloomberg reports:

“Gene-Test Services Mislead Public, U.S. Report Says” [Would it not be a better title: "U.S. Report Misleads Gene-Test Services"? - AJP]

“Gregory Kutz led a probe for the Government Accountability Office by setting up customer accounts with Navigenics of Foster City, California, 23andMe Inc. of Mountain View, California, Pathway Genomics Corp. of San Diego and DeCode Genetics Inc. of Reykjavik, Iceland, and sending them DNA from five people. The companies’ reports assessing health risks were “medically unproven and so ambiguous as to be meaningless,” Kutz said in his report, presented today at a hearing in Washington”

This brutal error is easy to spot. The Report (both in its “Highlights” and on its Page 1.) clearly states that the findings of “medically unproven and so ambiguous as to be meaningless” were in the previous GEO Report four years ago (in 2006), referring to four “Nutrigenetic Testing” websites (not the same set as currently investigated) and states at the outset of the (2010) “Highlights” that “new companies have since been touted as being more reputable”. Still in total confusion, the general newsmedia attributes the obsolete statement of one set of companies four years ago to the present state of the art of a different set of companies!

A third glaring error is, that it was verbally stated at the hearing, as if an accusation, that DTC provides “medical advice”. Such statement actually never appears in writing in the Report – moreover all (good) mothers provide “medical advice” to their kids, e.g. “eat more vegetables”, “drink more water”, “exercise”, “use sunscreen lotion on the beach” (etc). A good mother might be keenly aware of the medical fact that a fair-skinned child might develop (potentially deadly) melanoma e.g. if exposed in a prolonged manner to the intense California or Arizona solar radiation. Should she refrain from transmitting “medical advice” to her loved ones? Clearly absurd. The web, too, is teaming with all kinds of advice and recommendations; often quite medical. This is not a problem. The problem would be if mothers, friends (etc) would provide medical advice while pretending that they are licenced medical doctors. To the contrary, however, all DTC websites clearly indicate that their recommendations are not to be confused with, and not instead of, prescriptions and/or diagnosis and/or therapy and/or cure by licenced medical doctors!

In the hearing, the available “peer review” was conspicuous by its absence. Neither Founder and CEO of the first ever DTC genome testing company DeCodeMe in Iceland (warned by a US-letter) Kari Stefansson (actually, not only a World-leader genomist but also a Medical Doctor and Ph.D…) was forgotten to have been invited to testify to Congress – in addition to (or instead of) non-scientist under-cover agents but the “peer” who literally wrote the exceptionally lucid yet scientifically rock-solid book on Genome Testing as a basis of Personalized Medicine, Francis Collins, M.D., Ph.D., Head of NIH, formerly head of the “Human Genome Project” was not called as witness, either. Though Dr. Collins, M.D., Ph.D., in his quality as Head of NIH, just weeks ago co-authored in the New England Journal of Medicine the “laying down of the path towards Personalized Medicine” with FDA Commissioner Margaret Hamburg, M.D.

We can all hope – the real witnesses have not been summoned yet. However, the damage inflicted upon the US innovation, jobs and the economy is outrageous and calls for an emergency repair.

[Further coverage is here here here -241 in all, before the end of the day - AJP]

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Message arrived ... "the scientific community had to re-think long held beliefs"

Perhaps the best coverage of the 10th Anniversary of "The Human Genome Project" was the interview by Charlie Rose with skeptic NYT reporter Nicholas Wade, and two top scientists of the establishment, Drs. Francis Collins (NIH Chief) and Eric Lander (Director of the Broad Institute and Science Advisor to the President).

As seen from the screen-shot taken on July 16 eve (PT), there was a huge peak of close to a million hits for "recursive genome function". Apparently, the message of the Rose interview arrived; the Second Decade will be about "recursive genome function". To remind readers, a short clip from the copyrighted transcripts is here:

[Excerpts are available in full on Charlie Rose' website. Here, only the brief "conclusion" is reproduced from the copyrighted material - AJP]

"... CHARLIE ROSE: Have there been any operating hypotheses that have been proven to be not the best route to go?

FRANCIS COLLINS: Oh, goodness.

ERIC LANDER: That’s a good question. What do you think, Francis?

FRANCIS COLLINS: I think perhaps our original expectations about what was going on in the genome that was not coding for protein may have underestimated the complexities of what’s going on there. New discoveries about micro RNAs and something from Eric’s group called link RNAs, a whole new category of RNA transcripts that have really opened our eyes to regulation and sophisticated complexities. That’s been exciting and I don’t know that we anticipated that. [Some do know to have anticipated. Prior to even NIH asking Congress for money for ENCODE I publicly announced FractoGene (2002) - AJP]

ERIC LANDER: I think that’s an interesting and important point. The genome has a lot more secrets in it. But by laying out the whole sequence of the genome, we were able to find that, oh, one percent of the genome encoded for the proteins that we’d been focusing on before, the hemoglobins and collagens and things, and three or four times as much of the genome is devoted to other things. [Four times? Why not say forty-four times of the 1.3% of protein-coding "genes"? - AJP]

We knew this because in fact evolution conserved those sequences telling us they had to be functional. So shining a light for us on things we’d never known about, gene regulation ..."

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A Proving Ground for P4

GenomeWeb
July/August 2010
By Matthew Dublin

Personalized medicine — the crossroads at which biotechnology, genomics, and medical treatment meet — is a concept that is often touted, though rarely seen in action. As with any radical idea, there needs to be a proving ground before it achieves wider acceptance among professionals and the public. The concept of a healthcare system that can someday provide predictive, preventive, personalized, and participatory medicine, or "P4 medicine" — a term coined by Leroy Hood of the Institute for Systems Biology back in 2003 — is being put to the test.

In early May, The Ohio State University Medical Center and ISB announced a partnership to establish the P4 Medicine Institute, a nonprofit consortium based in Seattle. The new institute's mission is the delivery of a healthcare model with the four-pronged "P" approach, through which patients can be treated proactively throughout their lifetime, instead of the current model of reactive clinical treatment.

While ISB is positioned to bring its biotechnology expertise to the table, OSU's clinical delivery infrastructure, including its own insurance company OSU Health Plan, will give the P4 a chance to try out lots of new ideas in a closed system with roughly 55,000 university employees enrolled in the campus health plan. By creating a matrix of genomics, protein metabolics, and molecular-based diagnostic information tailor-made for each patient, the leaders of the P4 Medicine Institute hope to map out individualized plans for health maintenance, wellness evaluation, and the diagnosis and treatment of illness.

"We're working on trying to come up with an understanding of how the healthcare system can be changed from one that is disease-based care, without an understanding of the real deep, precise biology underlying the health and wellness, to one which really looks at predicting and preventing disease by focusing on wellness in a very personal way," says Clay Marsh, executive director of Ohio State's Center for Personalized Healthcare. "We see the P4 Medicine Institute as a conduit for connecting the best people in the world, for really transforming how we do things. Our goal is to try and connect with the best people and, as a team, really define where the healthcare ecosystem is today — what elements are needed to create a tipping point or create a culture change that will transform medicine — and work as a group to do that."

Putting it together

Part of the new institute's strategy to bring genomics-based healthcare to the clinic is to connect researchers working in biology and medicine with those working in computer science and IT, as well as bringing in thought leaders from the legal, business, and medical device manufacturing sectors. "P4 is really about combining the systems biology-driven innovations and insights into human biology of ISB and the translational research and clinical delivery capabilities of one of the largest academic medical centers in the country," says Frederick Lee, the executive director of the P4 Medicine Institute. "It's really about that pragmatic and tangible bringing together of the things that we are learning about not only human biology itself, but really driving those into how the care is going to be delivered — health, wellness, and disease management — in a real P4 manner."

Lee says that ISB's decision to partner with OSU came only after a serious survey of the academic medical landscape of the United States. "ISB had spent some time evaluating and meeting with a lot of the top academic medical centers in the country, but we found that OSU had really embraced the concepts of personalized healthcare and the leadership was already very open to this approach to medicine as the way to really shine," Lee says. "Back in 2005, OSU established their own personalized healthcare center. They have also been having for the past few years a personalized medicine conference. All of these things were something that we just didn't see at any [of the] other universities."

The P4 Medicine Institute's first project will focus on using novel molecular modalities, including organ-specific proteomics, mRNA analysis, and deep sequencing of genomes in the context of families. They aim to combine that data with more conventional clinical data to establish an individual's base level of health and to determine when he is veering off that baseline into illness. A series of wellness clinics will also be established at OSU from a population base of their employees. The institute will then apply the molecular modalities and technologies from ISB along with the clinical delivery models that they will design together with OSU. "This is really interesting because OSU can and will be a closed-loop system — it's the payor for that large employee base, it's the provider of care, and it's also the patient population itself," says Lee. "We can really rewrite the rules for how care is paid for, provided, and received, and then draw out pragmatic things so that industry partners can develop the technical infrastructure to power this new type of healthcare."

The researchers at OSU have already set about one pilot project focused on wellness, a buzzword that is the cornerstone of any discussion about the P4 concept. The wellness project will include programs in exercise, nutrition, and biorhythms in order to better understand patient needs and how P4 can create "modules" to help the patient achieve optimal health. "We're very interested in looking to stratify people into groups according to exercise, nutrition, stress, sleep, and age, and merge that with genetic data and other molecular profiles so that we can then start to assign a predictive and preventive approach," OSU's Marsh says. "We'd like to give people feedback into how to improve and make changes to their lifestyle."

OSU will also initiate a chronic disease pilot project, which Marsh says will look at ways to build a team of clinicians around chronically ill patients using molecular profiling and other genomic elements to improve their quality of treatment.

Finding partners

Marsh says that one of the biggest challenges facing the P4 Medicine Institute at this early stage is making sure that additional partners are chosen carefully. Because this is still very much an experimental endeavor contained within the confines of the OSU healthcare system, those institutes looking to join in the hopes of making a profit from this new brand of healthcare are barking up the wrong the tree. "We want to produce wins for everyone involved, but we're looking for people who understand the long-term opportunity and also understand that if you're looking for some sort of committed return on an investment in a relatively short period of time, this is probably not the right partnership," he says. "We're spending a huge amount of time to make sure we're assessing the partners that are interested in what we're doing and making sure we have a level of compatibility with them so that we don't have any problems down the road because we failed to expressed our goals to each other clearly. That's a key element that we need to make this run smoothly. "

The Breakdown

Members: The Institute for Systems Biology and The Ohio State University Medical Center

Funding: ISB and OSUMC internal funding, with each institute contributing $500,000 annually for the next two years.

[LeRoy Hood' brainchild, the P4 Medicine (Participatory, Predictive Personalized Prevention) is both his "brand" - but he has gracefully consented to a generic use (like Mercedes Benz gives away all their safety patents, royalty-free, in the interest of the public at large). Thus, at the "P4 Conference in Silicon Valley" (December 9-10, 2010) Fred Lee will uphold the flag, while others like the Conference Chairman (AJP) will explore, particularly because of the location, the Personal (Holo)Genomics- and Information Technology aspects, much needed for P4. -Pellionisz_at_JunkDNA.com]

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Ion Torrent, Stealthy Company Tied to Harvard’s George Church, Nabs $23M Venture Deal

Xconomy
Luke Timmerman 11/6/09

Ion Torrent Systems, a company advised by Harvard University genomics pioneer George Church, has raised $23 million in new capital to develop what it calls on its website “groundbreaking and highly disruptive technology” and to hire people who “want to do what it takes to put a dent in the universe.”

The company, which has a location near Yale University in Guilford, CT, and one in San Francisco, has raised $23 million in equity out of a financing round that could be worth as much as $26 million, according to a regulatory filing released today.

The document doesn’t say who invested, and Ion Torrent didn’t immediately respond to a request for comment. But the new company is associated with some big names, including Church and Stanford University’s Ron Davis, who serve on the company’s scientific advisory board, and CEO Jonathan Rothberg, who was the founding CEO of 454 Life Sciences before that company was sold to Roche two years ago for $140 million in cash.

Ion Torrent Systems website is pretty vague about what it is really up to, although its job postings offer some clues. It says it is looking to hire molecular biologists and biochemists to do the aforementioned universe denting, and that it offers that it offers the opportunity to work with top scientists “and have a profound impact.” It is also looking to hire software developers and “evangelists” who want to “create the biotech software platform of the future and share it with the world. Build powerful tools and create a tight-knit community that will use and develop them for years to come.”

GenomeWeb speculated back in March, based on a patent application filed by Ion Torrent Systems, that it is working on new DNA sequencing technologies, although the company wouldn’t confirm that. Major players in the field—such as Carlsbad, CA-based Life Technologies, San Diego-based Illumina, and Roche—have been in a competitive frenzy to lower the cost of sequencing full human genomes. One Mountain View, CA-based startup, Complete Genomics, raised $45 million in venture capital earlier this year to support its new model for sequencing entire genomes for as little as $5,000 apiece or less.

[While this piece of news is somewhat dated, it seems important to provide a perspective of the "lead group" of nanosequencing, especially from the news below on PacBio's F-Round - Pellionisz_at_JunkDNA.com]

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PacBio Nabs $109M to Make Cheaper, Faster Gene Sequencing Tools

Luke Timmerman 7/14/10

The idea of sequencing entire human genomes for $1,000 or less, in a matter of minutes, has never been hotter, if the flow of venture capital to Pacific Biosciences is any indication. The Menlo Park, CA-based developer of super-fast gene sequencing machines has raised another $109 million in a Series F round of financing.

The company, known as PacBio for short, has now snagged a total of about $370 million in venture capital since it was founded in 2004. The company didn’t say who invested in the latest round other than San Diego-based Gen-Probe (NASDAQ: GPRO), which said it pumped in $50 million last month. But PacBio has a long list of existing investors that include Kleiner Perkins Caufield & Byers, Mohr Davidow Ventures, Alloy Ventures, and Intel Capital—as well as few names more familiar on the public-company circuit—Morgan Stanley, T. Rowe Price, Deerfield Management, and AllianceBernstein.

The vision at PacBio is to develop new gene sequencing instrument powerful enough to deliver the complete genome sequence from a human being in about 15 minutes and for a few hundred dollars. It’s the kind of technology that could enable basic researchers to run all sorts of experiments about the subtle variations in DNA that make people different, and which differences in genetic coding might be related to disease and wellness. San Diego-based Gen-Probe invested in PacBio’s technology with an eye toward using this sequencing technology as a tool doctors could use to diagnose disease.

“These funds will be used to support our operations as we begin ramping production capabilities for the commercial launch of our PacBio RS system,” said Hugh Martin, PacBio’s chairman and CEO, in a statement.

The company didn’t say in today’s statement when the machine would be commercially available.

PacBio is facing intense competition in the field of gene sequencing. Mountain View, CA-based Complete Genomics is pursuing a different business model, in which it asks researchers to send samples to a central facility instead of asking them to buy an expensive machine and run it themselves. Guilford, CT and San Francisco-based Ion Torrent Systems wowed researchers at a meeting in March when it unveiled a benchtop sequencing machine that can perform a lot of a basic experiments in a machine that only costs $50,000. The incumbents in the field whose machines generally cost 10 times that much—San Diego-based Illumina (NASDAQ: ILMN) and Carlsbad, CA-based Life Technologies (NASDAQ: LIFE)—have been launching pre-emptive strikes against the upstarts by continual improvements that have brought the cost of sequencing a human genome down to about $10,000 today.

[As the "Dreaded DNA Data Deluge" is upon us, perhaps it is worthy to look up the 2008 "Pellionisz" YouTube (about 8,333 views) if our theoretical (algorithmic) preparedness is up to the scientific challenge. My central argument was (and is) that "Big IT" will rise to the challenge, as it represents major business opportunities. However (as e.g. the Charlie Rose interviews show below) the scientific paradigm-shift towards recursive algorithms still calls for more support - Pellionisz_at_JunkDNA.com]

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Recursive Genome Function at the crossroads - Charlie Rose Panel on Human Genome Anniversary

Human Genome Anniversary with Nicholas Wade of "The New York Times," Francis Collins of the National Institutes of Health, Eric Lander of MIT and the Broad Institute
Monday, July 12, 2010

Click here to play ...

[My FaceBook entry: The Panel is remarkable in not saying that without the theory of recursive genome function - where genomics and epigenomics are mathematically treated as the hologenome - we'll continue to be frustrated at looking at our medicine cabinet half-empty (or half full?) of genomic medicines. Every panelist is correct in what they do say, either from the skeptical viewpoint (Wade) implying that the meager results show that we overspent, since the paradigm failed that sequencing automatically translates into understanding (recursive) genome function (and diseases). No journalist can pinpoint what is missing, as it is up to advanced theory. Drs. Collins and Lander, to defend the establishment, dwell on the positives, how half-FULL is our "medicine cabinet" and how spectacular our technological (sequencing) and medical (genomic medicine) results are. True; the end alludes to “Junk DNA” (98.7%), acknowledging that it hides keys to regulation; yet none announce the paradigm-shift of the principle of recursive genome regulation. - AJP]

[A further comment contrasts the "stand-off" by pointing out that "recursive genome function" broke the 100,000 hits on Google (see in Table of Contents). There can be a debate if it is a fractal iterative recursion or some will publish a contending theory, but e.g. Eric Lander et al. (2009) featured on Science cover the fractal nature of the genome. - Pellionisz_at_JunkDNA.com]

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The Sudden Death of Longevity

The Little Flaw in the Longevity-Gene Study That Could Be a Big Problem
Newsweek, 7/7/2010

How a faulty DNA chip [an Illumina 610-Quad microarray - AJP], lax editorial review, and a few skipped steps turned a good study into bad science.

Remember that Science study from last week linking a whole bunch of genes—including unexpectedly powerful ones—to extreme old age in centenarians? NEWSWEEK reported that a number of outside experts thought it sounded too good to be true, perhaps because of an error in the way the genes were identified that could cause false-positive results. Since last Thurday, they’ve been trying to figure out what might be lurking in the data, and now there’s a suspect: a DNA chip called the 610-Quad, which is used to identify and sequence the chemical letters of DNA [not really "sequencing" but interrogating SNP-s in oligos - AJP], and which has an apparent tendency to get some small but critical details wrong. The flaw with the chip and the way it was used could cast serious doubt on the study’s strongest results, suggesting that they stem from a lab mishap rather than a real link to long life.

The flaw in question could be easily addressed with a little follow-up research. In very simplified terms, all that’s needed is for someone to rerun the analysis using a single different DNA chip. But this should have been done already, before publication. The fact that it wasn’t raises the question of how a paper with a missing piece like this got approved and published by Science.

The paper—which identified 150 genetic variants that might increase a person’s chances of making it to age 100, apparently by protecting the body against disease—had as one of its two principal components a type of research called a genome-wide association study (GWAS). These surveys, the bread and butter of modern genomics, use chips to analyze large amounts of DNA in many people, looking for variants that are more common in “cases” (here, that means centenarians) than “controls” (regular people). The variants that turn up more often in “cases” are the ones linked to the trait the scientists are curious about. The studies are usually very thoughtfully designed and reliable. What happened with this one?

The first thing to know is that not all gene-identifying chips are created equal. They [microarrays - AJP] occasionally identify letters of DNA incorrectly, and—to complicate things further—each type of chip makes different errors at different points in the genome. That phenomenon can lead to false-positive results if it's not well-controlled by experimental design, says David Goldstein, the Duke University geneticist who first raised this issue here last week. “Unfortunately, different chips have their own little problems for specific [genetic variants],” he says. The key to keeping false positives at bay is to ensure that cases and control groups are analyzed using exactly the same techniques. If you use one type of chip to analyze your cases and a different type to analyze your control group, “you can see any [variants] that are genotyped differently on the different chips ‘lighting up’ as apparently associated with the trait,” says Goldstein, when in fact that pattern is just an experimental artifact.

All of the chips used in the Science study came from the same manufacturer, Illumina, but they weren’t identical. According to a brief description in the paper, the researchers used two different chips to look at their centenarians, analyzing most people with a 370 chip that examines 370,000 genetic variants and a smaller fraction of people with a different chip (the 610-Quad) that examines 610,000 variants. The reason, says Paola Sebastiani, the Boston University biostatistician who led the study, is that at one point the 370,000-variant chip went off the market and the 610-Quad “was the best option for us in terms of costs and coverage.” The controls involved an even more varied assortment of technology—some were analyzed with the 370, some with the 610, and some with two other types of chips.

Kári Stefánsson, the Icelandic geneticist who founded deCode Genetics, knows something about the 610-Quad—his company has used it too. He says it has a strange and relevant quirk regarding two of the strongest variants linked to aging in the BU study, called rs1036819 and rs1455311. For any given gene, a person will have two “alleles,” or forms of DNA. In the vast majority of people, at the rs1036819 and rs1455311 locations in the genome, these pairs of alleles consist of one “minor” form and one “major” form. But the 610-Quad chip tends to see the wrong thing at those particular locations. It always identifies the “minor” form but not the “major” form, says Stefánsson—even if the latter really is present in the DNA, which it usually is. If you use the error-prone chip in more of your case group than your control group—as the BU researchers did—you’re going to see more errors in those cases. And because what you’re searching for is unusual patterns in your cases, you could very well mistake all those errors (i.e., false positives) for a genetic link that doesn’t actually exist.

Stefánsson says he is “convinced that the reported association between exceptional longevity and most of the 33” variants found in the Science study, including all the variants that other scientists hadn’t already found, “is due to genotyping problems.” He has one more piece of evidence. Given what he knows about the 610-Quad, he says he can reverse-engineer the math in the BU study and estimate what fraction of the centenarians were analyzed with that chip. His estimate is about 8 percent. The actual fraction, which wasn’t initially provided in the Science paper, is 10 percent, the BU researchers tell NEWSWEEK. That’s close, given that Stefánsson’s calculations look at just two of the variants found in the study and there may be similar problems with others.

