Personalized medicine

Medicine becoming a data-driven science?

2011-02-25T05:23:00.000-08:00

- CAn the electronic medical record ccontain an entire genome?, ACP Internist

GenomeQuest Joins Personalized Medicine Coalition

2011-02-25T05:08:00.001-08:00

Westborough, MA, February 24, 2011 - GenomeQuest Inc. announced today that it joined the Personalized Medicine Coalition (PMC), a not-for-profit advocacy and educational coalition that advances the understanding and adoption of personalized medicine. GenomeQuest also announced that it would sponsor the personalized medicine conference at Harvard Medical School. Now in its seventh year, the meeting serves as PMC’s annual conference and brings together leaders from across the personalized medicine field.

"With unsustainable costs and an aging population, our health care system faces major challenges. Personalized medicine can be a major part of the solution -- more precise, genomic-driven medicine will result in better and more cost-effective health care,” said Richard Resnick, CEO of GenomeQuest. “We're proud and pleased to be joining the PMC. They are doing a masterful job of leading the collaboration of the health care industry as we collectively plan, communicate, and implement this more personalized approach to medical care."

"A major challenge to advancing personalized medicine is understanding the clinical utility of large amounts of genomic data. Researchers need to be able to analyze new data and clinicians need to be able to generate medically actionable information from these results,” said Edward Abrahams, President of PMC. “We're excited to welcome GenomeQuest, a leader in sequence data management, to PMC to enhance our collaborative effort to see the implementation of a new medical paradigm.”

This announcement follows earlier news from GenomeQuest on a step forward for personalized medicine in diagnostics reporting: clinical practitioners can now interactively produce and query a patient report for genetic tests spanning over 2000 inherited diseases from a single whole-genome or exome sequence. That full announcement is available here.

Also, today at Molecular Med Tri-Con 2011 at 3:20pm (PST), GenomeQuest and medical experts are participating in an industry panel on "Whole-Genome Diagnostics and its Emerging Significance to the Health Care Industry" that will include a demonstration of this new capability for diagnostics companies. More on that panel, including webex live viewing and replay is available here.

About GenomeQuest

GenomeQuest, the global leader in sequence data management, helps life science organizations realize the full promise of genomics. Over 160 leading health and agriculture companies use GenomeQuest for mission-critical work, including nine of the top ten pharmaceuticals. The core technology of the company is the GQ-Engine—a sequence database engine that is purpose-built for storing, managing, and analyzing sequence data at whole- and multi-genome scale.

Learn more at www.genomequest.com.

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Contact: Dana Wormer, +1 215.888.0960

2,227 genes highly predictive & medically actionable.

2011-02-25T01:54:00.000-08:00

@EricTopol at @LIFECorporation: 2,227 genes highly predictive & medically actionable.

A Big And Dangerous Day For Personalized Medicine

2011-02-25T01:41:00.000-08:00

References

- A Big And Dangerous Day For Personalized Medicine, Matthew Harper, Forbes, Feb. 23 2011

- Why Matthew Herper has it wrong, prospectivehealth.blogspot.com, Wednesday, February 23, 2011

- Vertex May Make History With Cystic Fibrosis Drug, Forbes, Feb. 23 2011

- Life Tech Pushes Speed Of Small, Fast DNA Sequencer, Forbes, Feb. 23 2011

- Rare Disease Drugs: A $1 Trillion Market?, Forbes, Nov. 19 2010

The Road to the $1,000 Genome

2010-09-28T00:15:00.001-07:00

Bio-IT, September 28, 2010 |

The term next-generation sequencing (NGS) has been around for so long it has become almost meaningless. We use “NGS” to describe platforms that are so well established they are almost institutions, and future (3rd-, 4th-, or whatever) generations promising to do for terrestrial triage what Mr Spock’s Tricorder did for intergalactic health care. But as the costs of consumables keep falling, turning the data-generation aspect of NGS increasingly into a commodity, the all-important problems of data analysis, storage, and medical interpretation loom ever larger.

“There is a growing gap between the generation of massively parallel sequencing output and the ability to process and analyze the resulting data,” says Canadian cancer research John McPherson, feeling the pain of NGS neophytes left to negotiate “a bewildering maze of base calling, alignment, assembly, and analysis tools with often incomplete documentation and no idea how to compare and validate their outputs. Bridging this gap is essential, or the coveted $1,000 genome will come with a $20,000 analysis price tag.”

“The cost of DNA sequencing might not matter in a few years,” says the Broad Institute’s Chad Nusbaum. “People are saying they’ll be able to sequence the human genome for $100 or less. That’s lovely, but it still could cost you $2,500 to store the data, so the cost of storage ultimately becomes the limiting factor, not the cost of sequencing. We can quibble about the dollars and cents, but you can’t argue about the trends at all.”

But these issues look relatively trivial compared to the challenge of mining a personal genome sequence for medically actionable benefit. Stanford’s chair of bioengineering, Russ Altman, points out that not only is the cost of sequencing “essentially free,” but the computational cost of dealing with the data is also trivial. “I mean, we might need a big computer, but big computers exist, they can be amortized, and it’s not a big deal. But the interpretation of the data will be keeping us busy for the next 50 years.”

Or as Bruce Korf, the president of the American College of Medical Genetics, puts it: “We are close to having a $1,000 genome sequence, but this may be accompanied by a $1,000,000 interpretation.”

Arbimagical Goal

The “$1,000 genome” is, in the view of Infinity Pharmaceuticals’ Keith Robison, an “arbimagical goal”—an arbitrary target that has nevertheless obtained a magical notoriety through repetition. The catchphrase was first coined in 2001, although by whom isn’t entirely clear. The University of Wisconsin’s David Schwartz insists he proposed the term during a National Human Genome Research Institute (NHGRI) retreat in 2001. During a breakout session, he said that NHGRI needed a new technology to complete a human genome sequence in a day. Asked to price that, Schwartz paused: “I thought for a moment and responded, ‘$1,000.’” However, NHGRI officials say they had already coined the term.

The $1,000 genome caught on a year later, when Craig Venter and Gerry Rubin hosted a major symposium in Boston (see, “Wanted: The $1000 Genome,” Bio•IT World, Nov 2002). Venter invited George Church and five other hopefuls to present new sequencing technologies, none more riveting than U.S. Genomics founder Eugene Chan, who described an ingenious technology to unfurl DNA molecules that would soon sequence a human genome in an hour. (The company abandoned its sequencing program a year later.)

Another of those hopefuls was 454 Life Sciences, which in 2007 made Jim Watson the first personal genome using NGS, at a cost of about $1 million. Since then, the cost of sequencing has plummeted to less than $10,000 in 2010. Much of that has been fueled by the competition between Illumina and Applied Biosystems (ABI). When Illumina said its HiSeq 2000 could sequence a human genome for $10,000, ABI countered with a $6,000 genome dropping to $3,000 at 99.99% accuracy.

Earlier this year, Complete Genomics reported its first full human genomes in Science. One of those belonged to George Church, whose genome was sequenced for about $1,500. CEO Cliff Reid told us earlier this year that Complete Genomics now routinely sequenced human genomes at 30x coverage for less than $1,000 in reagent costs.

The ever-quotable Clive Brown, formerly a central figure at Solexa and now VP development and informatics for Oxford Nanopore, a 3rd-generation sequencing company says: “I like to think of the Gen 2 systems as giant fighting dinosaurs, ‘[gigabases] per run—grr—arggh’ etc., a volcano of data spewing behind them in a Jurassic landscape—Sequanosaurus Rex. Meanwhile, in the undergrowth, the Gen 3 ‘mammals’ are quietly getting on with evolving and adapting to the imminent climate change... smaller, faster, more agile, and more intelligent.”

Nearly all the 2nd-generation platforms have placed bets on 3rd-gen technologies. Illumina has partnered with Oxford Nanopore; Life Technologies has countered by acquiring Ion Torrent Systems; and Roche is teaming up with IBM. PacBio has talked about a “15-minute” genome by 2014, Halcyon Molecular promises a “$100 genome,” while a Harvard start-up called GnuBio has placed a bet on a mere $30 genome.

David Dooling of The Genome Center at Washington University, points out the widely debated cost of the Human Genome Project included everything—the instruments, personnel, overhead, consumables, and IT. But the $1,000 genome—or in 2010 numbers, the $10,000 genome—only refers to flow cells and reagents. Clearly, the true cost of a genome sequence is much higher (see, “The Grand Illusion”). In fact, Dooling estimates the true cost of a “$10,000 genome” as closer to $30,000, by the time one has considered instrument depreciation and sample prep, personnel and IT, informatics and validation, management and overheads.

“If you are just costing reagents, most of the vendors could claim a $1,000 genome right now,” says Brown. “A more interesting question is: ‘$1,000 genome—so what?’ It’s an odd goal because the closer you get to it the less relevant it becomes.”

Special Interests

This special issue of Bio•IT World contains a series of stories and essays that provide some useful perspectives on the march to the $1,000 genome, which some regard as a medical imperative and others a grand illusion.

We get an up-close look at sequencing operations at the Broad Institute, which has been the U.S. flagship genome center for a decade (see page 30). We also meet the leaders of BGI Americas, which aims to provide sequencing capacity and analysis for labs big and small, while managing editor Allison Proffitt gleefully visits BGI’s prized new sequencing center under construction in Hong Kong (page 42).

We look at the genesis of Solexa, the British company that provided the raw technology for Illumina, the best-selling NGS platform to date (page 52). We meet Kevin Ulmer, a man who has spent more than three decades trying to develop the killer app for the $1,000 genome (page 64). And we meet NABsys, a 3rd-generation technology taking aim at the myriad clinical applications of NGS (page 61).

Given that the costs of data analysis and storage will increasingly dominate the NGS equation, Alissa Poh reviews some of the latest software solutions on offer (page 58), while Allison Proffitt appraises some of the latest data storage technologies (page 38).

Finally, we meet some of the organizations—from bioinformaticians and medical geneticists to pathologists and software engineers—who are developing new ideas and resources for clinical genomic interpretation (page 48). And we profile Hugh Rienhoff, physician and founder of My Daughter’s DNA.org, and follow his inspirational quest to solve his daughter’s mystery condition (page 34).

Also in this report are invited commentaries from genomics experts at two big pharma—Amgen’s Sasha Kamb and Novartis’ Keith Johnson and colleagues—discussing the potential applications and adoption hurdles to NGS in pharma. We also have our regular columns, including BioTeam’s Michele Clamp and our colleague Eric Glazer on social media and a preview of an exciting online community called NGS Leaders.

We hope you enjoy this special report on the road to the $1,000 genome as much as we have enjoyed reporting and preparing it.

—Kevin Davies, Mark Gabrenya and Allison Proffitt

Medicine and the human genome project

2010-08-25T02:05:00.000-07:00

References

- The Medical Revolution. Where are the cures promised by stem cells, gene therapy, and the human genome? By Emily Yoffe. Updated Tuesday, Aug. 24, 2010.

The neanderthal in us

2010-07-20T03:40:00.000-07:00

Blogs

- Testing for traces of Neanderthal in your own genome, genomes unzipped, 13/07/2010

How to read a genome-wide association study

2010-07-20T03:39:00.001-07:00

How to read a GWAS?

See

- How to read a genome-wide association study, genomes unzipped, July 18th 2010

The Future of Personal Genomics (BioIT 2010)

2010-07-01T04:45:00.001-07:00

Webcast - The Future of Personal Genomics (2010)

Panel: (From left) Jamie Heywood (co-founder and chairman, PatientsLikeMe), Dietrich Stephan (founder, Ignite Institute), Kari Stefansson (president, deCODE Genetics) and Dan Vorhaus (attorney and founder, Genomics Law Report)
Moderator: Kevin Davies, Ph.D., Editor-in-Chief, Bio-IT World
Topic: The Future of Personal Genomics
Date: April 2010 / Bio-IT World Expo / Boston
Length: 51:00

Technology for Turning the Promise of Personalized Medicine into a Reality

2010-07-01T03:52:00.001-07:00

Steve Hamm in Smarter Planet / new intelligence, July 1st, 2010

This is the way innovation sometimes happens: Two people who work for the same organization but have different areas of expertise meet by chance, start talking, and come up with an idea that has the potential to make a big difference in the world.

In this case, the people are Gustavo Stolovitzky and Stanislav Polonsky, two scientists at IBM Research in Yorktown Heights, New York. Gustavo’s specialty is genomics and Stas’ is semiconductors. Three years ago they met in a corridor at the lab and began talking about some of the challenges in biology. Gustavo said great things could be accomplished in medical science if researchers had the ability to sequence an individual’s entire genome quickly and inexpensively. The two discussed the possibility of using semiconductor technology to help create a quick and inexpensive gene sequencing machine. Within a few weeks they came up with the idea for what we now call DNA Transistor–a new way of sequencing the genome.

That bold concept came a major step closer to the marketplace today when Roche and IBM announced a partnership to develop a gene sequencer based on the DNA Transistor that the companies hope will directly read and decode DNA quickly and efficiently. “The big potential payoff from such technology is the ability to do things cheaper, faster, and better,” says Ajay Royyuru, the senior manager at IBM Research’s computational biology center.

Cheaper, faster, and better could make a big difference in the effort to draw knowledge from genomic research that will dramatically improve physicians’ abilities to correctly diagnose and treat diseases. It required $3 billion in research spending to sequence the first individual genome, in the US-funded Human Genome Project, and, so far, only a handful of people worldwide have had their entire genomes read. As a result, the great promise of genomics research has yet to be realized. A June 12 article in the New York Times marking the 10-year anniversary of the first draft of the Human Genome Project concluded that “medicine has yet to see any large part of the promised benefits.” Roche and IBM hope that their joint research make it possible to analyze an individual’s genome for a cost of between $100 and $1,000. A cost that low would make it practical to sequence the entire genomes of many individuals–enough to draw reliable conclusions. Roche and IBM will jointly develop the technology and hope to produce a working prototype in three years.

Here’s how the DNA Transistor works: A silicon membrane is placed vertically in a solution-filled chamber, dividing it in two. Strands of genetic material are placed in one side of the chamber, and electrical charges are applied–negative in the part of the chamber where the genetic strands reside, and positive on the other side. The positive charge draws a strand of genetic material into a tiny opening, or nanopore, in the membrane. As the strand passes through the opening, the combination of the electrical charges and the composition of the membrane has the effect of ratcheting the strand through one bead of genetic material at a time. This mechanism makes it possible to accurately and quickly read the genetic makeup of the strand.

There are plenty of challenges remaining for the researchers. Gustavo and Stas have shown through simulations and experiments that the ratcheting effect should work. Now, working with Roche scientists, they have to do more inventing to put the concept into practice. In addition, they need to develop a sequence-reading mechanism.

The collaboration got off to a promising start on June 29, when a dozen Roche scientists met with a dozen IBM scientists for discussions and a brainstorming session at the Yorktown lab. It was an emotional experience for Gustavo: “I remembered when this was a pie-in-the-sky idea, and I suddenly had this great feeling that you rarely get–when you feel you’re doing something that’s very worthwhile.”

The two companies seem well matched–even to the point of having the code-name “Watson” in common. Roche’s 454 Life Sciences subsidiary demonstrated the effectiveness of its existing gene sequencing technology by reading the genome of James Watson, the scientist who along with collaborator Francis Crick defined the structure of DNA in 1953. Watson, of course, is also the name of IBM’s first CEO, T.J. Watson, and the code-name of our new question-answering computer, which is in training to take on champions of the Jeopardy! TV quiz show early next year.

The code-name for the joint Roche/IBM project is what you would expect: DNA Transistor.

For additional info, see:

https://researcher.ibm.com/researcher/view_project.php?id=1120
http://www.research.ibm.com/compsci/compbio

and links to videos
http://www.youtube.com/v/pKi30ai35mU&hl=en_US&fs=1&rel/=0&showsearch=0&showinfo=0
http://www.youtube.com/v/wvclP3GySUY&hl=en_US&fs=1&rel/=0&showsearch=0&showinfo=0

Technorati Tags: DNA Transistor, genome, IBM, personalized medicine, Roche

Symposium: Genomics and the Consumer:The Present and Future of Personalized Medicine

2010-07-01T00:00:00.000-07:00

Genomics and the Consumer:The Present and Future of Personalized Medicine - Hosted by California State Senator Alex Padilla and 23andMe - Wednesday, July 14, 2010 - Organized by 23andme

Full agenda

SNPedia, a wiki dedicated to human SNPs

2010-06-30T23:52:00.000-07:00

- SNPediais a wiki investigating human genetics. SNPedia shares information about the effects of variations in DNA, citing peer-reviewed scientific publications. It is used by Promethease to analyze and help explain your DNA.

http://www.snpedia.com/index.php/SNPedia

Genome-wide association mapping and rare alleles: from  population genomics to personalized medicine. Session at PSB 2011

2010-06-30T23:42:00.000-07:00

PSB 2011 - Full paper submission deadline: July 12 2010 (let the co-chair know if you need a few days extension)

Genome-wide associations studies (GWAS) have been very  successful in identifying common genetic variation associated to  numerous complex diseases.

However, most of the identified  common genetic variants appear to confer modest risk and few  causal alleles have been identified. Furthermore, these  associations account for a small portion of the total  heritability of inherited disease variation.

This has led to the  reexamination of the contribution of environment, gene-gene and  gene-environment interactions, and rare genetic variants in  complex diseases.

There is strong evidence that rare variants  play an important role in complex disease etiology and may have  larger genetic effects than common variants.

Currently, much of  what we know regarding the contribution of rare genetic variants  to disease risk is based on a limited number of phenotypes and  candidate genes.

However, rapid advancement of second  generation sequencing technologies will invariably lead to  widespread association studies comparing whole exome and  eventually whole genome sequencing of cases and controls.

A  tremendous challenge for enabling these "next generation"  medical genomic studies is developing statistical approaches for  correlating rare genetic variants with disease outcome.   

The analysis of rare variants is challenging since methods used  for common variants are woefully underpowered (e.g., accurately  estimating allele frequencies in cases vs. controls requires ~10  observations of the minor allele; however, many of the  functional rare alleles may be present only once in the  resequence data).

Therefore, methods that can deal with genetic  heterogeneity at the trait-associated locus and that can be  applied to both in cases vs. controls and quantitative trait  studies are needed.

Currently, these approaches are in their  infancy and very basic criteria (such as functional annotation,  sequence conservation, or biological pathway classification) are  used.

There is tremendous opportunity to apply data mining  methods outside of the standard statistical toolkit to this  problem.

Additionally, deep sequencing will reveal many variants  that are not causal, and in order to reduce the problems of  misclassification, i.e. inclusion of non-causal variants and  exclusion of causal variants in the analysis, it is beneficial  to predict their potential functionality.

Thus, methods to  classify and annotate rare variants for subsequent analysis are  necessary.   

The session of PSB 2011 would focus on distilling current  knowledge in assessing rare variant functionality and their  correlation with complex traits, and more importantly bring  forth methodological questions that need to be addressed for  successful analysis of rare variants.

"GWAS by sequencing"  presents many new challenges and proposed solutions for  interpreting sequencing data from clinical case/control cohorts  will be of particular interest to a diverse audience.

The  session will similarly consider application-specific algorithms,  analysis methods, or study planning and design tools with  emphasis in the leveraging rare genetic variation in complex  trait/disease correlation.   

Deadline for full paper submission: July 12, 2010. Deadline for poster abstracts: November 1, 2010.   

