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NGS Leaders Blog

Celebrating the 10th Anniversary of the Human Genome Project

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genomicMay 1, 2013
Kevin Davies :  On DNA Day, April 25, a parade of leading genome scientists gathered at NIH to celebrate the 10th anniversary of the completion of the Human Genome Project (HGP). NIH assembled an outstanding list of speakers, including NIH Director Francis Collins, ENCODE project leader Ewan Birney, Princeton geneticist David Botstein, cancer geneticist Levi Garraway and experts in evolutionary and population genetics and healthcare.

I was honored (and a little petrified) to be included in the line-up. After all, my most significant contribution to biomedical research was hanging up my lab coat 25 years ago to seek refuge in the cramped, dilapidated offices of Nature magazine in London.

I was asked to speak on public perceptions of the HGP and the inexorable march of sequencing technology towards the $1,000 genome. Preparations did not go smoothly: despite the lack of coffee (a victim of the sequester), I managed to procure a cup, only to spill the contents down my jacket mid-morning. Hopefully it's not evindent in the video…

The talk was enjoyable (for me anyway): Along the way, I worked in a plug for the new film Decoding Annie Parker, on which I served as a genetics consultant; showed off a little Welsh; and had a little fun at the expense of current NIH Director, whose next book almost certainly will not be entitled The Language of Love – or 46 Shades of Grey - for that matter.

The video of my talk is below and is below and the entire set of event videos can be viewed at the NHGRI Genome TV channel.  



Nancy Kelley Steps Down as New York Genome Center Executive Director

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March 18, 2013 

Bio-IT World Staff : Nancy KelleyNancy J. Kelley, the founding executive director of the New York Genome Center (NYGC) and the person most responsible for conceiving and bringing the ambitious institute to fruition, is stepping down from her leadership role.

She will remain an advisor and a member of the Board of Directors.

“Working with the New York Genome Center and all of its supporters and partners has been an extraordinary experience,” said Kelley in a statement released today. “This is an exciting time in science and medicine. The Center is now well positioned to become a world-class collaborative center for translational genomic research under the strong leadership of [Bob] Darnell… I will always value my experience there.”

Kelley “was instrumental in nurturing NYGC from an idea to a reality, to the inestimable benefit of scientific research and New York City,” said Russ Carson and Ivan Seidenberg, co-chairs of the NYGC Board of Directors, in a statement. “We are extremely appreciative of her vision, persistence, and accomplishments, and we look forward to continuing to work with her as an advisor and a member of NYGC’s Board of Directors."

As Kelley detailed in a lengthy interview with Bio-IT World in 2011, she saw the faintest possibility of building a world-class genomics institute in the middle of Manhattan and ran with it. Working with Columbia University professor Tom Maniatis and a number of key administrative and philanthropic supporters, Kelley forged a coalition of 11 founding institutions, including most of the major research and clinical centers in and around New York City.

NYGC was officially launched in 2011. Many of the center’s foundational elements, including its Pilot Laboratory at Rockefeller University, the NYGC Innovation Center, and key technology partnerships, were established under her leadership. Kelley also oversaw the selection and build out of NYGC’s permanent facility at 101 Avenue of the Americas in New York City, which is scheduled to open this summer.

Late last year, NYGC appointed Rockefeller University physician scientist Robert Darnell as president and scientific Director.

Reached by Bio-IT World, Kelley declined to comment on the record other than to say she is looking forward to taking some time off. It is unlikely that NYGC will be her last contribution to the biomedical enterprise.

Ed Note: The Bio-IT World Conference in April 2013 will include a session on building out the IT infrastructure at NYGC.  

Putting Science on Screen: The Perfect 46

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 Editor’s Note: We are pleased to share a guest post submitted by Brett Bonowicz, Author and Director of "The Perfect 46". 

March 5, 2013 :  “The Perfect 46” is a film about the CEO of a personal genetics company and what happens when he creates a website that pairs individuals with their ideal genetic match for children. The CEO – Jesse Darden – bares some similarities to the brilliant game-changing innovators such as Steve Jobs or Mark Zuckerberg, and ties that entrepreneurial spirit to the fascinating world of direct-to-consumer (DTC) personal genomics. 

What would happen if a personality so tied to the identity of his company had the chance to change the nature of our relationships. What if facebook started telling us who we should be with? The script is written and is pretty good – of course, as the author, I’m a little biased. If we can raise enough money, we aim to start shooting this May and all going well, release the film later in 2013. 