One of the oddest things about this potential error is how much it stands out in an otherwise carefully designed study. The BU researchers made a serious attempt to deal with confounding factors—a challenge given that centenarians are by definition different from any possible control group, because they were born earlier—and, Sebastiani says, the team “conducted extensive quality-control procedures and cleaning of the data.”

What the group apparently didn’t do, however, is obtain a third-party analysis of their centenarians’ and controls’ DNA using a single chip for everyone. There’s “nothing in the world simpler to do,” says Goldstein. “We would do this for any ‘discovery’ we had in this kind of a situation, but when the results themselves are a bit improbable, as the results are here with the exceptional genetic control, then there is all the more necessity for that quality-control step.” Goldstein adds that such a step is standard practice for most GWAS research. That's why you can trust many other GWAS papers while withholding judgment on this one. Yes, it’s tempting to look at this study and wonder what other flaws may be hiding in other GWAS papers, even those in top-flight publications. But this episode shouldn’t be read as evidence that genome-wide association studies are untrustworthy as a rule, because the rigor that seems to be missing from this study is almost always found in others that haven’t yielded such dramatic results.

It’s possible that when that replication study is done, the genetic associations in the longevity study will hold up. (At least a few of them, such as the link between long life and APOE—which is also linked to Alzheimer’s—surely ought to, since they have been found in other studies.) The BU paper’s critics aren’t out-and-out saying it’s wrong. They’re just saying it could be.

Still, one has to wonder how the paper wound up in Science, which, along with Nature, is the top basic-science journal in the world. Most laypeople would never catch a possible technical glitch like this—who reads the methods sections of papers this complicated, much less the supplemental material, where a lot of the clues to this mystery were?—but Science's reviewers should have. It’s clear that the journal—which hasn't yet responded to the concerns raised here—was excited to publish the paper, because it held a press conference last week and sent a representative to say as much.

The BU scientists are holding a public Web chat today at 1 p.m. ET. Most of the questions they take probably won’t concern highly technical stuff like this. Sebastiani would prefer that critics’ questions be addressed directly to her in journals rather than, say, relayed to her by NEWSWEEK writers: “So far we were not approached by any of these investigators directly, only by reporters,” she says, which is “rather surprising and disappointing to me.” The Web conference, Sebastiani adds, is being held primarily to address the fact that several companies are already thinking about selling a test based on the Science paper, a notion that the study’s authors abhor and are trying to prevent. “We strongly feel that results of such a test should continue to be for research use and that it is not at all ready for use in the public domain,” says Sebastiani. “There are just too many opportunities for misuse and misinterpretation at this very early point.” Not at all ready for use in the public domain: that’s the one thing that everyone involved with this paper does seem to agree on.

One more important thing: the BU researchers put together a model for predicting whether a given person would live to 100 or not, and it was widely reported that the model had 77 percent accuracy. That was true in the study, where the researchers were applying the model to people from groups of roughly equal size—they had about the same number of centenarians as they did controls. In reality, however, only 1 in every 6,000 people lives past 100, so the real-life sample sizes, if you will, are very different. Both Stefánsson and David Altshuler, a geneticist who leads GWAS research at the Broad Institute, say that fact renders the model much less useful than you might think, because it actually tells you only that your chance of living to 100 is either really small (much less than 1 percent) or really, really small (even less than that). “For most practical purposes,” Stefánsson notes, this “makes no difference for an individual.” It’s a good reason not to rush out and get your longevity genes tested, although at this point, you don’t need another one.

UPDATE: Within an hour of this story's publication, the Science study's authors released a statement which a BU spokeswoman described as appearing "because of your inquiry and a similar one from the New York Times concerning methodology used to test 2 of the 150 genetic variants." Here is what the statement says: "Since the publication of our study in Science, which was extensively peer-reviewed, a question has been raised about two elements of the findings. One has to do with two of the 150 genetic variants included in the prediction model, while the other is related to the criteria used to determine the significance of the individual variants. On the first concern, we have been made aware that there is a technical error in the lab test used on approximately 10% of the centenarian sample that involved the two of the 150 variants. Our preliminary analysis of this issue suggests that the apparent error would not effect the overall accuracy of the model. Because the issue has been raised since the publication of the paper, we are now closely re-examining the analysis. Another question that was raised concerns the criteria used to determine if an association between a genetic variant and exceptional longevity was statistically significant. We used standard criteria for the analysis, and we are confident that the appropriate threshold was used."

[I was greatly impressed by the sub-title of first report: "Scientists Discover the Fountain of Youth! Or Not." Apparently, Mary is just as skeptical about non-existent "cancer gene", "happiness gene", "fountain of youth gene" etc. as leading scientists like Kári Stefánsson are. "Genes" (with as many definitions as the number of scientists you ask) don't do any complex phenotypes as "longevity" - they just turn out the "basic building materials" (amino-acids for proteins) as called for by the design (in intergenic and intronic sequences). True, if e.g. the concrete is defective, the "longevity" of the architecture may be reduced to the sudden death of a quick collapse. It may be time to come to realize that "the genes failed us" in old-time genomics to explain recursive genome function (hologenomics) of today. It is hard to find imperfection in Mary's science writing. With the "DNA chip" of IBM (for sequencing) coming, perhaps we should distinguish Illumina's ChIP (bead array, otherwise called "microarray") and "chip" that is usually meant either a piece of semiconductor, or that of a potato - AJP]

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23andMe Letter to Heads of FDA and NIH

The Spittoon
June 24, 2010

At 23andMe, our goal is to give people the best information possible about their personal genetic data. [This brilliant sentence focuses on the key issues, virtually assuring that both DTC Genome Testing and a renewed FDA will prevail. Hopefully, the process will be cut blazingly short, to avoid the US being deprived of one her few global competitive advantages that could generate jobs and rescue health care by prevention. Contrary to the the astonishing belief that some people should be protected against information about their bodies - Esther Dyson, a board member at the company, has even called the FDA’s position “appallingly paternalistic.”- NIH Chief Dr. Collins appears to concur with sharing the information with their owners (see below in this column): "I would be very uncomfortable with a system that says no, we know better than you do, you won't understand this information so we're not going to let you have it. There's something that doesn't feel right about that." Thus, the eventual outcome of a new legislation for FDA (only to safeguard quality, not to infringe with the citizens' civil rights of accessing [genomic] information about their bodies, updating the 1976 mandate of FDA), seems assured: "to give people the best information possible about their personal genetic data" - AJP]

We believe that this goal is shared by all genetic testing providers. [Another brilliant sentence, uniting the entire US DTC Business - AJP]

You may be aware that different personal genetic testing companies, while providing completely accurate test results, may provide differing risk estimates for some diseases and conditions. While there are valid scientific reasons for such different estimates, they might nevertheless cause confusion for some consumers and physicians.

23andMe has sent a letter to Dr. Margaret Hamburg, Commissioner of the Food and Drug Administration, and Dr. Francis Collins, Director of the National Institutes of Health, asking for their respective agencies’ help in developing broadly applicable standards and guidelines to achieve consensus regarding how to provide information on genetic test results and risk estimates. The contents of this letter are reprinted below (links to the referenced article and blog post are provided here instead of attachments):

June 24, 2010

Dr. Margaret Hamburg
Commissioner of Food and Drugs
Food and Drug Administration
10903 New Hampshire Ave
Silver Spring, MD 20993-0002

Dr. Francis Collins
Director
National Institutes of Health
9000 Rockville Pike
Bethesda, Maryland 20892

Dear Drs. Hamburg and Collins,

We are writing to ask your assistance in resolving an issue of concern to 23andMe and, likely, all genetic testing companies, whether they report their results to physicians or to consumers. As you are aware, though results from 23andMe and other genetic testing companies are typically consistent, there have been reports of inconsistencies (Ng et al. 2009). We believe that it is important to emphasize that different genetic testing companies can report inconsistent results even when based on tests with proven analytical validity. The reasons for this may include: companies employ slightly different statistical models for making risk estimates; companies establish different criteria for the inclusion of associations in their reports; new associations are being discovered at a faster rate than companies’ development cycles; companies may test for an imperfectly overlapping set of genetic variants for reasons including the ability of different genotyping technologies to assay certain variants.

Although inconsistent results may have a scientifically valid basis, we recognize that they may be confusing to physicians and consumers. However, we, as an individual company, cannot address this issue alone. Therefore, we are writing to ask your two agencies to engage with us on this issue, to work towards solutions that can be broadly applied. We offer the following ideas as a starting point for discussion. An organization or group of organizations could develop:

• guidelines for acceptable analytical validity;

• standards for the positive and negative predictive value of all tests;

• “best practices” for companies, for instance necessitating transparency in reporting the positive and negative predictive values of their tests, so that results could be readily compared across companies.

We note that any framework developed for genetic testing companies must consider the multiple high throughput technologies on the horizon, including genome, exome and transcriptome sequencing. For this reason, the set of ideas we present above does not include having an organization define a specific set of markers as an acceptable genetic test.

The issue of inconsistent results was one of several discussed in an Opinion piece by Pauline C. Ng, Sarah S. Murray, Samuel Levy and J. Craig Venter that appeared in the October 8, 2009 issue of Nature. A joint response from 23andMe and Navigenics submitted to Nature but not published by Nature was posted on our web site on November 19, 2009. We have attached our open letter to Nature, and a response from one of the authors for your consideration.

Our goal is to provide the best possible information to consumers and health care practitioners. We would appreciate the opportunity to work with you towards this goal and, more broadly, to promote innovation in personalized medicine. We will follow up with a call to your offices.

Sincerely yours,

Ashley Gould

on behalf of Anne Wojcicki

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Amazon Sees the Future of Biology in the Cloud

By Luke Timmerman, Xconomy.com

July 6, 2010

The future of biology, if Amazon.com (Nasdaq: AMZN) has its way, will be in the cloud.

The Seattle-based online retailer has generated buzz the past few years with its foray into cloud computing through Amazon Web Services. This is the model in which customers rent server space on a pay-as-you-go basis, and get access to their data anytime via the Internet. It's supposed to allow small businesses, governments, and anybody else to save cash and hassles by not having to buy and maintain their own in-house servers. The model is credited with enabling a new generation of lean tech startups to build businesses using far less capital. [The easiest metaphor to understand what "cloud computing" is to think of it as "car rental" instead of buying/leasing your own automobile. It immediately follows that no car rental company will tell you where and how to go (might provide a map if you don't have a GPS) - but will certainly not drive the car for you. If you want to be actually driven to a destination, think of Limousine-service with driver included (or most simplistically a "taxi cab"). For genomics, they do not exist - and ultimately they are rather expensive solutions for the long haul - AJP]

Biological researchers haven't embraced the new model as quickly as their tech brethren, but the cloud computing wave is coming to life sciences, says one of Amazon's biotech liaisons, Deepak Singh. The trend is coming out of necessity. [Like when you fly abroad, car-rental or taking a cab are frequent option, based on necessity - AJP] Gene sequencing has been on a breakneck pace of innovation over the past few years, as instrument makers like San Diego-based Illumina (Nasdaq: ILMN) and Carlsbad, CA-based Life Technologies have lowered the cost of sequencing an entire human genome to as little as $10,000. Upstarts like Mountain View, CA-based Complete Genomics seek to sequence entire genomes for as little as $5,000, while a rival, Pacific Biosciences, is aiming to sequence genomes in 15 minutes. Since every human genome has 6 billion chemical units of DNA, this faster and cheaper form of sequencing is creating enormous datasets that somebody will need to store, analyze, compare, and visualize. Without that capability, it's just a vast pile of data that doesn't really lead to valuable new insights for medicine. [Moreover, the entire sequencing industry might become unsustainable and sequences worthless unless someone actually knows what to do with the data to transform them into understanding - "the cloud has similarly limited intelligence" as a cab driver; if you tell the address, might get you there (often purposefully not along the most economical path FOR YOU)" - AJP]

Computing challenges have become a "serious blocker" to people trying to make sense of the genomic wave, Singh says. And Amazon has made it a high priority over the past couple years to become the company that stores genomic data in a cheaper and more accessible way for researchers. Customers, Singh says, "have started looking at the cloud very seriously as a possible option. Over the last year or so, that curiosity has turned into serious adoption."

Amazon's pay-as-you-go, rented server model has attracted partners and customers all over the country. The Broad Institute of MIT and Harvard in Cambridge, MA, is a user, along with Harvard Medical School. Life Technologies, an instrument maker, and Seattle-based Geospiza, a bioinformatics software company, have a partnership to use Amazon's servers to store genomic data. Palo Alto, CA-based DNAnexus, an intriguing bioinformatics startup, has built its business model around using Amazon Web Services. And one of the leading evangelists for cloud computing in genomic research is C. Titus Brown, a computer science and microbiology professor at Michigan State University, who is teaching students how to use Amazon Web Services to store the data for their experiments.

Precisely how important this is to Amazon, a company with $24.5 billion in revenue in 2009, is hard to say. In keeping with Amazon's close-to-the-vest culture, Singh would only offer vague adjectives when I asked for specifics on the number of customers, the percentage of Amazon Web Services business that comes from life sciences customers, the number of employees devoted to this effort, and the size of the market that Amazon ultimately sees for cloud computing services in life sciences.

There are still major barriers to be cleared before this can become a real earnings driver for Amazon. Much sequencing is done at centralized labs around the country that already have invested in expensive servers to store their data in a secured place on campus. So there's incentive to keep using those tools to get the most value out of them. Some labs are generating so much data from the instruments that they aren't always sure they have enough bandwidth to transmit it all to Amazon's servers. The raw experimental data is so precious to a biologist's career that it can be hard to just send it away to a vendor for safe-keeping, rather than have it under lock and key on campus.

And many researchers struggle with how to analyze, visualize and interpret the data being spit out by the sequencing machines. The software that needs to run on top of Amazon's storage capacity and databases -- the bioinformatics piece of the puzzle -- is still a cottage industry with home-made programs, piecemeal open source alternatives, and a lot of researchers still using old-school spreadsheets like Microsoft Excel.

Yet even before companies like DNANexus achieve major market traction with simple and easy-to-use bioinformatics software, many researchers still feel compelled to store the data in anticipation of the day when it will be easier to sift through. And Amazon isn't the only company wooing them. Microsoft and Google have their own cloud computing services to offer. At least one competitor, Seattle-based Isilon Systems, is making visible inroads in the life sciences market by selling of clustered servers. Isilon now generates 15 to 16% of its revenues from life sciences customers, up from 2% in early 2008, CEO Sujal Patel said at a recent Xconomy forum. Isilon's customer roster includes a lot of heavy hitters, like Merck, Genentech, Sanofi-Aventis, Bristol-Myers Squibb, Illumina, Complete Genomics, the Broad Institute of MIT and Harvard, Stanford University, and Johns Hopkins University.

Amazon's Singh knows this terrain well himself. He got his doctorate in chemistry from Syracuse University, and spent eight years of his career in the biotech industry, including stints at San Diego-based Accelrys and Seattle's Rosetta Inpharmatics. The past two years, he's been working as a business development manager for Amazon Web Services, with a particular emphasis on getting to know what the life sciences market wants from cloud computing.

Amazon has done a number of things to ease the transition for customers to cloud-based storage, Singh says. It has worked to obtain public databases and make them available to researchers. One example last month came from three recently completed pilot projects for the 1,000 Genomes Project. Putting that data out there for researchers, and enabling them to share it, has generated a lot of interest. "There's been a lot of demand for 1,000 genomes pilot data in Amazon Web Services," Singh says.

Showing the scientific value is one part of the equation, but the business proposition is just as important. Amazon's case is a pretty simple one. A lab can make a big capital expenditure upfront, but they usually have peaks and valleys of computing power needs. That means the lab isn't really fully utilizing its server capacity all the time. Plus, the new breed of sequencing instruments are getting so cheap and fast that there's no way a lab can really anticipate its server capacity needs in the future. Instead of buying expensive equipment and risk getting it maxed out in a year or two, the argument goes, why not lean on Amazon and its basically limitless capacity and flexible pay-as-you-go pricing model?

That may make sense for a lot of labs, but Amazon has found it needs to tailor its product a bit more for life sciences customers. The feedback prompted Amazon to make one curious old-economy concession to help with cloud computing. For some customers who don't have the bandwidth to efficiently communicate with Amazon's cloud, the company has set up what it calls an "import/export" service, which allows the lab to save their data on disk and physically ship it to Amazon via FedEx. This helps with some customers who want to know they can get their data to and from Amazon in a reliable way, on a predictable time schedule, without hogging up too much bandwidth on campus.

As much as academic labs might be interested in what Amazon is offering, they can only do as much as their funding agencies really allow. And there are rumblings that the U.S. National Institutes of Health, the world's primary funding agency for biomedical research, might be facing budget cuts in not so distant future.

Budget cuts at NIH could actually benefit Amazon, Singh says. It could put pressure on labs to be more careful with their capital spending, think a little harder about whether to build their own server clusters, and look more closely at alternatives like cloud computing. Even though the cloud is supposed to be cheaper, Amazon has felt the need to offer customers discounts on price. The company has started offering a cloud infrastructure service with less backup capability for the data, or "redundancy." That offering is still a more durable backup option than a lab can build on its own, Singh says, and it comes at a lower price than Amazon's regular cloud offering. The "Reduced Redundancy" service makes sense, he says, for a dataset that can be quickly reproduced (like another sequencing run on a blood sample, if the data is lost, for example).

Most of the interest in Amazon's offering is from academic labs, rather than with biotech companies and Big Pharma, Singh says. If Amazon can gain a toehold first in academia, it will almost certainly look to continue the momentum in Big Pharma, which spent an estimated $45.8 billion on R&D last year. Big Pharma spends all that money, and is still living with an abysmal success rate, in which only one out of 10 drugs that enters testing ever becomes an approved product.

Sequencing of individual human genomes, and analysis of how they differ, is one of the ways researchers are hoping to someday lower the cost and increase the odds of success in developing new medicines. It's a long-term trend that Amazon wants to be in position to reap.

"Over the past 12 months, there's been significant interest. All you have to do is look at conference agendas," Singh says. "The nature of the conversation has shifted from 'What should we do?' to 'What are we doing, and how should we do it?'"

[If we'd know what we were doing, we would'nt call it "research" - Albert Einstein - AJP]

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Calling GWAS Longevity Calls into Question [Gene(s)]

GenomeWeb
July 06, 2010

According to Nature's The Great Beyond blog, the GWAS published in Science last week that identified SNPs for "exceptional longevity" has generated some criticisms within the community. Critics are calling the findings of Paola Sebastiani et al. into question amid inquiries of "subtle biases" and the team's use of "different versions of the SNP chips" from Illumina, according to Nature. The Wellcome Trust Sanger Institute's Jeffery Barrett told the Guardian that "some of the genetic variants in this study are claimed to have much, much stronger effects on longevity than we've seen in similar studies of diabetes, heart disease, and cancer. For instance, the strongest single effect makes someone 10 times more likely than average to be extremely long-lived, compared to other complex diseases where typical variants only make someone, say, one and a half times as likely to be diabetic," highlighting his skepticism. According to Nature, Sebastiani says that the variants they've reported have larger effects since becoming a centenarian is a much rarer condition than having diabetes.

Last week, the New York Times' Nicholas Wade reported that DeCode Genetics' Kari Stefansson, who has run a similar experiment using a larger group of centenarians, did not find any of Sebastiani et al.'s 150 variants in his cohort.

Nature reports that Sebastiani and her team are considering "holding an online chat next Wednesday to answer questions" and to quell any confusions that their work has generated.

[We have spent dollar billions (probably trillions) and close to half a Century trying the find the "cancer gene", "epilepsy gene", etc., etc., - only to came to a realization when the recursive genome function pinpointed that complex phenotypes (such as longevity - or even cancer) are likely to be lurking in (holo)genome regulation (via epigenomic channels) - rather than to be tied to a single (or even small enough identifiable number of) "genes". Maybe time is ripe to spend monies on the much-neglected (holo)genome regulatory functions; and e.g. to research why the absence of hereditary- and/or epigenomic damages to DNA (not just to "genes" but mostly to derail recursive regulation) lead to accelerated aging process and untimely deaths. - Pellionisz_at_JunkDNA.com]

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IBM setting up cloud for genome research
July 2, 2010 10:35 AM PDT
by Lance Whitney

IBM is looking to help genome experts further their research by providing a cloud where they can better share information with their colleagues.

IBM and the University of Missouri announced Friday a new initiative to develop a cloud-computing environment where universities and medical professionals could work together on genome research on a large-scale, regional basis.

Tapping into Big Blue's high-performance computers, the joint IBM-Missouri cloud would let researchers share their findings and discoveries with each other more quickly and efficiently than they do now. Such an advancement would push the university's current bioinformatics research even further, potentially improving people's lives, IBM said.