CONFERENCE INFORMATION  

The Pacific Symposium on Biocomputing (PSB 2011) is an  international, multidisciplinary conference for the presentation  and discussion of current research in the theory and application  of computational methods in problems of biological significance.  

PSB 2011 will be held at the Big Island of  Hawaii on January 4-7, 2011.   For more information see the official PSB 2011 Web page:   http://psb.stanford.edu

See also

- How to read a genome-wide association study, genomes unzipped, July 18th 2010

Personalized Therapy at AACR

2010-06-24T06:04:00.000-07:00

- Clinical Applications of Genomics and Biomarker Cancer Research

Ari M. VanderWalde, MD, MPH

The paradigm in cancer care is shifting toward individualized therapy. This was the message reiterated by speaker after speaker at the 101st Annual Meeting of the American Association for Cancer Research (AACR), held in Washington DC, April 17-21, 2010.

As Levi Garraway of the Dana-Farber Cancer Institute in Boston, Massachusetts, explained at Monday's plenary session, the hope is that any patient with cancer would have their tumor biopsied and profiled. The profile would then be displayed as a unique genetic signature, which would in turn predict which therapy is most likely to work.

Personalized Therapy

An early example of this approach was described by Edward Kim[2] from the MD Anderson Cancer Center in Houston during Sunday's plenary session when he presented the first results from the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial in lung cancer.

In this trial, real-time biopsies were performed and an adaptive approach toward enrollment was used that, for the first time, attempted to predict which molecular markers in individual cancers would respond to which agents.

The BATTLE study identified 4 molecular markers: epidermal growth factor receptor (EGFR), Ras-Raf, RXR/cyclin D1, and vascular endothelial growth factor (VEGF). Patients were then randomly assigned to receive to erlotinib (an EGFR inhibitor), sorafenib (a VEGF inhibitor), vandetanib, or a combination of erlotinib and bexarotene.

The investigators found that 8-week disease control as determined by biopsy before and after this period was a good predictor of overall survival. Specifically, patients who had 8-week disease control had overall survival of 11.3 months vs only 7.3 months in those who did not have 8-week disease control.

Total disease response across all groups was 46%. However, response to sorafenib was very good in all non-EGFR groups; response was especially robust in the KRAS mutation group (79% disease control). Erlotinib yielded the best outcomes in the EGFR mutant group, but response to this agent was poor in the other groups.

Developing and Implementing Predictive Therapeutic Markers for Cancer

During Sunday's plenary session, Martine Piccart-Gebhart, founder and chair of the Breast International Group (BIG), presented the structure of the Neo-BIG program, which is being developed by BIG to accelerate drug development and biomarker discovery in early breast cancer.

The plan is to develop several concurrent clinical trials in the neoadjuvant setting that will evaluate genomics to determine predictive models of efficacy that can later be validated in the adjuvant setting.

Dr. Piccart-Gebhart explained that attempts to bring various tumor markers into the clinical setting have been unsuccessful owing to subjectivity of interpretation of histology or gene expression, as well as lack of specificity of the marker in predicting outcome or response to treatment. However, she noted that "genomic grade" seems to be a promising tool.

She explained that "early readout" of proliferation or signaling in the genetic signature of the tumor may predict response of the tumor to various agents, particularly in luminal-B cancers, a more aggressive genetic group of breast cancer. These data will be incorporated into the next Neo-BIG trial.

Elucidating the Cancer Genome

Monday's plenary session focused on how to make current research elucidating the cancer genome into something meaningful for clinical practice. Most speakers commented that cancer research is in the midst of a paradigm shift. They stated that the field of oncology is moving away from an anatomy- and histology-based view of cancer toward a genomic view the disease.

Bert Vogelstein of The Johns Hopkins University in Baltimore, Maryland, described the astounding progress scientists have made in identifying cancer-specific mutations since the announcement of the completion of the human genome project in 2003.

Dr. Vogelstein's laboratory studied the genomes of 68 tumors and found that genomic alterations in tumor cells occur at different rates and amounts in different tumors, with mutations accumulating as the tumor ages.

Most mutations are "passengers," meaning that they do not fundamentally determine the behavior of the tumor. However, using genetic mapping techniques, the researchers found that about 15% of a tumor is composed of "drivers": 2 or 3 oncogenes and tumor suppressor genes in each tumor, or about 320 "driver" genes across all human cancers combined, that have activity in 12 key cellular or nuclear pathways.

Using the cancer genome, Dr. Vogelstein identified 2 approaches toward development of targeted agents, which he dubbed the "mutant-gene" and "mutant-pathway" approaches. The benefit of the mutant-pathway approach is that 90% of drivers are tumor suppressor mutations that turn cellular genes off.

Because a therapeutic agent cannot turn a gene back on but can disrupt an overexpressed gene, and because resistance patterns are more likely if only 1 gene is targeted, he advocated using the mutant-pathway approach and suggested that it is likely to be more useful than targeting an individual gene.

He concluded with the inspiring assertion that we may now, for the first time, truly understand cancer. The hope is that what we do know can be used to help people.

The Human Genome and Cancer Risk

Rather than describing genomics of tumors themselves, Stephen Chanock[5] of the National Cancer Institute in Bethesda, Maryland, described progress in the identification of causal and contributory mutations in cancer genetic germ-line syndromes. This is the search for such syndromes as BRCA and Li-Fraumeni syndromes, wherein a mutation that affects every cell in the body predisposes for various types of cancer.

Whereas focus had previously been on looking for candidate genes, it is now shifting toward genome-wide association studies, which identify "soft spots" in the genome that seem to confer susceptibility.

For example, multiple cancers have been mapped to 2 distinct regions: 8q24 and 5p15.33. 8q24 is a 600-megabase region toward the middle of the chromosome from the MYC gene that harbors a series of independent markers associated with chronic lymphocytic leukemia and with breast, colorectal, prostate, and bladder cancer.

5p15.33 harbors the TERT-CLPTM1L locus and contains several variants associated with lung, brain, skin, and pancreatic cancers. Dr. Chanock noted that the success of genome-wide association studies has opened new horizons for exploration, and he expressed hope that common variants will be identified and applied in clinical and public health venues.

Conclusions

At the AACR Annual Meeting, cancer researchers expressed hope that the time to use genomics to create personalized cancer care is coming. The insights from their research and from their future planned studies confirmed this hope and left the audience optimistic and inspired.

Genome project at Kaiser: From Californians’ DNA, a Giant Genome Project

2010-06-23T02:54:00.000-07:00

From Californians’ DNA, a Giant Genome Project, By SABIN RUSSELL. New York Times, May 28, 2010.

Still in fine fettle at the age of 87, Ruth Young, a retired Oakland school nurse, jumped at the chance, she said, to “spit for the cause.”

Mrs. Young is one of more than 130,000 members of Kaiser Permanente in Northern California who have volunteered to have their DNA scanned by robotic, high-speed gene-reading machines as part of the largest human genome study of its kind ever attempted.

The goal of the study they are participating in is to help scientists uncover the genetic roots of chronic disease and, perhaps, to find out why some people live longer than others.

This month, researchers at Kaiser Permanente in Oakland and the University of California, San Francisco began the highly automated, large-scale process of analyzing that DNA, which is being extracted from tens of thousands of saliva samples donated by Kaiser members in Northern California since 2008.

Each sample of ordinary spit is laden with cells containing the volunteer’s entire set of genes, their genomes, which carry in sequences of DNA the coded instructions for building and maintaining life. The hope for this so-called genome-wide association study is that, when the genes of people with diseases like cancer and multiple sclerosis are compared with the genes of those in good health, computer analysis will pinpoint genes responsible for the illnesses.

With a speed that would have seemed preposterous to contemplate a decade ago, the work of collecting, purifying and digitizing billions of discrete bits of chemical information will be finished in less than 18 months, providing a rich resource for scientists to analyze for decades to come.

Winifred K. Rossi, who is managing the project for the National Institute on Aging, said most genome-wide association studies scan between 5,000 and 8,000 participants, although data from multiple, smaller studies can be pooled to form a larger group. What makes the Kaiser study unique is that members of a single, colossal cohort will have their genomes scanned uniformly, then paired with their medical histories. “It is absolutely the largest study of its kind, and it has enormous statistical power.” Ms. Rossi said.

Mrs. Young, a Kaiser member for 63 years, suffers from arthritic knees and Type II diabetes, which took her father’s life at an early age. “I’m conscientious about my diet, but I do love sweets,” she said.

She had originally been one of nearly two million patients asked in 2007 about participating in the Kaiser study. A huge group of volunteers, ranging in age from 18 to 107, filled out questionnaires. Tens of thousands of them, like Mrs. Young, were asked for specimens.

Following instructions found in a kit mailed to her Oakland home, Mrs. Young deposited the requested spit into a special plastic cup. She sealed it with a blue lid fitted with a built-in preservative and sent it back to Kaiser. Along with her saliva, the samples from the other 130,000 people began arriving in Kaiser’s mailbox.

Experiments like this one underscore how quickly gene-scanning technology is moving from the lab to the home. Last week, officials of the University of California, Berkeley, disclosed that 6,000 incoming freshman and transfer students will be asked to swab their cheeks at home for DNA, to participate in a collective lesson in genetics and a preview of the predicted era when medicine will be tailored to each person’s genetic makeup.

Each student who agrees to participate will be able to tap in a security code on a laptop and check whether they carry gene variants that might affect their ability to process lactose, alcohol or folate, a vitamin found in leafy greens. The Kaiser study participants will not have the same option. Their names are scrubbed from their samples, and only researchers — working with codes instead of names — will be able to link the gene scans to medical histories. Their goal is to discern the larger picture, hoping to spot associations between genes and health that would not show up until very large numbers of individuals are compared at once.

Although this vast experiment has been contemplated for years, it was given a boost last year when Kaiser and the university won a $25 million grant from the National Institutes of Health as part of the stimulus package.

However, the study has begun just as some scientists have started to question the value of these experiments, and when private ventures, like 23andMe, are struggling to find a consumer market for gene tests.

David B. Goldstein, a Duke University researcher, said he believed “interesting and valuable information” would come from the Kaiser study, but he questioned whether it was the most efficient way to gather information about the genetic links to disease. “It’s an awfully expensive study,” Dr. Goldstein said in an e-mail message.

He added, “We have literally hundreds of genome-wide association studies for common diseases, and in most cases we are having trouble making much use of them.” While Dr. Goldstein stresses that discoveries are being made using that technique, he believes that a different approach — sequencing the entire genetic code of fewer patients rather than scanning the genome for variations — “is likely to yield more useful returns.”

For Kaiser, the federal grant is just the beginning of a long-term endeavor.

In the coming years, 400,000 more members will be asked to contribute their DNA to the project when they come in for routine blood work. Kaiser is spending $9 million to build a repository for the blood samples.

“It’s an idea whose time has come,” said Dr. Pui-Yan Kwok, an investigator at the Institute for Human Genetics at the University of California, San Francisco, where the genes are being scanned. “The genotyping technology is here, the electronic medical records are here.”

Using high-precision robots to process each sample, the genomes of 2,500 participants are being analyzed each week. The genetic information will be stored in computers for future studies by scientists all over the globe.

At the same time, Elizabeth Blackburn, a Nobel-prize winning biologist at the university, and her lab will be conducting a mass experiment on a separate set of 100,000 samples of DNA from the Kaiser patients. They will be measuring the length of telomeres — wads of DNA at the top and bottom of every chromosome that, like shoelace tips, keep them from unraveling when a cell divides. Telomere length tends to shorten with age, and shorter telomeres tend to be linked with shorter life spans.

“Telomere length is more reflective of things that happen in your life than the genetic hand you are born with,” said Dr. Blackburn.

She said that the Kaiser patients are a valuable resource for science because their detailed medical histories can be matched with the varied measurements of telomere length and matched to the gene scans that will be done for each participant as well. Her targets are the three top diseases that kill the elderly: cancer, cardiovascular disease and diabetes.

At the Kaiser research lab, a production line of robotic equipment has been set up to process the 130,000 cups of saliva that have been mailed by patients and stored, at room temperature, in racks of cardboard “pizza boxes,” 50 cups to a box. Here, the robots draw out a sample of spit, and chemically process it to extract the donor’s DNA.

One set of Mrs. Young’s DNA will be sent to Dr. Blackburn’s lab, where the length of its telomeres will be measured. A second set will arrive at Dr. Kwok’s newly equipped facility, where the genome of each Kaiser participant will be scanned using an array of robots, each costing about a quarter million dollars.

At Dr. Kwok’s ninth-floor lab, three sets of robots prepare the DNA samples shipped from Oakland. The full complement of DNA from each volunteer is washed over a custom-designed silicon chip about this size of small fingernail. Microscopic wells etched into the chip are each engineered to pluck out one of 675,000 possible gene variants.

“Our biggest fear is a power-failure,” said Dr. Kwok. Each array, filled with 96 processed DNA samples, costs $10,000.

Biology 2.0

2010-06-22T06:12:00.000-07:00

The Economist, June 17th 2010

A decade after the human-genome project, writes Geoffrey Carr (interviewed here), biological science is poised on the edge of something wonderful.

TEN years ago, on June 26th 2000, a race ended. The result was declared a dead heat and both runners won the prize of shaking the hand of America’s then president, Bill Clinton, at the White House. The runners were J. Craig Venter for the private sector and Francis Collins for the public. The race was to sequence the human genome, all 3 billion genetic letters of it, and thus—as headline writers put it—read the book of life.

It quite caught the public imagination at the time. There was the drama of a maverick upstart, in the form of Dr Venter and his newly created firm, Celera, taking on the medical establishment, in the form of Dr Collins’s International Human Genome Sequencing Consortium. There was the promise of a cornucopia of new drugs as genetic targets previously unknown to biologists succumbed to pharmacological investigation. There was talk of an era of “personalised medicine” in which treatments would be tailored to an individual’s genetic make-up. There was the frisson of fear that a genetic helotry would be created, doomed by its DNA to second-class health care, education and employment. And there was, in some quarters, a hope that a biotech boom based on genomics might pick up the baton that the internet boom had just dropped, and that lots and lots of money would be made.

And then it all went terribly quiet. The drugs did not appear. Nor did personalised medicine. Neither did the genetic underclass. And the money certainly did not materialise. Biotech firms proved to be just as good at consuming cash as dotcom start-ups, and with as little return. The casual observer, then, might be forgiven for thinking the whole thing a damp squib, and the $3 billion spent on the project to be so much wasted money. But the casual observer would be wrong. As The Economist observed at the time, the race Dr Venter and Dr Collins had been engaged in was a race not to the finish but to the starting line. Moreover, compared with the sprint they had been running in the closing years of the 1990s, the new race marked by that starting line was a marathon.

The new race has been dogged by difficulties from the beginning. There was a false start (the announcement at the White House that the sequence was complete relied on a generous definition of that word: a truly complete sequence was not published until 2003). The competitors then ran into numerous obstacles that nature had strewn on the course. They found at first that there were far fewer genes than they had expected, only to discover later that there were far more. These discoveries changed the meaning of the word “gene”. They found the way genes are switched on and off is at least as important, both biologically and medically, as the composition of those genes. They found that their methods for linking genetic variation to disease were inadequate. And they found, above all, that they did not have enough genomes to work on. Each human genome is different, and that matters.

All is revealed

One by one, however, these obstacles are falling away. As they do so, the science of biology is being transformed. It seems quite likely that future historians of science will divide biology into the pre- and post-genomic eras.

In one way, post-genomic biology—biology 2.0, if you like—has finally killed the idea of vitalism, the persistent belief that to explain how living things work, something more is needed than just an understanding of their physics and chemistry. True, no biologist has really believed in vitalism for more than a century. Nevertheless, the promise of genomics, that the parts list of a cell and, by extension, of a living organism, is finite and cataloguable, leaves no room for ghosts in the machine.

Viewed another way, though, biology 2.0 is actually neo-vitalistic. No one thinks that a computer is anything more than the sum of its continually changing physical states, yet those states can be abstracted into concepts and processed by a branch of learning that has come to be known as information science, independently of the shifting pattern of electrical charges inside the computer’s processor.

So it is with the new biology. The chemicals in a cell are the hardware. The information encoded in the DNA is the preloaded software. The interactions between the cellular chemicals are like the constantly changing states of processing and memory chips. Though understanding the genome has proved more complicated than expected, no discovery made so far suggests anything other than that all the information needed to make a cell is squirreled away in the DNA. Yet the whole is somehow greater than the sum of its parts.

Whether the new biology is viewed as rigorously mechanistic or neo-vitalistic, what has become apparent over the past decade is that the process by which the genome regulates itself, both directly by one gene telling another what to do and indirectly by manipulating the other molecules in a cell, is vastly more complicated and sophisticated than anybody expected. Yet it now looks tractable in a way that 20 years ago it did not. Just as a team of engineers, given a rival’s computer, could strip it down and understand it perfectly, so biologists now believe that, in the fullness of time, they will be able to understand perfectly how a cell works.

And if cells can be understood completely in this way, then ultimately it should be possible to understand assemblages of cells such as animals and plants with equal completeness. That is a much more complicated problem, but it is different only in degree, not kind. Moreover, understanding—complete or partial—brings the possibility of manipulation. The past few weeks have seen an announcement that may, in retrospect, turn out to have been as portentous as the sequencing of the human genome: Dr Venter’s construction of an organism with a completely synthetic genome. The ability to write new genomes in this way brings true biological engineering—as opposed to the tinkering that passes for biotechnology at the moment—a step closer.

A second portentous announcement, of the genome of mankind’s closest—albeit extinct—relative, Neanderthal man, shows the power of biology 2.0 in a different way. Putting together some 1.3 billion fragments of 40,000-year-old DNA, contaminated as they were with the fungi and bacteria of millennia of decay and the personal genetic imprints of the dozens of archaeologists who had handled the bones, demonstrates how far the technology of genomics has advanced over the course of the past decade. It also shows that biology 2.0 can solve the other great question besides how life works: how it has evolved and diversified over the course of time.

As is often the way with scientific discovery, technological breakthroughs of the sort that have given science the Neanderthal genome have been as important to the development of genomics as intellectual insights have been. The telescope revolutionised astronomy; the microscope, biology; and the spectroscope, chemistry. The genomic revolution depends on two technological changes. One, in computing power, is generic—though computer-makers are slavering at the amount of data that biology 2.0 will need to process, and the amount of kit that will be needed to do the processing. This torrent of data, however, is the result of the second technological change that is driving genomics, in the power of DNA sequencing.

The new law

Computing has, famously, increased in potency according to Moore’s law. This says that computers double in power roughly every two years—an increase of more than 30 times over the course of a decade, with concomitant reductions in cost.

There is, as yet, no sobriquet for its genomic equivalent, but there should be. Eric Lander, the head of the Broad Institute, in Cambridge, Massachusetts, which is America’s largest DNA-sequencing centre, calculates that the cost of DNA sequencing at the institute has fallen to a hundred-thousandth of what it was a decade ago (see chart 1). The genome sequenced by the International Human Genome Sequencing Consortium (actually a composite from several individuals) took 13 years and cost $3 billion. Now, using the latest sequencers from Illumina, of San Diego, California, a human genome can be read in eight days at a cost of about $10,000. Nor is that the end of the story. Another Californian firm, Pacific Biosciences, of Menlo Park, has a technology that can read genomes from single DNA molecules. It thinks that in three years’ time this will be able to map a human genome in 15 minutes for less than $1,000. And a rival technology being developed in Britain by Oxford Nanopore Technologies aspires to similar speeds and cost.

