Precision Medicine: Seeking Impact, Needing Champions

This weekend, I had the opportunity to present a short talk, entitled “Precision Medicine 2.0: Seeking Impact, Needing Champions” at the Stanford Medicine X conference. I thought I’d share a short digest of the talk; the slides are here.

(Disclosure/reminder – also highlighted during my presentation: I’m Chief Medical Officer of DNAnexus, a cloud genomics company intensively involved with precision medicine; while this talk reflects my views, and not necessarily the views of DNAnexus, my experiences at DNAnexus have obviously informed my perspective. My relationship with DNAnexus should be kept in mind by the reader.)

Genomics 1.0

To understand where we are now, it’s useful to consider the excitement, promise, and extravagant expectations around the conceptualization and execution of the original human genome project, what you might call Genomics 1.0. Early proponents like Sydney Brenner stated in 1982 that with a complete DNA sequence and a big enough computer, “you could compute the organism,” while sequencing pioneer Wally Gilbert suggested in 1991 that with the complete genome in hand, “we’ll know what it is to be human” (see here for reference).

In a memorable response to this apotheosis of reductionism, Harvard geneticist Richard Lewontin penned a memorable essay in the New York Review of Books in 1992, suggesting proponents might be fetishizing DNA. His piece helpfully included this OED definition of fetish: “An inanimate object worshipped by savages on account of its supposed inherent magical powers, or as being animated by a spirit.”

Our tendency to imbue emerging technologies with almost mystical powers isn’t limited to DNA, of course, and might be applied equally well to “big data,” “design,” and “mobile.”

[Denny Ausiello and I offered our reaction to the completion of the sequencing phase of the first human genome announced by Celera in April 2000, in an essay for the New York Times “Week in Review” here.]

Following the completion of the human genome project, many in medicine felt a palpable sense of disappointment and disillusionment – where were the cures that genomics had promised? “We fought cancer…and cancer won” asserted a thoughtful 2008 Sharon Begley Newsweek article from this period. “Advances elusive in drive to cure cancer,” Gina Kolata of the New York Times detailed in 2009, as part of a memorable series, “The Forty Years War.”

Genomics 2.0

Flash forward to the present, what might be called Genomics 2.0, defined by two important features: next generation sequencing (NGS), which has dramatically reduced the cost and increased the speed of sequencing, and cloud computing, which provides a way to manage the deluge of data that’s now emerging. Interestingly, in testimony before a Congressional committee last summer, genome pioneer (and Human Longevity Institute founder) Craig Venter said that the most important changes occurring in genomics technology involve computing, and added, “The cloud is the entire future of this field.”

The Precision Medicine Initiative, announced at the White House in January, captured much of the contemporary hopes and vision around the potential of the science, excitement not only around genomics but also around the ability to leverage digital health to provide greater visibility into patient-participants, and enable deeper connection with them.

The often breathless excitement around the promise of precision medicine has generated a pointed response from skeptics (see herehere, here, and here), who ask – quite reasonably and appropriately – whether the science has been oversold.

Needed: Tangible Impact

The only way to escape the expectation/disillusionment cycle is for genomics and precision medicine to demonstrate palpable utility, tangible impact. We’ll be there when sequencing is embraced not because it’s interesting or edgy, but because it’s so obviously useful that once you’ve seen the benefits you can’t imagine not availing yourself of it.

The obvious analogy is Uber, though the point is not to become the “Uber of X” (as helpful as that would be to your buzzword bingo card). Uber is immediately appealing. You don’t routinely reach for Uber to express your solidarity with the gig economy, or to project hipster cred. Rather, to use Uber once is to understand it’s utility, and recognize what an elegant solution it is for a problem you might not have even known you had. The challenge for precision medicine is to be as intuitively and immediately useful as Uber.

Early Signs Of Progress

While genomics may not quite be at this point yet, I think we’re seeing many early signs of progress. Examples include:

  • Reproductive Health – Arguably the most tangible impact of precision medicine to date has been in the area of reproductive health, particularly carrier screening and non-invasive prenatal testing; see my recent discussion here.
  • Oncology – I am moved by the progress represented by the story of Corey Wood, a young woman diagnosed with lung cancer, and discovered, via a Foundation Medicine test, to have a mutation for which a category of targeted therapies was available.
  • Mendelian Disease – Consider the inspiring story of Bill Elder Jr., a patient (and medical student) with cystic fibrosis caused by a relatively unusual mutation, for which a targeted therapy (Vertex’s ivacaftor) is available.
  • Infectious Disease – You may have seen the the New York Times feature on 14-year-old Joshua Osborn, whose life-threatening occult infection was identified by a genetic testing approach pioneered by UCSF’s Charles Chiu; Osborn was then treated for the detected pathogen, and he recovered completely. Chiu recently received funding from the California Precision Medicine Initiative to expand this approach (disclosure: DNAnexus is involved in the effort).
  • Drug Development – In a concept I’ve previously described as “happy genetics,” the identification of “human knockouts” such as Sharlayne Tracy contributed to the development of anti-PCSK9 drugs, and inspired broader efforts to integrate genotype and phenotype to drive both drug discovery and healthcare research. The canonical example here may be the Regeneron/Geisinger partnership, described here by the New York Times. (Disclosure: the DNAnexus platform is foundationally involved in this effort.)
  • Undiagnosed Genetic Disease – The story of Bertrand Might, as reported so eloquently by Seth Mnookin in the New Yorker last summer, highlights both the potential of DNA sequencing to identify causative mutations and end diagnostic odysseys, but also the lack of existing medical resources to identify and bring together rare disease patients. To find other families, Bertrand’s father Matt needed to intentionally deploy traditional social media, which he did extremely effectively.