As I begin to promote the film and raise funding, I have some trepidation about reaching out to the scientific community. Why should people that work incredibly hard to create the wonderful reality of tomorrow care about someone making fictional art?   

My best answer is that the reflection they might see of themselves in the film might spark debate. And perhaps not just within the scientific community, but with an entirely different audience that wouldn’t normally be engaged in such a discussion. theperfect46 

I started to think about where the film could go and where the two subjects – the genetics visionary and the social networking aspect -- might begin to overlap. As I began to formulate the film in my outline, I read a lot about the field of personal genomics. I found myself highlighting pages in books that came right out of my outline. Ideas that I thought might be science fiction were already becoming reality.

I seemed to be on the right track with the story, and every time I started to veer off into subject matter that was fantasy I would reign it back in because sticking closer to the reality was always more interesting. I discovered fascinating facts about eugenics and the very American history of how it began at the beginning of the 20th century.

By making the film as factually accurate as possible, the conversation that the film creates should, I think, spark something that a more futuristic, fantastic treatment perhaps cannot. The topics we cover in the film -- genetics, eugenics, the moral and ethical implications of a consumer genetics service, and the role of government vs. a DTC model -- are discussions that deserve to be out in the public. This is a film of the moment. We have an amazing opportunity to make something right on the cutting edge of what is possible in personal genetics.

Science is rarely, if ever, treated well in film. Outside the realm of documentaries, it is hard to find more than a handful of films that truly respect the scientific community. I am frustrated with that fact, and I cannot be alone in thinking that works like this have an audience and that they deserve to be made and to be seen.

I read the works of Arthur C. Clarke and I wonder why they never made it to the screen? I read the wonderful literature of George Dyson, and I can imagine a perfect film coming from the story of Project Orion. But where is it? Where are those films? If an audience can be found, I guarantee those films will start to crop up.

It’s been over 15 years since Andrew Niccol’s excellent, thought-provoking film Gattaca (tagline “There is no gene for the human spirit”) came to theatres. A lot of our perceptions about genetics have changed in those years. What we’re making can be looked at as a sort of prequel to Gattaca. We’re looking at the moment when society might begin to shift. We’re looking at the discussions and the realities of a service of this kind.

Please help us get the word out about this film. We are using the popular crowd-sourcing model via a website called Indiegogo to raise some modest funding to begin shooting the movie.

The fund-raising campaign is for 46 days, with the goal of raising $46 thousand. Please take a look at what we've been creating at: www.theperfect46.com 

Okay, You've Sequenced My Genome: Are You Sure You Got it Right?

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Editor’s Note: We are pleased to share a guest post submitted by Justin Zook and Marc Salit from the National Institute of Standards and Technology. 

January 3, 2013 : Clinical application of “Next-Generation Sequencing” for hereditary genetic diseases, oncology, and other purposes is rapidly growing.  At present, there are no widely accepted genomic standards or quantitative performance metrics for confidence in variant calling. These are needed to achieve the confidence in measurement results expected for sound, reproducible research and regulated applications in the clinic.  On April 13, 2012, the National Institute of Standards and Technology (NIST) convened the workshop Genome in a Bottle to initiate a consortium to develop the reference materials, reference methods, and reference data needed to assess confidence in human whole genome variant calls. A principal motivation for this consortium is to develop widely accepted reference materials and accompanying performance metrics to provide a strong scientific foundation for the development of regulations and professional standards for clinical sequencing.

The consortium has four working groups with the listed responsibilities:

  • Reference Material (RM) Selection and Design
  • Select appropriate cell lines for whole genome RMs and design synthetic DNA constructs that could be spiked-in to samples
  • Measurements for Reference Material Characterization,
  • Design and carry out experiments to characterize the RMs using multiple sequencing methods, other methods, and validation of selected variants using orthogonal technologies
  • Bioinformatics, Data Integration, and Data Representation
  • Develop methods to analyze and integrate the data for each RM, as well as select appropriate formats to represent the data
  • Performance Metrics and Figures of Merit
  • Develop useful performance metrics and figures of merit that can be obtained through measurement of the RMs

The products of these working groups will be a set of well-characterized whole genome and synthetic DNA RMs along with the methods (documentary standards) and reference data necessary for use of the RMs. These products will be designed to help enable translation of whole genome sequencing to clinical applications by providing widely accepted materials, methods, and data for performance assessment.