This increase in speed and reduction in cost is turning the business of biology upside down. Up until now, firms that claim to read individual genomes (see article) have been using a shortcut. They have employed arrays of DNA probes, known as gene chips, to look for pre-identified variations in their clients’ DNA. Those variations have been discovered by scientific collaborations such as the International HapMap Project, which search for mutations of the genetic code called single-nucleotide polymorphisms, or SNPs, in blocks of DNA called haplotypes. A SNP (pronounced “snip”) is a place where a lone genetic letter varies from person to person. Some 10m SNPs are now known, but in the forest of 3 billion genetic letters there is reason to believe they are but a smattering of the total variation. Proper sequencing will reveal the lot.

Finding the sequence—even the full range of sequences—is, though, just the beginning. You then have to do something useful with the result. This is where the computing comes in. Computers allow individual genomes—all 3 billion base pairs of them—to be compared. And not only human genomes. Cross-species comparisons are enormously valuable. Laboratory experiments on creatures ranging from yeast to mice can reveal the functions of genes in these species. Computer comparison then shows which human genes correspond in DNA sequence and thus, presumably, in function, to the genes in these “model” organisms.

Cross-species comparison also shows how species differ, and thus how they have diverged. Comparing DNA from populations within a species can show how that species is evolving. Comparing DNA from individuals within a population can explain why those individuals differ from one another. And comparing the DNA from cells within an individual can show how tissues develop and become differentiated from one another, and what goes wrong in diseases like cancer.

Even before cheap sequencing became available, huge databases were being built up. In alliance with pathology samples, doctors’ notes and—most valuable of all—long-term studies of particular groups of individuals, genetic information can be linked to what biologists refer to as the phenotype. This is an organism’s outward expression: its anatomy, physiology and behaviour, whether healthy or pathological. The goal of the new biology is to tie these things together reliably and to understand how the phenotype emerges from the genotype.

That will lead to better medical diagnosis and treatment. It will result in the ability to manipulate animals, plants, fungi and bacteria to human ends. It will explain the history of life. And it will reveal, in pitiless detail, exactly what it is to be human.

The next advances in genomics may happen in China

2010-06-22T06:11:00.000-07:00

China: The dragon's DNA, The Economist, June 17th, 2010

IN AN old printing works on an obscure industrial estate in Hong Kong’s New Territories a little bit of history is being made. Most of the five-storey building is dusty and derelict. One floor, however, is state-of-the-art. The paintwork shines. The metal gleams. And in the largest room the electrical sockets in the floor sit in serried ranks awaiting contact.

That contact will shortly be made with the delivery of 120 spanking new top-of-the-range Illumina sequencing machines. When they have all been installed the building will, so it is claimed, have more DNA-sequencing capacity than the whole of the United States. And that is just the start. According to Alex Wong, who runs the facility, the other four floors will also soon be refurbished and the whole building will become a powerhouse ready to generate information for biology 2.0.

The building belongs to the BGI, once known as the Beijing Genomics Institute. Mr Wong manages the institute’s Hong Kong operation, but the institute itself is based over the border in the People’s Republic proper, in Shenzhen. The BGI itself is one part—arguably the leading one—of China’s effort to show that it can be the scientific peer of the West.

Its boss, Yang Huangming, is certainly the peer of people like Dr Venter, Dr Lander and Dr Collins. He is a man on a mission to make the BGI the first global genomics operation. Part of the reason for building his newest sequencing centre in Hong Kong is to reassure researchers from other countries that the facility will operate inside a reliable legal framework. If all goes well, laboratories in North America and Europe will follow.

The BGI began in 1999, when Dr Yang muscled his way into the human-genome project, cornering part of the tip of chromosome three (about 1% of the total human genome) as the Chinese contribution to that international project. From this humble beginning it now plans to sequence 200 full human genomes as part of an international collaboration called the 1,000-genome project. Half these genomes will be Chinese, but the institute’s researchers intend to sample the full geographical range of humanity. And not only human genomes. The BGI has already solved the genomes of rice, cucumbers, soyabeans and sorghum, honeybees, water fleas, pandas, lizards and silkworms, and some 40 other species of plant and animal, along with over 1,000 bacteria.

And it, too, is interested in cancer. According to Dr Yang the institute will not merely compare healthy and tumorous tissue from the same individuals, as the International Cancer Genome Consortium (of which it is a part) plans to do, it will actually be able to follow the pattern of mutation, in the order that it happened, within an individual that has led to his cancer. That may allow pre-emptive treatment to be developed for people whose tumours are not yet malignant. Indeed, as the price of sequencing drops, this “internal phylogenetics”, as Dr Yang calls it, might be extended to trace the pattern of mutation that develops in even an apparently healthy body as cells proliferate within it. That may yield nothing interesting. On the other hand it might help explain patterns of disease associated with ageing as cells whose ancestors were genetically identical slowly diverge from one another.

A better balsa

The BGI also has non-medical ambitions. Its researchers are examining fast-growing plants with interesting structural properties, such as balsa, a lightweight South American wood familiar to generations of schoolboy model-makers, and bamboo, a traditional construction material in China. They are experimenting, too, with animal cloning. The BGI was the first outfit to clone pigs, and it has developed a new and more effective way of cloning mammals that might ultimately be applied to humans, if that were ever permitted.

But the organisation is involved in even more controversial projects. It is about to embark on a search for the genetic underpinning of intelligence. Two thousand Chinese schoolchildren will have 2,000 of their protein-coding genes sampled, and the results correlated with their test scores at school. Though it will cover less than a tenth of the total number of protein-coding genes, it will be the largest-scale examination to date of the idea that differences between individuals’ intelligence scores are partly due to differences in their DNA.

Dr Yang is also candid about the possibility of the 1,000-genome project revealing systematic geographical differences in human genetics—or, to put it politically incorrectly, racial differences. The differences that have come to light so far are not in sensitive areas such as intelligence. But if his study of schoolchildren does find genes that help control intelligence, a comparison with the results of the 1,000-genome project will be only a mouse-click away.

At the moment this frenetic activity is paid for mostly by regional development grants and loans from state-owned Chinese banks, but Dr Yang hopes to go properly commercial. The Hong Kong operation will work partly as a contractor, and Mr Wong hopes to persuade biologists around the world to send their samples in and have them sequenced there rather than relying on their own universities to do the sequencing. Whether the BGI’s researchers can turn their mass-produced DNA sequences into new scientific insights and bankable products remains to be seen, but the world is watching.

Special reports

No predicting value of 100 genetic variants linked to heart disease

2010-06-20T23:56:00.000-07:00

- 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.

Reference

- The Genome, 10 Years Later, NYT, June 20, 2010

Geneticist George Church: Sequencing human genome ‘high priority’ for China

2010-06-15T23:38:00.000-07:00

smartplanet.com, By Boonsri Dickinson | Jun 10, 2010

Long before he could grow his signature beard, geneticist George Church fantasized about sequencing the genomes of mankind. Today, that dream is a reality. Three years before anyone else thought to sequence genomes — 1987, to be precise — Church was in his Harvard University laboratory unraveling the DNA data code.

Hype is mounting for the 10-year anniversary of the announcement of the first draft of the human genome, officially this June. But Church admits that he’s not at all impressed — despite $3 billion already invested, humanity is far from completely decoding the human genome.

Perhaps no one has seen genomics as up-and-close as Church, who became his own guinea pig in the Personal Genome Project, or PGP. To date, the project counts more than 16,000 volunteers — but only a select dozen has made their genetic and medical history public. Eventually, 100,000 people will be sequenced through the project.

This week, Church is in Steamboat Springs, Colorado, where he’ll be speaking at the FASEB Summer Research Conference on Genome Engineering. I spoke with him yesterday about why genetic engineering is about selective application — and why the U.S. needs to defend its lead in genomic technology.

BD: Now, how exactly are you going to program biology to do what you want?

GC: There are two sides to my research: reading and writing biology.

The genome engineering is on the writing side. It’s not so much about changing every part of a genome at once, but cost-effectively engineering many parts of genomes that matter — for example, engineering them for resistance to all viruses.

On the other side, we are reading genomes for personal genomics. But there are many ways that reading and writing interact. We need to read the genomes of nature to get ideas then re-write these in novel combinations, and then re-read them to see that we made what we intended or see how lab evolution has made our constructs even better.

BD: Did you learn anything from having your genome sequenced?

GC: We are writing software for everyone to use. We have 32 public genomes already on which we are testing this software. We stare at the output from 32 genomes. Mine is probably among the most boring.

For example, PGP number 6 had the allele of hypertrophic cardiomyopathy. It’s a condition, where one day you are shooting a basketball and then suddenly drop dead. It’s not part of standard medical care to look out for this. We recommended that PGP 6, get an endocardiogram.

It’s a perfect example that can happen to you late in life. You can look at the many highly predictable and highly actionable gene variants like fire insurance. Everybody is at risk. You can’t say that you aren’t at risk until you look at your genome.

BD: Can you tell me more about how you were among the first to start sequencing the human genome?

GC: As a teenage researcher in 1974, I typed in all the DNA into a computer. At the time, almost no biologists used computers. I thought it would be nice to take these strings of [the letters of DNA] A, C, G , T, and fold them up and see if they looked like each other when they were folded. This was exciting and I wondered what about folding up these strings from many humans . So I went to Harvard where Wally Gilbert was interested in sequencing.

At the time, very few molecular biologists were working full-time on new technology. It was considered not a suitable occupation. They said to me, you should be studying science instead of developing technology. It didn’t earn you respect. They would say things like, “well this is taking a long time, why don’t you just do an experiment, and learn about the real biology.” And they would ask, “are you just playing games or do you care about the answer?”

In 1984, I published a paper called “Genomic Sequencing”. That year, the US Dept of Energy had a very small meeting - about a dozen of us were there and we said we could sequence a human genome. One of the administrators at DOE saw the report and encouraged us to apply for a grant. So I did.

BD: You must have gotten your hands dirty early on in the sequencing game.

GC: Up until 1984, I was a grad student at Harvard. I was a post doc from 1984 to 1986 at the University of California at San Francisco. Then I went back to Harvard as a professor in 1986. As a starting professor, did a lot of experiments myself - and began to get help from students.

I was pretty sure that sequencing many human genomes would work. I was considered optimistic by my colleagues, but now I realize how I underestimated how fast sequencing would change. The last five years it has been meteoric. Even fast technologies like computers advance by a factor of 1.5 per year, according to Moore’s Law. But genomics has improved by 10-fold per year for the last 5 years. I thought it would follow the same curve as computing. But it hasn’t.

The field of genetics depends on computers. But even though computers are moving more slowly, they are adequate.

Computers handle the sequencing information, processing trillions of bits of information, and those images are compressed and analyzed. Interpreting the genome involves more than computers. It involves new studies on many people to see how variations in genome plus environments produce our distinctive traits .

BD: Are you excited about the 10-year anniversary?

GC: It’s kind of an arbitrary number. For one thing, no one even sequenced an entire human genome. They made an announcement, saying it was over. They sequenced 93 percent of one genome. [People have two genomes]. They completely disregarded the issue of traits. It wasn’t even from one person. The other 7 percent is so hard, we still haven’t done it.

I’m excited that we can now actually get enough genomes and trait data from volunteers so that we can work together to add value to the 10 year-old crude genome sequence that we celebrate today.

BD: Are other countries trying to get in on this genetic race?

GC: Beijing was a minor player in human genome 10 years ago and is a major player today. I’m working with them through my company, Knome, to sequence personal genomes of early adopters. The Chinese government has set this as a high priority.

It’s like in the 60s, the U.S. decided to put a man on the moon. The U.S. was a leader in the human genome project and is now leading in genomic technology. The U.S. could launch another project, but maybe we’ve been waiting for the cost of sequencing to drop.

BD: So how much does an entire genome cost these days?

GC: The price of a genome is a little less than $10,000. The cost is $1,000. There is a gap between the price and the cost.

The gap is shrinking and the costs are still dropping.

We are going to start hearing stories about people getting their entire genome sequenced. What might these stories miss?

One thing that they might do, is try to interpret the data the same way they did for companies like 23andMe and focus on common variants.

The real story is in the rare alleles. One in ten percent of us are very affected by these, and the sequencing tests reveal them as long as we are looking for them.

Almost all common diseases have a rare allele component to it. What happened before is that we went through a fad. Scientists were looking where the light was in the common variants and they mostly ignored rare alleles.

My company, Knome, can test for all 1,800 genes that have known medically actionable rare alleles. While every gene has rare alleles, a lot don’t have an impact.

Clinical geneticists order these tests of rare alleles that have large and well-known impacts all the time, but just one or two tests at a time because it is so expensive. That’s going to change.

BD: Do you think you’ll accomplish your dream soon?

GC: I suspect everyone who wants to have their genome sequenced could have it done in the next few years. It depends on the complexity of the social interactions. Even if the price is right, it depends on who else is getting their genome sequenced. If celebrities do it, then it will become a fad and will be accepted more quickly.

Susceptibility loci for Alzheimer disease

2010-06-15T06:33:00.000-07:00

While we have understood the bases for mendelian, early-onset Alzheimer disease for nearly 2 decades, elucidation of the genetic risks for late-onset disease beyond the apolipoprotein E locus, discovered in 1993, had been painfully slow until the last year.

From 1993 to 2009, thousands of genetic association studies on Alzheimer disease had been published without any becoming generally accepted as true risk loci for the disease.

With the benefit of hindsight, we now have some indication of why no other risk loci were found during this period; simply, there are no other loci with similar effect sizes to apolipoprotein E to be found.

Now, however, with the advent of whole-genome associations, we are beginning to find the weaker risk loci for the disease.

Whole-genome associations rely on the observation that, within a certain population, genetic variability at 1 point predicts (tags), with reasonable accuracy, the other genetic variability within approximately 20 kilobases (kb).

This means that assessment of variability across the whole genome can be achieved by assessment of these tagging single-nucleotide polymorphisms.

In practice, this means that genetic variability across the genome can be systematically tested for association with disease by genotyping about 400 000 evenly spaced tagging single-nucleotide polymorphisms in large numbers of cases and controls. The larger the series of cases and controls, the smaller the effect that can be detected.

Through the application of this technology and the use of approximately 2000 Alzheimer cases and a greater number of controls, 2 recent studies have identified 3 loci as being clearly implicated in Alzheimer disease6-7: CLU, CRI, and PICALM, with other loci, including BIN1 and CNTN5, almost reaching significance.

References

- Identification of Alzheimer Risk Factors Through Whole-Genome Analysis. John Hardy, PhD; Julie Williams, PhD. Arch Neurol. 2010;67(6):663-664.

What Five FDA Letters Mean for the Future of DTC Genetic Testing

2010-06-15T01:20:00.000-07:00

A interesting post from Dan Vorhaus at genomicslawreport.com.

Genetic Testing Companies in San Diego, Boston, & San Francisco Studying FDA Letters

2010-06-14T01:28:00.000-07:00

Bruce V. Bigelow 6/14/10, xconomy.com

Five companies that provide genetic testing services—including San Diego’s Illumina (NASDAQ: ILMN), 23andMe and Navigenics in the San Francisco Bay Area, and Knome in Cambridge, MA—no doubt spent the weekend parsing letters issued Friday by the FDA.

The letters, which were posted on the FDA website and signed by Alberto Gutierrez of the FDA’s office of In Vitro Diagnostic Device Evaluation and Safety, notify the companies that genome-sequencing tests they offer to consumers are medical devices that require the agency’s approval. The Food and Drug Administration says it wants to make sure that direct-to-consumer (DTC) genome test kits are “analytically and clinically accurate so that individuals are not misled by incorrect test results or unsupported clinical interpretations.”

The FDA challenge, which also was sent to deCODE Genetics, which is headquartered in Iceland, follows the agency’s move last month to prevent San Diego-based Pathway Genomics from selling its personal genome test kit through Walgreens stores. The letters sent by the FDA do not order the companies to stop selling the tests, but suggests that some genetic testing services they offer may not be marketed legally.

The San Diego Union-Tribune says the FDA letters prompted Escondido, CA-based Palomar Pomerado Health to suspend sales of DNA kits from 23andMe of Mountain View, CA. Palomar Pomerado spokesman Andy Hoang told the newspaper, “we believe the future of medicine is genomics and that personalized medicine, driven by a deeper understanding of the patient’s own unique genetic profile, represents the way medicine will be practiced in the future.

The letters likely were a surprise, as Illumina CEO Jay Flatley said nothing about it when we discussed the FDA’s regulation of personal genome testing the previous day. Illumina declined to comment to the Union-Tribune Friday, except to say the company is studying the content of the letter the FDA sent to Flatley concerning Illumina’s Infinium HumanHap550 array. Illumina doesn’t sell its services directly to consumers, but provides its HumanHap550 array to 23andMe and deCODE Genetics.

Other news accounts explaining the FDA challenge are available at The New York Times and Washington Post, but I found an excellent analysis of the issue by attorney Dan Vorhaus of Charlotte, N.C., here at the Genomics Law Report.

Bruce V. Bigelow is the editor of Xconomy San Diego. You can e-mail him at bbigelow@xconomy.com or call 858-202-0492

A Decade Later, Genetic Map Yields Few New Cures

2010-06-12T23:58:00.000-07:00

By NICHOLAS WADE, NYT, Published: June 12, 2010

Ten years after President Bill Clinton announced that the first draft of the human genome was complete, medicine has yet to see any large part of the promised benefits.

For biologists, the genome has yielded one insightful surprise after another. But the primary goal of the $3 billion Human Genome Project — to ferret out the genetic roots of common diseases like cancer and Alzheimer’s and then generate treatments — remains largely elusive. Indeed, after 10 years of effort, geneticists are almost back to square one in knowing where to look for the roots of common disease.

One sign of the genome’s limited use for medicine so far was a recent test of genetic predictions for heart disease. A medical team led by Nina P. Paynter of Brigham and Women’s Hospital in Boston collected 101 genetic variants that had been statistically linked to heart disease in various genome-scanning studies. But the variants turned out to have no value in forecasting 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, Dr. Paynter reported this February in The Journal of the American Medical Association.

In announcing on June 26, 2000, that the first draft of the human genome had been achieved, Mr. Clinton said it would “revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.”

At a news conference, Francis Collins, then the director of the genome agency at the National Institutes of Health, said that genetic diagnosis of diseases would be accomplished in 10 years and that treatments would start to roll out perhaps five years after that.

“Over the longer term, perhaps in another 15 or 20 years,” he added, “you will see a complete transformation in therapeutic medicine.”

The pharmaceutical industry has spent billions of dollars to reap genomic secrets and is starting to bring several genome-guided drugs to market. While drug companies continue to pour huge amounts of money into genome research, it has become clear that the genetics of most diseases are more complex than anticipated and that it will take many more years before new treatments may be able to transform medicine.

“Genomics is a way to do science, not medicine,” said Harold Varmus, president of the Memorial Sloan-Kettering Cancer Center in New York, who in July will become the director of the National Cancer Institute.

The last decade has brought a flood of discoveries of disease-causing mutations in the human genome. But with most diseases, the findings have explained only a small part of the risk of getting the disease. And many of the genetic variants linked to diseases, some scientists have begun to fear, could be statistical illusions.