As one example, specific genetic changes in cancer cells help doctors decide how best to treat their patents for breast cancer, colon cancer, lung cancer, and leukemia. To detect those changes, DNA samples must currently be sent out to labs for sequencing and analysis, a process that can take weeks. But by accessing IBM's genomics cloud, medical staff could sequence and analyze those samples in just a few minutes, according to IBM. [Wait a minute ... there are actually three bottlenecks. Presently, as the statement acknowledges, the main bottleneck is "sequencing" ("can take weeks"). Presently, the second bottleneck of storage and transfer to the sites of "DNA Analysis and Interpretation" is usually not through the net (requires too much bandwith, too much time - UPS of physical hard drives, laughable as it is, still "a preferred choice"; takes very few days. The third bottleneck is the actual analysis and interpretation. Presently, some projects take forever, some limited analyses can be produced in weeks, using pre-genomics computing architectures. In the future (a rough estimate is 5 years), all three bottlenecks should add up to 30-60 minutes COMBINED, to be practical e.g. in a hospital environment to do biopsy, full DNA sequencing, full DNA analysis and interpretation (and personalized recommendation e.g. of the most suitable cancer-treatment, as predicted in my 2008 YouTube). Forget UPS. Forget even the Internet-2. Hospitals will demand e.g. Ion Torrent desktop-sequencers ($50k) with on-rig serial/parallel (FPGA) hybrids, to cut out storage and transfer, and accelerate analysis and interpretation of low-bit huge-scale strings (DNA); also forecast in the above YouTube. - Pellionisz_JunkDNA.com]

"This collaboration with IBM provides our researchers, and those being trained to become tomorrow's researchers and educators, access to critical high performance computing resources needed to process massive data sets and apply increasingly more sophisticated bioinformatics tools and technologies," Gordon Springer, scientific director of the University of Missouri Bioinformatics Consortium, said in a statement. "The availability of these resources will enable discoveries that will benefit mankind and the environment."

In the first phase of the cloud project, IBM said it will offer Missouri an iDataPlex high-performance computer and software that will tie in the university's existing computers and speed up the DNA sequencing and analysis of humans, plants, and animals. In the second phase, Big Blue and the university will work together to create a prototype of the cloud environment. The final phase should see the genomics cloud become fully operational and expand to a regional scale. [Sounds like 5 years to me - AJP]

No specific time frame was given as to when the project would formally get off the ground or how long it might take to reach the final phase.

This isn't Big Blue's first foray into the world of genomics research.

Last year IBM announced new research into technology that can quickly and relatively cheaply conduct genetic testing. In the past the company has also donated hardware and software to remote areas to further study human DNA around the world. And the original job of IBM's Blue Gene supercomputer was to predict how chains of biochemical building blocks described by DNA fold into proteins.

[The "IBM/Roche DNA Transistor" and the "IBM Genome Cloud Computing". One might believe (as most did think so when the "IBM CP and its OS/2" came out, that this time "IBM cornered genomics". The bottom line is that nobody can tell the future - it may or may not happen to IBM - but "the race is on" with IBM/Roche having produced the Big One earthquake (the tectonic plates of "Big IT" and "Big Pharma" piled upon one another (that I predicted half a Century ago). Indeed, the very same IBM already "almost did it" with the World's fastest supercomputer (at that time), Blue Gene under historical governance of Caroline Kovac - upon completion of The Human Genome Sequencing Project. Also, presently a Seoul-based microarray - followed by Full DNA Sequencing Institute is backed by SAMSUNG. In the USA, Microsoft HealthVault, Google Health, DELL Life Science Division, Oracle's foray into Personalized Medicine (etc) are also "Big Players". Not everybody is "sold on the Cloud", however (e.g. see Larry Ellison going ballistic in a 4:25 minute YouTube on "Cloud Computing" in an a Churchill Club's excerpt , see full 1:26 hour YouTube , yet you can also download "Oracle Cloud Computing"... Now take Christensen's book "The Innovator's Dilemma;- When New Technologies Cause Great Firms to Fail" and factor in what happened to "IBM PC/OS2". It looks like Genomics needs a Microsoft-type "pure-play genome software start-up" for the fastest growth possible ... Pellionisz_at_JunkDNA.com]

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Scientists Discover the Fountain of Youth! Or Not.

Mary Carmichael
Newsweek, July 1, 2010

They say getting old is better than the alternative, and it's much better if you manage to do it like Florrie Baldwin, who died in May after 114 years of great health. (She was still climbing ladders at 104 and almost never took any medication.) Baldwin attributed her long, hale, and hearty life to a daily fried-egg breakfast, but her true advantage was probably in her DNA. Scientists have long suspected that she and others who grow very old have genetic variants that protect against the molecular ravages of age.

The trick, though, is finding those genes [and genetic variants, more often than not, in the intergenic and intronic regulatory regions - AJP]. Much of the research so far looks more clear-cut in mice or worms or fruit flies than it does in humans. And because the topic of old age and genes in general inspires so much excitement, it's often hard to tell where any given study falls on the continuum between brilliant (last year, the Nobel Prize for medicine went to three scientists who studied the relationship between DNA and aging) and ridiculous (this year, the cosmetics company Lancôme launched an eye cream that purports to "boost genes' activity and stimulate the production of youth proteins," which is about as believable as Baldwin's fried-egg theory).

What, then, to make of the new headline-grabbing paper that identifies somewhere between 33 and 70 genes (depending on how definitive you like your results) associated with extreme longevity—and also introduces a model that claims to predict with 77 percent accuracy whether you're going to be one of those ripe old folks? If the study's findings are correct, they are a very big deal, with the potential to overhaul how scientists think about aging and genetics. Indeed, they're so striking that some of the world's top geneticists think they can't possibly be right. More on that in a bit, but first, a point that even the study's authors have to concede: the research doesn't actually describe normal aging. It concerns only genes that may govern the process in people who make it to 100 or more. "The question is, of course, do the findings apply to the general population? Can we apply your model and predict the average lifespan?" says Paola Sebastiani, the Italian researcher who led the team. "And the answer is no, we can't." So what exactly can we learn from the new study?

The paper, published today in Science, has two basic parts. The first is what's called a "genome-wide association study," or GWAS. Researchers obtained genetic data (300,000 variants) from about 1,000 very old people (those over 100 years of age) enrolled in the New England Centenarian Study, and then compared the readouts to results from a same-size group of average people often used as a standard control in genetic studies. They found 70 genes that were more common in the centenarians. Then they repeated their study with smaller groups and confirmed 33 of those. They also looked at known disease-causing genes in both centenarians and regular subjects. It turned out that the centenarians had just as many dangerous variants as everyone else, which suggests that the 70 longevity genes (or 33, if you prefer the confirmed ones) were actively protecting them against illness. In other words, very long life isn't just about not having genes that make you sick—it's also about having genes that keep you well.

Next, the researchers employed some unusual math to build a model that described the combined effects of 150 variants they had found in the centenarians. (Some of those variants were related to the same genes, so the final number of suspected genes was still 70.) Then they applied the model to each of their study subjects, blinding themselves as to whether an individual was a centenarian or a member of the control group. Seventy-seven percent of the time, the model rightly predicted which group a given person belonged to—a success rate that is not only statistically significant but unprecedentedly high for a model that predicts a complex trait. It also pointed to 19 different genetic "signatures," or combinations, that seemed to confer long and healthy life in the centenarians.

Here's the weird thing: 15 percent of the control group had those signatures, too. That means that, genetically speaking, 15 percent of us should be living to 100 or more, when in reality only about 1 in 6,000 people do. What's happening to the rest of the would-be centenarians? Thomas Perls, a co-author of the paper and a geriatrics researcher at Boston University, says that maybe they're getting bumped off by things no gene can prevent. "Remember, this generation [in the New England Centenarian Study] lost a quarter of its population to childhood infectious diseases," he says. "And just because you've been handed the genetic blueprint for long life doesn't mean you're going to get there if you smoke a lot or you get killed in World War I or you're hit by a bus."

These are provocative ideas, and that may explain the wide variety of reactions that scientists had upon seeing the paper. Some said it was groundbreaking and could lead to drugs that mimic the protective genes in those who aren't blessed with them naturally. "What this paper answers, which I think is very important, is how many variants are there that can assure longevity," says Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York City. "Now scientists can start tracking those genes down and leading the findings toward drug development." Barzilai, who has collaborated with the study's authors on previous projects, has done some of that work already, probing a gene that influences how the body processes a hormone called IGF-1.

But other researchers were concerned about the new study's methods, calling the results everything from "somewhat surprising" to "preposterous." The problems start, they say, with the size of the group the researchers examined. The New England Centenarian Study is the largest cohort of very well-seasoned people in the world, but compared to the numbers typically used in GWAS-style research, it's actually quite small. Modern GWAS techniques usually involve groups of tens of thousands or hundreds of thousands of people. To attain statistical significance in a GWAS as small as the one in the Science paper, any gene would have to have a hugely strong effect in the body. It's odd that the Science paper finds not just one strong gene but a whole raft of them, especially since common diseases are usually caused not by strong genes but by weak genes acting together. (Why is a bit of a mystery, though it's possible that many strong genes have been weeded out over time by natural selection.) Aging, of course, is humanity's most common ailment. "I am very surprised that in a cohort of this size they have found 33 variants of genome-wide significance in extreme longevity," says Kári Stefánsson, the Icelandic researcher whose company, deCODE Genetics, has led many GWAS efforts. "We haven't seen any of them in our work with a different kind of cohort, but [a] much larger [one]." Other work at deCODE has also suggested that extreme old age is influenced by just a few genes—certainly not as many as 33 or 70.

The study's authors have a response to that. Yes, they admit, the sample is smaller than you'd need to do a GWAS of a common disease (which isn't really their fault, since there aren't many centenarians available for study in the first place). But common diseases, with their panoply of weak genes, aren't the right comparison to make, they say. Centenarian status isn't just an extreme form of the common condition known as aging, they argue; it's a rare condition of its own, and rare conditions are often caused by genes with powerful effects.

There are other potential problems with the new study. David Altshuler, a leading geneticist at the Broad Institute (a collaboration between MIT and Harvard), says that "one has to be cautious in interpretation, because the cases and controls were drawn from different times and places, and the DNA from cases and controls was measured using different technologies, which could lead to false apparent relationships." Duke University's David Goldstein, also a prominent geneticist, echoed those concerns. (And Altshuler and Goldstein are renowned for rarely agreeing on anything.) The control data in the Science study came from a standard set of numbers that Goldstein's lab has used, too. "We have found when we compare samples run at Duke to the [standard] control panel, there are a lot of [variants] that appear significant just because the samples were run in different ways," he says. Until the data has been replicated using identical technologies for the centenarians and controls, he adds, "I think we've got to hold judgment on this."

The authors of the Science paper are respectable researchers, and they're not trying to sell anyone genetically enhanced snake oil. (Tom Perls, in fact, has been such a vocal critic of anti-aging hype that he was once sued by the American Academy of Anti-Aging Medicine for defamation. They settled.) Sebastiani, Perls, et al. will be doing lots of follow-up research, including, they hope, a whole-genome sequencing project that will shed more light on their findings.

But for now, their research isn't ready to be translated from the lab to the clinic. You don't need to rush out and get tested for all the genes found in the Science study (although someone somewhere is surely making plans right now to sell you such a test). You can probably get a good idea of your risk just by looking through your family scrapbooks. "Using this technology might be helpful," says Robert Marion, a clinical geneticist at Montefiore Medical Center in New York. "But I would think that by just asking how old the person's parents and grandparents were at their time of death, the accuracy would probably be higher." So, if you want to know your chances of making it to 100, you should learn your family history and eat right and exercise while you're at it. Surely you didn't need a highly technical Science paper to tell you that.

[I got fairly technical in my Google Tech Talk YouTube - 8,230 views, rising steady since late 2008 - about aging; as the result of recursive genome function running out of auxiliary (regulatory) information by de novo methylation (rendering non-coding sequences "canceled" upon perusal). Growth is fueled by information - and since we all have a finite amount of it, eventually must run out. And, indeed, one can tell the average expected lifespan from the genome fairly precisely. (Yes, you can do, too). Ever wondered why a mouse, with 98% same set of genes only lives for 2-4 years, while we can last over twenty times longer? Just look at a genome (genes are nearly identical for species from lowly worms to homo sapiens) - but the regulatory mechanism (the amount of information, as well as the "clock speed" of recursion) can be rather different. The mosquito fish lives about 2 years, a catfish about 60. Look for recursive genome function in regulatory (non-coding) part of the DNA. One can not exclude it - but "genes" are unlikely to be the clue. Your "Junk DNA" can be the treasure chest of your longevity. - Pellionisz_at_JunkDNA.com]

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IBM DNA Decoding Meets Roche for Personalized Medicine
eWeek.com
Brian T. Horowitz
2010-07-01

[IBM-Roche DNA Transistor - AJP]

IBM and Roche are working together to decode DNA more quickly and cheaply, potentially allowing patients to receive customized prescription drugs. In the future, this kind of health care IT could also allow patients to purchase their own DNA code information for as little as $100.

IBM and Roche, a pharmaceutical and diagnostics company based in Basel, Switzerland, are working together to fine-tune a DNA decoding process that could lead to faster and more affordable sequencing and personalized medication.

As part of the July 1 agreement, Roche's subsidiary, 454 Life Sciences, will market and distribute future products based on IBM's DNA Transistor technology. In addition, IBM will license the technology and continue to provide expertise and resources.

Roche, which describes itself as the largest biotech company in the world, holds "expertise in medical diagnostics and genome sequencing," IBM announced.

"Sequencing is an increasingly critical tool for personalized health care," Manfred Baier, head of applied science at Roche, said in a statement. "It can provide the individual genetic information necessary for the effective diagnosis and targeted treatment of diseases. We are confident that this powerful technology, plus the combined strengths of IBM and Roche, will make low-cost whole genome sequencing and its benefits available to the marketplace faster than previously thought possible."

Ajay Royyuru, senior manager of the IBM Research Computational Biology Center, explained that DNA sequencing has come a long way in 10 years, as originally genome sequencing was not yet possible. Now the technology is available but costly, he said.

"The next step we need to take is to make it faster and better in quality of readout and scale of operation. Once we reach that point, which could be [in] the next five years or 10 years, then I think we have the potential of being able to apply that routinely to the practice of medicine," Royyuru said in an interview with eWEEK.

The goal of the project is to read DNA quickly and efficiently at a low cost. If successful, this process would allow doctors to more effectively match medication to patients.

IBM's DNA Transistor technology, comprising a combination of metal and silicon insulation, uses electrodes to thread DNA molecules through a nanopore, a hole the size of a nanometer, or one-billionth of a meter.

Royyuru compared the creation of the nanopore to punching a small hole through a piece of paper with a pencil.

"We're able to drill a hole small enough and operate it electrically to put the DNA through the pore. All of that we have shown is workable," he said.

In the next phase of development, IBM and Roche will work on moving the DNA through the nanopore.

"Then we will have shown at that point that we can control the passage of DNA," Royyuru said.

Slowing down the DNA as it travels through the nanopore makes genetic data readable, he said.

Personalized medication can eliminate some adverse side effects of current drugs. Some preliminary cancer drugs based on the DNA Transistor technology have already reached the market, Royyuru noted.

"Today what everybody does with medicine is trial and error," Royyuru said. "They give a certain treatment because it worked on most people before. But they have no way of knowing if it will work on you or not. They have side effects that are worse than what you're trying to treat."

Ultimately, the technology has the potential to improve throughput and reduce costs, so human genome sequencing could be purchased for $100 to $1,000.

In addition to the announcement, IBM has posted a video of how the DNA Transistor technology works. [See above - AJP. This announcement, though may appear "earth-shaking" for the shere size and dominance of Big IT by IBM and Big Pharma by Roche, has been expected for a long time, and both the announcement and the video actually fall short of the expectations. "Nanopore Sequencing" is not lead by IBM, but Pacific Biosciences (with IntelVC $100 M investment is about to ship their equipment to R&D labs ($695,000 apiece), Oxford Nanopore (UK, backed by Illumina) is also ahead with the technology development. Last but not least, mastermind and developer of the original 454 Roche sequencer (now largely obsolete) Jonathan M. Rothberg, Ph.D. Founded and is CEO of Ion Torrent - with a desktop-printer-size nanosequencer priced at about $50k. The announcement is particularly disappointing since it erroneously refers to "decoding DNA" - while there is not a word anywhere that IBM would focus on the NEXT STEP (beyond "sequencing" that the DNA transistor will do who knows when), and target "recursive genome function". By far the most positive aspect is, truly making history, that "doing genomics" is now branded by the world's two largest monsters as "thinking physical". Now the question is that in addition to physics of the sequencing device, where is the theoretical physics that Schrodinger started in 1943 "What is Life" with his prediction of an aperiodical chrystal where covalent bondings of H ions encode life. We can now proceed to substitute "aperiodical' with the more precise "nonlinear dynamical, fractal & chaotic arrangement (and re-arrangement... through normal and derailed recursion) of the bonding sequence. That is the true "decoding" task. - Pellionisz_at_JunkDNA.com]

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How to Build a Better DNA Search Engine

The techniques for indexing Chinese language websites could dramatically improve the speed of bioinformatic searches, according to research by SOSO, the third-largest Chinese search engine.

If there's one thing that Google has taught the current generation of web savvy surfers, it is that internet searches are quick. The small print at the top of every search it delivers stamps this idea into the culture of search.

Type the word "physics" into the search engine, for example, and it delivers 102,000,000 results in 0.21 seconds. That's mind-blowingingly fast.

That might sound like good news for researchers combing bioinformatic databases. These databases are huge and growing exponentially. They contain, for example, the rapidly increasing number of genomes from different species around the planet as well as the genomes of different individuals within the same species.

Given our experience with web search, it's easy to imagine that finding a gene that is common to more than one organism or individual ought to be as quick as searching Google. But it isn't.

The reason according to Wang Liang, a computer scientist at SOSO.com, one of the big three search engines in China, is that bioinformatics has failed to exploit the basic search techniques that have made search engines like Google so quick.

Most bioinformatic searches use either the BLAST or FASTA algorithms. These essentially compare the data from one genome with the data from another, then with another and so on. That's satisfactory when there are a relatively small number of genomes but it quickly becomes unmanageable as the number of genomes increases exponentially.

Search engines faced exactly this problem 20 years ago with the growth of the world wide web. Search engines initially indexed the web by recording the words that each document contained. Searching for a specific word then meant looking for it in one web page, then in another and another and so on. This approach becomes increasingly slow as the number of documents grows..

So the engines took another approach: they turned the indexing process on its head creating what is known as an inverted index. "The idea of an inverted index is very simple," says Liang.

Instead of creating a list of web pages and the words on each page, the indexing process records for each word, a list of webpages where it appears.

So a search now looks only through the list of words that a search engine has indexed. When it finds the word, that entry also records the webpages where it appears. In other words, instead of searching an index of webpages to find a specific word, you search though an index of words to find the webpages where it appears.

That dramatically simplifies things but there are various complexities that making the indexing process tricky. For example, in English, the spaces between words show clearly where each word starts and finishes. That isn't the case in genetic data. So one important questions is what constitutes a word. [This venerable question was poised by the classic approach by Stanley et al., 1994 to "arbitrarily assume that a 'word' is a random 3-8 nucleotide string - AJP]

Liang says that an important clue comes from the way search engines index languages like Chinese where there are no spaces between words either. One way to index a Chinese document is to segment the text into n-grams, words that are n-letters long. So you start by segmenting it into 1-grams, one letter words, then 2-grams, two letter words. A search for a 3 letter word, such as ABC, can then be done by searching for the 2-grams AB and BC.

In fact, some Chinese search engines work in exactly this way, by indexing all the 2-grams.

But how many letters are there in a genetic word, what n-grams should a search engine index? A 1-gram segmentation gives only four words, the base nucleotides A, T, C and G. But that's no good because the combined searches needed for longer words are then unmanageable.

The answer comes from the statistical distribution of words in DNA sequences which Liang says follows Zipf's law. This essentially states that in any long document, 50 per cent of the words appear only once. This can be used to find a kind of average length length of DNA words.

In Chinese for example, the percentage of 1-gram words that appear only once is less than 50 per cent, the percentage of 2-gram words that appear only once is about 50 percent and the percentage of 3-gram words is less than 50 per cent. So 2-gram words are a good average.

Liang applies the same criteria to find the average length of words in the genomes of arabidopsis, aspergillus, the fruit fly and the mouse. And he finds that a good average word length is about 12 letters. So the best way to index genome data is to look for 12-grams, he says.

None of this needs any new technology to complete. Liang says that the open source search engine Lucene is the perfect forum in which to do the work and, impressively, has even used it to build a rudimentary bioinformatics search engine himself.

It makes sense that the huge improvements in search that have been made by commercial search engines ought to find application in the bioinformatics world. Perhaps there's even a decent business model in such a plan, for example by serving ads targeted at the kind of people who do bioinformatics search.

The only question is who will lead the way in this area. And if this work is anything to go by, it looks as if the Chinese search engine SOSO has the lead.

[The idea that the DNA is a "language" (certainly not English, not even a "Russian novel" as Esther Dyson likes to allude to, and while wishing good luck to the Chinese, the FractoGene approach suggests that it is no human language at all - goes back at least to Eugene Stanley et al, 1994, as elaborated by AJP in Simons and Pellionisz, 2006. However, as it was presented by Pellionisz in Cold Sping Harbor 2009 , the early approach by was tainted by (totally arbitrarily, as the authors admit) assigning a "DNA word" randomly, as a 3-8 nucleotide string. The seminal work by Rigoutsos (2006) is referenced there as a method of identifying "words" of DNA - and on that basis Pellionisz' FractoGene shows that a full DNA sequence, when broken up to "repetitive words" follows the Zipf-Mandelbrot Parabolic Fractal Distribution curve. If Dr. Collins is right that "the DNA, like mathematics, is God's language" - it is unlikely that it is English or Chinese (or any human language) - but Nature's Geometry speaks Fractal. This, actually, may be rather fortunate for creating the "universal search engine" - not optimized for either English or Chinese, but for the MEANING of concepts - AJP]

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'Jumping genes' make up roughly half of the human genome

Wired
By Brandon Keim
2010-06-25

Recursion Life Cycle of a Retrotransposon

Geneticists have revealed that Transposons or 'jumping genes', which create genomic instability and are implicated in cancer and other diseases, make up roughly half of the human genome.

"Now it looks like every person might have a new insertion somewhere," says senior author Scott Devine, associate professor of medicine at the University of Maryland School of Medicine's Institute for Genome Sciences.