Four Areas To Focus Efforts

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To accelerate progress, we can consider four broad categories:

  • More Push – Precision medicine requires significantly more data. This will be accelerated by the continued reduction in the cost of sequencing, and by the rise of engaged patients, as it seems unlikely most healthcare organizations will make it easy to access data within their control any time soon (see here, and summarizing a recent Medicine X discussion, here).
  • More Pull – The sequencing that’s done needs to be more meaningful, along the ACCE framework highlighted by Muin Khoury and others at the CDC (I’ve described this framework here and here). Specifically, we need improvements in analytic validity (I’m excited by the precisionFDA pilot platform [disclosure: DNAnexus was contracted by the FDA to develop this]); in clinical validity (a key focus of ClinGen/ClinVar, under the inspired leadership of Heidi Rehm (of Partners Healthcare and the Broad) and others; and, perhaps most importantly, clinical utility – the ability to tie the results of genetic tests to meaningful clinical outcomes.
  • Basic Research – It’s essential to recognize the importance of basic research – research conducted for its own sake, rather than in search of any particular downstream use. A great current example is CRISPR DNA editing technology, which was discovered in the context of basic research trying to understand how bacteria defend themselves from viruses. A vibrant NIH is critical to basic research – as is the ability collaborate better and increase the rate of knowledge turns, a point Josh Sommer made so eloquently at the first Sage Bionetworks Congress.
  • Translational Research – Science generally doesn’t find it’s way into application without deliberate effort. Turning a promising Nature paper into a robust therapy you can confidently administer to a patient is distinctly non-trivial. There are critical roles to be played by engaged patient-participants, front-line providers, and entrepreneurs, whom I see as vitally important drivers of medical translation (here, here).

Impassioned Champions

As we contemplate the future of genomics, and of precision medicine, it’s easy to get caught up in the technologies, in all the amazing gadgets and devices that we hear about every day. Yet, we must remember that while the promise of precision medicine may reflect advances in technology, realization of this potential will require impassioned champions.

The need for champions has been made by Flowers and Melmon, in the context of pharmaceutical drug discovery, and by the late Judah Folkman, who said medical progress is driven by “inquisitive physicians” and “inquisitive researchers.” In a sense, this is all just a restatement of Margaret Mead, “Never doubt that a small group of committed citizens can change the world; indeed, it’s the only thing that ever has.”

Precision medicine is especially fortunate to have already attracted so many inspiring champions – research champions such as CRISPR pioneers Emmanuelle Charpentier and Jennifer Doudna, patient champions such as the Might family, data champions such as Regina Holliday, clinical champions such as Alice Shaw of MGH, regulatory champions such as the FDA’s Taha Kass-Hout, collaboration champions such as Sage Bionetwork’s Stephen Friend and John Wilbanks, translational champions such as Susan Desmond-Hellmann, formerly at Genentech and UCSF, and now at the Gates Foundation.

And, hopefully, precision medicine will be fortunate to attract and inspire future champions, people like you.

Dr. Shaywitz is Chief Medical Officer of DNAnexus. He also holds an adjunct appointment as Visiting Scientist in the Department of Biomedical Informatics at Harvard Medical School, and is co-host, with Lisa Suennen, of “Tech Tonics,” a podcast “focused on the people and passion at the intersection of technology and health,” available on iTunes (here).

DNAnexus at ASHG: Supporting Diverse Applications from cfDNA Technology in the Clinic to High-Resolution Physical Genome Mapping

ASHG 2015American Society of Human Genetics (ASHG) will be taking place in less than 2 weeks. One of the largest human genetics meetings worldwide, ASHG provides an outstanding forum for exchanging information on the latest scientific advances, covering a broad range of human genetics. If you’re headed to Baltimore for ASHG please visit the DNAnexus booth (#1821) to learn about our latest projects with precisionFDA, BioNano Genomics, Regeneron Genetics Center, CareDx, ViaGenetics and more. We’ve added plenty of new features and enhancements to the Platform, stop by our booth for a demo or to simply say “Hi”.