The Human Genome Project was started in 1989 with the goal of sequencing, or identifying, all three billion chemical units in the human genetic instruction set, finding the genetic roots of disease and then developing treatments. With the sequence in hand, the next step was to identify the genetic variants that increase the risk for common diseases like cancer and diabetes.

It was far too expensive at that time to think of sequencing patients’ whole genomes. So the National Institutes of Health embraced the idea for a clever shortcut, that of looking just at sites on the genome where many people have a variant DNA unit. But that shortcut appears to have been less than successful.

The theory behind the shortcut was that since the major diseases are common, so too would be the genetic variants that caused them. Natural selection keeps the human genome free of variants that damage health before children are grown, the theory held, but fails against variants that strike later in life, allowing them to become quite common. In 2002 the National Institutes of Health started a $138 million project called the HapMap to catalog the common variants in European, East Asian and African genomes.

With the catalog in hand, the second stage was to see if any of the variants were more common in the patients with a given disease than in healthy people. These studies required large numbers of patients and cost several million dollars apiece. Nearly 400 of them had been completed by 2009. The upshot is that hundreds of common genetic variants have now been statistically linked with various diseases.

But with most diseases, the common variants have turned out to explain just a fraction of the genetic risk. It now seems more likely that each common disease is mostly caused by large numbers of rare variants, ones too rare to have been cataloged by the HapMap.

Defenders of the HapMap and genome-wide association studies say that the approach made sense because it is only now becoming cheap enough to look for rare variants, and that many common variants do have roles in diseases.

At this point, some 850 sites on the genome, most of them near genes, have been implicated in common diseases, said Eric S. Lander, director of the Broad Institute in Cambridge, Mass., and a leader of the HapMap project. “So I feel strongly that the hypothesis has been vindicated,” he said.

But most of the sites linked with diseases are not in genes — the stretches of DNA that tell the cell to make proteins — and have no known biological function, leading some geneticists to suspect that the associations are spurious.

Many of them may “stem from factors other than a true association with disease risk,” wrote Jon McClellan and Mary-Claire King, geneticists at the University of Washington, Seattle, in the April 16 issue of the journal Cell. The new switch among geneticists to seeing rare variants as the major cause of common disease is “a major paradigm shift in human genetics,” they wrote.

The only way to find rare genetic variations is to sequence a person’s whole genome, or at least all of its gene-coding regions. That approach is now becoming feasible because the cost of sequencing has plummeted, from about $500 million for the first human genome completed in 2003 to costs of $5,000 to $10,000 that are expected next year.

But while 10 years of the genome may have produced little for medicine, the story for basic science has been quite different. Research on the genome has transformed biology, producing a steady string of surprises. First was the discovery that the number of human genes is astonishingly small compared with those of lower animals like the laboratory roundworm and fruit fly. The barely visible roundworm needs 20,000 genes that make proteins, the working parts of cells, whereas humans, apparently so much higher on the evolutionary scale, seem to have only 21,000 protein-coding genes.

The slowly emerging explanation is that humans and other animals have much the same set of protein-coding genes, but the human set is regulated in a much more complicated way, through elaborate use of DNA’s companion molecule, RNA.

Little, if any, of this research could have been done without having the human genome sequence available. Every gene and control element can now be mapped to its correct site on the genome, enabling all the working parts of the system to be related to one another.

“Having a common scaffold on which one can put all the information has dramatically accelerated progress,” Dr. Lander said.

The genome sequence has also inspired many powerful new techniques for exploring its meaning. One is chip sequencing, which gives researchers access to the mysterious and essential chromatin, the complex protein machinery that both packages the DNA of the genome and controls access to it.

The data from the HapMap has also enabled population geneticists to reconstruct human population history since the dispersal from Africa some 50,000 years ago. They can pinpoint which genes bear the fingerprints of recent natural selection, which in turn reveals the particular challenges to which the populations on different continents have had to adapt.

As more people have their entire genomes decoded, the roots of genetic disease may eventually be understood, but at this point there is no guarantee that treatments will follow. If each common disease is caused by a host of rare genetic variants, it may not be susceptible to drugs.

“The only intellectually honest answer is that there’s no way to know,” Dr. Lander said. “One can prefer to be an optimist or a pessimist, but the best approach is to be an empiricist.”

Next: Drug companies stick with genomics but struggle with information overload.

F.D.A. Faults Companies on Unapproved Genetic Tests

2010-06-12T06:35:00.001-07:00

By ANDREW POLLACK, NYT, Published: June 11, 2010

The Food and Drug Administration is cracking down on 23andMe and other companies that sell genetic tests directly to consumers.

The F.D.A. sent letters this week to five companies involved in that business, saying their tests are medical devices that must receive regulatory approval before they can be marketed.

“Premarket review allows for an independent and unbiased assessment of a diagnostic test’s ability to generate test results that can reliably be used to support good health care decisions,” Alberto Gutierrez, who leads diagnostic test regulation at the F.D.A., wrote in the letters.

The letters, posted on the F.D.A. Web site on Friday, say the companies must apply for approval or discuss with the agency why certain test claims do not require such approval.

But the letters stop short of saying the tests must be taken off the market until they are approved. Dr. Gutierrez said in an interview that it would be unfair to remove the tests from the market because the agency had not clearly told the companies that the devices needed approval.

23andMe and two other recipients of the letters, Navigenics and DeCode Genetics, sell tests that scan a person’s DNA, looking at genetic variations that can suggest whether a person is at a higher or lower risk of getting diseases like cancer or diabetes. The most prominent of the companies, 23andMe, is backed by Google and run by Anne Wojcicki, the wife of Google’s co-founder, Sergey Brin.

Illumina, which also received a letter, sells so-called DNA chips that are used by some companies to do the DNA scans. The fifth recipient, Knome, offers consumers a complete sequence of their DNA, which can be used to glean disease risk information.

The F.D.A. action is the latest salvo in a long-running debate about whether and how such tests should be regulated.

On one side are some doctors, geneticists and state regulators who say the tests should be regulated because the results might be used to make medical decisions. Some also say a doctor should be involved in ordering the tests and interpreting results.

On the other side are those, especially 23andMe executives, who argue that the services merely provide information, not medical diagnosis, and that consumers have a right to the information contained in their genes. At a time when consumers are taking more control of their health care, denying them such information would be, as one director of 23andMe recently put it, “appallingly paternalistic.”

The companies have also said that their tests do not require F.D.A. approval because they have been developed and are offered by a single laboratory. The F.D.A. has typically refrained from regulating such tests, as opposed to test kits that are widely sold to laboratories, hospitals and doctor’s offices.

The F.D.A. is now clearly deciding in favor of regulation, saying the tests of disease risk can have medical consequences.

“It is not unknown for women to take out their ovaries if they are at high risk of ovarian cancer,” Dr. Gutierrez said. Some of the services are also offering consumers information that could be used to determine the doses they should get of particular drugs, like the blood thinners, warfarin and Plavix.

But Dr. Gutierrez denied that the agency was being paternalistic. “We really don’t have any issues with denying people information,” he said. “We just want to make sure the information they are given is correct.”

In a statement Friday, 23andMe said it disagreed with the F.D.A.’s conclusion but was open to discussion on ways to regulate the personal genetics industry. “We are sensitive to the F.D.A.’s concerns, but we believe that people have the right to know as much about their genes and their bodies as they choose.”

By contrast, Kari Stefansson, head of research at DeCode, said the interest by the F.D.A. was “timely, appropriate and welcome” because the company wanted its test to become part of standard medical care. A spokesman for Knome said the company would cooperate with the F.D.A.

The F.D.A. recently sent a similar letter to another company, Pathway Genomics, which had planned to sell its test through Walgreen drugstores and other chains. Walgreen dropped its plans to sell the test, though Pathway still offers it online.

The House Energy and Commerce Committee is also looking into these tests and sent letters last month to 23andMe, Navigenics and Pathway Genomics requesting extensive information.

Concern about the tests was also raised this week when 23andMe said that because of a laboratory mix-up, up to 96 customers might have received information on someone else.

Daniel Vorhaus, a lawyer specializing in regulation of genetic testing and author of the blog Genomics Law Report, said some of his clients were holding back tests because it was unclear which would be regulated.

“No one has a clear understanding of where the F.D.A. is drawing the line at this point,” said Mr. Vorhaus, who does not represent any of the five companies that received the letters. He said the F.D.A. was “trying to keep up with a commercial space that is moving way faster than they are capable of.”

References

- Three Ways FDA Can Lift 'Barriers' to MDx Development, GenomeWeb, June 28, 2010

Autism Genome Project Consortium Implicates Rare CNVs in Autism

2010-06-10T00:08:00.000-07:00

June 09, 2010

Members of the Autism Genome Project Consortium reported online today in Nature that they have identified a host of rare copy number variants (CNVs) that appear to contribute to autism susceptibility.

The team, which includes more than 100 researchers from centers around the world, used high-density microarrays to assess CNV profiles in about 1,000 families affected by autism and nearly 2,000 control individuals.

Their results suggest that while individuals with autism don't necessarily have more CNVs overall than unaffected individuals, they tend to carry more CNVs that affect genes — particularly those involved in processes such as brain cell communication and cellular proliferation.

The results substantiate the importance of genes in autism susceptibility, corresponding author Stephen Scherer, a molecular genetics researcher at the University of Toronto and director of the Hospital for Sick Children's Centre for Applied Genomics, said during a telephone briefing with reporters this week.

Those involved in the study also emphasized the potential of the new findings for helping to diagnose autism earlier and for finding pathways that might serve as targets for improved autism treatments.

Although a fraction of autism cases correspond to conditions — such as fragile X syndrome — resulting from changes to a single gene, most cases appear to be a consequence of much more complex and heterogeneous genetic patterns.

In an effort to uncover new autism risk genes and gain insights into commonly affected molecular pathways, consortium members used the Illumina Infinium 1M SNP microarray to evaluate CNV patterns in 1,275 individuals with autism spectrum disorders and their parents as well as 1,981 unaffected control individuals.

After their quality control steps, the team was left with data for 876 family trios, including 996 individuals with ASD, and 1,287 controls. The CNVs they identified were larger than 30,000 bases and present at less than one percent frequency overall.

Although the team did not find more CNVs overall in individuals with ASD, they found that more of these CNVs — especially deletions — affected gene coding regions in the ASD group than in unaffected individuals.

On average, individuals with ASD had about 19 percent more genic CNVs than control individuals. In addition, some 5.7 percent of children with ASD carried de novo CNVs not present in either of the child's parents.

Some, but not all, of the affected genes have been implicated in autism previously. Among the genes not found in past studies of autism: SHANK2, SYNGAP1, DLGAP2, and the DDX53-PTCHD1 locus.

"Most individuals with autism are probably quite unique," Scherer said, noting that even the most common CNVs detected turn up in less than one percent of the ASD cases tested.

Now that researchers have a catalog of genes affected by rare CNVs, Scherer added, it's possible to begin tying these genes together in pathways and looking at effects on brain function. For example, the researchers reported that the CNVs they detected often impacted genes involved in cellular motility, proliferation, and communication pathways.

By further characterizing these pathways, the team hopes to find clues to detecting autism earlier. Early detection and intervention, in turn, are expected to improve autistic children's social, intellectual, and language outcomes, noted co-author Geraldine Dawson, chief scientific officer for Autism Speaks and a member of the National Institutes of Health's inter-agency autism coordinating committee.

Such analyses are also expected to highlight biological pathways that might be targeted by new or existing drug treatments.

The current findings "give us an idea of what the picture [of autism genetics] may look like," Anthony Monaco, a researcher with the University of Oxford's Wellcome Trust Centre for Human Genetics and study co-author, told reporters.

Nevertheless, the researchers explained, since the rare CNVs found so far account for just 10 to 15 percent of autism risk, more research is needed to understand autism genetics and the interplay between autism susceptibility genes and environmental risk factors.

That will likely require studies using high-throughput sequencing of autism families to find additional genetic changes in genes and genomes, Monaco said, along with studies aimed at finding the best ways of translating genetic research into the clinic.

In an effort to get a better handle on the predictive statistics available from microarray data, Scherer and his colleagues in Ontario plan to use arrays to assess some 5,000 newly diagnosed autism cases in that province over the next few years.

Researchers in Oxford reportedly hope to do a similar pilot study involving at least 1,000 children with autism.

"By identifying the genetic causes of autism, we hope in the future to be able to improve the diagnosis and treatment of this condition which can affect children and their families so severely," Monaco said in a statement.

"[K]nowing about these genetic changes can help the families involved come to terms with why their child has autism, but it can also be important where there are siblings too in determining future risk."

Illumina Slashes Cost of Individual Genome Sequencing Service

2010-06-09T01:31:00.000-07:00

Denise Gellene 6/9/10, xconomy.com

The cost of getting your genome sequenced continues to drop. San Diego’s Illumina (NASDAQ: ILMN) has lowered the cost of its individual sequencing service to $19,500 from $48,000.

The company is offering a discounted price of $9,500 for people with serious medical conditions who could potentially benefit from having their genomes decoded.

Last year, doctors at Yale University reported using whole-genome sequencing to diagnose the mutation responsible for an infant’s persistent diarrhea. The information allowed doctors to tailor their treatment.

Illumina also is offering a discounted price of $14,500 to groups of five or more from the same physician.

“It’s very clear as the price comes down that we’ve been able to open broad new markets,” says Illumina CEO Jay Flatley.

Illumina’s announcement last week came on the heels of Pathway Genomics’ aborted plans to market its genetic test kits in Walgreen drug stores. The retail chain reversed plans to carry the kits after the FDA questioned the company’s decision to market the test without the agency’s approval.

Pathway Genomics, which is based in San Diego, has maintained it is in compliance with “currently applicable” regulations. Now a Congressional committee is looking into genetic tests marketed on the Internet by Pathway and competitors 23andMe and Navigenics.

The service Pathway Genomics intended to offer was cheaper than Illumina’s and far from the comprehensive genome sequence that Illumina provides.

Pathway Genomics planned to sell the kits at $20 to $30 each and charge $79 to $249 to analyze customers’ saliva for relatively few specific genetic characteristics, such as links to certain diseases or how their bodies respond to caffeine or certain prescription drugs.

Illumina’s Flatley says he sees huge opportunities for using the information that can be gleaned from a patient’s genome, adding that he thinks FDA regulators “are as excited to the possibilities as we are. I think they’re just trying to figure out the best way to make that happen, and their concerns are about the process.”

Illumina formed an internal ethics committee to study its handling of the process, and Flatley says it took roughly a year to develop internal protocols that require customers to obtain a doctor’s prescription for the genomic sequencing.

The company’s protocols require that a doctor takes a patient’s sample and that results of Illumina’s genetic analysis are returned to the doctor—not the patient.

“Illumina is taking the high road to make sure it’s done right,” Flatley says.

In its press release, Illumina says its process requires individuals to undergo pre-service consultation, consent and a seven-day cooling-off period.

How useful is all that information to a healthy consumer? My guess is not very, since a great deal of genetic information remains to be discovered.

To Flatley, the really important stake in the ground is the special $9,500 pricing for patients with very serious, life-threatening diseases.

In such cases, Flatley says sequencing a patient’s genome could be beneficial to making a diagnosis or a path for treating the disease.

Denise Gellene is a former Los Angeles Times science writer and regular contributor to Xconomy. You can reach her at dgellene@xconomy.com

On a Mission to Sequence the Genomes of 100,000 People

2010-06-08T23:37:00.000-07:00

New York Times, June 7, 2010

Traditionally, biology is about taking apart things like cells to better understand them. For the geneticist George M. Church, the main objective is to put the pieces back together.

Strolling through his laboratory, one of the larger ones at Harvard Medical School, Dr. Church, 56, points out benches where students and colleagues work on everything from basic genetics, proteomics and biocomputing to synthetic biology and the impact of the millions of microbes that inhabit our guts.

“I’m a polyglot who believes in integration,” he said. “That’s my specialty.”

Dr. Church — a tall man with a long graying beard and rumpled clothes — oversees 45 students in his lab and has co-founded or advises some 22 businesses, many of them startups that focus on things like synthetic biology, genetic sequencing and companies that provide genetic testing to consumers.

His most visible work is the Personal Genome Project, which has 16,000 volunteers, 12 of whom have had their genomes sequenced and made publicly available. These include science and technology celebrities like the Internet pioneer Esther Dyson and the Harvard psychologist and best-selling author Steven Pinker.

Eventually Dr. Church wants to sequence the entire genomes of 100,000 people — nearly every one of the six billion As, Cs, Gs and Ts that occur in a human.

“The goal of getting your genome done is not to tell you what you will die from,” he said, “but it’s how to learn how to take action to prevent disease.”

So far, the science of predicting a person’s health future using genetic markers has not produced much useful information for common diseases, although Dr. Church believes that this will change.

“We need full genome sequences to understand what is really going on genetically,” he said. “Until recently, this wasn’t feasible.”

The project is becoming possible as the speed and efficiency of sequencing increase dramatically, and the once-prohibitive costs drop from millions of dollars for a genome two years ago to under $10,000 today.

Ultra-low sequencing costs will also allow researchers to study interactions between genes and environmental components — microbes, allergens, viruses, toxins, autoimmunity.

Typically, Dr. Church has been at the center of the development of the technologies that are making this possible. He advises or has licensed technology to most of the companies active in this field. This makes his potential conflicts of interests almost byzantine, since many are rivals, particularly in the hotly competitive field of genetic sequencing.

But he is undisturbed and open about his various commercial and scientific involvements — and seems to be like Teflon in avoiding the sort of criticism that other scientists often face for such entanglements.

Indeed, he starts his frequent lectures with a disclosure slide packed with the logos of companies he is involved with — among them LS9 (biofuels), Knome (personal genomes), Alacris Pharmaceuticals (cancer) and Joule Unlimited (photosynthesis).

“I want to move the science into application,” Dr. Church explains, “and I’ll support anything that gets it there. I won’t support one over the other. If they tell me something secret, I can’t tell anyone until it comes into the public domain.”

Dr. Edward R. B. McCabe, a geneticist and physician at the University of California, Los Angeles, said: “George has been an important figure in molecular genetics and its evolution, including genomics and bioinformatics. If we are to understand the complexity of biological systems, then integration on the scale George recommends will be essential.”

A leader in the Human Genome Project during the 1980s and ’90s, Dr. Church first came to prominence while still a graduate student, for developing some of the earliest genetic sequencers. These machines and processes combined a love of computers, engineering and science that began in high school.

“I always loved computers — it’s something inside you,” he said in an interview. But as a boy growing up in Clearwater, Fla., Dr. Church did not have access to computers. “So I made one myself,” he said. Later, when his mother married a physician, he became interested in biology.

As an undergraduate at Duke University, he majored in zoology and chemistry and worked in a lab that used sophisticated X-rays to identify the shapes of crystallized proteins.

“I got to use math, physics, chemistry and computers,” he said. “This was also one of the few areas of biology at the time that used robots.”

As scientists go, Dr. Church is an active public figure who gets more than his share of news media attention, which he clearly enjoys and takes in stride. In fact, little seems to disrupt his equilibrium.

“I’m pathologically calm,” he said — which may be one reason he has ruffled so few feathers in the hypercompetitive world of high-stakes science.