Transposons are like small self-replicating sequences that transfer themselves from one generation to another. But the scientists faced the overwhelming problem of finding a new insertion within three billion base pairs.

Their study indicated transposons are jumping in tumours and are generating a new kind of genomic instability. They are already known to interrupt genes and cause human diseases, including neurofibromatosis, hemophilia and breast cancer.

Scientists believe a process called methylation, which silences genes during differentiation also shuts off transposons' ability to jump. Analysing the patterns of mutations in the lung tumours suggested that during tumour formation, modified methylation patterns may be allowing transposons to re-awaken, Devine says.

The results are published in the June 25, 2010 issue of Cell. (ANI)

Reference:

R.C. Iskow, M.T. McCabe, R.E. Mills, S. Torene, E.G. Van Meir, P.M. Vertino and S.E. Devine. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell (2010).

[The First Decade after The Human Genome Project was a painful transition. The Second Decade will be the Revelation of "Recursive Genome Function". While Barbara McClintock was ridiculed as a "Kook" for her "Jumping Genes" notion, and 35 years after her publication received the Nobel Prize in 1983, "The Human Genome Project" still (erroneously) assumed that the DNA is "static" (i.e. the sequence of 6.2 Bn A,C,T,G-s explains everything. In 2002, the FractoGene notion suggested nonlinear dynamics (fractal and chaotic properties) of genome function, but the "double heresy" of running against both Crick's "Central Dogma" and the "Junk DNA" axioms made it possible for the "old school" to hold the line till "The Decade of Recursion" (now "recursive genome function" stands at 69,300 hits on Google). Cancer, as the epitome of regulation-derailment, is likely to become a central target of the now liberated new decade of research, analysis, interpretation - and up to personalized therapy and cure. - AJP]

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A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

Laura Poliseno1,4,5, Leonardo Salmena1,4, Jiangwen Zhang2, Brett Carver3, William J. Haveman1 & Pier Paolo Pandolfi1

Nature 465, 1033-1038 (24 June 2010) | doi:10.1038/nature09144; Received 21 September 2009; Accepted 22 April 2010

Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

FAS Research Computing & FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA

Human Oncology and Pathogenesis Program, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA

Abstract

The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.

[Bye Junk DNA - one more time... - AJP]

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Business Models for the Coming Decade of Genome-Based Economy - the past and transition

June 26, 2010
Andras J. Pellionisz,
Ph.D. in Computer Engineering, Ph.D. in Biology, Ph.D. in Physics
Former Research Professor of New York University,
Founder of International Hologenomics Society
Founder of HolGenTech, Inc.
Founder of HelixoMetry
Silicon Valley, California, USA

Genomics is a Science of Heredity, right? Nuclear Physics is a Science of Fission and Fusion of Atoms, is that correct? Yes -- both Nuclear- and Genome-Experimentation and Theory started with Pure Science, before Technology Applications cut in with full force. Both “pure science approaches” quickly became mostly government-supported R&D projects of significant size and potential. After the initial paradigm-shifts of Atoms splitting, or Genomics becoming integrated with Epigenomics and transformed into Informatics (HoloGenomics), a Nuclear Industry and likewise, a new phase in Genome-Based Economy resulted. It may not grab the attention of headline-makers that the true success or failure of (untrue) “Decoding the Human Genome” really lies in the soundness of underlying business models.

With the 10th Anniversary of the “Completion” of the “Human Genome Project” (HGP) upon us by the 26th of June, 2010, there is an increasing, and increasingly controversial debate over its origin and aftermath through its First Decade. The controversial origins, as they are amply documented, will not be belabored here. Let’s take a look on the future from the perspective the sheer force of business models.

In the aftermath, the First Decade was a turbulent transition. The coming second is re-shaping the World, and some picture the US on a potential brink of a decline.

Juan Enriquez, now director of Excel Venture Management (Boston) sums it up this way: (also in his book: The Untied States of America):

“Countries that fail to commercialize their research discoveries remain diminished,” Enriquez points out. “Take the U.K., for example: They discovered penicillin and DNA, but preferred to let the knowledge sit in a college lab somewhere, rather than let the professor, god forbid, benefit from the discovery. The moment we start adopting those same attitudes in the United States, we will begin to decay.”

This perilous inflection point, leading us to the second Decade after HGP, did not come without an almost decade-old warning by Excel Venture Manager Juan Enriquez. The assessment of the past decade was actually predicted by Harvard Center of Economics director Juan Enriquez (2001) in his epoch-making bestseller “As the Future Catches You”. He established the historical comparison of “Genomics” and “Digital” for their role in Empires rising or falling.

His prediction was based the core Business Model of Genome-Based Economy-Round One, that has happened in the 1970-s - although it is not much talked about these days. Dr. Enriquez refers to Norman Burlag’s “Green Revolution” that elevated tenfold yields of crops such as rice, to a large extent by means of genetic improvements, thereby saving the lives of at least 2 Billion people from starvation. Lives saved were mostly Chinese and Indian – thus is the appreciation of about 3 Billion of presently 7 Billion people of the World. Norman Borlag’s ouvre, selling seeds of high-yield crops was based on a rock-solid simple business model for the World, driving it by feeding the starving – and as corollary making him not only the Nobel Peace Prize Laureate in 1970 but also the most decorated person of all times - second only to Mother Theresa.

The Science of Genomics, by recombinant DNA, was “consolidated” in 1972 (Ohno) into an oversimplified view of the structure of the Genome, derailing it from underlying business models. The “all-important Genes” (fairly short sequences of DNA producing RNA and then proteins), while those parts not obviously coding for proteins (as turned out later, 98.7% of human DNA) were to be "safely ignored" as “Junk DNA”, based on Crick’s “Central Dogma” (originated in 1956 that Protein information never recurses into DNA – why bother with the “Junk”?).

Based on research and technology, recombinant DNA focused therefore on genes, they industrialization was based on research by Boyer and Norman (1973). GenenTech generated a business model for Genomics, entering Medicine through Big Pharma: by the “One gene, one disease, one billion dollar pill”. Almost at once, the FDA, regulating the US business model was Chartered in 1976 based on the (false) premises to the effect that “since we all have the same genes, criteria of clear benefits overriding acceptable risks should apply to everyone; ‘one size fits all’”. The first and most significant Gene-business (Genentech, expressing a human gene in bacteria) produced hormone somatostatin in 1977, and synthetic human insulin in 1978.

In a parallel line of developments, 1975, Fredrick Sanger (the only living double Nobel-Laureate) announced that he had developed an efficient method to determine the order of base pairs of DNA. Alan Maxam and Walter Gilbert (Harvard) independently developed a completely different method. This method was announced to molecular geneticists in the summer of 1975 at scientific conferences and circulated as recipes among molecular geneticists until formal publication in 1977. Half a decade later, many groups began successfully to automate the process, in North America, Europe and Japan. The first practical prototype was produced by a team at the California Institute of Technology in 1986, under the direction of Lloyd Smith, as part of a large team under Leroy Hood. This prototype was quickly converted to a commercial instrument by Applied Biosystems, Inc., and reached the market in 1987.

Independent of business models (if any), inherent in genome sequencing, the remote possibility of sequencing the entire human genome caught the fancy of Big Science of the US Government. With the Office of Management and Budget's approval, the DOE committed its first funds for human genome research in October 1986. After the NIH started its own genome effort the next year, a coordinated project was formally launched. In 1988, the DOE and the NIH signed a Memorandum of Understanding that committed the two agencies to work together by coordinating activities and leveraging their respective strengths as assets. The official "clock" on the project was started on October 1, 1990 with Dr. Watson behind the wheel. Assumably, with a major (publicly known) motivation that his son, Rufus, is affected by schizophrenia, and a complete catalogue of all human DNA would hopefully cast the net big enough to catch “the missing gene” for this and other feared diseases. Thus the NIH-DOE led, multi-agency and multi-national (multi-governmental) HGP became perhaps overly “one gene – one disease” oriented. Since governments don’t tend to think in terms of “business model(s)”, HGP was not directed by business model(s), nor did it proceed with the diligence for speedy accomplishments. (Government-sponsored R&D projects are usually wished to be kept alive forever, understandibly with well thought-of cost-overruns, enough to justify an ever-increasing budget from year to year, yet not too big to raise eyebrows resulting in a shut-down of the government project).

Oh yes, a huge business opportunity in DNA sequencing did not escape the attention of those not so much medical research- but business-oriented. Head of the US NIH, Bernadine Healy wished that the US goes down on the pathway of patenting human genes – only to collide “head-to-head” with Jim Watson who, as an epitome of “pure research scientist” wanted Genomics remain a “free for all”. As a result, in 1992 Watson resigned and Dr. Francis Collins, M.D., Ph.D., already “with a claim to fame to his name” (having identified the gene of Cystic Fibrosis) took over governance of The Human Genome Project. With Francis Collins at the helm, the US government (with a number of countries in tow) proceeded at a snail-pace, “but free for all”, and even more “gene-focused”, with Dr. Collins, as a formerly practicing M.D. focusing on the possibility of eventually transforming medicine.

Enter Craig Venter, Ph.D., the maverick doer, turned-off by both by “medicine” as applied to some of the 70,000 Vietnam-victims with hundreds dying in his arms, and also (as someone who experienced how NIH worked, by working for it), disenchanted e.g. when one of his NIH proposals was not only rejected, but pontificated as “un-doable” (thus he did the multi-year project in a few months, with your taxpayer's money spent on who knows what).

Craig Venter threw his hat into the ring, with the much-ridiculed idea that he would sequence the human DNA by applying the “shotgun sequencing” (“even a monkey can do that…”) and would patent the found genes (“he wants to own the genome like Hitler wanted to own the World”) – and all would be based on private enterprise money (“he can’t raise that kind of money, anyway”). Craig did raise the money, deployed his “super fast monkeys” (computers) to assemble the shotgunned fragments, and while officially it was a tie exactly ten years ago, Craig Venter clearly won the race for sequencing – but lost the opportunity to patent any of it, since that business model he was banking on was invalidated. (Thus he turned later to the business model of patenting modified DNA, to be synthesized for energy and new materials business).

However, as the Human Genome Project neared its “first draft” in 2000 – with the 140,000 expected genes were nowhere to be found, the Business Model of Big Pharma with “one gene, one disease, one billion dollar pill” was dead on arrival on the news of “finishing” the Human Genome Project. As a long-shot result, as of 2009 the Swiss pharmaceutical conglomerate Hoffman-La Roche now completely owns the US pioneer-business based on gene-technology (Genentech).

Sequencing Business, however, took off as now the third generations of private enterprise-built sequencers – based on the dubious business model that Big Science US government projects (e.g. ENCODE) and foreign governments (e.g. China) did and would go ahead and sequence DNA “no matter what” (both China and Russia claims “national security” in the integrity of the Chinese and Russian genome…, Koreans are sequencing the Korean genome, the Arabs the Arab sequence, Jews the Jewish sequence) – and the general public would just get themselves sequenced once the price dips below the magic number of $1,000 per "affordable full human DNA sequence". (For what? Detroit must have been more worried about providing the network of gas-stations for their assembly-line affordable Ford T vehicles, useless without the other half of the business-model…)

There is a lot to be read these days how the First Decade spectacularly fell short of declared expectations that it would “revolutionize medicine” – that just did not happen as expected. Why don't we talk about the Business Models?

Genomics is Science and Technology -- while Medicine is a Business (in the US – in other civilized countries it is a government service). One can not turn apples into oranges. Therefore is the “surprise of the first decade” – that rather than finding cures for diseases (the much hoped for and hyped up “medical revolution”) – postmodern genomics found Business Models for Prevention faster than Business Models, while “Personalized Medicine” has to develop its verified Business Models to work.

“Medical Genomics” is to collide with the Medical Establishment; will be the strictly regulated, meticulous but high-yield "slow track". “Consumer Genomics” will be the “fast track”, since it empowers by user-friendly automated those daily decisions based on consumers’ freedom of choice that could be done “the old fashioned way” (see the much-belabored YouTube "Shop for your Life!" business model by HolGenTech, Inc.to proceed on the “fast track”

[Other emerging business models will be reviewed as this series continues - AJP]

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Business Models for the Coming Decade of Genome-Based Economy - the transition and future

Representative samples (beyond the Consumer Genetics Business Model shown above) are as follows - all based on the key question of postmodern genomics; (holo)genome regulation:

INDUSTRIALIZATION OF GENOME REGULATION RESEARCH

At a first glance, this appears to be a contradiction. How can "research” be advanced by “industrialization”? A highly visible precedent provides an explanation that it is not an oxymoron. Nuclear Physics faced (and still faces) several scientific challenges – and the most notable how energy can be harvested from nuclear fission and fusion was (and is) driven by the massive force of "industrialization" (including defense industry) - rather than the relatively meager resources available for "pure research".

Likewise – as acknowledged by the new generation (over 127,000 views of YouTube "Regulatin' Genes") “regulating genomes is crucial for development”. However, though a peer-reviewed science article that opened the way by surpassing two obsolete axioms (Crick’s “Central Dogma” and Ohno’s “Junk DNA”) that together blocked genome informatics for over half a Century (“The Principle of Recursive Genome Function”) appeared in 2008 and Google yields for "Recursive Genome Function" 69,100 hits - there seems to be no program by any US government Agency that would invite spearheading a focused effort in advanced fractal & neural network theory to resolve the crucial problem of genome regulation. At least two Business Models, however, will fuel and assure progress; since both “Synthetic Genomics” and DTC of "Structural Variants" require an algorithmic (software enabling) understanding of (holo)genome regulation..

INDUSTRIALIZATION OF SYNTHETIC GENOMICS

As mentioned in the overview of the past, the Business Model by Craig Venter; patenting industrially useful genomic applications was invalidated by government decree of 2000. While patenting “genes", therefore, is not viable, the Venter Institute (with Craig Venter, Ham O’ Smith, Clyde Hutchison, John Glass et al.) invented the Business Model of modifying gene-sets of organisms with small enough DNA to synthesize them – and since a modified gene-set is not an existing product of Nature, it is patentable. However - until and unless the regulatory mechanism is understood (even in the Mycoplasma Genitalium with 7% non-coding DNA), any modification of the gene-set must be “stealth” to the largely retained regulatory sequences. Thus the 15 years to find the combination of small enough modifications to "boot the synthetic DNA". While the enormous potential in Synthetic Genomics was never questioned, and now with an "existence proof“ delivered, this Business Model will be a major industrial driver towards understanding genome regulation.

INDUSTRIALIZATION OF DTC STRUCTURAL VARIANTS

Never believing in either Crick’s Central Dogma or Ohno’s JunkDNA mistaken axioms, in 2005 I established the International PostGenetics Society, which became the first international organization to officially abandon the "Junk DNA" misnomer on its European Inaugural, October 16, 2006 (8 months before the US government’ ENCODE program concluded in the same). At the establishment of the Society (in 2008 becoming International HoloGenomics Society), I posted (and updated) the site of “Junkdna diseases” – since with the notion that 98.7% of the human DNA is not there (as Ohno stated, p.367) for “the importance of doing nothing” it followed that structural variants (to systematically describe the common patterns of human genetic variation revealed in the HAPMAP project, with the original span from 2002-2005, costing $138 Million, extended twice, 2007, 2009 with the overall cost exceeding $500 M) even in the "non-coding DNA” are associated with identifiable diseases. The fact of all kinds of “structural variants” raises both a scientific and practical dilemma. Scientifically, it seems obvious that “structural variants” could either represent harmless “human diversity”, or “genomic defects” with an impact on hologenome function. The brute force approach would have to plough through all variants and parse them according to variant genotypes if associated with harmful phenotypes or innocent to the function. In contrast, any algorithmic (software enabling) understanding of genome function would show parametric variants, separated by defects that affect the required syntax. (For instance, in a Mandelbrot set, the Z=Z^2+C, with different numbers of the C constant all yield “parametric variants”, while glitches in squaring through some of the recursions the complex number Z result in syntax errors; fractal defects.) Thus I proposed the FractoGene (2002) algorithmic approach (cost was shouldered and thus is now unencumbered by the IP-developer, AJP), and FractoSoft is now acquired by HolGenTech, Inc., with IP held under HelixoMetry.

Since the practical tool of interrogating DNA was hitherto available by Affymetrix/Illumina microarrays, yielding Single Nucleotide Polymorphisms (SNP-s), the "Industrialization of Structural Variants" started by DTC genome testing companies (DeCodeMe, 23andMe, Navigenics, etc). As reported in this column, 23andMe started a veritable revolution to correlate, in a "data-driven model", patterns of SNP genotypes with (patterns) of phenotypes. Lately, however, a great assortment of "structural variants" emerged, e.g. “copy number variations” (different numbers of repeats of sequences containing many thousands of nucleotides), etc. Structural variants with complexities beyond SNP-s require tools beyond microarrays - and call for "affordable full DNA sequences".

The Business Model of mining for, and establishing correlation of complex structural variants and pathological phenotypes will be a major driver for algorithmic (software enabling) understanding of (holo)genome regulation. An extremely complex, and socio-economically towering example is cancer research, therapy and cure, where the massive rearrangement of the genome (that a layperson might describe with the colloquial meaning of “chaotic”) – indeed (in a mathematical sense) a fractal and fractured alteration of DNA sequence – widely acknowledged to be a disease (derailment) of genome regulation (with fractal defects, “jumping genes” of retrotransposons, copy number variations, fractures of entire chromosomes). Successes of algorithmic approaches will put an enormous economic pressure both on privately held genome informatics (genome computing) companies, as well as on Big Pharma, to build the required Business Model.

INDUSTRIALIZATION OF GENOME REGULATION IN BIG PHARMA

Perhaps the biggest "disappointment" of the First Decade after The Human Genome Project was that it has not developed "cures" for some of the most dreaded hereditary diseases. In my opinion, it was (and is) entirely unrealistic to expect cures e.g. for "regulatory diseases" (like cancers) without a hard-core understanding of genome regulation. While this topic was mentioned above, another class of medications, with a historical precedent, can also illuminate the same point. Alexander Fleming did not quite understood in 1928 how the fungus Penicillium notatum stopped the growth of bacteria - could still create a revolution of antibiotics. There is already a modern precedent (Merck's aquisition of SiRNA for $1.1 Bn) to show how small interefering RNA-s could be applied - but it is also obvious that the "Big Pharma Business Models" (e.g. of the use of microRNA-s) will be fiercely proprietary. - AJP

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The Genome and the Economy

June 18, 2010
Genomeweb

Mike Mandel, from the Mandel on Innovation and Growth blog, says the most "significant economic event of the past decade" is the "failure of the Human Genome Project to deliver medically significant results."

Ballooning healthcare spending, low job growth and a big trade deficit are strangling the US economy, he says, and "the Human Genome Project had … the potential to be a powerful antidote to all three of these problems." But Mandel says there's reason to be optimistic. The US has invested heavily in biotech, new technology and health, and "the research has gone great." All we need to do to capitalize on this investment is to bridge the gap between research and commercialization, which has been done before, Mandel adds. "So I'd say that the odds are good that the Human Genome Project will have a significant economic impact over the next 5 to10 years," he says....

[I agree with Mandel - but see some need to spell out how the Industrialization of Genomics is to be implemented; see the news on 23andMe below, and my ensuing essays - AJP]

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23andMe Publishes Web-Based GWAS Using Self-Reported Trait Data

June 25, 2010
By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) - In a paper appearing online last night in PLoS Genetics, Web-Based, Participant-Driven Studies Yield Novel Genetic Associations for Common Traits researchers from 23andMe and Columbia University reported the first genome-wide association findings stemming from 23andMe's web-based, participant-driven research program.

The study, which involved more than 9,000 individuals genotyped through 23andMe's direct-to-consumer testing service, looked for genetic associations related to nearly two-dozen common traits. Using this web-based survey approach, the researchers verified previously reported associations for five traits and identified new SNPs linked to four of the traits, including hair curl, freckling, sneezing in response to light, and the ability to detect asparagus metabolite odors in urine.

"[W]e confirm that self-reported data from our customers has the potential to yield data of comparable quality as data gathered using traditional research methods," co-author Anne Wojcicki, president and co-founder of 23andMe, said in a statement.

For the study, the team drew from 23andMe's direct-to-consumer genetic testing community, bringing together SNP and survey data for thousands of customers. As such, they explained, the researchers were able to put together "a single, continually expanding cohort, containing a self-selected set of individuals who participate in multiple studies in parallel."

"Our ability to contact individuals multiple times and ask follow-up questions puts us in a position to zero in on associations that could be the building blocks for future research aimed at prevention, better treatments, and potentially cures for a multitude of diseases and conditions," lead author Nicholas Eriksson, a statistical geneticist at 23andMe, said in a statement.

Each of the 9,126 participants provided information on at least one of the 22 common traits. These traits were selected, in part, based on heritability and the feasibility of collecting related phenotype data easily in a web-based setting. The traits included everything from hair and eye color to "photic sneezing," a predisposition for sneezing when looking at the sun or other bright light.

The team then integrated this data with genotype data for 535,076 SNPs assessed using the Illumina HumanHap550+ BeadChip. At least 1,500 unrelated individuals of northern European ancestry were evaluated for each of the 22 traits.

Using this approach, the researchers found associations for eight of the 22 traits. Among them: previously reported associations for traits such as eye color, hair color, and freckling and new associations for four of the traits.

For instance, a new freckling-associated SNP turned up in an intron of the zinc finger gene BNC2, while hair curl was associated with SNPs near the TCHH, LCE3E, WNT10A, and OFCC1 genes.

In another new association, the team found that the tendency to sneeze when looking into light was linked to two SNPs: one near the ZEB2 gene and the PABPCP2 pseudogene and another near the NR2F2 gene.