We’ll also be a hosting a lunchtime talk on Thursday, discussing what the next five years might hold for the genomics and informatics industry. Come learn about the cutting-edge research being conducted at Washington University with BioNano next-generation mapping analysis, how CareDx is using NGS and cfDNA technology to deliver non-invasive clinical tests for transplant surveillance, and hear Regeneron Genetics Center present their Geisinger Health System pedigree analysis efforts. We are proud that the DNAnexus Platform provides a flexible and integrated genome informatics solution across such diverse applications.

DNAnexus Lunchtime Talk Details:
Title: Genomics and Informatics for the Next Five Years – Challenges, Solutions, and Opportunities
When: Thursday, October 8th, 1:00pm-2:30pm
Where: Convention Center, Room 345, Level 3
Tina Graves, PhD, Washington University, St. Louis
David Ross, PhD, CareDx
Jeff Staples, PhD, Regeneron Genetics Center

Other ASHG Activities Featuring DNAnexus

Breakfast Talk
Title: Genomes for Breakfast: A Technical Deep-dive into the Most Powerful System for Mining and Collaborating with Large-Scale NGS and Phenotype Data
When: Wednesday, October 7th, 7:15am-8:45am
Where: Convention Center, Room 336, Level 3
Hakon Gudbjartsson, PhD, WuXi NextCODE
Andrew Carroll, PhD, DNAnexus
Tom Chittenden, PhD, WuXi NextCODE

Posters Featuring DNAnexus
Poster #1791/F
Author: Alpha Diallo, DNAnexus
Benchmarking well known bioinformatics aligners and variant callers using the Pilot Genome (NA12878) and Ashkenazim Father-Mother-Son trio

Poster #1684/W
Narayanan Veeraraghavan, Baylor College of Medicine
A virtuous cycle of large cohort research, personal genome analysis, and clinical deployment

Poster 3150/T
Frederick Dewey, Regeneron Pharmaceuticals, Inc.
Distribution and clinical impact of functional variants in 31,000 whole exome sequences from the DiscovEHR study

Poster 620/T
 Colm O’Dushlaine, Regeneron Genetics Center
Whole exome sequencing, blood lipids, and cardiovascular outcomes in 31,000 participants in the Regeneron Genetics Center – Geisinger Health System (DiscovEHR) human genetics collaboration

Visit us in booth #1821 to check out what we’ve been up to and get a demo of the DNAnexus platform.

BioNano Genomics and ViaGenetics will also be joining us in our booth. Learn how researchers can use BioNano’s Next Generation Mapping analysis on the DNAnexus platform, providing push-button access to preconfigured assembly and hybrid-scaffolding pipelines. ViaGenetics will be demonstrating their bioinformatics pipeline, which translates raw sequence data into interpretable variants that can be exported seamlessly from DNAnexus to the GENESIS Platform for clinical interpretation.

  • BioNano Hour
    Thursday, Oct 8th at 2:30pm
  • ViaGenetics Hour
    Thursday, Oct 8th at 10:00am
    Friday, Oct 9th at 1:00pm

New 3000 Rice Genomes AWS Public Dataset – Easy Access on DNAnexus Platform

shutterstock_110850977In June we announced that DNAnexus was powering the 3000 Rice Genomes Project (3K RGP).  You can read the press release here and blog here.   The project, a partnership between the Chinese Academy of Agricultural Sciences (CAAS), the International Rice Research Institute (IRRI), and BGI in China along with their numerous collaborators globally, are attempting to help feed the world’s growing population.  Rice is a diet staple for half of the world’s human population.  It is estimated that the production of rice must increase by at least 25% by 2030 in order to keep up with global population growth and demand.

3K RGP partnered with DNAnexus to develop the bioinformatics pipeline to analyze the sequence data of 3,000 different rice varieties against five published draft genomes. Performing the analysis on the DNAnexus Platform allowed them to leverage the scalable computing capability at AWS to process more than 100 TB of source genomic data across 37,000 concurrent compute cores in just two days — more than 200 times faster than would have been possible on local computing infrastructure. Located across the globe in 10 countries, the 3K RGP investigators were able to access results and collaborate in real time. The result has been the identification of hundreds of new genetic markers, each a potential pathway to improving outcomes for rice production.

Today we are happy to share with you that AWS has made available the genomic analysis data of 3,000 rice varieties as an AWS Public Dataset. The data contains over 30 million genetic variations spanning across all known and predicted rice genes. By making this dataset public, AWS hopes to accelerate research efforts and breeding programs. Knowing the genetic makeup of a rice variety will allow researchers to identify critical genetic markers related to specific phenotypic traits. With this information breeders will be able to make more intelligent choices in variety selection for cross breeding, resulting in more rapid development of rice varieties of higher nutritional content, or improved climate stress tolerance and disease resistance.

DNAnexus has made it easy to access Amazon public resources on the platform. Documentation for accessing the AWS 3K RGP public dataset can be found in the DNAnexus wiki. In addition, the 3K RGP analytical tools and pipelines used to produce the results are available on the DNAnexus Platform listed as a featured project: ‘3000 Rice Genomes’.