His lab includes cold rooms filled with tissue samples, machine shops with clamps and drills, and benches overflowing with electronics equipment. He points out where teams are studying antibiotic drug resistance, microbial fuels, metabolic engineering and epigenetics (the turning on and off of genes, usually by environmental influences).

He presides over his bio-empire with a tiny Sony laptop that he carries like someone else might cradle a baby, or a poodle. Shuffling from bench to meeting to lecture, he mostly listens to students and colleagues, asking a few pointed questions while multitasking on his computer.

Sometimes, Dr. Church seems to veer into science fiction. At a dinner a few months ago, he sat with colleagues discussing a project that involves “mirror biology” — the creation of DNA, cells and organisms that are exact opposites of the natural versions.

He explained that this was like building a replica of an old-fashioned clock by looking only at its reflection. “The copy will predictably tell time, but the numerals will be flipped and the hands will rotate counterclockwise,” he said.

“While mirror life may look identical to current life,” he said, “it is radically different in terms of resistance to viruses, pathogens and enzyme digestion, among other things, because molecular interactions of life are very sensitive to the mirror arrangement of the atoms.”

Dr. Church expects to have a proof of concept — a functioning mirror cell that serves some useful purpose — in two years. “The mirror project is challenging because it requires building an entire cell from parts,” he said.

He added that this was more complicated than creating, say, the entire genome of a microbial organism and inserting it into a living cell — a feat recently announced by the geneticist J. Craig Venter.

When a student stopped by his small office to chat about a just-published study in Science about the genetic sequencing of a Neanderthal, he said playfully, “Maybe one day we’ll make Neanderthals.”

Maybe so. He prizes imagination in his students and associates.

“I like to keep the median age in my lab low because they will indulge me in my dreams,” Dr. Church said. “They don’t yet think things are impossible.”

The Genome 10K project

2010-06-07T00:55:00.000-07:00

The Genome 10K project aims to assemble a genomic zoo—a collection of DNA sequences representing the genomes of 10,000 vertebrate species, approximately one for every vertebrate genus.

The Genome 10K project aims to assemble a genomic zoo—a collection of DNA sequences representing the genomes of 10,000 vertebrate species, approximately one for every vertebrate genus. The trajectory of cost reduction in DNA sequencing suggests that this project will be feasible within a few years. Capturing the genetic diversity of vertebrate species would create an unprecedented resource for the life sciences and for worldwide conservation efforts.

The growing Genome 10K Community of Scientists (G10KCOS), made up of leading scientists representing major zoos, museums, research centers, and universities around the world, is dedicated to coordinating efforts in tissue specimen collection that will lay the groundwork for a large-scale sequencing and analysis project.

The Personal genome project

2010-06-07T00:53:00.000-07:00

Personal genome project wants to sequence and compare 100 000 people.

Links

- personalgenomes.org

100 genetic risks by genome

2010-06-07T00:45:00.000-07:00

In the April 30, 2010 online issue of The Lancet, Ashley Caplan, PhD, director of the Center for Bioethics at the University of Pennsylvania and several of his colleagues note in an article that the average person will discover he or she has about 100 genetic risks.

"Even if [counseling on] that information averaged only three minutes per disorder, this process would take more than five hours of direct patient contact, after many hours of background research," they calculate.

And there are only about 2,500 trained genetic counselors and 1,100 clinical geneticists in North America, all now busy with other work.

Projects

The Personal genome project (PGP) wants to sequence and compare 100 thousand people.

The Genome 10K project aims to assemble a genomic zoo—a collection of DNA sequences representing the genomes of 10,000 vertebrate species, approximately one for every vertebrate genus.

The trajectory of cost reduction in DNA sequencing suggests that this project will be feasible within a few years. Capturing the genetic diversity of vertebrate species would create an unprecedented resource for the life sciences and for worldwide conservation efforts (nextbigfuture.com).

References

- $1,000 Personal Genome Coming: Are We Ready?, medicinenet.com, April 29, 2010

- Clinical assessment incorporating a personal genome. Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, Dewey FE, Dudley JT, Ormond KE, Pavlovic A, Morgan AA, Pushkarev D, Neff NF, Hudgins L, Gong L, Hodges LM, Berlin DS, Thorn CF, Sangkuhl K, Hebert JM, Woon M, Sagreiya H, Whaley R, Knowles JW, Chou MF, Thakuria JV, Rosenbaum AM, Zaranek AW, Church GM, Greely HT, Quake SR, Altman RB. Lancet. 2010 May 1;375(9725):1525-35. PMID: 20435227

- The personal genome--the future of personalised medicine? Samani NJ, Tomaszewski M, Schunkert H. Lancet. 2010 May 1;375(9725):1497-8. PMID: 20435212

- Challenges in the clinical application of whole-genome sequencing. Ormond KE, Wheeler MT, Hudgins L, Klein TE, Butte AJ, Altman RB, Ashley EA, Greely HT. Lancet. 2010 May 15;375(9727):1749-51. PMID: 20434765

What is the Cost of Human Genome Sequencing?

2010-06-04T01:31:00.000-07:00

Two groups tied in first sequencing a human genome, the Human Genome Project, funded by the US Department of Energy, and Celera Genomics, a private company.

The Human Genome Project took 10 years and cost $3 billion USD (US Dollars), while the Celera genome sequencing project took two years and cost just $300 million USD. Both projects concluded in 2000 or 2001, depending on what is considered a "complete" human genome sequencing.

Gene sequencing costs have been dropped exponentially since the sequencing of the human genome in 2000.

In 2007, the genome sequencing of James Watson, a co-discoverer of the structure of DNA, was completed at a cost of $2 million USD.

In 2008, the first full genome sequencing services were sold commercially to customers for a cost of $100,000 USD.

By March 2008, one company, Applied Biosystems, completed a human genome sequencing in two weeks for $60,000 USD, the best cost yet.

Another company, Intelligent Bio-systems, has developed a system that can sequence a full human genome in 24 hours for $5,000 USD.

A price has been offered for the first to sequence 100 human genomes for $10,000 USD each in ten days or less. The $10 million USD prize, donated by diamond prospector Steward Blusson, will continue to be available until the deadline of 4 October 2013.

If the cost of genome sequencing falls below $1,000 USD, or better yet, $500 USD, many futurists have predicted qualitative changes in the way we do medicine.

1000$ genome is coming

In the April 30 online issue of The Lancet, Ashley Caplan, PhD, director of the Center for Bioethics at the University of Pennsylvania and several of his colleagues note that the average person will discover he or she has about 100 genetic risks.

"Even if [counseling on] that information averaged only three minutes per disorder, this process would take more than five hours of direct patient contact, after many hours of background research," they calculate.

And there are only about 2,500 trained genetic counselors and 1,100 clinical geneticists in North America, all now busy with other work.

Personal genome project wants to sequence and compare 100 thousand people. The Genome 10K project aims to assemble a genomic zoo—a collection of DNA sequences representing the genomes of 10,000 vertebrate species, approximately one for every vertebrate genus.

The trajectory of cost reduction in DNA sequencing suggests that this project will be feasible within a few years. Capturing the genetic diversity of vertebrate species would create an unprecedented resource for the life sciences and for worldwide conservation efforts (nextbigfuture.com).

30$ genome

According to nextbigfuture.com, a Harvard University physicist is promising an even cheaper price, the ability to sequence a human genome for just $30.

David Weitz and his team are adapting microfluidics technology that uses tiny droplets, a strategy developed in his lab, to DNA sequencing.

While the researchers have not yet sequenced DNA, they have successfully demonstrated parts of the process and formed a startup, GnuBio, to commercialize the technology.

Weitz's team had previously developed a way to create picoliter droplets of water, which act as tiny test tubes. The droplets can be precisely moved around on a microfluidics chip, injected with chemicals and sorted based on color.

Smaller drops means smaller volumes of the chemicals used in the sequencing reaction.

These reagents comprise the major cost of sequencing, and most estimates of the cost to sequence a human genome with a particular technology are calculated using the cost of the chemicals.

Based solely on reagents, Weitz estimates that they will be able to sequence a human genome 30 times for $30.

In Weitz's approach, droplets are injected with short strands of DNA of a known sequence, and these strands are labeled with an optical bar code.

Pieces of the sample with an unknown sequence are also injected into the droplets--if the sample has a stretch of sequence complementary to the known strand, the two pieces will bind, triggering a change in color. Repeat this 1,000 times with 1,000 different known strands and you can generate the sequence of 1,000 letters of DNA, says Weitz.

Both the optical bar code and the color change are detected using a microscope and camera with automated detection software. Weitz says they can produce and process a million drops per second.

Synopsis

- 2000: $3 billion USD (The Human Genome Project)
- 2000: $300 million USD (Celera genome sequencing project)
- 2007: $2 million USD (genome sequencing of James Watson)
-2008: $100,000 USD (first full genome sequencing services sold commercially)
- March 2008: $60,000 USD (Applied Biosystems, two weeks)
- August 2009: $50,000 (Illumina)
- 2009: $50,000 (Helicos Biosciences)
- 2010: $10 000 (Illumina HiSeq 2000)

New susceptibility loci for nasopharyngeal carcinoma

2010-06-03T09:32:00.000-07:00

Researchers identify three new susceptibility loci for nasopharyngeal carcinoma in the genome-wide association study they've published in Nature Genetics. The team examined 464,328 autosomal SNPs in 1,583 cases and 1,894 controls, and found that TNFRSF19, MDS1-EVI1, and the CDKN2A-CDKN2B gene cluster were associated with NPC. "Our findings provide new insights into the pathogenesis of NPC," the authors write.

References

- A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Jin-Xin Bei, Yi Li, Wei-Hua Jia, Bing-Jian Feng, Gangqiao Zhou, Li-Zhen Chen,Qi-Sheng Feng, Hui-Qi Low, Hongxing Zhang, Fuchu He, E Shyong Tai, Tiebang Kang, Edison T Liu, Jianjun Liu & Yi-Xin Zeng. [Nature Genetics->http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.601.html#a1] (2010)

New Genetic Associations Revealed for Nasopharyngeal Carcinoma

2010-06-02T23:55:00.000-07:00

Source: spittoon

Nasopharyngeal cancer (NPC) arises in the upper part of the throat, behind the nose. It is rare in most areas of the world—affecting only about 1 in every 100,000 people—but about 25 times more common in southern China, earning it the name “Cantonese Cancer.” NPC rates are also high in southeastern Asia, northern Africa and the Arctic.

Environmental factors play a very large role in NPC. Smoking increases risk, as does infection with the Epstein-Barr virus. Diets high in salt cured food, which are common in many of the areas where increased rates of NPC are seen, have also been shown to increase risk. These foods can be very high in nitrates and nitrites, which react with protein to form DNA-damaging chemicals.

It’s also been known for quite some time, however, that genetics contribute to NPC susceptibility. In 1970s, certain immune markers were associated with increased risk. Now a large genomewide association study has revealed three more immune related areas of the genome that are associated with risk for NPC. These results, published online this week in the journal Nature Genetics, could eventually help develop models for prediction and screening, which in turn would help with early diagnosis.

Researchers from Singapore, China and the United States studied about 5,000 people with NPC and 5,000 controls, as well as more than 250 families, all of southern Chinese descent. As expected, a strong genetic effect was seen in areas of the genome that encode the previously identified immune markers. But variants in three other regions were also associated with NPC risk. Two of these associations were statistically significant. The third SNP did not make the cut off, but was highly suggestive.

(23andMe Complete Edition customers can check their data for these SNPs using the links in the table at the end of this post.)

The statistically significant genetic associations variants were in the TNFRSF19 and MDS1-EVI1 genes. Previous research has shown that these genes encode proteins that may be involved in the body’s response to Epstein-Barr virus infection, possibly providing a neat connection between the new findings and a known environmental risk factor for NPC.

The third association was with a variant near the CDKN2A and CDKN2B genes. This gene cluster is deleted in about 40% of NPC tumors, suggesting that they are crucial for preventing cancerous growth. Additionally, this same SNP CDKN2A/CDKN2B SNP associated with NPC risk has been linked to glioma in European populations.

All of the genes identified in this study—TNFRSF19, MDS1-EVI1 and CDKN2A/CDKN2B—have previously been shown to be involved in leukemia. This suggests that there might be common disease mechanisms between that disease and NPC. Significantly, leukemia is found at higher than average rates in people with NPC.

According to the authors, the next step for research is to investigate the interactions between the genetic susceptibility factors identified by them and others with the environmental risk factors known to influence NPC.

SNP Gene Less Common Version Effect on Odds of NPC of Less Common Version
rs9510787 TNFRSF19 G 1.2
rs6774494 MDS1-EVI1 G 0.84
rs1412829* CDNK2A/CDNK2B G 0.78

* The association of this SNP with NPC was not statistically significant, but was highly suggestive.

What is the number of genes in the human genome ?

2010-06-02T01:34:00.000-07:00

The number of genes in the human genome was found to be 20,000-25,000, smaller than predicted.

Kaiser Permanente and their "Giant" Genome project

2010-05-31T01:22:00.000-07:00

Sunday, May 30, 2010 http://ducknetweb.blogspot.com/2010/05/kaiser-permanente-and-their-giant.html

Many members of Kaiser have been asked if they want to participate in this study, and the results of which are going to be used for genomic research. The information when all culminated will contain information without any personal data included. Actually the request for donations started back in 2008. This is to be the largest study of it’s type.

All patients had to do to participate was to spit into a container sent to them by mail and return it to Kaiser. As the article states though, participants will not have the ability to see their results as again this is being done to allow scientific analysis and not necessarily for patient treatment at this point. Kaiser was given a grant of $25 million from the NIH to conduct the project as part of a stimulus package.

Additional members will be asked to contribute later as they intend to build a repository for blood samples, in other words when patients come in to have blood word done, they will be asked if they want to participate and give a DNA sample at that time. The processing of the DNA has all be set up to be “robotically” processed and it further states here that 2500 samples can be tested per week, pretty amazing number. As mentioned here too their biggest fear is a power failure as the cost per each individual analyzed is around $10,000.

This month, researchers at Kaiser Permanente in Oakland and the University of California, San Francisco began the highly automated, large-scale process of analyzing that DNA, which is being extracted from tens of thousands of saliva samples donated by Kaiser members in Northern California since 2008.

Each sample of ordinary spit is laden with cells containing the volunteer’s entire set of genes, their genomes, which carry in sequences of DNA the coded instructions for building and maintaining life. The hope for this so-called genome-wide association study is that, when the genes of people with diseases like cancer and multiple sclerosis are compared with the genes of those in good health, computer analysis will pinpoint genes responsible for the illnesses.

Following instructions found in a kit mailed to her Oakland home, Mrs. Young deposited the requested spit into a special plastic cup. She sealed it with a blue lid fitted with a built-in preservative and sent it back to Kaiser. Along with her saliva, the samples from the other 130,000 people began arriving in Kaiser’s mailbox.

However, the study has begun just as some scientists have started to question the value of these experiments, and when private ventures, like 23andMe, are struggling to find a consumer market for gene tests.

David B. Goldstein, a Duke University researcher, said he believed “interesting and valuable information” would come from the Kaiser study, but he questioned whether it was the most efficient way to gather information about the genetic links to disease. “It’s an awfully expensive study,” Dr. Goldstein said in an e-mail message.

In the coming years, 400,000 more members will be asked to contribute their DNA to the project when they come in for routine blood work. Kaiser is spending $9 million to build a repository for the blood samples.

At the Kaiser research lab, a production line of robotic equipment has been set up to process the 130,000 cups of saliva that have been mailed by patients and stored, at room temperature, in racks of cardboard “pizza boxes,” 50 cups to a box. Here, the robots draw out a sample of spit, and chemically process it to extract the donor’s DNA.

At Dr. Kwok’s ninth-floor lab, three sets of robots prepare the DNA samples shipped from Oakland. The full complement of DNA from each volunteer is washed over a custom-designed silicon chip about this size of small fingernail. Microscopic wells etched into the chip are each engineered to pluck out one of 675,000 possible gene variants.

“Our biggest fear is a power-failure,” said Dr. Kwok. Each array, filled with 96 processed DNA samples, costs $10,000.

From Californians’ DNA, a Giant Genome Project - NYTimes.com

Technorati Tags: DNA, Kaiser Permente, genomics, University of California, San Francisco, Oakland, patients, tests, automation, technology, arrray

DNA As Crystal Ball: Buyer Beware

2010-05-20T08:57:00.000-07:00

by Sharon Begley, Newsweek, May 18, 2010

When it comes to predicting risk of disease, Alzheimer's genes—and others—strike out.

When James Watson, codiscoverer of the double helix, had his genome fully sequenced in 2008, there was one piece of DNA he insisted the lab not tell him about: whether he had a genetic variant that significantly increases the chance of developing Alzheimer’s disease. Called apoE, the gene comes in three variants, of which APOE4 increases the risk of Alzheimer's between 10- and 30-fold. Different people have different feelings about learning what lies in their medical future, especially if it is something for which there is neither cure nor treatment. (House got good mileage out of this dilemma when Thirteen, played by Olivia Wilde, decided to find out whether she carries the gene for the inevitably fatal, incurable Huntington's disease. She does.) If studies coming out over the last few months are any indication, however, most of us can postpone making this difficult decision: the revolution in using DNA to read people's medical future is turning out to be more hype than hope.

The latest research to throw cold water on the crystal-ball powers of DNA is a paper in the current issue of the Journal of the AmericanMedical Association. It starts out as a standard genomewide association study (GWAS) in which scientists sequence genomes of people with and without particular diseases and identify genetic variants associated with those illnesses. In this case, Monique Breteler of the University Medical Center in Rotterdam and her colleagues analyzed the genomes of just over 35,000 people, some healthy and some with Alzheimer's, and found that four DNA misspellings (or, in the vernacular, single-nucleotide polymorphisms) were connected to Alzheimer's in that they were common to people with the disease but were not found in healthy people.

Until recently, that would have been that: a rigorous, thorough analysis—just over 35,000 genomes—leading to headlines about newly discovered genes linked to this dreaded disease. (Two of the four identified misspellings were previously known, and two are new.) But to their credit, Breteler's team took the next step. They used the four misspellings, along with individuals' age and sex and whether or not they carried the apoE4 genetic variant that so frightened Watson. The results were not pretty. Adding the newly discovered genes "did not improve the ability of a model that included age, sex, and apoE to predict" whether someone would develop Alzheimer's. The genes, concluded the scientists, were "not clinically useful."

In a phone interview, Breteler went further. "Adding these genes to traditional risk factors, such as age and sex, does nothing to aid prediction" of whether someone will develop Alzheimer's, she told me. "Knowing your genetic status will not help. We may still be in the Stone Age when it comes to gene-based prediction." Identifying risk genes isn't pointless, however: they can identify new causes of the disease, and therefore new ways to treat it.

The finding that adding Alzheimer's-risk genes to plain old age, sex, and apoE status does not improve the accuracy of disease prediction seems to defy everything the public is being told about the dawn of a new era of personalized medicine, in which knowing our genomes will tip us off about what diseases we are most at risk for. Such genome-based forecasting is deemed vastly superior to such antediluvian methods as family history. And it is the basis for the explosion in consumer-based genome testing, such as that offered by 23andme, Navigenics, and Pathway Genomics, whose plan to sell its saliva-swab DNA collection kits at Walgreens stores was shot down by the FDA last week.