An open meeting was held August 16-17, 2012 at NIST in Gaithersburg, MD to receive public comment on this proposed work plan for the “Genome in a Bottle” Consortium.  Each working group developed a more detailed work plan, which is available in the slides and summary of the workshop. 

Since the workshop, there has been considerable discussion about what is an appropriate informed consent for whole genome Reference Materials from NIST. The consortium has decided to use the extensive existing data fromHapMap/CEPH/Utah Genetic Repository sample NA12878 and her pedigree for bioinformatics methods development, and NIST is seeking guidance from its IRB regarding the propriety of the current consent for a NIST Reference Material.  In parallel, the consortium has selected three father-mother-child trios with a more recent open consent from the Personal Genome Project for an initial set of NIST Reference Materials. When cell lines for these trios are available (hopefully in the next few months), the consortium will begin sequencing them with multiple sequencing technologies and library preparation methods. Over the next year, the consortium plans to select five additional trios from the Personal Genome Project as additional ethnic groups may choose to enroll.

On March 21, 2013 at 8:30am, the Genome in a Bottle Consortium is planning a morning session co-located with the XGen Congress in San Diego, CA. Each working group will present their progress and work plans and NIST will present its work forming consensus variant calls from multiple datasets on a single genome, followed by an open panel discussion with questions from the audience. All are welcome to attend this event free of charge, and we hope to see many of you there.  More information about the consortium can be found on the website www.genomeinabottle.org, and the consortium is always open to new members from public, private, and academic sectors. To receive updates, you can register and choose to receive newsletters by email on the website.

Does Whole Genome Sequencing Circumvent Gene Patents?

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Editor’s Note: We are pleased to share a guest post by Nicholson Price, an Academic Fellow at the Petrie-Flom Center for Health Law Policy, Biotechnology and Bioethics at Harvard Law School. 

December 10, 2012 : W. Nicholson Price II :  What happens when, during the course of whole-genome sequencing (WGS) a patient or research subject, an investigator sequences and analyzes a disease gene that has been patented? The U.S. Supreme Court will shed some light on this question next year when it issues its ruling in the long-running Myriad Genetics saga.

Last month, the Supreme Court voted to hear the case of Association for Molecular Pathology v. Myriad Genetics to consider the question whether human genes are patentable. The plaintiffs -- doctors, patients, researchers, and the American Civil Liberties Union – have challenged Myriad’s patents on the breast cancer genes BRCA1 and BRCA2, which cover, among other things, isolated DNA molecules with the sequences of those genes. A federal district court in New York ruled that the patent claims on isolated DNA molecules were invalid, but that ruling was reversed on appeal by the Federal Circuit in D.C. The Supreme Court decided to review the Federal Circuit’s decision and will likely rule on whether isolated human gene sequences are patentable next summer.

This case has profound implications for biotechnology, and diagnostics, as well as the emerging field of personalized medicine. Among the fascinating issues that will likely be addressed is whether WGS—an essential foundation for truly personalized medicine—violates human gene patents. 

As WGS involves determining the sequence of an individual’s entire genome, there is concern in many quarters that WGS could violate essentially every patent covering an isolated human DNA sequence – of which there are thousands. Indeed, this concern has been raised by scholars, policy analysts and lawyers, including before the Federal Circuit and in the arguments over whether the Supreme Court should hear the case.

However, a closer look at the technology suggests that, rather than violating thousands of gene patents, WGS methods violate few, if any, existing gene patents. Whatever the Supreme Court decides next summer, the widespread adoption of clinical WGS is not particularly threatened by gene patents.

Patents and WGS 

Gene patents, it is worth emphasizing, do not mean that the patentee owns the gene, in all forms and for all uses. Instead, a patentee has only the ability to prevent others from making or using what is specifically claimed in a patent; the patent claims determine the precise boundaries of the protected invention. While it is impossible to analyze comprehensively all the claims in all gene patents, an analysis by law professor Christopher Holman of a set of representative gene patents (including those at stake in the Myriad case) suggests that most claims in gene patents will not be infringed by WGS. 

The claims in gene patents generally fall into two categories: (1) composition of matter claims, which claim physical isolated DNA molecules; and (2) method claims, which claim methods of comparing the sequence of an individual with known reference sequences, and sometimes using that information to draw medical conclusions. 