The researchers also found that individuals who can smell an asparagus metabolite called methanethiol in urine tend to carry SNPs in a linkage disequilibrium block in and around 10 olfactory receptor genes. Of these, the most significant SNP fell upstream of the olfactory receptor gene OR2M7.

In an editorial appearing in the same issue of PLoS Genetics, the journal's deputy editor-in-chief Gregory Copenhaver and its gene expression profiling and natural variation section editor Greg Gibson, who are affiliated with the University of North Carolina at Chapel Hill and the Georgia Institute of Technology, respectively, addressed ethics, consent, and data access concerns related to the 23andMe study.

The pair noted that the study's publication was delayed because the journal wanted to deal with several such issues — for instance, ensuring that individuals included in the study were not pressured into partaking in the study and understood that they were participating in genetic research. The editorial also addressed institutional review board questions arising from the study.

"After considering all of the evidence, we decided that publication, accompanied by an editorial providing transparent documentation of the process of consideration was the most appropriate course," Gibson and Copenhaver wrote. "[W]e have had extensive discussion with the authors of this study to address our concerns and to update their processes, but we anticipate broad evolution of GWAS consent and review in the near future."

Meanwhile, the 23andMe team is setting its sights on additional web-based GWAS studies. In their current paper, they noted that the approach makes it possible to ask research questions using data from an ever-expanding group of individuals.

"Our research model makes possible studies that might be infeasible otherwise due to the low marginal cost of asking additional questions over the web and the speed of broadcasting recruitment messages in parallel online," the team wrote, adding that "providing participants with well-explained descriptions of their genetic data can substantially benefit genetic research as a whole."

In addition, 23andMe said yesterday that it has now secured IRB approval for its web-based research protocol. According to the company's blog, The Spittoon, 23andMe customers will now be given more leeway over how their genetic information is used and must "explicitly choose to allow their genetic and survey data … to be used in published research."

[What 23andMe started is an Industrial Revolution of conducting scientific research in the future; a Google-type "data-driven" approach that will minimize the "brute force" necessary for handling masssive amounts of data. Of course, one may ask why was the effort focused on "frivolous traits" like freckles or smelling asparagus in the urine - when it is obvious that the methodology eminently applies to severe phenotypes with massive medical impact. It is noteworthy that the paper was delayed over a year since among others it alters the way how volunteers provide information. This is almost nothing (a technicality) compared to how the methods revolutionize possibly the entire medical research. Since this collides "head on" with "medicine as is", the approach carefully avoided hard-core "medical" questions - still 23andMe is one of the 5 DTC genome testing companies that will be investigated by FDA and the Congressional Committee (on Energy and Commerce...)- AJP]

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Francis Collins: the extended genome anniversary interview

The Times
06/24/2010

Ten years ago on Saturday, Francis Collins and Craig Venter walked onto the White House lawn with Bill Clinton, to announce the completion of the first draft of the human genome. I had the opportunity to sit down this week with Dr Collins, who's been visiting the UK ahead of the anniversary, and my interview with him appears in the paper today.

My piece has focused on Collins's prediction that most of us, at least in the developed world, will probably have had our complete genetic codes sequenced by the time the reference genome is 20 years old. But we spoke about much more than that, and I've included some of the highlights of our conversation here.

Perhaps of greatest current interest, given the FDA's current clampdown on direct-to-consumer genomics companies, were his thoughts on how this fledgling industry should properly be regulated. He accepts that there is a case for some regulation, which should focus on risk and accurate test results. But he is very wary of over-zealous regulation that might stifle innovation, or unreasonably restrict individuals' access to the contents of their DNA. And he doesn't think such access needs always to be mediated by a doctor.

The direct quotes follow after the jump...

On regulation

I started by asking Collins what he thought of FDA's intervention on DTC genomics. He said:

"The FDA is being fairly reasonable about their approach, in the sense that I think they are sensitive in not wanting to shut down a set of scientific advances that are potentially going to become a valuable commercial enterprise.

"I think the approach they're going to take is to focus on those kinds of test that are associated with risk, and have a risk-based oversight system rather than a knee-jerk system of 'oh, it's a genetic test, we need to review it no matter what'. That's clearly what's needed, and some groups have been arguing for that for 10 years.

"I do think the time has come, when you look at some of things that are out there on the web that are quite unsubstantiated scientifically, to pay some attention to that. Peggy [Hamburg, the FDA Commissioner] and Josh Sharpstein [Hamburg's deputy] are aware of the need to do this on a rational basis and not to slam the door. But I do think the public is increasingly concerned about whether this occurring in a completely unregulated way is going to be of benefit to them.

"I'm not sure exactly where this will go over the next year or two, or what the implications will be for access to genetic information. I am both a strong proponent of the need for quality of what's offered, but I also believe in patient empowerment, and the opportunity to find out something about themselves if they want it seems like something we should be reluctant to get in the way of, so long as the information is scientifically valid.

"Regulators have a tough job. They need to be sensitive to not stifling innovation, but they also need to protect the public against really unscrupulous use of new technologies. And in that regard, by preventing the real misuse of technology, they're certainly protecting the innovators from seeing a complete meltdown and a distrust of technology that might persist for years to come.

"So in many ways the regulators are also the guardians of science, in the sense that they keep it from slipping into snake oil, which ultimately does a lot of damage to science. But there is a tough balance, which is one of the reasons the FDA has had such a hard time figuring out how to regulate genetic technology. I give Peggy and Josh a lot of credit for being willing to take this on and do something."

Collins has himself been tested by several of the DTC genomics companies, and I asked how his experience as a consumer had influenced his thoughts on regulation:

"My own experience with this did inspire me to take some action which I probably should have taken anyway. No-one should generalise from your own personal experience to make federal policy, but there's plenty of other data to show that when individuals are given predictive information about the future, at least some of them do find that useful and do modify their health behaviours, and are able to understand that these are not yes-no black-white answers, but risk factors they might want to pay attention to, just as they pay attention to their cholesterol."

Medical supervision of DTC genetic tests

Next we moved onto the sometimes vexed issue of medical supervision. Should genetic testing always be conducted in concert with a doctor or genetic counsellor? Collins said:

"That of course is one of the hot potatoes. Even within the field of medical genetics there are strong differences. The American Society of Human Genetics thinks that having a medical professional involved is not required. The American College of Medical Genetics thinks that oh yes, there are great dangers if a medical professional is not involved.

"I think my view is that people are in many instances capable of absorbing this educational information without the need for a professional to walk them through, but if they want that they should have access to it quite easily, and should not be hit with information without a medical professional to assist them.

"I've been impressed by the way in which the direct-to-consumer companies have worked pretty hard at this, in terms of providing information and what it does and doesn't mean. But there is probably no substitute for having the opportunity to ask questions of someone who is an expert in the field after you have begun to absorb your own results, and I think people ought to have a chance to do that if they want to.

"I would be very uncomfortable with a system that says no, we know better than you do, you won't understand this information so we're not going to let you have it. There's something that doesn't feel right about that."

Validity and utility

To what extent should test be regulated for scientific validity and clinical utility? Collins said:

"A lot of this debate relates to what you call clinical utility. If you're going to have a test that's marketed to the public, it should have analytical validity, that is the lab should be able to prove that they can do a DNA test and get the sequence right. And it should have clinical validity, that is the test if it says it means something, that should be clearly true. If it says your risk for this SNP goes up for diabetes, then there ought to be evidence to back that up.

"But what about clinical utility? That's so much in the mind of the beholder. I mean you may say knowing your Alzheimer's risk from APOE has no clinical validity because you can do nothing to change your risk by changing your diet or taking drugs or doing Sudoku or whatever. But for somebody who wants to know that information for purposes of planning, and that was shown very clearly by Bob Green's REVEAL study, that is useful to them. So don't tell these people this is not clinically useful. It is clinically useful from their perspective, and we shouldn't be paternalistic about it."

So, I asked, is a light touch what's called for? Collins replied:

"A light touch but a touch that is also focused on risk. For instance, if a lab is offering individuals BRCA1 testing, to individuals with a strong family history of breast cancer, with no pre-test or post-test counselling, that's a problem. If you're talking about highly penetrant conditions where the test result has high medical significance, that's probably not something you should get at Walgreens. For example."

Also important, he said, are the interpretation services that are offered:

"I gather Ozzy Osbourne has had his genome sequenced. Ozzy's probably going to need a little help figuring out what this means."

Cancer genomics

Like many observers, Collins feels that cancer will be a standard-bearer for genomic medicine:

“Cancer is I think going to be right out in front here. And I think we would all expect that within the next decade every cancer identified, at least in countries that have the resources, a full enumeration of what is going wrong in that tumour, and then an ability to match that up with the available therapeutics so you are doing the best possible job of throwing smart bombs, instead of the carpet bombing of traditional chemotherapy.”

"The question is will that be helpful because we have a nice menu of therapies, and we'll be able to pick just one or two that are going tobe active against that patient's malignancy. We have a lot of work to do.

"Could I tell you that in ten years most patients will have both a complete genomic analysis and a choice of compounds that should be clinically active? I don't know, I would hope we will be pretty close to that, and certainly well beyond the menu we have now of targeted therapeutics, which is still a pretty short list. It's going to grow."

Pharmacogenomics as a driver of widespread sequencing

Collins was clear that he thought the potential of pharmacogenomics would be the main driver of widespread sequencing.

"I think it's another great payoff over the fairly near future, and certainly over the next decade. 10 per cent of FDA approved drugs have a label saying something about genetics and its ability to predict a side effect, or something about whether that person is going to respond or have a dose adjustment.

"The problem with pharmacogenomics now, in terms of real mainstream application, is in a certain way logistic. We already know enough variations that could be used in dose adjustments, in terms of the CYP genes, but most of the time the physician doesn't know that much about the science anyway, and there's the problem of sending off the drug sample know, and where do I send it to, and I want the sample now. But, how's it going to change?

"Well, when the sequencing of your genome or mine really does drop into the affordable range of less than 1,000 dollars, it will become very compelling for pharmacogenomics in particular to do it just once, to do it right, to get it into the medical record. There would be no need to take more blood samples, it’s just a click of your mouse to know whether that drug dose ought to be adjusted, or whether there’s a risk of a nasty side-effect you want to avoid. That will be a moment when a lot of the barriers to pharmacogenomics go down." [This is hitherto the clearest endorsement of the need to automate, in a user-friendly manner, choices that by hand would require unacceptable time requirement - AJP]

"When you see the cost of sequencing dropping much faster than Moore's law for computers, we're now down to about $10,000 for a reasonably complete sequence. I can't believe it won't drop to less than 1000 within five years. Will that become the moment then, where at least to people in some kinds of health plans, when it becomes compelling to do it? Good heavens, we spend a lot more than that on all sorts of unnecessary scans.

"Why not just make the case for each of us that this is information that will only gain in value over time, and if it's possible to do it accurately it would be cost-effective, both in terms of prevention and pharmacogenomics and so on? I think that will get pretty compelling.

"What will the timetable be from when it's possible to when it actually happens? That's the key question. A lot will depend on reimbursement and who's going to pay for it? Will third parties see it as a key investment? Where's the capacity going to come from to do all these genomes? Will we have that kind of throughput abilities? I don't know.

"But certainly within ten years I will be very surprised and very disappointed if most people in the developed world will not have their genomes sequenced as part of their medical record, and I would hope it will come even sooner."

Complex disease and the missing heritability

How confident, I asked, was Collins that the "missing heritability" of complex, common diseases would be unlocked over the coming years? He said:

"Nobody knew what the structure would be of genetic variation that contributes to heritability until we started to look for it. But there's certainly a lot more there hiding in the dark matter of the genome. Presumably, that will start to come to light as we are able to look for less common variants with sequencing of lots and lots of genomes from lots and lots of studies. I'm not despondent about that at all. It's just that the structure is not what we thought it might be. [This part of high science would need much elaboration - not possible in a popular science article. Clearly, the "structure we thought it might be (Genes and JunkDNA) are officially out. Francis Collins, at the 10th Anniversary is clear about the obsolete notions on gene/junk structure of the genome, but at this time-stamp he is not yet at the (confessed) realization that the DNA is fractal - AJP]

"It doesn't seem we were wrong about heritability and its contribution to diabetes and heart disease, all of those common diseases, it looks as if heritability is about 50 per cent, which means it's somewhere in there. We just need a finer lens to discover it. That probably means that within the next decade, our ability to make finer predictions about disease risk are going to get pretty good. Then it will be I think increasingly compelling to use programmes for prevention. It's something you can do right now, so long as you're aware you're not dealing with all the information that's lurking in the genome."

Sequencing children

In April, I broke the story that the children of the Solexa entrepreneur John West, Anne and Paul, had become the first minors to be sequenced for non medical reasons. I asked Collins how he felt about that:

"Frankly, that one did make me a little bit uneasy, because here were two kids who were promoting the idea that they were glad to have this, but you have to wonder how could they say otherwise when their dad was the company founder. There are statements out there in the literature, that genetic data on minors should not be obtained unless the data needs to be known, but those may start to look a little dated.

"This leads us to the question about newborn screening, because we do after all already determine a fair amount of genetic information about every newborn. Newborn screening is recommended in the US for 29 diseases. The time will come when it's cheaper to do that by sequencing than by 29 different tests, and at that point wouldn't it make more sense just to do it, and then to have a plan to release that information in a graded fashion as it becomes actionable. I do think we need to preserve the right not to know. That's a substantial component of our resonsibilities. If every newborn is being sequenced, those newborns should have the opportunity to say at 18: 'the rest of that sequence, forget about it.'"

[This is a shining example of popular science reporting (that was obviously proofed by Dr. Collins) - thus devoid of the usual journalistic mistakes that a decade ago "The Genome was deciphered, etc, etc."). Also, the interview is extremely reassuring, especially in view of the almost inevitability that Dr. Collins will testify for the Congressional Committee investigating legislative aspects of "DTC regulators". While in the joint article in NEMJ of Drs. Hamburg (FDA) and Collins (NIH) it appeared that a multi-agency advisorship might be needed for proposing new legislation to update the 1976 mandate of FDA, presently Dr. Collins mentions YEARS, and also points out a turf-war within the Medical Establishment (about the civil rights question if the American people should have all the information about their bodies, including DNA). Thus, the prediction that a) the DTC regulatory issues will likely be parsed into "risk/no risk" subsets, and b) FDA might not have the legal mandate to "shut down" DTC and thus (especially if Dr. Collins leans towards "letting the private industry figure it"), an FDA "moratorium" on existing California legislation on DTC may be the best solution - AJP]

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The Big Surprise of the First Decade - The Genome Affects You to Prevent Diseases, Before it Cures Diseases

[Cover of GEO International - with Specials on Genomics/EpiGenomics - AJP]

The "Human Genome Project" will be a Decade Old in two days. Here, in a series of articles, I present the public acceptance of the significance of HoloGenomics (YouTube, 2008, today with 8,171 views) what may become the quickest route to build a business model on results of a Big Science Government Research Project ("The Human Genome Project" - that had fiercely debated a possible "business model" - patenting "140,000 genes"; but ended up finding only about 24,500 genes, patenting none and ending with no business model at all). Francis Collins (see his YouTube at lower left, today with 1,529 views) outlines what the Genome Era may practically mean to us - but as a government administrator not in terms of business models (though his haunch of mobile devices catapulting into lead-role is visually obvious). Genome Computing applications for both genome-testing and for commercial applications were debated (YouTube [not shown], today with 2,093 views) - but the "killer app" of postmodern genomics may well become the user-friendly automation by your smart phone how to shop for goods befitting your genome (see YouTube at lower right, today with 2,100 views). At times when "Home Computers" became available, many asked the question "what it means to me to have a computer in my home?" The trump-card was provided by the software app "Visicalc" (predecessor to Excel), developed in Sunnyvale, CA; that did the same that anybody could do by hand (re-calculating values of cells in a huge spreadsheet) - but did it in an automated, user-friendly manner; blazingly fast. HolGenTech, Inc. "Your Genome; there's an app for that" does very much the same. A huge number of ingredients in myriads of goods can be cross-referenced by hand (in theory...) with known dietary- and environmental impacts of "genomic glitches". It is just not very practical if you have difficulties in memorizing e.g. the 60,000 pages of numbers (listed e.g. in your "23andMe Raw SNP file") and hold in your head that exploding knowledge-base how their dietary/environmental impacts affect your genome. HolGenTech' "killer app" is to automate it for you - AJP

Sergey Brin’s Search for a Parkinson’s Cure

By Thomas Goetz

June 22, 2010 |
Wired July 2010

Several evenings a week, after a day’s work at Google headquarters in Mountain View, California, Sergey Brin drives up the road to a local pool. There, he changes into swim trunks, steps out on a 3-meter springboard, looks at the water below, and dives.

Brin is competent at all four types of springboard diving—forward, back, reverse, and inward. Recently, he’s been working on his twists, which have been something of a struggle. But overall, he’s not bad; in 2006 he competed in the master’s division world championships. (He’s quick to point out he placed sixth out of six in his event.)

The diving is the sort of challenge that Brin, who has also dabbled in yoga, gymnastics, and acrobatics, is drawn to: equal parts physical and mental exertion. “The dive itself is brief but intense,” he says. “You push off really hard and then have to twist right away. It does get your heart rate going.”

There’s another benefit as well: With every dive, Brin gains a little bit of leverage—leverage against a risk, looming somewhere out there, that someday he may develop the neurodegenerative disorder Parkinson’s disease. Buried deep within each cell in Brin’s body—in a gene called LRRK2, which sits on the 12th chromosome—is a genetic mutation that has been associated with higher rates of Parkinson’s.

Not everyone with Parkinson’s has an LRRK2 mutation; nor will everyone with the mutation get the disease. But it does increase the chance that Parkinson’s will emerge sometime in the carrier’s life to between 30 and 75 percent. (By comparison, the risk for an average American is about 1 percent.) Brin himself splits the difference and figures his DNA gives him about 50-50 odds.

That’s where exercise comes in. Parkinson’s is a poorly understood disease, but research has associated a handful of behaviors with lower rates of disease, starting with exercise. One study found that young men who work out have a 60 percent lower risk. Coffee, likewise, has been linked to a reduced risk. For a time, Brin drank a cup or two a day, but he can’t stand the taste of the stuff, so he switched to green tea. (“Most researchers think it’s the caffeine, though they don’t know for sure,” he says. [And in my Google Tech Talk YouTube 2008 where at 7:55 I referred to Sergey's public blog and at 39:36 showed a 2003 science paper asserting modern evidence to the ancient Chinese medicine that ingredients in green tea might help mitigate predilection to Parkinson's - AJP] Cigarette smokers also seem to have a lower chance of developing Parkinson’s, but Brin has not opted to take up the habit. With every pool workout and every cup of tea, he hopes to diminish his odds, to adjust his algorithm by counteracting his DNA with environmental factors.

“This is all off the cuff,” he says, “but let’s say that based on diet, exercise, and so forth, I can get my risk down by half, to about 25 percent.” The steady progress of neuroscience, Brin figures, will cut his risk by around another half—bringing his overall chance of getting Parkinson’s to about 13 percent. It’s all guesswork, mind you, but the way he delivers the numbers and explains his rationale, he is utterly convincing.

Brin, of course, is no ordinary 36-year-old. As half of the duo that founded Google, he’s worth about $15 billion. That bounty provides additional leverage: Since learning that he carries a LRRK2 mutation, Brin has contributed some $50 million to Parkinson’s research, enough, he figures, to “really move the needle.” In light of the uptick in research into drug treatments and possible cures, Brin adjusts his overall risk again, down to “somewhere under 10 percent.” That’s still 10 times the average, but it goes a long way to counterbalancing his genetic predisposition.

It sounds so pragmatic, so obvious, that you can almost miss a striking fact: Many philanthropists have funded research into diseases they themselves have been diagnosed with. But Brin is likely the first who, based on a genetic test, began funding scientific research in the hope of escaping a disease in the first place. [Watch for the fireworks, China-style, if he is told by anyone that his software, helping eliminate any chance of him ever developing Parkinson's has to be censored ... AJP]

His approach is notable for another reason. This isn’t just another variation on venture philanthropy—the voguish application of business school practices to scientific research. Brin is after a different kind of science altogether. Most Parkinson’s research, like much of medical research, relies on the classic scientific method: hypothesis, analysis, peer review, publication. Brin proposes a different approach, one driven by computational muscle and staggeringly large data sets. It’s a method that draws on his algorithmic sensibility—and Google’s storied faith in computing power—with the aim of accelerating the pace and increasing the potential of scientific research. “Generally the pace of medical research is glacial compared to what I’m used to in the Internet,” Brin says. “We could be looking lots of places and collecting lots of information. And if we see a pattern, that could lead somewhere.”

In other words, Brin is proposing to bypass centuries of scientific epistemology in favor of a more Googley kind of science. He wants to collect data first, then hypothesize, and then find the patterns that lead to answers. And he has the money and the algorithms to do it.