Yet, as the JAMA study shows, there are serious doubts about how useful genomic information is going to be, outside of a few rare applications such as the ability of a child with leukemia to metabolize chemotherapy, one of the earliest attempts to pair genomics with medicine. Just last year, a study in JAMA concluded that determining whether a patient carries genes that affect the risk of blood clots (venous thromboembolisms) does not necessarily prevent blood clots. In a related setback last year, Medicare concluded that genetic tests that indicate how well patients metabolize the clot-buster warfarin does not meaningfully help doctors determine the safe dose; the agency therefore declined to pay for the tests. This year, another JAMA study, of 19,313 women, found that using multiple genetic markers to assess someone's risk of cardiovascular disease produces no better a risk assessment than old-fashioned tests such as cholesterol level, blood pressure, and family history. And this was a study that used 101 genetic variants. Not to pile on, but let me mention one more, on assessing a woman's risk of breast cancer. A study of almost 12,000 women by scientists at the National Cancer Institute, published in TheNew England Journal of Medicine in March, found that supplementing traditional risk factors (whether first-degree relatives such as a mother or sister developed breast cancer; reproductive history) with 10 genetic variants associated with breast cancer did no better at predicting whether a woman would get the disease than the traditional factors alone.

How can knowing whether or not someone has genes associated with a disease not be helpful in predicting whether that disease will strike? No one knows for sure. But it must reflect the fact that the effect of a gene depends on a person's "genetic background"—all the other genes he or she has. And it also reflects a person's environment. In some environments a gene does lead to disease; in others, it doesn't.

Individuals can differ in whether or not they even want to know their risk of Alzheimer's. Some prefer not knowing; others believe it will help them plan, financially and personally. One in every five of us who reaches age 65 will develop Alzheimer's disease. But at minimum, believers in personalized medicine should not be selling the public a bill of goods. I spent a week at Harvard Medical School last year, meeting with scientists, and one of my most surprising conversations was with geneticist David Altschuler, who to all appearances should be a cheerleader for genome-based personalized medicine. (He was a leader of the HapMap project to link large swaths of genetic variation to disease.) Yet he told me that using an individual's genome to assess the risk of disease is "overhyped." He continued, "If you ask what percentage of diagnostic tests in the history of medicine have been helpful, the answer is very few. There is a long history of new technologies being applied broadly beyond their utility." He echoes Breteler's view that the greatest benefit of GWAS and similar studies of genes and disease will be to illuminate the mechanisms that cause disease, and thus offer ways to intervene in those mechanisms to prevent or treat an illness.

Personalized medicine has many high-profile partisans, such as Francis Collins, director of the National Institutes of Health, who made the case for the field in his recent book. Nevertheless, second thoughts are clearly setting in as a result of studies like those I outlined above. Last year, geneticist Steve Jones of University College London wrote in The Daily Telegraphthat despite the billions of dollars that governments, industry, and foundations have poured into genomics and personalized medicine, "the mountain has labored and brought forth a mouse," one that will have little effect on how medicine is practiced, let alone predicting someone's risk of disease.

2010-05-11T03:54:00.000-07:00

Genetic tests on shelves - Usefulness of consumer screenings questioned
By Keith Darcé, UNION-TRIBUNE STAFF WRITER

Tuesday, May 11, 2010 at 12:02 a.m.

Consumer interest in genetic testing could receive a major boost this week when kits from Pathway Genomics of San Diego hit the shelves of Walgreens drugstores nationwide, even as some scientists question the usefulness of the screenings.

Pathway and the three other big companies that make genetic-testing products, sold mainly on the Internet or through doctors’ offices, have attracted relatively few customers since debuting the items less than three years ago.

Estimates put total sales at 50,000 to 100,000 tests.

Prices have been part of the problem. The cost ranges from about $400 to $2,000 for a comprehensive genetic-marker test that seeks to identify risks for adverse drug reactions, passing on mutations to children or developing certain diseases and health conditions.

Pathway’s kit will sell for about $20 in Walgreens stores. The buyer spits into a specialized container and then ships the saliva to the company for an analysis that costs $79 to $249, depending on the tests requested.

On Pathway’s website, the company offers a single testing package for $399.

“We are really doing this to increase consumer awareness, not just for us but for the entire genetic-testing industry,” said Jim Woodman, vice president of corporate strategy for Pathway.

The move represents a big step for the privately owned company, which launched its service in September. About 50 people work at Pathway’s laboratory and headquarters in the Sorrento Valley area of San Diego.

Interest in genomics has soared as the pace of research in the field has accelerated. Scientists are regularly uncovering new mutations in human DNA sequences that are tied to cancers, chronic health conditions, Alzheimer’s disease and illnesses that run in families.

More than 60 prescription drugs, including the anti-blood-clotting medications Plavix and Warfarin, have been associated with genetic markers indicating that a patient might have trouble taking them.

Not everyone welcomes the services of Pathway and its counterparts.

Officials for the American Medical Association said genetic tests shouldn’t be done without direct supervision of a doctor who can help interpret the results and recommend care based on the findings.

Consumers can easily misunderstand the test results if left on their own, said Dr. Eric Topol, a cardiologist and geneticist who serves as chief academic officer for San Diego-based Scripps Health.

Several states have banned direct sales of genetic tests to consumers.

In California, companies that offer such services must obtain a laboratory license from the Department of Public Health. The state has issued licenses to all of the major genetic-testing businesses — Pathway, 23andMe of Mountain View, Navigenics of Forest City and DECODE Genetics of Reykjavik, Iceland.

For the past year, Palomar Pomerado Health has sold 23andMe test kits at its “expresscare” retail clinics inside Albertsons grocery stores in Escondido and Rancho Peñasquitos.

The Federal Trade Commission, which oversees labeling for the tests, is the only federal agency that regulates the industry.

One concern about the retail genetic testing involves what isn’t covered.

Some scientists believe accurate measurements of each person’s disease risk aren’t possible without looking at all 3 billion DNA base pairs that make up that individual’s genome. That process costs more than $10,000 and requires the work of supercomputers.

Instead, the companies offering consumer genetic testing isolate only several hundred thousand genetic variations for review.

The results can be misleading, Topol said.

For example, a test could indicate that a person has a 30 percent risk of developing a particular type of cancer while the average risk is half that amount. The difference might seem alarming, but it may not matter if the likelihood of getting the cancer is more strongly driven by rare genetic variances occurring in particular family lines, Topol said.

In another case, a person might take false comfort in test results showing genetic markers for lower-than-average risk of a heart attack. The patient might push aside the more important fact that numerous relatives going back several generations have suffered congestive heart failure.

“Our ability to look at an individual’s DNA sequence and tell them their risk for these types of health conditions is low,” said Kelly Frazer, chief of genome information sciences for the department of pediatrics at the University of California San Diego’s School of Medicine.

The main businesses offering retail genetic testing said they’ve been careful to market their products as educational information rather than medical advice or a diagnosis.

“We make it very clear that this doesn’t mean (customers) are going to get a condition, but it’s something they should be aware of, and here are things they can do to mitigate that risk,” Woodman said.

But even among these companies, there often is wide variation in how genetic results are explained.

Francis Collins, director of the National Institutes of Health, reported in an October article in The New England Journal of Medicine that he sent his personal DNA sample to the three leading genetic-testing companies.

“They were not consistent in how they interpreted the results,” said Collins, a geneticist who helped guide the Human Genome Project. “I think all the companies probably overrepresented the degree to which we already can predict people’s future risk of illness and underrepresented how much of heritability has yet to be discovered.”

Keith Darcé: (619) 293-1020; keith.darce@uniontrib.com

DNA testing at Walgreens

2010-05-11T00:40:00.000-07:00

Pathway Genomics with have genetic testing kits selling at Walgreens Pharmacy.
Walgreen will start offering the kits in about 6000 stores (It will not be available in New York because of a state law)

Walgreen plans to offer Pathway's Insight Saliva Collection Kit at retail from $20 to $30. The saliva test, which will be done at Pathway's labs, will cost between $79 and $249. Genetic tests typically cost about $300.

Credits

- nextbigfuture.com

GET10 conference: Mapping the Personal Genomics Landscape

2010-05-05T04:41:00.000-07:00

genomicslawreport.com, Posted by Dan Vorhaus on May 4, 2010

Last week saw the first annual Genomes, Environments, Traits (GET) Conference, in Cambridge, Massachusetts. Timed to coincide with DNA Day 2010, the conference marked one decade since the publication of the draft consensus human genome sequence. The GET Conference was billed as “the last chance in history to collect everyone with a personal genome sequence on the same stage to share their experiences and discuss the important ways in which personal genomes will affect all of our lives in the coming years.” Not quite everyone with a public personal genome sequence attended – Craig Venter, Desmond Tutu, Glenn Close were all unavailable – but a majority of the genomic pioneers were in attendance and the GET Conference was a one-of-a-kind event.

For those who missed the GET Conference, several high quality recaps are available. The most detailed is A Day Among Genomes, by Carl Zimmer of Discover’s blog The Loom. More targeted reflections on the conference and related events come from Emily Singer of Technology Review summarzing key trends highlighted by the genome pioneers (Singer also has a related piece on the difficulties of understanding human genomes), David Dobbs of Neuron Culture on genomes, cool conferences, and what the hell to tell people about behavioral genes, and Turna Ray of Pharmacogenomics Reporter on the recent Myriad Genetics decision, and its impact on the business of patenting genes. If you’d like even more detail, the Twitter community provided real-time play-by-play.

While there’s no need for a further summary, the GET Conference does provide an occasion to look at the evolving personal genomics landscape in a more holistic fashion.

Genomes GET Personal. Personal genomics refers to the generation and delivery of an individual’s genomic or genetic information. The data itself ranges from testing a single base (referred to as a single nucleotide polymorphism, or SNP) to attempting to sequence each of the approximately six billion bases that make up a human genome. Data generation occurs on a variety of platforms, but it takes more than data to make genomics personal. We must move beyond merely inexpensive genomics to truly personal genomics. That requires analysis of the data, linking it to the life of the individual donor, and, ultimately, using the data in some fashion.

For those of us who frequently read and think about such topics, it’s easy to develop a slightly myopic view of the significance of personal genomics. For example, as Carl Zimmer noted in his review of the GET Conference, it was a challenge to evaluate personal genomics critically “in front of an audience made up of genome scientists, people from the biotech sector, venture capital folks, and other assorted people who are, shall we say, already in the genomic tank.”

The reality is that, to date, personal genomics has been the province of a comparative few. Academic researchers, a fraction of healthcare patients supported by too few providers conversant in clinical genetics, and a handful of companies, entrepreneurs and early adopters striving to deliver genetic information to consumers outside of the clinical setting. But the rest of the world – including a majority of consumers, patients, healthcare providers and payors – is waiting in the wings.

With the cost of generating genomic data dropping, and their possible uses expanding, personal genomics is poised to enter the mainstream. When that happens, certainly by the end of this decade, and possibly far sooner, what will the personal genomics landscape look like? To put it another way, what are the channels or pathways through which ordinary individuals – those of us who are not geneticists or early adopters – will explore their own genomes?

Personal Genomics Pathways. The first step in answering that question is to sketch the personal genomics landscape as it exists today – to understand the pathways through which individuals are currently entering personal genomics.

The following sections outline four different categories of personal genomics: clinical, consumer, research and unintended. Delineating these categoris is not an easy task, and there are frequent examples of companies or technologies that reside in more than one of these four categories. Nevertheless, as the field continues to evolve, mapping the “big picture” can facilitate more precise dialogue, regulatory actions and commercial predictions.

Research. Genomic research is distinguished from the categories described below by its intended use (to improve our understanding of the genetic bases for complex human diseases and traits). But it is important to note that not all genomic research is personal genomic research. This is due to the fact that, in most research settings, genomic information flows in only one direction: from the individual to the researcher. Even aggregate research findings, let alone individualized data, are rarely returned to volunteer participants. Thus, despite the explosion over the past five years of genome-wide association studies (GWAS) and, more recently, the construction of large-scale genomic databases (including the UK Biobank and the Kaiser Permanente Research Program on Genes, Environment, & Health), the vast majority of genomic research does not qualify as personal genomic research.

This is partly due to a timing delay. The proliferation of individual-level genomic research data is a relatively new phenomenon, and research norms have been slow to adapt to a growing body of evidence suggesting that people are interested in learning the results of research carried out using their DNA, and that it is ethical for researchers to return such results. It also reflects some legal uncertainty, specifically whether research conducted (in the United States) in non-CLIA environments can be returned directly to participants without violating federal law. Driven by increasingly vocal calls from both research participants and researchers themselves – including several commentators in the GLR’s What ELSI is New? series – the government agencies that supply the bulk of the funding for genomic research are continuing to examine the issue of genomic data-sharing in the research context.

For the moment, the number of individuals participating in personal genomic research is on the rise. At the GET Conference, George Church provided an update on the Personal Genome Project, which is using unique informed consent protocols to build a research cohort of 100,000 individuals who will have the opportunity to actively participate in personal genomic research, and who will have direct access to their individualized genomic sequence information. The first ten participants (the “PGP-10”) have already made their data available online.

There have also been attempts to develop DTC genomic research initiatives and, while the yields so far have been modest, the model is an intriguing one that promises to involve increasing numbers of individuals in the research aspect of personal genomics.

Clinical. One of the key drivers of the personalized medicine movement is clinical personal genomics. It is defined by its application of genomic data (to clinical care) and its mode of delivering that data to the individual (through a licensed healthcare provider). Extremely wide-ranging, clinical personal genomics has the potential to integrate individualized genetic or genomic information into nearly every aspect of patient care.

Clinical personal genomics includes genetic testing for autosomal dominant genetic traits (e.g., Huntington’s disease), diagnostic testing to predict the likelihood of the development or recurrence of a disease with a known genetic component (e.g., breast cancer) and carrier testing for prospective parents concerned about passing on genetic traits (e.g., cystic fibrosis) to their children. (Arguably, reproductive personal genomics – including carrier testing and other reproductive technologies, such as prenatal testing and pre-implantation genetic diagnosis (PGD) deserve their own category but, since such services are typically offered under the supervision of healthcare providers, they are considered clinical personal genomics in this post.) Clinical personal genomics also involves testing for genetic variants that influence whether and how certain therapeutics will behave in an individual patient, often referred to as pharmacogenetics.

Providers of clinical personal genomics include numerous laboratories offering either FDA-approved genetic testing “kits” or laboratory developed tests (LDTs) (which are not currently regulated by the FDA) targeted at specific genes (as well as at other biomarkers). In addition to the companies that supply the tests or kits, clinical personal genomics also requires genetic counselors, clinical geneticists and other healthcare providers capable of helping patients to understand and act on their genomic data.

A pair of recent announcements by CVS Caremark (acquiring a majority stake in Generation Health) and Medco (acquiring DNA Direct), the country’s two largest pharmacy benefit managers (PBMs), suggest that personal genomics is primed to play an increasingly prominent role in the delivery of medical care. However, there is broad-based concern that there are insufficient numbers of trained healthcare professionals, especially genetic counselors and primary care providers with an adequate understanding of genetics, to handle the expected increase in patients seeking, or needing, clinical personal genomics services.

Consumer. Also referred to as direct-to-consumer (DTC) genomics, the distinguishing features of consumer personal genomics are its intended use (informational, educational or recreational, but not clinical) and its mode of delivery (directly to the consumer, without the requirement of a licensed intermediary).

Consumer genomic services run the gamut from genealogy (Ancestry.com), to paternity (Paternity Experts) to genetic matchmaking (Scientific Match), and everything in between. While some consumer personal genomics services are both popular and uncontroversial (ancestry testing) or are clearly niche products (MyRedHairGene.com), others have straddled the line between consumer and clinical personal genomics, creating confusion for consumers, healthcare professionals and regulators alike.

As an example, 23andMe tests more than half a million SNPs and reports back information relevant to more than 130 traits and conditions, many of which appear unambiguously aimed at influencing their customers’ clinical or medical decision-making. 23andMe also offers a popular genetic genealogy service, and has repeatedly expressed an interest in using its customers as the basis for a personal genomics research platform. What results is a single company with multiple overlapping products that could easily be viewed as a hybrid of the clinical, consumer and research personal genomics types.

What keeps companies like 23andMe in the consumer personal genomics category, at least for the time being, is an insistence on direct-to-consumer access. With a few important exceptions (e.g., New York and Germany), individuals worldwide can purchase and use these services without the involvement of a healthcare provider.

With the list of DTC providers growing rapidly, it can be difficult to keep track of everything that is out there. At present, the only publicly accessible registries of DTC providers are maintained by private entities, including AccessDNA, DNA Test Index, and the Genetics & Public Policy Center (pdf) at Johns Hopkins University.

Recently, however, the NIH launched a new genetic testing registry (GTR) which has the potential to serve as a more comprehensive resource for tracking DTC genomics services. The GTR, which will include providers of both clinical and consumer personal genomics services, is not yet operational. Listing in the GTR is also voluntary so, even once it is in place, it is unlikely to serve as a comprehensive directory of all consumer personal genomics services. There are reports, however, that Representative Patrick Kennedy is attempting to revive the Genomics and Personalized Medicine Act in a form that would include a mandatory genetic testing registry.

Of all of the personal genomics categories listed here, consumer services is the one most likely to rapidly splinter into multiple categories. At the moment, there are few regulations that deal directly with DTC genomics companies and the services they provide. As the generation of genomic data becomes increasingly inexpensive and commonplace, the spectrum of consumer services will expand considerably. As was true of the development of personal genomic research norms, regulatory activity in this area has lagged commercial and scientific development. At some point, however, additional regulations will arrive, helping to further define this category. For instance, it is possible that the GTR will serve as a precursor to a more comprehensive system of regulation for genetic testing. Additional regulation, whatever its impetus, would likely produce further fragmentation within this category, with some companies sliding into defined regulatory boxes and others changing their offerings to avoid regulatory control (and expense).

Predicting precisely which consumer services will be offered and how, if at all, they will be regulated, is impossible. All we know is that personal genomics consumers ten years from now are certain to have many, many more options than they do today.

Unintended. This final category is a catch-all, characterized by a single shared feature: these individuals did not intentionally confront their personal genomic information. At the Genomics Law Report, we have discussed a variety of ways in which an individual might receive an unintended, and possibly unwanted, introduction to personal genomics. Paternity identification, surreptitious testing, genetic testing of a first-degree relative, forensic activity and the re-identification of previously de-identified genetic information all have the capacity to introduce unsuspecting individuals to their genetic information. It’s also possible that individuals who have agreed to share or to explore only certain aspects of their genetic information will be unexpectedly presented with personalized genetic information beyond the originally intended scope of their agreement. No doubt there are other means of unintended exposure as well.

While not every unintended exposure to personal genomic information will be undesirable, such occurrences should clearly be minimized. Although the GET Conference featured a self-selecting audience largely enamored of personal genomics, not every individual shares the desire to peer deeply, or at all, into his or her own genome. An introduction to personal genomics, no matter the context, should be expected, if not always desired (e.g., certain clinical testing), with ample opportunity afforded for pre-test education and, where necessary, informed consent.

Unfortunately, as the cost of generating individualized genomic data declines, more and more such data will be generated. The proliferation of personal genomic data, and the increasing array of valuable applications of such data, is likely to increase the incidence of unintended personal genomics exposures. A combination of public education and policy and legal reforms will be needed to minimize the number of such events and mitigate their impact when they invariably occur.

