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).

Post Medicine X: Reflecting on a More Open Approach to Genomic Medicine

george medxLast week, our Director of Science & Clinical Solutions, George Asimenos, Ph.D., gave a talk at Stanford’s Medicine X conference, titled, “Open-source genomic analyses on open-source patients”.  It was a timely talk given the recent release of the NIH’s proposed Genomic Data Sharing Policies, which, in essence, say that scientists who use government money to conduct genomic research will be required to share the data they gather in a timely manner.  This is an important step towards a more open approach, which is essential to the greater good, despite the challenges that come with it. Based on the Twitter response, his talk obviously struck a chord.


The talk started off with the view of planet earth from space, and quickly zoomed in to a park next to Lake Michigan, to a couple having a picnic in the park, to the individual’s hand and ultimately to the DNA within the individual’s cells.  The realization being, our molecular make up plays an important role in our health and wellbeing.  It’s also highly valuable information to the biomedical research community.

Patient data has always been a highly informative and useful resource, but has grown in value as additional types of data, like genome sequences are layered on top of it.   Currently, if you end up getting your genome sequenced within the healthcare system, only a select few have access to your genome, this practice limits the opportunity for diagnosing or otherwise analyzing your genome.

Recently, efforts such as the Personal Genome Project have demonstrated the value of individuals making available their genome, health, and trait data to the public in the name of science. The emergence of these “open-source patient” models, where individuals are motivated to publicly disclose personal information about themselves, such as their name and age, their genomic information, as well as information on their conditions, have the potential to give us the much-needed examples of how they can influence the development of new medical treatments for their diseases.

In George’s talk, he looked at one such cancer patient, who uploaded both his DNA sequence as well as his colorectal cancer tumor sequence.  Using the DNAnexus platform, we analyzed the two samples using available open-source tools: BWA, SomaticSniper, and Variant Effect Predictor.  Analyzing the patient’s genome revealed that there is a tumor-specific premature stop codon in the adenomatous polyposis coli (APC) gene. As it turns out, a large proportion of all sporadic colorectal cancer cases occur as a result of premature nonsense mutations (creating a stop codon) in an individual’s APC gene.

Reviewing the literature on NIH’s clinical trials website, we discovered that members of the aminoglycoside family of antibiotics have been found to induce ribosomal read-through of nonsense mutations, leading to expression of a full length, functional protein. Investigators have recently shown that members of the aminoglycoside and macrolide antibiotic families can induce read-through of the nonsense mutations in the APC gene and lead to reduced oncogenic phenotypes in CRC cells and in different mice models.”  In other words, what if something as common as erythromycin could treat this particular cancer?

Only at the end, while researching if erythromycin would be a good match for this patient, did we discover his identity, Jay Lake, who crowd funded the sequencing of his genome and tumor, passed away recently. But it was his wish that people would still use his information in the hopes that future cancer treatments might be found to help other patients.

What this conceptual experiment shows is, that with a more open approach new treatments or new uses for old treatments might be available to help patients. George’s talk asked an important question, should we be incentivizing and enabling the sharing of genomic data in ways that support this kind of open model in the practice of medicine?

It’s an important question with many policy and ethical follow-on questions that must be addressed; there are also technical hurdles to overcome, as well as consumer education requirements to tackle. The more of us that add to the population of genomics data available for research and interpretation, the easier it will be for us to find the meaningful, and actionable, needles in the haystack.

It’s an exciting time in the practice of medicine. Powerful cloud technologies are intersecting with robust DNA sequencing technologies and data analysis tools that can streamline the sharing and interpretation of data. There is a shifting mindset from sick care to well care. We have innovative new sensors, and apps in our pockets, on our wrists and on our bodies that are allowing us to take a more active roll in managing our wellbeing. Now the challenge becomes, how can we harness large genomic and phenotypic data flows to improve patient care?

At Stanford Medicine X: How Will Emerging Technologies Advance Healthcare?

Stanford_Medicine_XWe are very excited about the upcoming Stanford Medicine X conference that is taking place right here in our backyard September 5-7th.  The conference will explore the rapidly growing market at the intersection of technology and healthcare and how “emerging technologies will advance the practice of medicine, improve health, and empower patients to be active participants in their own care.”

George Asimenos, Director of Science & Clinical Solutions at DNAnexus will be speaking on Sunday, September 7th at 11:40am.  His talk, titled “Open-source genomic analyses on open-source patients,” will question the traditional healthcare paradigm, where patients are regarded as precious entities whose information is sensitive and highly restricted.   The Personal Genome Project, dedicated to making public genome, health, and trait data available to anyone for the greater good, has posed an interesting “open-source patient” model, where individuals publicly volunteer a vast amount of information about themselves, such as their name and age, their genomic information, as well as information on their conditions. By open-sourcing themselves, patients effectively open the doors to new collaborative models for medical research and medicine. Since their genomic data is readily available (and no other form of approval is required), anybody from interested scientists to genome hobbyists can download and analyze that data.

George will explore how the DNAnexus platform can be used to facilitate open-source genomic analyses on open-source patients and demonstrate how we combined cloud computing and advanced bioinformatics to analyze a real open-source patient.  It’s an engaging talk that ultimately looks at how collaborative, crowdsourced online medicine may empower patients to go beyond webMD to learn about their health, and potentially disrupt the diagnostic model as it becomes more accessible for individuals to explore their genomes.

This year’s lineup of presentations and panels will surely ignite continued conversations after the event to inspire and challenge our thinking.

For more details on the conference, check out Stanford Medicine X (you can also watch the conference live by signing up for the Stanford Medicine X Global Access Program).