[When I presentated my FractoGene (fractal algorithmic) approach in Cold Spring Harbor Personal Genome-2 meeting last September, a leading cancer-research center director elaborated on the newly found facts (since now full DNA sequences of several cancerous humans are available), that their informaticians found all kinds of "patterns" - presently hard to interpret. There, I mentioned that in my first paradigm-shift (from Artificial Intelligence to Neural Networks) "algorithmic pattern recognition" was a core of industrialization of the new science, since sound-patterns of Soviet submarines had to be discerned from the mostly harmless underwater cacophony - and suggested the re-deployment of available technology; this time against cancer. The director, whose forte was not in Informatics, asked "are you looking for a job?" Well, my HolGenTech, Inc. is open for business... - AJP]

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Data-Driven Discovery Research at 23andMe

Genomeweb
June 23, 2010

In the July 2010 issue of Wired, on newsstands now, Thomas Goetz details Google co-founder Sergey Brin's investments in Parkinson's disease research. Brin, whose wife Ann Wojcicki co-founded the DTC genetic testing firm 23andMe, is pouring money into a data-driven approach to find the causes of — and potential cures for — the neurodegenerative disease that affects his mother, and that he has learned he carries a genetic disposition for. "Brin is likely the first who, based on a genetic test, began funding scientific research in the hope of escaping a disease in the first place," Goetz reports. Goetz outlines 23andMe's ambitious Parkinson's Disease Genetics Initiative, in which the company plans to mine data from 10,000 individuals "who are willing to pour all sorts of personal information into a database," he writes. So far, Brin has contributed $4 million to the initiative, which has acquired nearly 4,000 participants. "Brin proposes a different approach, one driven by computational muscle and staggeringly large data sets," Goetz writes. "In other words, Brin is proposing to bypass centuries of scientific epistemology in favor of a more Googley kind of science. He wants to collect data first, then hypothesize, then find the patterns that lead to answers. And he has the money and the algorithms to do it."

... Brin calls the effort and "information-rich opportunity," and tells Goetz that 23andMe plans to publish "several new associations that arose out of the main database, which now includes 50,000 individuals, that hint at the power of this new method." Brin also says that he is "in line to have his whole genome sequenced," and that "23andMe is considering offering whole-genome tests" at a yet-undisclosed price.

[The point at this historical announcement ("leak"- rather...) is, that speculation has been rampant that 23andMe was nearing to close business on the news of "a co-Founder having left" (for personal reasons), or that "sales were sagging", or that "regulatory pressures may become unbearable". Back to Mark Twain: "Reports on the death of 23andMe are greatly exaggerated" - AJP]

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ACI Personalized Medicine Congress in Silicon Valley postponed from June 23-25 to December 9-10, 2010

The First Silicon Valley Conference on Health Care affected by Personalized Genomics, in view of impending Congressional Investigation of DTC Genomic Testing and possible new legislation proposed by NIH/FDA for updating the 1976 FDA Charter is postponed from 23-25 June, 2010 to 9-10 December. Some of the highlights from the new website:

[The 5 months advantage given away to DTC in Soul, Korea (backed by SAMSUNG) and Barcode shopping screening for allergens to Deakin University in Melbourne, Australia (backed by NESTLE) is not yet a strategical failure. Should the US be bogged down in the kind of "legislatory renovation" that took for the National Superhighways 37 years from formulating concepts (1919) to signing them into law (1956) with the project still not completed with 91 years and counting and in 1966 dollars with over a tenfold overrun is not a very rosy picture - AJP]

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The Genome, 10 Years Later
EDITORIAL of The New York Times
Published: June 20, 2010

On June 26, 2000, two scientific teams announced at the White House that they had deciphered virtually the entire human genome, a prodigious feat that involved determining the exact sequence of chemical units in human genetic material. An enthusiastic President Clinton predicted a revolution in “the diagnosis, prevention and treatment of most, if not all, human diseases.”

Now, 10 years later, a sobering realization has set in. Decoding the genome has led to stunning advances in scientific knowledge and DNA-processing technologies but it has done relatively little to improve medical treatments or human health.

To be fair, many scientists at the time were warning that it would be a long, slow slog to reap clinical benefits.

And there have been some important advances, such as powerful new drugs for a few cancers and genetic tests that can predict whether people with breast cancer need chemotherapy. But the original hope that close study of the genome would identify mutations or variants that cause diseases like cancer, Alzheimer’s and heart ailments — and generate treatments for them — has given way to realization that the causes of most diseases are enormously complex and not easily traced to a simple mutation or two.

The difficulties were made clear in articles by Nicholas Wade and Andrew Pollack in The Times this month. One recent study found that some 100 genetic variants that had been statistically linked to heart disease had no value in predicting who would get the disease among 19,000 women who had been followed for 12 years. The old-fashioned method of taking a family history was a better guide. Meanwhile, the drug industry has yet to find the cornucopia of new drugs once predicted and is bogged down in a surfeit of information about potential targets for their medicines.

In the long run, it seems likely that the genomic revolution will pay off. But no one can be sure. Even if the genetic roots of some major diseases are identified, there is no guarantee that treatments can be found. The task facing science and industry in coming decades is as at least as challenging as the original deciphering of the human genome.

[Some "mainstream" US journals (e.g. Newsweek) excel by consulting actual scientists when attempting to write about science - without some gross errors that characterize e.g. the above "Editorial". There are 6 more days to correct errors... - more on my FaceBook wall as follows:

Two cardinal mistakes in the opening one sentence: (1) The code of the genome was not "decoded" - but only the sequence was (approximately) established (as Esther Dyson puts it, resulting in "The Big Russian Novel with a 100-word dictionary"...). More importantly, (2) The Human Genome Project" did deliver "scientific knowledge" (the "first draft" of the sequence...), but two further requirements were skipped (or went unnoticed by some): (a) knowledge of the genome had to be transformed into an algorithmic (not "statistical") understanding of how through epigenomic channels the fractal recursive iteration of the hologenome can be interacted with, towards equilibrium (health). (b) Even "scientific understanding" is totally inadequate if it did not come with a business model and actual business, since "medical treatments or human health" in the USA is not a science, but a business (as Francis Collins puts it "Sick Care"). - AJP]

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The Path to Personalized Medicine

This article (10.1056/NEJMp1006304) was published on June 15, 2010, at NEJM.org

By Margaret A. Hamburg, M.D., and Francis S. Collins, M.D., Ph.D.
Dr. Hamburg is the commissioner of the Food and Drug Administration, Silver Spring, and Dr. Collins is the director of the National Institutes of Health, Bethesda - both in Maryland.

Major investments in basic science have created an opportunity for significant progress in clinical medicine. Researchers have discovered hundreds of genes that harbor variations contributing to human illness, identified genetic variability in patients' responses to dozens of treatments, and begun to target the molecular causes of some diseases. In addition, scientists are developing and using diagnostic tests based on genetics or other molecular mechanisms to better predict patients' responses to targeted therapy.

The challenge is to deliver the benefits of this work to patients. As the leaders of the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), we have a shared vision of personalized medicine and the scientific and regulatory structure needed to support its growth. Together, we have been focusing on the best ways to develop new therapies and optimize prescribing by steering patients to the right drug at the right dose at the right time.

We recognize that myriad obstacles must be overcome to achieve these goals. These include scientific challenges, such as determining which genetic markers have the most clinical significance, limiting the off-target effects of gene-based therapies, and conducting clinical studies to identify genetic variants that are correlated with a drug response. There are also policy challenges, such as finding a level of regulation for genetic tests that both protects patients and encourages innovation. To make progress, the NIH and the FDA will invest in advancing translational and regulatory science, better define regulatory pathways for coordinated approval of codeveloped diagnostics and therapeutics, develop risk-based approaches for appropriate review of diagnostics to more accurately assess their validity and clinical utility, and make information about tests readily available.

Moving from concept to clinical use requires basic, translational, and regulatory science. On the basic-science front, studies are identifying many genetic variations underlying the risks of both rare and common diseases. These newly discovered genes, proteins, and pathways can represent powerful new drug targets, but currently there is insufficient evidence of a downstream market to entice the private sector to explore most of them. To fill that void, the NIH and the FDA will develop a more integrated pathway that connects all the steps between the identification of a potential therapeutic target by academic researchers and the approval of a therapy for clinical use. This pathway will include NIH-supported centers where researchers can screen thousands of chemicals to find potential drug candidates, as well as public–private partnerships to help move candidate compounds into commercial development.

The NIH will implement this strategy through such efforts as the Therapeutics for Rare and Neglected Diseases (TRND) program. With an open environment, permitting the involvement of all the world's top experts on a given disease, the TRND program will enable certain promising compounds to be taken through the preclinical development phase — a time-consuming, high-risk phase that pharmaceutical firms call "the valley of death." Besides accelerating the development of drugs to treat rare and neglected diseases, the TRND program may also help to identify molecularly distinct subtypes of some common diseases, which may lead to new therapeutic possibilities, either through the development of targeted drugs or the salvaging of abandoned or failed drugs by identifying subgroups of patients likely to benefit from them.

Another important step will be expanding efforts to develop tissue banks containing specimens along with information linking them to clinical outcomes. Such a resource will allow for a much broader assessment of the clinical importance of genetic variation across a range of conditions. For example, the NIH is now supporting genome analysis in participants in the Framingham Heart Study, obtaining biologic specimens from babies enrolled in the National Children's Study, and performing detailed genetic analysis of 20 types of tumors to improve our understanding of their molecular basis.

As for translational science, the NIH is harnessing the talents and strengths of its Clinical and Translational Sciences Award program, which currently funds 46 centers and has awardees in 26 states, and its Mark O. Hatfield Clinical Research Center (the country's largest research hospital, in Bethesda, MD) to translate basic research findings into clinical applications. Just as the NIH served as an initial home for human gene therapy, the Hatfield Center can provide specialized diagnostic services for rare and neglected diseases, offer a state-of-the-art manufacturing facility for novel therapies, and pioneer clinical trials of other innovative biologic therapies, such as those using human embryonic stem cells or induced pluripotent stem cells.

As genetics researchers generate enormous amounts of new information, the FDA is developing the regulatory science standards and evidence needed to use genetic information in drug and device development and clinical decision making. The agency's Critical Path Initiative aims to develop better evaluation tools, such as biomarkers and new assays. Under the Voluntary Genomic Data Submission program, companies can discuss genetic information with the FDA in a forum separate from the product-review process. These discussions give the agency and companies a better understanding of the scientific issues involved in applying pharmacogenomic information to drug development and offer an opportunity for early, informal feedback that may assist companies in reaching important strategic decisions. The goal is to help companies integrate genomics into their clinical-development plans.

Today, about 10% of labels for FDA-approved drugs contain pharmacogenomic information — a substantial increase since the 1990s but hardly the limit of the possibilities for this aspect of personalized medicine.1 There has been an explosion in the number of validated markers but relatively little independent analysis of the validity of the tests used to identify them in biologic specimens.

The success of personalized medicine depends on having accurate diagnostic tests that identify patients who can benefit from targeted therapies. For example, clinicians now commonly use diagnostics to determine which breast tumors overexpress the human epidermal growth factor receptor type 2 (HER2), which is associated with a worse prognosis but also predicts a better response to the medication trastuzumab. A test for HER2 was approved along with the drug (as a "companion diagnostic") so that clinicians can better target patients' treatment (see table).

Increasingly, however, the use of therapeutic innovations for a specific patient is contingent on or guided by the results from a diagnostic test that has not been independently reviewed for accuracy and reliability by the FDA. For example, in 2006, the FDA granted approval to rituximab (Rituxan) for use as part of first-line treatment in patients with certain cancers. Since then, a laboratory has marketed a test with the claim that it can distinguish the approximately 20% of patients who will not have a response to the drug from those who will. The FDA has not reviewed the scientific justification for this claim, but health care providers may use the test results to guide therapy. This undermines the approval process that has been established to protect patients, fails to ensure that physicians have accurate information on which to make treatment decisions, and decreases the chances that physicians will adopt a new therapeutic–diagnostic approach. The FDA is coordinating and clarifying the process that manufacturers must follow regarding their claims, including defining the times when a companion diagnostic must be approved or cleared before or concurrently with approval of the therapy. The agency will ensure that claims that a test will improve the care of patients are based on solid evidence, and developers will get straightforward, consistent advice about the standards for review and the best way to demonstrate that the combination works as intended.

Genetic tests are not perfect, in part because most gene mutations do not perfectly predict outcomes. Clinicians will need to understand the specificity and sensitivity of new diagnostics. The agency's goal is an efficient review process that produces diagnostic–therapeutic approaches that clinicians can rely on and allows companies that invest in establishing the validity and usefulness of tests to make specific, FDA-backed claims about benefits.

Patients should be confident that diagnostic tests reliably give correct results — especially when test results are used in making major medical decisions. The FDA has long taken a risk-based approach to the oversight of diagnostic tests, historically focusing on test kits that are broadly marketed to laboratories or the public (e.g., pregnancy tests or blood glucose tests); such kits are sold only if the FDA has determined that they accurately provide clinically significant information. But recently, many laboratories have begun performing and broadly marketing laboratory-developed tests, including complicated genetic tests. The results of these tests can be quite challenging to interpret. Because clinicians may order a genetic test only once, getting the results right the first time is crucial.

There are reports of problems with laboratory tests that have not had FDA oversight: women were erroneously told they were negative for a mutation conferring a very high risk of breast cancer; an ovarian cancer test, marketed before the completion of an NIH-funded study,2 gave false readings that reportedly led to the unnecessary removal of women's ovaries; and flawed, mishandled data underlying a test for Down's syndrome were discovered only days before the test was to go on the market. Through a process that includes opportunities for public input, the FDA will work to ensure the quality of key diagnostic tests, helping to protect patients and giving clinicians confidence that personalized medicine will lead to real health improvements.

In addition, the NIH will address the fact that there is no single public source of comprehensive information about the more than 2000 genetic tests that are available through clinical laboratories. On the recommendation of a federal advisory committee,3,4 the NIH — with advice from the FDA, other Department of Health and Human Services agencies, and diverse stakeholders — is creating a voluntary genetic testing registry to address key information gaps.5 Readily available information about these tests, including whether they were cleared or approved by the FDA, will help clinicians and consumers make informed decisions about using the tests to optimize health care. The registry will also support scientific discoveries by facilitating the sharing of data about genetic variants.

In February, the NIH and the FDA announced a new collaboration on regulatory and translational science to accelerate the translation of research into medical products and therapies; this effort includes a joint funding opportunity for regulatory science. Working with academic experts, companies, doctors, patients, and the public, we intend to help make personalized medicine a reality. A recent example of this collaboration is an effort to identify new investigational agents to which certain tumors, identified by their genetic signatures, are responsive.

Real progress will come when clinically beneficial new products and approaches are incorporated into clinical practice. As the field advances, we expect to see more efficient clinical trials based on a more thorough understanding of the genetic basis of disease. We also anticipate that some previously failed medications will be recognized as safe and effective and will be approved for subgroups of patients with specific genetic markers.

When the federal government created the national highway system, it did not tell people where to drive — it built the roads and set the standards for safety. Those investments supported a revolution in transportation, commerce, and personal mobility. We are now building a national highway system for personalized medicine, with substantial investments in infrastructure and standards. We look forward to doctors' and patients' navigating these roads to better outcomes and better health.

References

1. Frueh FW, Amur S, Mummaneni P, et al. Pharmacogenomic biomarker information in drug labels approved by the United States Food and Drug Administration: prevalence of related drug use. Pharmacotherapy 2008;28:992-998. [CrossRef][Web of Science][Medline]

2. Ovarian cancer research results from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial: fact sheet. Bethesda, MD: National Cancer Institute. (Accessed June 11, 2010, at http://www.cancer.gov/cancertopics/cancertopics/factsheet/detection/plco-ovarian.)

3. Secretary's Advisory Committee on Genetic Testing. Enhancing the oversight of genetic tests: recommendations of the SACGT. Bethesda, MD: National Institutes of Health, 2000. (Accessed June 11, 2010, at http://oba.od.nih.gov/oba/sacgt/reports/oversight_report.pdf.)

4. Secretary's Advisory Committee on Genetics, Health, and Society. U.S. system of oversight of genetic testing: a response to the charge of the Secretary of Health and Human Services. Bethesda, MD: National Institutes of Health, 2008. (Accessed June 11, 2010, at http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS_oversight_report.pdf.)

5. Genetic Testing Registry. Bethesda, MD: National Center for Biotechnology, National Library of Medicine; 2010. (Accessed June 11, 2010, at http://www.ncbi.nlm.nih.gov/gtr.)

[The Plan by NIH/NSF is likely to be proposed to the Congressional Investigation, as the Guiterrez-video referred to the NSF Commissioner, by authorities above him, Drs. Collins and Hamburger quite certain to be in the lead roles. For the historical parallel to the National Interstate, see Wikipedia] - AJP]

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FDA Cracks Down on DTC Genetic Testing

GenomeWeb
June 14, 2010

[Excerpts]

...

Pharmacogenomics Reporter, one of the Daily Scan's sister publications, reported that these letters are what the FDA calls "untitled" letters, meaning the companies have been made aware of the FDA's concerns and have a chance to address them and make whatever changes the FDA deems necessary. Based on their responses, the FDA could upgrade to "warning" letters, which are more severe. PGx Reporter's Turna Ray also reported that several presenters at the Consumer Genetics Conference in Boston in the beginning of June said they thought federal regulation of DTC tests was "imminent."

Genomics Law Report's Dan Vorhaus says the letters may not be as significant to the five companies involved - 23andMe, Navigenics, Decode Genetics, Knome, and Illumina - as everyone thinks, especially since the FDA hasn't demanded that the companies remove the products from the market pending review. "So, at least for the moment, we may see little or no immediate change while these companies weigh their options internally and through discussions with the FDA," Vorhaus writes. He suggests the companies' best option would be to change the tests in such a way that would convince the FDA they no longer qualify as medical devices - "for instance by removing the ability of consumers to purchase the product without the participation of a healthcare provider."

Daniel MacArthur at Genetic Future thinks this turn of events could spell disaster for the personal genomics industry. "Excessive regulation would negatively impact on innovation in the field by increasing the barrier to entry for new products, as well as increasing costs for consumers," he says, adding that this move looks like it's motivated by publicity on the FDA's part - in the wake of the 23andMe test results mix-up - rather than by a genuine drive to protect consumers.

...

Reply (2)
Andras [Pellionisz_at_JunkDNA.com]

FDA Did Not Crack Down on DTC Genetic Testing

Juan Enriquez predicted in 2001 that "genomics" will compare to "digital" in global impact. No doubt, but on the way to the genome revolution isn't it hard to keep track of who is doing what and what is significant? The US FDA's actions last week represent just the kind of fluctuation that shifts the scene and changes the balance. Whether that's just for now or forever remains to be seen.

The revolution's drivers have long been aware that the many subfields of genomics: consumer genomics, educational genomics, recreational genomics, genomics of ancestry, etcetera must be distinguished from medical genomics. While each category may be regulated (or not) by government, legal, economic or medical agencies in countries worldwide, I believe there is a way to cut to the chase and get on with the genome revolution. That's why yours truly focused on developing the commercial business model for genome applications, as illustrated in the YouTube Shop for Your Life!. The commercial business model offers the fastest growth and the most immediate consumer adoption, based on consumers' freedom of choice, with the least interference from lawyers, regulators and governments. ...

[Shop for your Life! - HolGenTech]

but back to the US fracas and what is happening, or better said, not happening. I admire the legally precise analysis of Dan Vorhaus, who suggests that it may be a misunderstanding to think that "The FDA Cracks Down on DTC Genetic Testing". As he says, the Gutierrez letters (G-5) "may not be as significant". In fact, did FDA's Alberto Gutierrez "crack down" at all on DTC? There is no "cease and desist" order, no deadlines, no specific documentation to submit, but rather just the suggestion that there be a long brewing and largely ongoing dialog with the FDA. --doesn't sound like an enthusiastic endorsement of the genome revolution, but neither does it indicate the end of the U.S. version of the genome revolution. As he points out [at the end of] in his video, even the agency's director [Commissioner] could re-think and update somewhat blurred definitions; i.e., what "medical device" may mean in the genomic age - a giant leap away from the 1976 mandate of FDA:

Alberto Guiterrez (FDA)

Is it possible that the G-5 letters are just setting the stage for the widely heralded Congressional Investigation on DTC Genome Testing? Surely when Francis Collins, M.D., Ph.D., and Director of NIH, who wrote the book on Personalized Medicine, [now, within 6 months also in paperback, kindle and audio ...] is called to testify before the Congressional Committee on Energy and Commerce, he can be expected to offer his specific recommendations from the NIH Genetic Testing Registry and could well suggest that registration be made mandatory, pursuant to an endorsement of the Congressional Committee. Note his initiation comments this March NIH Genetic Testing Registry.

In the same spirit of educating the public through the political stage, the G-5 letters to Knome and Illumina may amount to invitations to two of the world's pre-eminent genome R&D and industrial experts, Harvard Genomics Professor George Church, co-Founder of Knome, and Illumina CEO Jay Flatley to deliver Congressional Testimonies.

With the nation watching, they could guide the Congressional Committee to bring the FDA into the genome revolution, or find/shape/create the agency or entity that will embrace it to the maximum benefit of the American public. Is it that the FDA has been remarkably passive for 3 years and now, with a Congressional Investigation imminent, feels the need to protect itself from all criticism that could suggest "it never flexed its muscles"? Sure, there was some muscle flexing when earlier G-3 letters seem to have scared Pathway Genomics away from DTC without resorting to anything that could be labeled "inappropriate regulation". The earlier Gutierrez salvo, G-3, was just a scary demand for a lot of documentation with a deadline so short there was no time for the Congressional Committee to act. Now, the G-5 may be entrée for participation in the genome revolution a la U.S. style with Congress dominant and the FDA retaining a scary innocence. So, let us watch the Congressional Committee conduct its eminently predictable hearings, and recommend appropriate legislation; through which "medical genomics" and "off-the-shelf genomics" (commercial and other non-medical utilization of information) should be clearly distinguished. We can be sure that if FDA is left to regulate Medical Genomics, it won't be the same FDA with the 1976 mandate Alberto Gutierrez notes in his video.

This said, it is still possible that forces in the U.S. may be getting ready for the big "crack down", or even planning to kill DTC in the U.S, and diminish the country's status in our Genomic Age. In fact, they could manage a big set-back for the U.S. just by imposing a cumbersome legal agenda that takes so long the U.S. could miss its chance just by having to wait, all while DTC in Asia soars. We can hope that Congress will be well aware that there isn't enough money to address escalating health care (sick care) and listen to "We the People" demanding genome-based prevention. The Congressional Committee would be well advised to keep DTC business open during legal renovations through a moratorium on any further regulation of DTC until legislation puts the regulatory houses in order.