Method claims are not especially problematic for WGS. Myriad’s method claims were held invalid by the district court; the Federal Circuit affirmed (relying on Mayo Collaborative Services v. Prometheus Laboratories, Inc., a March 2012 Supreme Court case which invalidated simple diagnostic correlation patents). Diagnostic methods patents thus have a somewhat uncertain future; it is unclear what genetic methods patents require to be valid. More importantly for the development of personalized medicine, diagnostic patents lack the same sort of potential hold-up problems as patents on isolated DNA. If any individual valid diagnostic patent covers a particular gene’s correlation with a disease and the patent is too hard or expensive for the person performing WGS to license, that result could just be left out of a WGS analysis without blocking the sequencing and the rest of the analysis. 

Composition claims, on the other hand, are the real source of worries for WGS and are squarely at issue in the Myriad case. Two characteristics of composition of matter claims are relevant: they claim physical DNA molecules which are (1) “isolated” and (2) generally quite long.  Because WGS typically does not make or use long isolated DNA molecules, it is unlikely to infringe composition claims.

Composition claims in gene patents almost always claim “isolated” or “purified” DNA molecules with the specified gene sequence (or a set of related sequences). The claims are limited to isolated molecules because otherwise they would cover the gene as found in nature, and would thus be invalid as including unpatentable subject matter. The term “isolated” is ambiguous, and no court has laid out a generally applicable definition. (Indeed, since each patent can define its own term, the exact contours of “isolated” cannot be precisely determined for the whole class of gene patents.) However, “isolated” must have a relatively narrow meaning to avoid patent claims which are too broad and thus invalid. At the least, to avoid claiming genes as found in nature, “isolated” must mean that the claimed DNA is largely separated from other cellular components and flanking DNA sequences.

The second relevant characteristic relates to the size of the claimed molecules. Most composition claims are for whole genes, or at least portions of genes long enough to encode functional proteins; in other words, composition claims generally cover lengthy DNA molecules of thousands of bases. (A handful of other claims cover all molecules containing a very short specified sequence—generally 15 or so bases—but these claims are almost certainly invalid as too broad and as anticipated by early public disclosures of matching DNA molecules.)

In Violation 

To violate gene patents, then, WGS would need to make or use long, isolated DNA sequences. But most WGS techniques do not rely on such DNA molecules. Shotgun sequencing generally reads very short DNA molecules, frequently in the tens to hundreds of bases; while these molecules are isolated, they are usually too short to include the full sequence of most claimed DNA sequences. And next-generation WGS methods avoid even that possibility. Techniques that do not rely on PCR amplification almost certainly do not create “isolated” DNA molecules, and neither do techniques like the Pacific Biosciences platform or nanopore sequencing, which in theory sequences very long molecules of many kilobases—much longer than the approximately gene-length sequences claimed by most gene patents.

Note that isolating the informational sequence of a particular gene—after the whole genome has been sequenced—does not violate composition claims because those claims cover physical molecules, and WGS never makes or uses the physical isolated DNA molecule containing that sequence. Thus, while there may be some residual uncertainty in this analysis from the sheer number of gene patents and their variation—and, as Robert Cook-Deegan has argued in Science, uncertainty itself can prevent innovative technologies from being adopted—it seems that WGS, especially next-generation WGS, likely infringes very few if any patents on isolated human gene sequences.

(The same analysis applies to whole-exome sequencing (WES), even though initially the technique appears more likely to violate composition claims. However, as in WGS, the genome is broken into very short fragments prior to WES. The method thus never makes or uses the physical isolated gene-length DNA fragments claimed in gene patent composition claims, and likely infringes as few patents as WGS.)

In addition to the legal analysis, there are some practical considerations that make it unlikely that gene patents will block widespread WGS. Most significantly, WGS has been going on for several years, and there have been no reports of specific gene patent holders trying to extract licenses or block WGS. Indeed, given that gene patents cover only very small portions of the genome, any successful infringement lawsuit would likely result only in small required royalty payments, rather than an injunction blocking the sequencing, making such a lawsuit not worth the time and cost of bringing it. Finally, of course, patents are granted for a limited time, many gene patents have expired, and it is much harder to get new gene patents. Gene patents, while still important, are a dying breed.

Overall, several important issues may turn on the outcome of the closely-followed Myriad case.  But the future of whole-genome sequencing is not one of them.

Editor’s note: This article is based on a more detailed analysis by the author published in 2012 in the Cardozo Law Review. 