The Future of Personal Genomics. The categories described above are roughly drawn, and they may well be incomplete. There is no question that they are neither exclusive nor exhaustive. All we really know is this: to the extent that they accurately reflect the current personal genomics landscape, they will not do so for long.

Genomic researchers with novel questions will continue to require novel, and increasingly participatory, research models. Clinical practice will grow and is likely to become simultaneously more specialized (e.g., increasing availability of genetic diagnostic tests) and more generalized (e.g., incorporation of whole-genome sequences into medical records as a default). Consumer personal genomics will go wherever the entrepreneurial imagination can take it and regulatory bodies permit it, leading to splintering and further blurring between its boundaries with other categories.

The 2010 GET Conference closed with the personal genomics company Knome awarding a free exome sequence to the most original audience-supplied idea applying personal genomics. The winning proposal, submitted by Jonathan Eisen, would supplement understanding of our ancestors by sequencing current and ancestral microbiomes. A sampling of the submissions that didn’t win – including sequencing of millions of sperm from an individual to understand germ line variation, replacing newborn blood-spot testing with genomic sequencing, using real-time genetic testing to identify and prevent allergic reactions, constructing encryption keys from an individual’s genomic code and the development of new commercial models to expand access to and participation in personal genomics – provides a glimpse at the untapped applications for personal genomics.

Where will personal genomics head from here? I, for one, am already looking forward to the 2011 version of the GET Conference by which time, if recent history is any guide, this roadmap will already be out of date. And that, without question, is the most exciting thing about personal genomics as we close the book on the 2010 GET Conference.

Filed under: Direct-to-Consumer Services, General Interest, Genetic Testing/Screening, Genomic Sequencing, Genomics & Society, Industry News, Pending Regulation
Tags: 23andMe, AccessDNA DNA Test Index, Carl Zimmer, carrier screening, CLIA, Craig Venter, CVS Caremark, David Dobbs, de-identification, Desmond Tutu, DNA Day, DNA Direct, DTC genomics, DTC research, DTC testing, Emily Singer, exome sequence, forensic DNA, Generation Health, genetic genealogy, genetic testing, Genetic Testing Registry, Genetics & Public Policy Center, GET Conference, Glenn Close, informed consent, Jonathan Eisen, Kaiser Permanente, Knome, laboratory developed tests, LDT, MedCo, NIH, Personal Genome Project, personal genomics, reproductive genetics, Turna Ray, UK Biobank

Study first to analyze individual's genome for risk of dozens of diseases, potential responses to treatment

2010-04-29T23:57:00.000-07:00

BY KRISTA CONGER, Stanford U, April 29, 2010

For the first time, researchers have used a healthy person's complete genome sequence to predict his risk for dozens of diseases and how he will respond to several common medications.

The risk analysis, from the Stanford University School of Medicine, also incorporates more-traditional information such as a patient's age and gender and other clinical measurements. The resulting, easy-to-use, cumulative risk report will likely catapult the use of such data out of the lab and into the waiting room of average physicians within the next decade, say the scientists.

"The $1,000 genome is coming fast," said cardiologist Euan Ashley, MD, assistant professor of medicine, referring to the cost of sequencing all of an individual's DNA. "The challenge lies in knowing what to do with all that information. We've focused on establishing priorities that will be most helpful when a patient and a physician are sitting together looking at the computer screen."

Priorities that include whether a certain medication is likely to work for that particular patient, or if it's likely to have adverse side effects. Priorities that include ascertaining how a patient's obesity or smoking combine with his or her inherent genetic risk for — or protection against — heart attack or diabetes. In short, priorities that result in concrete clinical recommendations for patients based on a degree of data that has never existed before.

"The $1,000 genome is coming fast," said cardiologist Euan Ashley, MD, assistant professor of medicine, referring to the cost of sequencing all of an individual's DNA. "The challenge lies in knowing what to do with all that information. We've focused on establishing priorities that will be most helpful when a patient and a physician are sitting together looking at the computer screen."

Priorities that include whether a certain medication is likely to work for that particular patient, or if it's likely to have adverse side effects. Priorities that include ascertaining how a patient's obesity or smoking combine with his or her inherent genetic risk for — or protection against — heart attack or diabetes. In short, priorities that result in concrete clinical recommendations for patients based on a degree of data that has never existed before.

"We're at the dawn of a new age in genomics," said Stephen Quake, PhD, who is the Lee Otterson Professor of Bioengineering. "Information like this will enable doctors to deliver personalized health care like never before. Patients at risk for certain diseases will be able to receive closer monitoring and more frequent testing, while those who are at lower risk will be spared unnecessary tests. This will have important economic benefits as well, because it improves the efficiency of medicine."

But it may also tell patients things they don't want to know.

Quake made national headlines last August when he used a technology he helped invent to sequence and publish his own genome for less than $50,000, and it is his genome that the researchers analyzed in this newest study. Ashley is the lead author of the research, published in the May 1 issue of the Lancet.

An accompanying article about the ethical and practical challenges of such research, authored by a subset of the researchers involved in the first study, will appear in the online-only version of the Lancet on the same day. Hank Greely, JD, professor and director of Stanford's Center for Law and the Biosciences, is the senior author of the online piece.

"Patients, doctors and geneticists are about to hit by a tsunami of genome sequence data. The experience with Steve Quake's genome shows we need to start thinking — hard and soon — about how we can deal with that information," said Greely.

"When combined with other sources of information, genomics has the power to predict the diseases a person is most likely to develop and how he or she might respond to certain medicines," said Jeremy Berg, PhD, director of the NIH's National Institute of General Medical Sciences, which funded a portion of the work. "This work provides a glimpse of how genomics can play a role in personalizing the medical care of individual patients."

The study began when the 40-year-old, seemingly healthy Quake asked Ashley's opinion about a particular snippet in his genome associated with an inherited disease called hypertrophic cardiomyopathy. People with the condition have enlarged hearts that don't beat effectively and are at risk for sudden cardiac death. Quake was interested because a distant relative had died unexpectedly in his sleep at the age of 19 — presumably from some type of heart problem. Ashley, who runs Stanford's Hypertrophic Cardiomyopathy Center, was alarmed.

"Given his family history and the particular genetic variation Steve has, I recommended that he be screened for the condition," said Ashley. Quake agreed, but the conversation got the two thinking about how to analyze the information in Quake's genome on a more global level.

"Several of us had already been thinking about how you would take someone's genomic profile, and translate what's in the billions of base pairs in that DNA to something that's clinically useful," said Ashley, who headed the group of geneticists, physicians, bioinformaticians and ethicists involved in the study. "Then we realized, 'Hey, we already have someone's genome.'"

What's more, Atul Butte, MD, PhD, assistant professor in bioinformatics, and his lab members had already done a lot of the necessary leg work: They'd spent the previous 18 months meticulously cataloguing publications that associated particular genetic changes called SNPs (for single nucleotide polymorphisms) with effects on specific diseases. It was the first time anyone had compiled all the information in one database.

"We read thousands of publications," said Butte, "and we made a list of every single spot in the genome where we know that, for example, the letter A raises the risk of a particular disease, or the letter T confers protection. And then came Steve with his genome, and we were ready."

Together the researchers designed an algorithm to overlay the genetic data upon what was already known about Quake's inherent risk — based on his age and gender — for 55 conditions, ranging from obesity and diabetes to schizophrenia and gum disease. For example, as a 40-year-old white male, Quake entered the study with a 16 percent chance of developing prostate cancer in his lifetime. But as the computer, based on Quake's genomic sequence, began to incorporate the data of study after study, his risk scooched first lower, and then higher. (The researchers weighted the contribution of each variant according to the number, and sample size, of published studies confirming the association.)

In the end, after incorporating information about 18 separate variants from 54 studies, they determined Quake's risk of prostate cancer is actually about 23 percent. The opposite is true for his risk of Alzheimer's disease, which began at 9 percent and ended — due to the presence of several protective variants — at about 1.4 percent. The scariest monsters in the closet, however, were obesity, type-2 diabetes and coronary artery disease, each of which Quake has a more than 50 percent chance of developing, and each of which can affect the development of the other.

Was it alarming?

"It's certainly been interesting," said Quake of the findings. "I was curious to see what would show up. But it's important to recognize that not everyone will want to know the intimate details of their genome, and it's entirely possible that this group will be the majority. There are many ethical, educational and policy questions that need to be addressed going forward."

Of course, a person's environment — in the form of choices he or she makes about diet, exercise and habits like smoking and drinking — can also powerfully affect disease risk. But if clinicians know that a patient has a higher-than-normal risk for a certain disease, they may recommend certain lifestyle changes more strongly.

"This opens the door to targeted environmental interventions based on a patient's genomics," said Butte. "People who may want more control over their destiny could choose to exercise more, or eat better, or even avoid pesticides more conscientiously."

There's hope, too, in the promise of more effectively using available drugs to combat or prevent disease. Russ Altman, MD, PhD, is the principal investigator of the Stanford-managed Pharmacogenetics and Pharmacogenomics Knowledge Base, or PharmGKB — a curated, international data repository to help researchers understand how genetic variation among individuals contributes to differences in reactions to common medications. Quake's genome gave his group some new opportunities.

"With Steve, we thought, 'Let's apply everything we know about the effect of human genetic variation on drug response to his entire genome,'" said Altman, who together with Quake chairs Stanford's bioengineering department. "And we came up with a table of drugs that are likely to work well for him, like statins, and others that he might need lower doses of, like warfarin."

The researchers also found five to 10 previously unknown SNPs in genes involved in drug response. "This is really exciting because we never would have found these if we'd just relied on our usual panel of suspects," said Altman. "What's more, with whole-genome sequencing, you only ever have to do it once. Our understanding of the information will keep evolving, but the core data set doesn't change."

That evolving knowledge base will present a particular challenge, the researchers believe. Keeping people up-to-date on new findings involving genetic variants that they carry will be a tricky business. Clinicians of the future will walk a tightrope of informing people who've opted to have their genome sequenced of ongoing discoveries while also presenting the information as uncertain and likely to change. Furthermore, how shall we deal with the fact that a patient's genome by definition harbors information about that person's parents, children and other relatives who may not want to peek into their shared genomic crystal ball? Clearly we have much with which to grapple.

"The world of medicine is going to change beyond belief," said Ashley. "We are all going to have to learn how to deal with questions like these."

But what of Quake?

A complete physical pronounced him free of any sign of cardiomyopathy. But it also turned up somewhat elevated lipoprotein levels. Normally, given Quake's health and age, most physicians would take a watch-and-wait approach before recommending medication. However, in the face of this new information about Quake's lifetime genetic risk, and the likelihood, based on the pharmacogenetic data, that he would respond positively to statins, Ashley suggested he consider taking the cholesterol-lowering drugs. It's the first time anyone's ever made clinical recommendations based on a cumulative assessment of a patient's entire genome.

And so it begins.

Other Stanford collaborators include postdoctoral scholar Matthew Wheeler, MD, PhD; bioinformatics specialist and software developer Rong Chen, PhD; senior researcher Teri Klein, PhD; internal medicine resident Frederick Dewey, MD; graduate student Joel Dudley; associate professor of genetics Kelly Ormond, MS; genetics liaison Aleksandra Pavlovic; graduate students Alexander Morgan and Dmitry Pushkarev; research manager Norma Neff, PhD; professor of genetics Louanne Hudgins, MD; scientific curators of PharmGKB Li Gong, PhD; Laura Hodges, PhD; Caroline Thorn, PhD; Katrin Sangkuhl, PhD; and Joan Hebert; former postdoctoral scholar Dorit Berlin, PhD; software developer Mark Woon; graduate student Hersh Sagreiya; software engineer Ryan Whaley; and clinical fellow Joshua Knowles, MD, PhD.

The research was funded by the National Institutes of Health, the Howard Hughes Medical Institute, the National Library of Medicine, the Lucile Packard Foundation for Children's Health, the Hewlett Packard Foundation and the Breetwor Family Foundation.

Altman is consultant to a direct-to-consumer genetic testing company, 23andme, and has received consultancy fees from Novartis. Ormond was a paid consultant as a member of the Genetic Counseling Task Force for Navigenics from June 2007 to August 2009. Quake is a founder, consultant and equity holder in Helicos BioSciences. Pushkarev is an equity holder in Helicos BioSciences. Butte is a scientific advisory board member and founder for NuMedii and Genstruct; is a scientific advisory board member for Johnson and Johnson; has received consultancy fees from Lilly, NuMedii, Johnson and Johnson, Genstruct, Tercica, and Prevendia and honoraria from Lilly and Siemens; and holds stock in NuMedii and Genstruct.

Personal Genomes meeting, Cold Spring Harbor Laboratory, September 2009

2010-03-25T02:42:00.001-07:00

Personal Genomes meeting, Cold Spring Harbor Laboratory, September 2009

Disease Cause Is Pinpointed With Genome

2010-03-11T01:12:00.001-08:00

By NICHOLAS WADE
The New York Times, March 10, 2010

Two research teams have independently decoded the entire genome of patients to find the exact genetic cause of their diseases. The approach may offer a new start in the so far disappointing effort to identify the genetic roots of major killers like heart disease, diabetes and Alzheimer’s.

In the decade since the first full genetic code of a human was sequenced for some $500 million, less than a dozen genomes had been decoded, all of healthy people.

Geneticists said the new research showed it was now possible to sequence the entire genome of a patient at reasonable cost and with sufficient accuracy to be of practical use to medical researchers. One subject’s genome cost just $50,000 to decode.

“We are finally about to turn the corner, and I suspect that in the next few years human genetics will finally begin to systematically deliver clinically meaningful findings,” said David B. Goldstein, a Duke University geneticist who has criticized the current approach to identifying genetic causes of common diseases.

Besides identifying disease genes, one team, in Seattle, was able to make the first direct estimate of the number of mutations, or changes in DNA, that are passed on from parent to child. They calculate that of the three billion units in the human genome, 60 per generation are changed by random mutation — considerably less than previously thought.

The three diseases analyzed in the two reports, published online Wednesday, are caused by single, rare mutations in a gene.

In one case, Richard A. Gibbs of the Baylor College of Medicine sequenced the whole genome of his colleague Dr. James R. Lupski, a prominent medical geneticist who has a nerve disease, Charcot-Marie-Tooth neuropathy.

In the second, Leroy Hood and David J. Galas of the Institute for Systems Biology in Seattle have decoded the genomes of two children with two rare genetic diseases, and their parents.

More common diseases, like cancer, are thought to be caused by mutations in several genes, and finding the causes was the principal goal of the $3 billion human genome project. To that end, medical geneticists have invested heavily over the last eight years in an alluring shortcut.

But the shortcut was based on a premise that is turning out to be incorrect. Scientists thought the mutations that caused common diseases would themselves be common. So they first identified the common mutations in the human population in a $100 million project called the HapMap. Then they compared patients’ genomes with those of healthy genomes. The comparisons relied on ingenious devices called SNP chips, which scan just a tiny portion of the genome. (SNP, pronounced “snip,” stands for single nucleotide polymorphism.) These projects, called genome-wide association studies, each cost around $10 million or more.

The results of this costly international exercise have been disappointing. About 2,000 sites on the human genome have been statistically linked with various diseases, but in many cases the sites are not inside working genes, suggesting there may be some conceptual flaw in the statistics. And in most diseases the culprit DNA was linked to only a small portion of all the cases of the disease. It seemed that natural selection has weeded out any disease-causing mutation before it becomes common.

The finding implies that common diseases, surprisingly, are caused by rare, not common, mutations. In the last few months, researchers have begun to conclude that a new approach is needed, one based on decoding the entire genome of patients.

The new reports, though involving only single-gene diseases, suggest that the whole-genome approach can be developed into a way of exploring the roots of the common multigene diseases.

“We need a way of assessing rare variants better than the genomewide association studies can do, and whole-genome sequencing is the only way to do that,” Dr. Lupski said.

With 10 genomes of healthy humans sequenced, Dr. Gibbs, a specialist in DNA sequencing, decided it was time to decode the genome of someone with a genetic disease and asked his colleague Dr. Lupski to volunteer.

Mutations in any of 39 genes can cause Charcot-Marie-Tooth, a disease that impairs nerves to the hands and feet and causes muscle weakness.

Fifty thousand dollars later, Dr. Lupski turned out to have mutations in an obscure gene called SH3TC2. The copy of the gene he inherited from his father is mutated in one place, and the copy from his mother in a second.

Both his parents had one good copy of the gene in addition to the mutated one. A single good copy can generate enough, or nearly enough, of the gene’s product for the nerves to work properly. Dr. Lupski’s mother was free of the disease and his father had only mild symptoms.

In the genetic lottery that is human procreation, two of their eight children inherited good copies of SH3TC2 from each parent; two inherited the mother’s mutation but the father’s good copy and are free of the disease; and four siblings including Dr. Lupski inherited mutated copies from both parents. These four all have Charcot-Marie-Tooth disease. The results are reported in The New England Journal of Medicine.

In Seattle, Dr. Hood and Dr. Galas have also applied whole-genome sequencing to disease. They analyzed the genome of a family of four, in which the two children each have two single-gene diseases, called Miller syndrome and ciliary dyskinesia. With four related genomes available, the researchers could identify the causative genes. They also improved the accuracy of the sequencing because DNA changes that did not obey Mendel’s rules of inheritance could be classed as errors in the decoding process.

The Seattle team believes whole-genome sequencing can be applied to the study of the common multigene diseases and plans to sequence more than 100 genomes next year, starting with multigenerational families.

The family whose genomes they report in Science were sequenced by a company with a new DNA sequencing method, Complete Genomics of Mountain View, Calif., at a cost of $25,000 each. Clifford Reid, the chief executive, said that the company was scaling up to sequence 500 genomes a month and that for large projects the price per genome would soon drop below $10,000. “We are on our way to the $5,000 genome,” he said.

Dr. Reid said the HapMap and genomewide association studies were not a mistake but “the best we could do at the time.” But they have not yet revolutionized medicine, “which we are on the verge of doing,” he said.

Dr. Goldstein, of Duke University, said the whole-genome sequencing approach that was now possible should allow rapid progress. “I think we are finally headed where we have long wanted to go,” he said.

Into the Personal Genomics Fray

2010-01-25T03:42:00.000-08:00

GenomeWeb, January 25, 2010

Counsyl, a Stanford University start-up, has announced its Universal Genetic Test that allows prospective parents to determine whether their child would be at risk for more than 100 genetic diseases.

The company’s press release says that the test “is free with insurance for more than 100 million Americans” and “is now offered by physicians at more than 100 prestigious medical centers.”

At Genetic Future, Daniel MacArthur, who has used a free kit from Counsyl, says he is intrigued by its approach, especially that it is covered by some insurance companies and that it will likely face question about the ethics of screening for carriers.

“Counsyl's offering is intensely focused: the goal is simply to pick up as many known serious disease-associated mutations as possible,” he writes.

New Machine From San Diego’s Illumina Intensifies Race for Faster, Cheaper Genome Decoder

2010-01-14T01:37:00.000-08:00

Denise Gellene 1/14/10, xconomy.com

The cost of sequencing a person’s genome continues to fall. Illumina this week introduced a machine that can sequence an individual’s genome for under $10,000.

That is one percent of the $1 million it cost to decode a human genome three years ago (2007).

The announcement pushes San Diego-based Illumina to the forefront in an intense race to develop faster and cheaper genome-decoding equipment. The next-cheapest technology costs five times more.