If the U.S. does bow out or just misses the boat, I look at Asia as particularly conducive to the kind of commercial genomics I promote, which are based on a genome computing architecture that applies smart phones to empower consumers to exercise their freedom of choice using genome-based recommendations. Asia is advanced in both mobile computing and genomics already, and backed by their Big IT. The really good news is that the number of lawyers per capita is a fraction of the U.S.'s, and so is the cost of labor... more for the U.S. Congress to consider, and they had better do so quickly.

[Genomeweb comments can not be burdened by overly detailed documentation - see many more hyperlinks here - AJP]

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Why the FDA Is Cracking Down on Do-It-Yourself Genetic Tests: An Exclusive Q&A

Newsweek, June 11, 2010
Mary Carmichael

Fresh off sending stern letters to five consumer-genomics companies indicating that, as currently marketed, the companies’ tests will require clearance by the FDA, Alberto Gutierrez - the agency’s director of the Office of In Vitro Diagnostics in the Center for Devices and Radiological Health - spoke to NEWSWEEK. Among the revelations: Pathway Genomics, the company that started the controversy by planning to sell its test in drugstores, will be withdrawing from the direct-to-consumer market. Gutierrez also clarified the agency’s reasoning and timing. Excerpts:

Just to clarify, it sounds like these consumer-genomics tests-as they’re marketed now - will require pre-market clearance because they qualify as medical devices under current law. Is that correct?

That’s correct. [That is; "the impression that it sounds like" is correct - AJP]

Why is this happening now instead of three years ago, when direct-to-consumer genomics tests first came to market?

Well, the claims [made by the companies] have changed constantly. The original claims from three years ago were very, very vague. For example, the claims they’re making now for the different drugs and how they’re metabolized, those weren’t being made previously. Even some of the health claims in terms of risk of chronic disease, those just started coming online about a year ago.

So the problem is that the companies are testing for genetic variants that might affect the way consumers make medical decisions?

That’s correct … If you’re making a claim about [a genetic variant that affects the metabolism of the anticoagulant drug] warfarin, and somebody decides based on the result they get that they want to change their dosing, that is a fairly risky decision. That could affect their health. If they’re not feeling well on their current dose and the drug is expensive, we don’t know what they would do.

Illumina and Knome are different from the other three companies, but they were also sent letters. Can you explain to me the thinking behind the letters to each of them?

Well, some of the other companies are buying the chip that Illumina is making. That chip is sold as for “research use only.” As such, Illumina has a responsibility. If the chip is being used for diagnostic tests instead, Illumina has to follow the law, and they are aware that the chips are not being used for research only.

Would Illumina still have to obtain pre-market clearance if it sold that chip to medical laboratories and doctors only?

Yes, if Illumina is selling their chips to clinical labs that are using those chips to provide results back to either physicians or patients, and if they know that is how the chips are being used. However, they could [sell the chips without pre-market clearance] to academic labs or clinical laboratories which are clearly in the research space - meaning they’re beginning to develop a new test and just looking what they can do with it. That’s different than providing clinical results to patients.

What Knome sells is more of a service than a device. It’s basically a software program that explains genetic data that consumers can have generated elsewhere. Can you explain to me why it requires pre-market clearance?

Software is a medical device, and they’re making medical claims. They’re taking results and making medical claims that come out of those results.

Is there a reason Pathway Genomics was not included in this round of letters?

As you’re aware, we sent Pathway a letter not too long ago. They have responded, and in that response they are noting that they are planning to move away from direct-to-consumer testing at this point. I believe they’re planning to change their business model.

What about other companies that sell their tests to doctors, rather than directly to consumers, such as Counsyl?

Counsyl actually used to be a direct-to-consumer company until we sent Pathway the “it has come to our attention” letter. Then they changed their business model. They’re going through clinics or doctors. In that case, it will depend on whether they fit under the model of a laboratory-developed test. If they don’t, they will have to come in and get their test cleared.

Is there any reason to think this action by the FDA will preempt congressional hearings?

Well, I can’t predict whether Congress will have hearings and whether it will make any difference.

[It is an interesting question if the above is an informal interview or an ex officio statement - AJP]

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Breaking: FDA Likely to Require Pre-Market Clearance for DTC Personal Genomics Tests

Newsweek, June 11, 2010
Mary Carmichael

The FDA has just sent letters to five personal genomics companies outlining its intentions for regulation of direct-to-consumer tests, and if 23andMe thought it was having a bad week before, it's sure not going to be happy now. In the letters, the agency says that its test and four others, as currently marketed, will need pre-market clearance because they qualify as medical devices "intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease."

Requiring pre-market clearance is a drastic measure, and it's precisely the one personal-genomics companies hoped to avoid by casting their results as "educational" or recreational instead of medical. That's not all; the letters do "not necessarily address other obligations" the companies may have in selling their tests directly to consumers.

Oddly, the FDA hasn't yet sent a letter to Pathway Genomics, the company that started this whole fracas by making a deal (quickly rescinded when it went public) to sell its genomic test in drugstores. The agency tells NEWSWEEK its discussion with Pathway is still ongoing. Here's what it's telling the other five companies:

23andMe. This is the big, Google-backed player in the industry. The company was initially more focused on "fun" DNA results (do you have wet or dry earwax?), but since its launch in 2007 it's been adding medically relevant genes to the list of variants it identifies, including variants in BRCA1 and BRCA2 (breast-cancer genes) and several pharmacogenomic tests that assess patients' responses to medications such as warfarin and clopidogrel. That seems to be what got the FDA's attention: the letter to 23andMe mentions the pharmacogenomic tests and also points out that "the data generated from the 23andMe Odds Calculator, a feature of the 23andMe Personal Genome Service, includes the contribution of single-nucleotide polymorphisms (SNPs) to disease risk. Consumers may make medical decisions in reliance on this information." In other words, laypeople will think of this as a medical device, and we're going to treat it accordingly, which means you'll need to get it officially approved before selling it directly to the public. It's also not a laboratory-developed test, apparently, "because the 23andMe Personal Genome Service™ is not developed by and used in a single laboratory." That matters, because these tests aren't regulated as strictly as other medical devices and kits.

Navigenics. The letter is almost a direct facsimile of what's been sent to 23andMe-the warfarin and clopidogrel tests are notable, and so is a proprietary feature that "provides patients with genetic predispositions for important health conditions and medication sensitivities."

DeCode Genetics. Same basic deal here: consumers may use the test to make medical decisions, ergo, it's a medical device. Here, it's not pharmacogenomic tests that bother the FDA, but tests for 12 genes linked to breast cancer and a statement on the company's Web site that although "the deCODEme Cancer Scan cannot tell you whether you are going to develop cancer, it can alert you to your possible genetic risk and lead to early detection."

Illumina. This is a different kind of company. Although it has a personal-genomics component (it will sequence your entire genome, more or less, for about $20,000), that's not what has the FDA concerned at the moment. Illumina is also the company that provides 23andMe and DeCode with the genetic arrays used to scan 550,000 variants in the DNA. Those, too, may require pre-market clearance as long as they're used in direct-to-consumer genomic tests, says the FDA: "Although Illumina, Inc. has received FDA clearance or approval for several of its devices, we note that the Illumina Infinium HumanHap550 array is not one of them and is labeled 'For Research Use Only.' Yet Illumina is knowingly providing the HumanHap550 array to 23andMe and deCODE Genetics for clinical diagnostic use without FDA clearance or approval."

Knome. This, too, is a different kind of company. Knome doesn't sequence the genome so much as try to make sense of it for consumers who get their data generated elsewhere. Or, as the FDA puts it, Knome offers "a software program that analyzes genetic test results that are generated by an external laboratory in order to generate a patient specific test report." This apparently qualifies as a medical device as well.

There's still a lot more that could happen with regulation of consumer genomics. All five letters offer the companies the chance "to meet with us to discuss whether there are tests you are promoting that do not require review by FDA" and to establish what kind of information the companies need to give the agency. "We're basically telling them they need to come discuss with us whether they're marketing these legally," says FDA spokeswoman Erica Jefferson.

Congressional action may still be in the works, too. [It is not "may still be" but "will certainly be" - AJP] Congress sent letters to 23andMe, DeCode, and Pathway in late May, and the companies were due to provide an enormous amount of documents to the government last weekend. So stay tuned: this debate is far from over.

[Newsweek' perspective brings to the surface some legal definitions that are aptly analyzed by Dan Vorhaus - AJP]

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The Gutierrez Letters from FDA to DTC Genome Testing Companies

Letter to Navigenics Concerning the NaviGenics Health Compass (PDF - 85KB)

Letter to Illumina, Inc. Concerning the Illumina Infinium HumanHap550 array (PDF - 88KB)

Letter to 23andMe, Inc. Concerning the 23andMe Personal Genome Service (PDF - 103KB)

Letter to Knome, Inc. Concering the KnomeCOMPLETE (PDF - 91KB)

Letter to deCODE Genetics Concerning the deCODEme Complete Scan (PDF - 96KB)

Letter to Pathway Genomics Corporation Concerning the Pathway Genomics Genetic Health Report

[For hyperlinks to facsimile-s click on headline of this entry - AJP]

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What Five FDA Letters Mean for the Future of DTC Genetic Testing

Posted by Dan Vorhaus on June 11, 2010

[Likely to be the most professional legal analysis of the US-aspects of the FDA-letters - AJP]

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Silicon Valley' Genome-Based Personalized Medicine Meeting Postponed to Dec 9-10

As Silicon Valley flexes its muscles with two of the leading DNA Sequencing companies (Complete Genomics and Pacific Biosciences), two of the leading DTC Genome Testing Companies (23andMe and Navigenics), two of the leading serial computer chip makers (Intel and AMD) and two of the leading parallel FPGA chip makers (Xilinx and Altera), several traditional computer integrator companies (HP, Apple) and the hybrid computer integrator (DRCcomputer), major health-care providers (Stanford just announcing its Genomic and Personal Medicine Center, El Camino Hospital and Palo Alto Medical Foundation already running theirs), with a provider excelling in digitalization of health records (Kaiser Permanente), and software giants engaged in "health data repositories" (Google Health and Microsoft HealthVault, Oracle), and HolGenTech positioned to become a "Center for Genome Analysis and Interpretation" (with every $3 investment in the USA $1 commanded from Silicon Valley VC-s), along came the news of the Congressional Investigation of DTC genome testing. Thus, the meeting originally planned for June 23-25 was postponed to the time when the dust will clear: December 9-10, 2010 - AJP]

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Would Regulation Kill Genetic Testing?

It could—but the FDA and Congress also could make the burgeoning biotech industry stronger.

Newsweek, June 4
Mary Carmichael

At the Consumer Genetics Conference in Boston this week, it was nearly impossible to go an hour without hearing the words “Pathway” or “Walgreens.” That wouldn’t have been the case had the meeting been held before May 11, when Pathway Genomics of San Diego made a deal to sell its genetic testing service in the nationwide drug chain. The product lets consumers spit in a $20 test tube, send the results to a lab, pay $250 or more, and find out some of what’s lurking in their DNA.

Easy, over-the-counter access to tests that consumers may not fully understand is spurring regulators to action. But as with any emerging industry, there’s concern that stringent or misguided government rules could hamper growth and innovation. Certainly, after going unregulated for three years, direct-to-consumer (DTC) genetic tests are about to face their biggest challenge.

Apparently blindsided by the Pathway-Walgreens news, the Food and Drug Administration signaled that it might, for the first time, regulate DTC genetic tests. Congress quickly got involved, sending letters to Pathway and two similar firms, Google-backed 23andMe and Navigenics, asking for documentation on almost everything the companies do. The deadline for the companies’ response is this weekend, and Capitol Hill hearings are probably on the horizon.

DTC genomics companies are already regulated in New York and California, and most experts agree that some federal oversight is needed. If done right, FDA rules could be good for the industry, consumers, and pretty much everyone, except perhaps the random firm promoting the genetic equivalent of snake oil. But if regulation is done wrong or overdone, it could harm the industry or send genomics startups packing for countries with less stringent laws.

“The complexity of some of these tests is such that it is really hard to come to consensus” on what to do about them, says Joann Boughman, executive vice president of the American Society of Human Genetics. “But it’s time we just had to grapple with this and understand that no matter what happens, not everybody is going to be happy.”

The FDA’s reluctance to regulate health-related DTC genomic tests so far has frustrated some in the industry—and critics outside of it—who would have preferred more guidance from the beginning. But the agency has not been ignoring the tests since 2007, when they first appeared. It has been gathering information on them all along. Even in 2000 the FDA was aware of some of the concerns it now has to confront; they were invoked in a report from the secretary’s Advisory Committee on Genetic Testing that year.

Some of the report’s conclusions were reflected in the FDA’s draft guidelines for regulating in vitro diagnostic multivariate index assays that were released in 2006 and again, in a second draft, in 2007. The industry reacted badly to those two proposals. “They were vague, and it would have been expensive for independent labs to comply with them,” says Dan Vorhaus, an attorney at Robinson Bradshaw & Hinson who focuses on genomics. “There was a lot of ambiguity in what the FDA was proposing. It wasn’t clear how it would be applied.”

Recently, FDA officials have said they hope to revamp those guidelines yet again. The current rules do not cover DTC genetic tests, but theoretically, they could be expanded to do so. That might mean that DTC companies would need premarket clearance from the FDA to sell their tests—a rule that would raise the barriers to entry, possibly discouraging startups or driving them overseas. China, in particular, might look appealing: institutes there have lately been buying genetic sequencing machines in droves.

But many observers think the FDA won’t go so far as to require premarket clearance for the tests because the agency itself may not want to deal with the “insane and unsupportable burden” that would present, says Paul Kim, an attorney at Foley Hoag who briefed the Consumer Genetics Conference audience on the issue. “Does the FDA really want to have an obligation to clear thousands of new tests every year?” he says. “It’s unsustainable, and I can’t imagine the FDA would welcome or look for that kind of responsibility.”

Perhaps an easier solution would be to piggyback onto the genetic-test registry that the National Institutes of Health is already planning to build so that consumers will have a way to compare different testing services side by side. So far, the NIH’s plan is for the registry to be voluntary, but Vorhaus argues it could be mandatory instead, with companies required to explain what genes they test for, how they do it, and how they interpret and aggregate the results for consumers. “The companies may already show you the [basic science] studies they’re using,” says Vorhaus, “but all those algorithms that go into producing their reports—those are the kind of things that are going to concern the FDA.”

At the very least, says Boughman, under new regulations, DTC genetics companies should have to start proving some basic cred: that their labs are CLIA-certified (most already are) and that they can correctly identify the variants for which they’re testing. Boughman would like to see the labs regularly checked by an outside agency such as the College of American Pathologists. “We think there should be a way to confirm a result in another laboratory, either with people flipping samples or sharing a [sample with a disguised identity] once in a while,” she says.

The FDA has not yet revealed its intentions; the agency told NEWSWEEK on Thursday that it “continues to look at tests being marketed directly to consumers, and will take appropriate steps as necessary to make sure that public health needs are met in a safe and effective manner.”

But Kim says there’s at least one concrete indication of what may be in store—at least from the Hill. Last week, Reps. Patrick Kennedy (D-R.I.) and Anna Eshoo (D-Calif.) reintroduced a personalized medicine bill that first surfaced three years ago under the sponsorship of a certain then-senator from Illinois. (Yes, that one.) The new, Kennedy-Eshoo version of the bill has several tweaks, among them the creation of a new office focused on personalized medicine; a proposal for a registry like the NIH’s; and a call for the FDA, the Federal Trade Commission, and the Centers for Disease Control to evaluate DTC genomic tests. The FDA is not involved with the legislation, but the bill may be “a good bellwether” for future regulation, says Kim, who has advised Kennedy’s office.

“What people like most of all with regulation is certainty and clarity,” Kim adds. “If you have a pathway laid out, even if it’s stringent, you know what you’re dealing with.”

[Theragen of Seoul, Korea - backed by SAMSUNG would be a primary beneficiary, should US regulation decide to throw out the baby with the bathwater - AJP]

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Stanford School of Medicine Launches Center for Genomics and Personalized Medicine

June 04, 2010

By a GenomeWeb staff reporter

[Michael Snyder, Stanford]

NEW YORK (GenomeWeb News) — Stanford University's School of Medicine this week announced the creation of a new Center for Genomics and Personalized Medicine designed to integrate genomics information with every aspect of medicine, as well as draw on collaborations between Stanford's basic scientists and clinical researchers, and on technologies developed in Silicon Valley.

Stanford says the center will promote personalized medicine by building on research from the sequencing of the genome of Stephen Quake, the Lee Otterson Professor of Bioengineering and co-chair of Stanford's bioengineering department. Quake made news last August by using a technology he helped invent — Helicos BioSciences' Heliscope single molecule sequencer — to sequence and publish his own genome for less than $50,000. Researchers published results from their study of Quake's genome in the May 1 issue of the Lancet.

"The center blends highly efficient, rapid sequencing technology with the research and clinical efforts of experts in genomics, bioinformatics, molecular genetic pathology and even ethics and genetic counseling to bring advances from the laboratory to the patient," Stanford said in its announcement.

The center's director is Michael Snyder, chair of the medical school's Department of Genetics. In the statement, Snyder said the center's sequencing facility is already operating with new equipment estimated to increase its sequencing capacity by about fivefold while also "significantly" reducing the cost.

Earlier this year, Snyder led a team of researchers in sequencing the transcriptomes of human embryonic stem cells in various stages of their differentiation into neural cells, using short- and paired-end reads generated with Illumina sequencing and long reads generated with the Roche 454 FLX and Titanium platforms. They identified both known and previously unannotated transcripts as well as spliced isoforms specific to the differentiation steps.

The center's equipment also includes a Single Molecule Real Time, or SMRT, DNA sequencing system purchased from Pacific Biosciences. Stanford was one of 10 institutions that purchased the system as part of Pac Bio's early access program in North America. The company has said it expects to launch commercial sales of the system in the second half of this year.

[This was only a matter of time! "The second half of this year" starts in less than 4 weeks... Pellionisz_at_JunkDNA.com]

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Your Genome Is Coming [to where? - AJP]

Forbes
June 3, 2010 - 5:32 pm
Matthew Herper, senior editor at Forbes

[Your Affordable Genome is coming to WHERE? - AJP]

Just keep waiting, and soon you'll be able to afford that genome sequence you've always wanted. Makers of DNA sequencers are dropping costs and increasing speed at a rate that would make microchip manufacturers blush.

Illumina, the maker of DNA decoders, today lowered the cost of its consumer gene-sequencing product from $48,000 to $19,500, with a cost of $14,500 for people in groups of five or more that use the same physician. It also introduced a new category of customer: for patients who might get actionable medical information, such as cancer patients who could use genomic information to pick medicines, the service will be available for $9,500. The announcement was made at the Consumer Genetics Conference in Boston.

That is a stunning drop in price. Sequencing the first human genome cost $3 billion. Knome, a company that also sells consumers access to their genome and analysis of it, launched its service for $350,000 in December 2007 . Now it will sequence your genome for $39,500. Earlier this year, Illumina announced a new DNA sequencer that would decode all the genes in the human genome for just $10,000, and said it expected prices to drop further; the $9,500 price tag for people who might have a medical reason to get sequenced indicates that costs have already dropped below that level.

It's a new notion that sequencing every DNA base pair could be more useful that just doing a targeted read of several genes, a cheaper and older technique. Last October, scientists at Yale diagnosed a baby with a genetic form of diarrhea by sequencing all of its protein-coding genes. Other examples of diagnosis-by-sequencing were published earlier this year in the New England Journal of Medicine.

Cancer patients are likely to be among the first to benefit from these dropping prices. The idea is that knowing the gene sequences of a patient will help patients pick targeted cancer drugs. At $9,500, the sequencing already costs less than a course of treatment with newer cancer medicines sold by Novartis and Eli Lilly.

Hoping to accelerate this trend, Life Technologies, Illumina's biggest competitor, today announced the creation of an alliance of cancer centers that will use gene sequencing to help patients pick treatments. The founding partners, including Fox Chase Cancer Center, Scripps Genomic Medicine and the Translational Genomics Research Institute (TGen), are also launching a pilot study aimed at determining whether whole genome sequencing can improve the management of hard-to-treat cancers. The announcement was also made at the conference.

Gregory Lucier, Life's chief executive, put up the inset graphic during his presentation. It shows the price drops in gene sequencing technology over the past decade, compared to Moore's Law, the axiom about increasing microprocessor speed coined by Intel founder Gordon Moore. What's amazing is that the gene sequencers now seem to be outpacing the microchips.

[The Affordable Personal DNA Is Coming - but "Is IT Ready for the Dreaded DNA Data Deluge?" - I asked and answered in my Google Tech Talk YouTube (2008). By 2009, it was obvious that the "DTC Genome Testing Business Model" (as it was, see my Churchill Club YouTube panel) was not complete, without "Personal Genome Computer" and "Personal Genome Assistant" genome computing architecture (see my 2010 PMWC2010 YouTube):

[Need for PGC & PGA Pellionisz_at_JunkDNA.com]

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Illumina Drops Personal Genome Sequencing Price to Below $20,000

BioIT World
June 3, 2010
By Kevin Davies

BOSTON – One year after Illumina introduced its personal genome sequencing service, CEO Jay Flatley announced a significant price drop to below $20,000, and potentially half that if there is clinical relevance.