At ASHG, Oxford Nanopore Execs Talk Non-Stop but Say Little

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November 16, 2012 
Kevin Davies :  If there was a more popular booth at last week's American Society of Human Genetics conference (ASHG) in San Francisco, I didn't see it. For three days, the British company's executive team led by CEO Gordon Sanghera and CTO Cive Brown, along iwth Spike Willcocks (VP Business and Croporate Development), Kristen Stoops (Business Development Director), and a new recruit Adam Lowe (VP Commerical Operations), talked themselves hoarse but deflected all the predictable, tedious questions about launch dates and data release.

Sanghera told me the same thing he told countless others: the company was standing by what it had said when Brown presented preliminary data at the Advances in Genome Biology and Technology (AGBT) conference last February: namely that it would be moving into its commercialization phase by the end of this year. I confess I don’t know what that means exactly – it doesn’t appear to mean that the GridION and MinION will be available for purchase before the New Year.

It’s stretching the definition of ‘commercialization’ pretty thin, but my best interpretation of Sanghera’s assertion was that the company was still on course to move into an important new phase en route to a full commercial launch by the end of the year.

That notion was reinforced when I independently heard during ASHG from one American source that their early access arrangement with Oxford Nanopore was slated to begin in January 2013. That should give those early partners a few weeks to pull some new data together for AGBT in 2013, right?

I saw little point in pressing the chaps for additional information, but Brown did offer a brief tour of the plumbing inside the GridION, which makes good use of field programmable gate arrays (FPGAs), despite their notorious difficulty to program. Meanwhile, an earnest Yaniv Erlich (Whitehead Institute) helpfully tweeted this diagram of a MinION prototype: Oxford Nanopore  

The throngs gathered around the Nanopore booth inevitably diverted attention from some other interesting new products on display. Knome was showing off the new knosys100 supercomputer, an imposing piece of hardware that the execs said was drawing considerable interest from core lab directors. Meanwhile, Stan Gloss, CEO of the BioTeam, was unveiling a custom-designed Dell computer to run the firm’s affordable miniLIMS software. I was also impressed with Illumina’s new app store for BaseSpace, which is already attracting applications from a number of vendors.

One new platform that caught my eye (no pun intended) was the Irys system from BioNano Genomics. Founded by Han Cao, the San Diego company is preparing to ship instruments in the New Year. The Irys platform images DNA molecules over long distances (up to 1 megabase) by linearizing the DNA through a series of nanochannels. The images are stunning and should provide valuable data for de novo genome assemblies, detection of structural variations, and deconvolution of repetitive sequence in heterochromatic regions of the genome.

At $295,000, the Irys is not cheap, but it will be interesting to see if BioNano Genomics can lure customers away from existing technologies such as fiber-FISH or more established competitors such as OpGen.

Would You Vote for Genomic Screening of Newborns?

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Editor’s Note: The following is a guest post by Robert C Green, MD, MPH, Associate Professor of Medicine in the Division of Genetics at Brigham & Women’s Hospital, Boston, and Director of the Genomes2People research program, www.genomes2people.org  

October 31, 2012 

Robert C Green : Genetic Screening NewbornsWhat would it be like to use genomic sequencing for newborn screening?

Would you want to know all, part or none of your baby’s genome?

Where will newborn sequencing save lives and where will it needlessly inflate fears and medical costs?

At Brigham and Women’s Hospital in Boston, there are 8,000 births a year, and a growing program in translational genomics research called Genomes2People.

We have been thinking about these questions and have started to gather pilot data from the parents of newborns. We’ve already learned that, when asked, more than 70 percent of nearly 300 parents of healthy newborns say that want genomic screening!

We have proposed a pilot study to complete this survey and start piloting newborn screening through genomic sequencing under carefully monitored conditions.

Our proposal is one of three finalists in a competition organized by the Brigham - the BRIght Futures Prize. The winner will be selected by competition for public votes, with a $100,000 grant at stake.

Anyone can cast a vote (once) before November 1st for any of the three proposals. To see more about the contest, visit:http://brighamandwomens.org/research/BFF/default.aspx


They are all excellent projects in their own right – the other two tackle questions in multiple sclerosis and the immune system - but I’m convinced that members of the NGS Leaders community will be particularly intrigued by our efforts to study the potential medical impact and ethical issues surrounding newborn genome screening.

If you agree, we’d welcome your vote for our project before November 1 at http://bwhbriwebmaster.partners.org/?p=708 

Thank you for voting!

I-Study: Genomic Interpretation - Who Will Pay?
During this webinar, members of the study review team present preliminary findings of the I-Study, conducted at the Harvard Medical School's 2011 Personalized Medicine Conference.
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