Illumina, which unveiled its HiSeq 2000 at the JP Morgan Healthcare Conference in San Francisco, clearly believes the machine will establish its leadership in the gene-sequencing category.

“Other companies are talking about future products, but we’re talking about products that are going to ship next month,” CEO Jay Flatley told Forbes.

Illumina says its first customer is BGI, formerly known as the Bejing Genomics Institute, which has ordered 128 of the new gene-sequencers for its new genome center in Hong Kong.

The HiSeq 2000, which can sequence two genomes simultaneously, is priced at $690,000.

Flatley said during Illumina’s R&D Day presentation today that the purchase will make BGI the world’s largest genome center.

In a statement issued by Illumina, BGI’s president says it is focused on using genetic analysis to enhance agriculture and food production and to develop the personal genomics field in China.

It will be interesting to see how the competition shapes up from here. Complete Genomics of Mountain View, CA, which Luke profiled in 2008, has a stated goal of sequencing individual genomes for $5,000 each. It has a different business model from Illumina.

Rather than selling sequencing machines, Complete Genomics does the genome decoding in-house and sends clients the results. In November 2009, the company published a “proof of principle” in the journal Science that demonstrated it could sequence and analyze a person’s genome for $8,005 to $1,726.

Another competitor is Helicos Biosciences of Cambridge, MA, which announced last year that it had sequenced the genome of one of its founders for $50,000. That is about the same price Illumina set in August 2009 for its sequencing service aimed at consumers.

Cheaper sequencing will enable more researchers to examine genomes from large numbers of individuals for differences linked to health risks or disease.

Some believe that the information will lead to personalized medical care, based on an individual’s genetic information. No one knows how low the cost of genome sequencing can go. But it’s probably fair to say we haven’t seen the bottom.

Denise Gellene is a former Los Angeles Times science writer and regular contributor to Xconomy. You can reach her at dgellene@xconomy.com

Welcome

2010-01-12T10:09:00.000-08:00

Welcome

Kaiser, UCSF awarded $25 million from NIH to build resource for genetic research

2009-10-13T01:26:00.000-07:00

October 13, 2009 UCSF News

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the University of California, San Francisco (UCSF) have been awarded $24.8 million over two years by the National Institutes of Health (NIH) to create a new resource for studying disease, health, and aging.

With this support, Kaiser Permanente’s RPGEH and UCSF will conduct a genome-wide analysis of DNA samples from 100,000 Kaiser Permanente members from Northern California who have volunteered to join the RPGEH. This new and detailed genetic information – which has never before been generated on such a large and diverse population – will be linked to decades of historical clinical and other health-related information on these participants, taken from health surveys and the Kaiser Permanente electronic health record, the world’s largest civilian electronic health record. Environmental information will also be included in the new resource, such as information about air and water quality, proximity to parks and healthy foods, and much more. The resulting resource will give researchers an entirely new platform for studying genetic and environmental influences over time on a wide variety of health conditions, across diverse populations.

The National Institute on Aging (NIA), part of the NIH, was the key driver for the grant, in part because the average age of those whose DNA will be genotyped is 65. “A body of research tells us that both genes and environmental factors influence how we age,” explains NIA director Richard J. Hodes, MD. ”We are very excited about the opportunity to develop this extraordinary database in an older population, to facilitate studies of gene-environment interaction as determinants of health, disease, and longevity.”

The UCSF Institute for Human Genetics is the partner on the project and will perform the actual genotyping. Grant funds will be shared by both institutions.

“This investment of federal dollars will provide researchers with access to a uniquely rich resource for research on genetic and environmental effects on health, aging, and disease,” says Cathy Schaefer, PhD, executive director of the RPGEH. “Providing access to genome-wide genetic data on such a large population, combined with rich clinical and environmental data, is without precedent.”

For example, the genetic information generated by the project will include new data regarding drug metabolism and drug response, information that may help researchers to discover genetic factors that explain differences between people in response to medications. This would in turn help doctors provide patients with the best medicines for them individually, with less trial and error, based on their genetic background. It may also help researchers understand why some patients with cancer or heart disease, for example, develop certain symptoms and other patients do not, insights that may lead to new treatments and, in some cases, new ways to lessen the severity or even prevent disease.

Neil Risch, Ph.D., co-director of the RPGEH, director of the UCSF Institute for Human Genetics, and co-chair of the Department of Epidemiology and Biostatistics at UCSF, will share lead investigator responsibilities for the grant with Schaefer. The genotyping will be performed at the UCSF Genomics Core Facility, part of the Institute for Human Genetics, under the director of Pui-Yan Kwok, MD, Ph.D., a co-investigator on the grant and the Henry Bachrach Distinguished Professor at UCSF.

“This award represents a landmark in the development of the RPGEH resource, and fulfillment of years of planning,” says Risch. “Following the human genome project, the development of very efficient and inexpensive high-density assays of genetic variation spanning the entire human genome is what has enabled this study to move forward. The marriage of this technology with the unrivaled comprehensive longitudinal health information in the Kaiser Permanente databases on a very large number of subjects provides an unprecedented opportunity to revolutionize genetic epidemiology research. We are delighted that the NIH shares in this vision, in addition to our prior funders.”

The two-year grant was awarded by the NIH with funds from the American Recovery and Reinvestment Act (ARRA). Funding for the grant came from three NIH sources: the Office of the Director, the National Institute on Aging, and the National Institute of Mental Health.

“This grant is recognition of the excellence of research that Kaiser Permanente is able to do. No other research institution can match the size of the genetic data base which we are developing through the RPGEH,” says Robert Pearl, MD, executive director and CEO of The Permanente Medical Group. “I am optimistic that the combination of quality research, physician excellence and technology will allow our nation to solve the healthcare challenges it faces today and in the future.”

Following several years of planning and development, Kaiser Permanente Northern California Division of Research launched the RPGEH in 2005 and initiated enrollment of participants from the Northern California region’s three million Kaiser Permanente members in 2007. The research program has already obtained biospecimens from more than 110,000 members for its biobank, as part of plans to collect DNA samples and health surveys from 500,000 Kaiser Permanente members in Northern California by 2013, which will make it one of the largest and most diverse population-based biobanks in the world.

This new NIH grant builds on an $8.6 million grant awarded in December 2008 by the Robert Wood Johnson Foundation’s Pioneer Portfolio (RWJF) that is funding the collection and storage of the first 200,000 DNA samples into the RPGEH, as well as the building of the secure health and environmental databases needed to power this groundbreaking genetic resource.

“The unequaled size and power of this biorepository will enable researchers to analyze genetic, environmental and other health data in ways that were never before possible. The findings they generate will help us target effective prevention and treatment strategies that dramatically improve people’s health and the quality of their care,” said RWJF President and CEO Risa Lavizzo-Mourey, MD, MBA. “We’re excited that this substantial new NIH funding positions the RPGEH to take major leaps forward toward realizing this vision.”

Research at Kaiser Permanente is funded almost entirely from grants, such as those from the National Institutes of Health and private foundations. Generous grants to support the RPGEH have also come from the Wayne and Gladys Valley Foundation and the Ellison Medical Foundation. Kaiser Permanente’s Community Benefit Program has also provided financial support for the RPGEH.

Participation in the RPGEH is completely voluntary. An individual’s genetic information is not used in genetic research studies without his or her written consent.

As with all studies carried out by the Division of Research, protecting confidentiality and security of member information is a first priority. The Division of Research maintains separate information and databases from the Kaiser Permanente health plan and members’ medical records.

Only Kaiser Permanente members in Northern California may participate in the RPGEH. Those who are interested in joining the RPGEH should look for information about the program in the U.S. mail from Kaiser Permanente.

OVP, Enterprise Partners See Big Opportunity in $5,000 Human Genome Sequencing

2008-10-07T01:49:00.000-07:00

Luke Timmerman 10/7/08, xconomy.com

It’s getting cheaper by the day to sequence the entire string of 6 billion chemical units of DNA that make up an individual human being.

Yesterday, Complete Genomics of Mountain View, CA unveiled plans for what amounts to a democratization of genomics. It will offer a service to sequence full human genomes for just $5,000, beginning in the second quarter of 2009.

At Xconomy.com, we normally focus on companies based in Boston, Seattle, and San Diego, but we couldn’t resist digging into this one, because it has multiple connections to our network cities.

Complete Genomics raised its seed capital in 2006 from OVP Venture Partners in Kirkland, WA, and Enterprise Partners in San Diego. It also counts a pair of Xconomists, Leroy Hood of the Institute for Systems Biology in Seattle, and George Church of Harvard Medical School, as scientific advisers.

So we tracked down OVP managing director (and Xconomist) Chad Waite to find out why he decided to invest in this technology versus all the other sophisticated instruments made by companies like Applied Biosystems, Illumina, 454 Life Sciences, and Helicos Biosciences. (He proudly pointed out that his Harvard Business School connection to CEO Clifford Reid gave him the inside track on this investment, and he invited Drew Senyei of Enterprise in on the action, but more on that later.)

It turns out Waite was sold on Complete Genomics because it has a fundamentally different vision of the market from its rivals.

Instead of trying to sell a machine to pharmaceutical companies and top academic labs for hundreds of thousands of dollars, Complete Genomics plans to keep the work in-house on its own proprietary machines and offer sequencing as a service.

The company plans to open 10 sequencing centers around the world over the next five years, with the capacity to sequence 1 million complete human genomes.

It will have enough bandwidth to sequence an entire genome for $5,000 in about four days, compared with $100,000 and six weeks to six months on currently marketed instruments, Waite says.

“We’re disruptive on technology, and on the business model,” Waite continues. “We’re not going out and trying to sell million-dollar machines. Is there really a competitive advantage for a pharmaceutical company to have the machine? The advantage for them is in the data. They want the data.”

So how might that be really useful for companies or academics?

At that high speed and low price, it’s conceivable that drug companies will want to sequence every patient who enters a clinical trial to provide clues as to why some patients respond differently than others to experimental drugs, Waite says.

Or, they might want to run big experiments that compare the genomes of 1,000 patients with diabetes to 1,000 other people as healthy controls, to look for tiny genetic variations that might offer clues.

They could look at a bunch of prostate cancer tumor samples to try to find genomic markers that explain why the disease spreads more quickly in some people than in others, Waite says.

These concepts are truly mind-boggling when you look at the recent history of gene sequencing.

Back in 1991, when many scientists were skeptical the full human genome could ever be sequenced, Congress was told it would cost $3 billion to sequence the human genome and it would be done by 2005.

It was actually done by 2003, at a cost of $2.7 billion, according to the National Institutes of Health.

Five years later, thanks to big improvements in sequencing technology, it can now generally be done for about $100,000, depending on how you account for the expense of labor to run the machines, Waite says.

Even at that high degree of efficiency, only a couple dozen human genomes have been fully sequenced, according to this report in the New York Times.

Complete Genomics hasn’t published its methods in a top peer-reviewed journal like Science or Nature, although it has double-checked its machine for accuracy against competitors internally, and plans to publish the work soon, Waite says.

The paper hasn’t come out yet, so the following comes with a grain of salt, but the company says it achieves its lower costs by using much less of chemical reagents than existing tools. It also uses ultra high-density DNA tests that can be read with commercial imaging equipment that keeps those costs down.

The company will need that validation to convince scientists and others that they are getting their money’s worth by getting sequences done at Complete Genomics.

Before the paper comes out, though, the company hopes to receive some validation already from two very prominent early partners—the Institute for Systems Biology in Seattle, and Genentech, the biotech industry’s No. 1 company by market value.

Complete Genomics’ partnership with the ISB is expected to sequence 100 individual genomes in 2009, and 2,000 more in 2010.

The new low-cost tool “will allow us to gain a more complete understanding of the genetic components and molecular processes of diseases in order to better manage, treat and prevent human disease and better understand human health,” Hood said in a statement.

Waite and Senyei invested together in Seattle-based Corixa back in the 1990s, so it was natural that they would go in together on Complete Genomics, Waite says.

Both OVP and Enterprise Partners have participated in all three rounds of funding in Complete Genomics, while Prospect Venture Partners led the second round and Highland Capital Management led the third, according to DowJones VentureSource data that my colleague in San Diego, Bruce Bigelow, found. The company has raised about $46.5 million since its founding, and has 100 employees.

People have been talking about the dream of the $1,000 genome, so I asked Waite how low can this sequencing really go. “We think it can go lower, but we’re not really going to talk about that,” Waite says. “But this is really exciting on many levels.”

Luke Timmerman is the National Biotechnology Editor for Xconomy. You can e-mail him at ltimmerman@xconomy.com, call 206-624-2374, or follow him on Twitter at http://twitter.com/ldtimmerman.

The Quest for the $1,000 Human Genome

2006-07-18T01:23:00.000-07:00

By NICHOLAS WADE, New York Times, Published: July 18, 2006

As part of an intensive effort to develop a new generation of machines that will sequence DNA at a vastly reduced cost, scientists are decoding a new human genome — that of James D. Watson, the co-discoverer of the structure of DNA and the first director of the National Institutes of Health’s human genome project.

Decoding a person’s genome is at present far too costly to be a feasible medical procedure. But the goal now being pursued by the N.I.H. and by several manufacturers, including the company decoding Dr. Watson’s DNA, is to drive the costs of decoding a human genome down to as little as $1,000. At that price, it could be worth decoding people’s genomes in certain medical situations and, one day, even routinely at birth.

Low-cost decoding may bring the genomic age to the doctor’s office, but it will also raise quandaries about how to safeguard and interpret such a wealth of delicate and far-reaching personal information.

The first human genome decoding, completed by a public consortium of universities in 2003, cost more than $500 million. With the same technology, dependent on DNA sequencing machines made by Applied Biosystems, a human genome could probably now be decoded for $10 million to $15 million, experts say.

Much greater efficiency is expected from the new generation of DNA sequencing machines, based on different, highly miniaturized technologies. One machine, made by 454 Life Sciences, has been on the market since March 2005. Another, made by Solexa, will start shipping this summer. Applied Biosystems will start marketing its own next-generation machine next year.

Last month, at a training course organized by the Cold Spring Harbor Laboratory on Long Island, researchers were learning how to use the DNA decoding machines made by 454 Life Sciences. Looking like a hybrid between a washing machine and a giant iPod, the machines cost $500,000 each, not counting the computer software needed to analyze the results.

At their heart lies a plate of light-sensitive chips, the same as those used in telescopes for detecting faint light from distant stars. On top of the plate sits a glass slide pitted with thousands of tiny wells, each containing a fragment of the DNA to be decoded.

As each unit of DNA is analyzed in a well, a flash of light is generated by luciferase, the enzyme that fireflies use to make themselves glow. The telescope plate records the twinkling lights from each well and, at the end of the run, which lasts four or five hours, the sequence of units in each well’s DNA fragment has been recorded. The fragments are about 100 units in length, and from their overlaps a computer can then be set to piece together the entire genome they come from.

In the training course, the project was to analyze DNA from a Tasmanian devil, a marsupial afflicted with a mysterious malady called devil facial tumor disease. The researchers found that the genome was laden with a virus that had integrated its sequence into the devil’s DNA.

The 454 machine can assemble small genomes like those of bacteria, which perhaps accounted for the presence at the course of three scientists from the Department of Homeland Security. But the human genome is about 600 times larger than a bacterium’s and includes many repetitive sequences that, like identical pieces in a jigsaw puzzle, make the solution much harder.

At the Cold Spring Harbor course, researchers heard Dr. Watson, the laboratory’s chancellor, say that 454 Life Sciences had asked to sequence his genome with their new machine. Only two human genomes have been sequenced to date. The genome sequenced by the public consortium was a mosaic of DNA from several anonymous people. The consortium’s rival, Celera Genomics, prepared a draft sequence, most of it from the genome of its former president, Dr. J. Craig Venter.

Dr. Watson told the students that he had given the company permission to publish the sequence of his genome, “provided they didn’t release to the world that I have some disease I don’t want to know about.”

Genomic information can already reveal a lot and will reveal much more as the roles of new genes are discovered.

“I think that personal genetic information should ordinarily be kept secret,” Dr. Watson said. “But I have said that 454 can put mine out there, even though it’s saying something about my sons.”

So far, however, 454 Life Sciences has not published Dr. Watson’s genome, and it is not clear how much progress the company has made. Christopher K. McLeod, its chief executive, said, “Technically, we’ve done a lot of good work on it.” But, he added, “I don’t think we want to discuss where we are.”

Mr. McLeod expressed reservations about releasing personal genetic information, despite having Dr. Watson’s permission to do so. “Jim feels there are certain things he’d be comfortable releasing,” he said. “I’m not sure we would agree.”

Another factor may be that the company is developing a more powerful model of its machine that will be able to read DNA fragments that are 200 or even 400 units in length. These longer-read lengths should make it more feasible to decode large genomes, like those of people.

The 454 machine is at present being bought chiefly by researchers and by the large genome sequencing centers established by the public consortium. But it has begun to show promise for the clinic. One new use is in screening tumors for genes known to be mutated in cancer, a task that existing machines do not do well. Spotting which mutation has occurred in a patient’s tumor can help in the choice of chemotherapy.

Although the 454 model is the only next-generation DNA sequencing machine on the market, it will be joined this summer by the machine from Solexa. The Solexa instrument, which will cost $400,000, works on somewhat similar principles but uses fluorescent dyes to visualize the structure of DNA. And next year Applied Biosystems will introduce its next-generation machine, based on a technology developed by George Church of Harvard, said Dennis A. Gilbert, the company’s chief scientific officer.

Each of the manufacturers claims special advantages for its technology, ensuring that researchers will have a rich choice.

David Bentley, Solexa’s chief scientist, said that the company’s DNA sequencing machine had already decoded several bacterial genomes and that he was planning to sequence a human genome — that of an anonymous man from the Yoruba people of Nigeria. An African genome was chosen because there is greater genetic diversity in African populations, Dr. Bentley said.

The demand for whole genome sequencing is a long way off, in Dr. Bentley’s view, but not so distant that it is too early to think about the consequences of generating such information. He advocates that two people should control access to a person’s genome sequence — the patient and the physician.

Why not the patient alone? Dr. Bentley said genomes would be so difficult to analyze correctly that interpretation should stay within the medical profession. Otherwise, freelance services will spring up, offering to predict whether a person will get heart disease or their age of death. This potential for misinformation “would have a huge adverse impact on the medical use of genetic information,” Dr. Bentley said.

A recent example of genetic misinformation occurred last month when a DNA testing genealogy company, Oxford Ancestors, told Thomas R. Robinson, an accountant at the University of Miami, that he was a descendant of Genghis Khan. Only because Mr. Robinson sought a second opinion did he find that the information was incorrect.

Technology, not medicine, is the immediate force behind the quest for the $1,000 human genome. The new decoding machines are being developed because they are possible, not because hospitals are demanding them. But the makers expect that demand will grow as researchers develop new uses.

“As we drop the price and increase the capability, there are applications that couldn’t be done before,” like a researcher being able to screen a thousand patients for cancer mutations, Dr. Gilbert said.

At present, only a handful of genes are monitored by doctors in clinical practice, and specific tests for these genes make it unnecessary to decode a person’s entire genome. But at some point, the new machines or their successors may make genome decoding a routine medical test.

Already, every newborn baby endures its heel being pricked to draw a few drops of blood, which are tested for a handful of enzymic deficiencies. But when genomes can be decoded for $1,000, a baby may arrive home like a new computer, with its complete genetic operating instructions on a DVD.

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