Illumina’s Individual Genome Sequencing service that Flatley debuted at the Consumer Genetics Show last year launched with a price of $48,000 for a whole genome sequence at 30-fold coverage. The service has to be ordered by a physician, and the results are also delivered back to the physician to discuss with the consumer. [This will open up the related questions; a) who pays for the sequencing, and "whose genome is it, anyway", b) In this construction, there will be a very limited number of physicians to understand the full DNA (since they have never been trained for an art non-existent at the time of their schooling) let alone "discuss" it with the "consumer" (since the the time of medical doctors is far too high for "consumer discussions"). The viable business model is that of HolGenTech (see below), where consumers are empowered by interoperable health- and genomic data to make a difference in their daily life; shopping by their genome - AJP]

With the introduction of the HiSeq instrument earlier this year, Illumina said the reagent cost of sequencing a full human genome had dropped to the $10,000 mark, which made the original IGS price tag of $48,000 appear a little steep by comparison. The new pricing that Flatley introduced today reflects the dramatic reduction in sequencing cost enabled by the HiSeq instrument.

The new cost of an individual genome sequence is $19,500. For groups of five people or more, the price drops to $14,500. Flatley also said that for a physician ordering a sequence for genuine clinical relevance, the price falls further to $9,500.

The only catch with the new pricing is that the sequence is no longer delivered on an iMac. “A little less elegant, a little less cool,” Flatley admitted.

Flatley disclosed that the IGS has sequenced at least 14 individuals to date. These include Flatley,venture capitalist Hermann Hauser, Henry “Skip” Gates and his father; Glenn Close; John West (former Solexa CEO) and his family of four; a cancer patient, two centenarians, and a severely ill child.

Goes to 11

Flatley briefly discussed analysis of his own genome sequence, illustrated with a live demo of his genome on an iPad app that had members of the audience drooling. Illumina shelved an earlier genome browser app for the iPhone after concluding the device didn’t have sufficient power to run the app. [This we knew from the outset - just a few hours before Illumina's show of iPhone "business model" I presented in last years' Consumer Genetics Conference the demo of empowerment of consumers to shop by their genome using their generic smart phone ("Personal Genome Assistant"). The architecture does call, however, for a robust enough "Personal Genome Computer" to be synced with; see photo from YouTube in the article above - AJP]

Flatley said that detailed analysis of his genome, searching for known variants in mutation databases such as HBMD and PharmKB, revealed 16 candidate homozygous and 48 heterozygous ‘disease-causing’ variants potentially associated with known genetic diseases. The accuracy of some of these annotations left a lot to be desired -- much to Flatley’s relief. In some cases, the mutations were annotated as “… death in early infancy highly likely.”

After further review, Illumina eliminated all 16 of the homozygous mutations as disease-related, and 37 of the 48 heterozygous variants. That leaves Flatley as a carrier of 11 confirmed ‘disease-causing’ alleles, for six recessive disorders and five dominant disorders, most of which Flatley admitted he had never heard of. Further analysis is being conducted.

Flatley presented a live demo of his genome using a custom-built app for the iPad. (The app is not yet publicly available.) The app presented a host of features, including a list of the disorders linked to Flatley’s known variants; an “about me” tab to build a family tree and enter health information, which is linked to Microsoft’s Health Vault.

A “Favorites” tab provides access to favorite genes (Flatley gave the example of “athletic tendency”) extracting SNPs in real time. There was also a genome browser, providing the ability to drill down from the whole chromosome level to the nucleotide level; a pathways tab; and a sharing tool that could provide access to a physician.

[The significance is NOT that Illumina dropped its full DNA sequencing price by a staggering 80% - since even their lowest price is already undercut by Complete Genomics, and release of Pacific Biosciences' sequencer, providing full human DNA "for a price of a meal in a restaurant" (in maybe half an hour or so). The significance is that with Illumina dropping the smart phone application, HolGenTech is now spearheading genome computing architecture. The business model, technology and IP is available by HolGenTech - email also to Pellionisz_at_JunkDNA.com]

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The Genome Project is 10 Years Old - Where is the Health Care Revolution?

Singularityhub.com
May 25th, 2010
Drew Halley

“It is fair to say that the Human Genome Project has not yet directly affected the health care of most individuals.” - Francis Collins, April 2010, Nature.

What’s in a genome? Ten years ago, the completion of the Human Genome Project promised to usher in a whole new era of heath care. Revolutionary gene therapies would soon conquer everything from cancer and heart disease to diabetes and autoimmunity. A roll-call of our genes would unlock the causes (and the solutions) to death and disease. But a decade on, most of these hopes have failed to materialize, and most of our lives haven’t changed. So where’s the revolution?

A recent retrospective in Nature includes some sobering reviews by such genetic gurus as Craig Venter and Francis Collins. Sure, there have been some significant gains. In vitro genetic screening has greatly reduced the risk of many common genetic diseases at the pre-birth stage. Risk factors for a range of adult diseases (including cancer) are coming into focus, and a host of new drugs have been developed. But as scientists expected to find common genetic determinants underlying common diseases, they quickly discovered that the genome was anything but straightforward. Instead, the genes behind disease have been shown to be highly complex and individually variable, even for widespread disorders. There isn’t a SNP for cancer.

The problem is that currently, the field of genomics is data-rich and application-poor. Thanks to companies like Complete Genomics, there is a flood of new genetic data and even more on the way - but we still don’t know how it works. So far, the primary focus of interest (and funding) has been the most easily quantifiable advances, such as sequencing speed and costs. Accomplishments in this arena have been impressive, but a complementary push for clinical applications is needed to sort through all of this genomic data that we still don’t understand.

The fate of commercial genetics hangs in the balance. Companies like deCODE and 23andMe were born on the hope that laypeople might be willing to pay for a glimpse at their own DNA. The bankruptcy of deCODE and troubling rumors about 23andMe raise the question of whether personal genomics is an industry born premature. So far, their products feed a curiosity niche, not a utilitarian one. When a genome points to little more than SNP-based correlations, few people can justify spending their recession-hit income on what remains a biotech novelty.

As Collins, Venter and others have suggested, a health care revolution requires bridging the gap between genomic data and its clinical utility. Any disappointments of the past decade point to the directions of the next. We’re learning that so-called “junk DNA” isn’t really junk, but can regulate the expression of other, coding sequences of the genome. Untangling the various networks of gene regulation will illuminate the pathways which result in a given phenotype, pathological or not. The roles of epigenetic processes are also undoubtedly complicating factors which will need to be better understood.

Most approaches over the past decade have used SNP chip analysis to identify mutations associated with particular phenotypes. This type of analysis only looks at small parts of the genome, and has largely failed to identify the genetic determinants of most diseases. The SNP chip approach will be phased out as whole-genome scans become faster and more affordable (costs should drop below $1000 within the next three years). Complete Genomics aims to sequence 1 million human genomes within the next five years, and that’s a lot of data to crunch. Venter is calling for two ways of making better sense of this flood of whole-genome scans: more detailed phenotype analyses, and the development of computational tools that can link them to their genetic counterparts.

It’s interesting to note the parallel between difficulties encountered in genomics and neuroscience. Recent years have seen an increasing shift in brain science from localization (areas of the brain that “do” things) towards neural-network approaches. Just as we’ll unlikely find a single gene that causes cancer, we’re not going to find the “irony zone” of the brain anytime soon. Reconceptualizing both genomics and the brain as complex, interactive networks remains a necessary step to significant advances in either field (e.g. a health care revolution or AI, respectively). And despite these setbacks, we can expect big things on the way.

Genetics has already revolutionized our health care in certain respects. Preimplantation genetic diagnosis (PGD) has already made huge progress towards eradicating genetic disease before birth, a significant but often overlooked accomplishment. But more lies ahead. Coming decades will see the creation of genetic therapies based around the specific molecular details of a given disorder. Diseases such as pediatric cancer are already the target of multi-year genomic research, and more diseases will benefit from genomic research as costs come down. And as the genetic underpinnings of disease come into focus, personal genetics will also undoubtedly enjoy a second life - regardless of whether today’s companies survive to see it.

[This is a remarkable overview of the "Decade since 'Genome Project'" - but is seriously flawed. It is trivial that the "Decade" was not that of any "Genome Project", but of the "Human Genome Project". More of a nuance is that the Decade since "the completion of the FIRST DRAFT" of a non-existent "human genome" (a composite of five individual donors...) WILL be a decade-old on June 25, 2010. Thus, we have some time for an unfolding national-global introspection, that is actually correct. Below, we'll draw some "talking points" that have been masked by waaaaay to much politics and ego-battles over the years. Perhaps the significant difference in viewpoints is, that IMHO one must separate "breakthroughs of science" from "industrialization of scientific achievements" - Pellionisz_at_JunkDNA.com]

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Scientist: 'We didn't create life from scratch'

From CNN reports

May 21, 2010 4:45 p.m. EDT

CNN) -- Genetics pioneer J. Craig Venter announced Thursday that he and his team have created artificial life for the first time.

Using sequences of genetic code created on a computer, the team assembled a complete DNA of a bacterium, then inserted it in another bacterium and initiated synthesis, or in Venter's words "booted up" the cell.

In a statement, Venter called the results "the proof of principle that genomes can be designed in the computer, chemically made in the laboratory and transplanted into a recipient cell to produce a new self-replicating cell," controlled only by the synthetic genome.

Venter answered questions Thursday about the achievement.

CNN: What exactly have you done?

J. Craig Venter: We announced the first cell that is totally controlled by a synthetic chromosome, that we designed in a computer based on an existing chromosome.

We built it from four bottles of chemicals.. that's over a million base pairs [of chromosomes]. We assembled that and transplanted it into a recipient cell and that new chromosome started being read by the machinery in the cell, producing new proteins, and totally transformed that cell into a new species coded by the synthetic chromosome.

So it's the first living self-replicating cell that we have on the planet whose DNA was made chemically and designed in the computer.

So it has no genetic ancestors. Its parent is a computer.

Time.com: Scientist creates life. That's a good thing, right?

CNN: What's its name?

Venter: "It is software.. It's DNA software."

CNN: How big a deal is this?

Venter: It's for others to describe. It's a big deal for us. We've been working on it for 15 years. It gives us tools to work with that haven't existed before. And we have some huge challenges.

We need new tools in science. Allowing us, for example, new organisms that more efficiently can capture C02 and convert it into fuel so we can get weaned off of oil.

We can create new food substances. ... We can create new ways to create clean water. We are already going to create new vaccines to treat diseases that emerge each year like the flu, so it's a new tool for scientists to work with.

But it's also a change conceptually. This is the first time we had a life form whose genetic code was made chemically. It tells us about the dynamic nature of life...That it changes second to second.

You take away the DNA, we're dead very quickly. You can't have life without the genetic code.

CNN: What does this mean for the average person?

Venter: This is a basic science breakthrough that now takes us from what was a hypothetical possibility -- that we could have synthetic life in these tools -- to rapidly advance to get some breakthroughs.

This is the first baby step that allows us to do that.

But it's a conceptual change... because we know it's possible. It should give people hope that we have new tools to tackle these problems.

CNN: Did you create new life?

Venter: We created a new cell. It's alive. But we didn't create life from scratch.

We created. as all life on this planet is. out of a living cell.

CNN: Some critics suggest you shouldn't make life from a computer.

Venter: People have been discussing this for the past decade since we've made incremental steps trying to get to this point. This is the fourth scientific publication in a series since 2003, so you can find 100,000 blogs out there discussing philosophically what this means, where does it take us, can we build things based on our imagination. So I think this will stimulate a lot of thinking, a lot of discussion.

CNN: Could you build an actual living organism - Frankenstein like?

Venter: Well these are very small cells. They are living. They are self-replicating. But if you're trying to advance life forms like you and me, I think that's still in the realm of science fiction.

CNN: This is a big deal ... What's next?

Venter: People keep asking me that at various dates. I was asked that 10 years ago after sequencing the human genome - you couldn't possibly top that - so we consider this a more important accomplishment than sequencing the human genome. So, following through on that is what's next for us, and see if we can create some of these cures for the planet

CNN: How excited were you? Did you pop champagne?

Venter: We did, but our initial emotion was more one of relief that it finally worked. You can imagine 99 percent of your experiments fail for one reason or another. This, when it finally worked, we were more relieved than excited.

CNN: What does it mean to you?

Venter: When you work on something for 15 years, it's a great sense of accomplishment. This is a demonstration of what new multidisciplinary team science is about. and I couldn't be prouder of our team.

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The Journal Science Interviews J. Craig Venter About the first "Synthetic Cell"

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Get Your Genotype Tests Now Before Congress Makes Them Illegal

Ronald Bailey | May 26, 2010

A couple of weeks ago, we saw the sorry saga of the Food and Drug Administration stomping on the effort by the direct-to-consumer (DTC) genotype screening company, Pathway Genomics, to offer its tests through drugstores. Pathway had reached an agreement with Walgreens to sell its test kits over-the-counter in its 6,000 or so stores. The FDA sent a threatening letter asking Pathway to justify the unregulated sale of a "medical device" to the public, and Walgreens backed away from its deal with the company.

Now the Congressional nanny-in-chief and head of the House Energy and Commerce Committee, Rep. Henry Waxman (D-Calif.) is demanding information by June 4 from three DTC companies, Pathway Genomics, Navigenics, and 23andMe. As Bloomberg reports:

The lawmakers gave the companies until June 4 to submit documents on the ability of the tests to identify consumers’ risks for illnesses. The legislators also requested information on the proficiency of the companies’ lab testing, policies on consumer privacy and whether the kits comply with FDA rules.

Some purchasers of the screening tests may be dissatisfied with their experiences, but I would suggest that most are first-adopter types who recognize the current limitations of genetic screening science. The way that consumers learn about the upsides and downsides of new products is to try them out; just as the way companies learn how to improve their products is through customer feedback. As often occurs, the "I'm-from-the-government-and-I'm-here-to-help" types are eager interfere with this kind of speedy social learning.

If you've been thinking about buying a gene screening test, you might want to go ahead now before Congress and the FDA make it illegal for you to get this kind of information. Just saying.

Disclosure: I [Ronald Baiely] am a happy customer of 23andMe (though I really wish their test had screened for the APOE4 allele associated with a much higher risk of Alzheimer's disease). Given this news, I am going to order a new test from another company today. I own no stocks in any gene screening companies. Finally, my article on the joys of DTC gene screening and the exaggerated concerns over genetic privacy has at last been submitted to my editors at Reason who are now busy making improvements to it.

[Just as when 23andMe offered a stunning discount of $99 for their usually $499 DTC service (on DNA day), the looming Congressional Investigation may trigger another avalanche of consumers who wish to ascertain their unelianable right to know their genome. I also encourage people to do that, with the specific note that leading DTC Genome Testing companies (like 23andMe and Navigenics) include in their price that the consumer can download from the secure site their own "raw SNP data file" - which is theirs, not only because it is their own characterization of individual diversity, but also because they have already paid for it. It is important to know that NOT all DTC Genome Testing companies provide you with the raw SNP data file - maybe since according to some unofficial statements of those companies that do provide this capability, very few customers actually download the "raw SNP data file". While for average customers it looks like just a bunch of numbers, it is a treasure, since e.g. the "Shop for your life" YouTube was made with Ms. Boonsri Dickinson kindly downloading her file from a DTC Genome Testing company and under a confidentiality agreement that HolGenTech will only use those results that she herself went public with, kindly sent us her "raw SNP data file" to make it eminently usable in daily life. - Pellionisz_at_JunkDNA.com]

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Who Should Control Knowledge of Your Genome?

SmartPlanet
Dana Blankenhorn | May 26

A Congressional investigation has brought into sharp relief some of the political implications of genetic testing.

Rep. Henry Waxman and his House Committee on Energy and Commerce have sent letters to the leading makers of genetic testing kits — Pathway Genomics, Navigenic, and 23andme — as the first step in an investigation of the direct to consumer (DTC) genetic testing industry.

This followed the FDA’s decision to send Pathway a letter demanding it show it either FDA approval of its tests or its reasons why such approval is not necessary.

This was prompted by Walgreens and CVS plans to offer the Pathway test in their stores. Pathway already sells its test online.

The Pathway test costs just $30 and involves collecting a bit of saliva, then sending it to the company’s lab.

(And to think just last month our Boonsri Dickenson was writing about $99 tests and her own experience with the $999 version, which said she was at risk for macular degeneration later in life.)

The investigations have sparked a hair on fire moment for the industry, with people like Andras Pellionisz (above) of HolGenTech ...

“Consumers must ask, ‘whose genome is it anyway?’” Pellionisz says.

His concern is that any restriction on Direct To Consumer (DTC) or Over The Counter (OTC) genetic testing will give foreign competitors like DeCodeMe of Iceland and Korea’s DTC Genome Testing institution (backed by Samsung) a leg-up on a lucrative market.

That may be true. But there are also some serious questions to be asked, questions that have not been asked yet, before we make genetic tests as ubiquitous as home pregnancy kits:

How useful are they, really – All of us have DNA which shows how we might die. [Not true, see e.g. George Church - AJP]. Are these kits just creating needless panic?

How accurate are they – There are reports of cancer-free women ordering mastectomies because there is breast cancer in their family history already.

Are we ready yet – Scientists don’t yet know what a complete genetic test means. Given that reality most of what a test delivers will be as useful as a palm reading.

It’s true that you can sell anything you want to people if you don’t claim it’s medicine. But genetic tests are medicine. [Not true, see below - AJP]

Even if the terms of service for 23andme prohibit sharing the data with your doctor, people will share the data with their doctors, as Steve Murphy of GeneSherpas recently noted. What other reason is there for getting the test?

Pellionisz is right about one thing. It may be way too late to put this one back in the box. Al Gore helped launch Navigenics. And 23andme co-founder Anne Wojcicki is also Mrs. Sergey Brin, as in Google co-founder Sergey Brin.

The industry has also been getting on TV, with celebrities like Larry David getting their DNA tests read out on the George Lopez Show.

It’s not the “consumer wanting to know what’s going to kill me” market that should be the political issue in any case. It’s the identification market.

This month the full U.S. House approved legislation that will pay states to collect DNA samples on all those people arrested for any crime, as a crime-fighting measure.

That’s where the money is. That’s where the politics is.

So where do you stand on the issue. Want your DNA tested? Want to be able to resist having it tested? It’s your DNA — who should know about it?

---Comment (1) by Pellionisz

05/26/10

RE: Who should control knowledge of your genome?

While I largely agree with Dana, there are some fine points to make. Perhaps the most significant disagreement is that in his opinion genome testing can be boxed into "Medical". IMHO there is plenty to think "outside the box". Indeed, establishing some A,C,T,G letters, in DTC up to 1.6 million, or in full DNA sequencing obtaining all the12.4 Megabits of information of the diploid DNA is just a mapping out of individual human diversity.

Humans differ from one-another in about 4% of their A,C,T,G bases. Such differences can [be] just individual traits with your eye color different from mine, or many Chinese friends of mine unable to metabolize lactose when they grow out of childhood while most Northern Europeans continue thrive on it. My YouTube-s ("Pellionisz"), especially the "Shop for your Life!" put an emphasis on the immediate impact on consumerism by using genomic information that is not medical, at all. Also, a genomic test that reveals your ancestry-tree is not medical.

I congratulate and support with my tax dollars those governments that well serve their taxpayers. Governments wasting resources or using them to try to prevent knowledge [for people] of their bodies are attempts that I disagree with. The US government has just poured an enormous amount of money into genomics (also because of an interest in bioenergy - nothing to do with "medical"...) and also re-vamped the health-care system.

It goes unmentioned in the posting that the US health-care will simply be unsustainable if genome-based prevention will not save trillions by preventing or delaying some of the most expensive and (not only individually, but also socially) devastating diseases (neurological disorders, cancers).

[This blog (and reply) was prompted by Dr. Pellionisz' posting in HolGenTech Blog "Justifying DTC Genome Testing with Consumerism" that (tries to...) make it clear that the fulcrum of the wild media coverage of "DTC debate" truly is that DTC Genome Testing is much bigger than "The Box of US Medicine" (and thus is a global issue, not even limited to USA). The debate is already sizable, and escalates rapidly. Thus far (as the above blog by Dana Blankenhorn also illustrates) the debate is extremely diffuse with all kinds of issues mentioned (and unmentioned...). Some of them, like "All of us have DNA which shows how we might die" are fairly common remnants of an obsolete gloomy (mis)understanding of genomics - already superseded by new knowledge supplied by epigenomics, giving us hope, that "The Genome is NOT Your Destiny". - Pellionisz_at_JunkDNA.com]

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'Junk' DNA behind cancer growth

ANI, May 21, 2010, 12.00am IST

Scientists have discovered a new driving force behind cancer growth.

Researchers from the University of Leeds, UK, the Charite University Medical School and the Max Delbruck Centre for Molecular Medicine (MDC) in Berlin, Germany, have identified how 'junk' DNA promotes the growth of cancer cells in patients with Hodgkin's lymphoma.

Professor Constanze Bonifer (University of Leeds) and Dr Stephan Mathas (Charite, MDC) who co-led the study suspect that these pieces of 'junk' DNA, called 'long terminal repeats', can play a role in other forms of cancer as well.

The researchers uncovered the process by which this 'junk DNA' is made active, promoting cancer growth.

"We have shown this is the case in Hodgkin's lymphoma, but the exact same mechanism could be involved in the development of other forms of blood cancer. This would have implications for diagnosis, prognosis, and therapy of these diseases," said Bonifer.

'Long terminal repeats' (LTRs) are a form of 'junk DNA' - genetic material that has accumulated in the human genome over millions of years.

Although LTRs originate from viruses and are potentially harmful, they are usually made inactive when embryos are developing in the womb.

If this process of inactivation doesn't work, then the LTRs could activate cancer genes, a possibility that was suggested in previous animal studies.

This latest study has now demonstrated for the first time that these 'rogue' active LTRs can drive the growth of cancer in humans.

The work focused on cancerous cells of Hodgkin's lymphoma th