On A Day When Apple Sidesteps Healthcare Technology, Mary-Claire King Shows How To Confront It

Mary Claire KingThe most interesting healthcare news of this week was manifestly not Apple AAPL +3.06%’s new watch; I can only assume that the Cupertino-based company concluded, after meeting with the FDA and consulting with a range of experts, that it made far more sense to go down the path of nutritional supplements, and stay as far from regulators as possible — as many of their brethren here in the Valley have emphatically suggested.

No, the more substantive healthcare contribution of the week came from the latest issue of JAMA, where 2014 Lasker Award winner Mary-Claire Kingwriting with several colleagues from Israel, audaciously suggested that all adult women should be screened for defined categories of BRCA1 and BRCA2 mutations – specifically, on “unambiguously loss-of-function mutations with definitive effect on cancer risk.”

(Disclosure reminder: I work at a genomic data management company.)

Today, patients with a family history of breast or ovarian cancer may be referred for BRCA1 and BRCA2 testing, but King is suggesting something more: she wants every adult woman to receive this testing, based on recent research she and her colleagues have published suggesting that relying on family history may miss half of the families with relevant BRCA1 or BRCA2 mutations; these families without a known history of breast or ovarian cancer tend to be smaller, King says, but members carrying the mutations have roughly the same chances of getting cancer as carriers from families with an established history of the disease.

The questions to ask about screening are captured by the ACCE framework (which I recently highlighted in the context of data from wearables, but which was originally developed for genetic testing).

Analytic validity – do the tests reliably and consistently measure the mutations they say they measure?

Clinical validity – how well does a positive test predict the likelihood of a cancer due to BRCA gene dysfunction?  To what extent can a negative test be relied on to conclude that a patient is not at elevated risk of cancer due to BRCA gene mutation?

Clinical utility – does a positive test provide actionable information?  King writes that “Among women who carry mutations in BRCA1 or BRCA2, surgical intervention, in particular risk-reducing salpingo-oophorectomy, reduces risk of both ovarian and breast cancer and reduces overall mortality.”

Ethical, legal, and social implications: What are the implications of population-level screening?  For example, might a negative screening test provide a false sense of security, resulting in reduced vigilance, and an ultimately an increase in non-BRCA-related breast cancers?

Is population-based testing for BRCA1 and BRCA2 mutations warranted?  The New York Times discussed this with King:

“Critics may object that ‘women aren’t ready for this,’ [King] said. But she argued: ‘Why should women be protected from information that will empower them and allow them to control their lives? We don’t need that kind of protection.’”

This is really the essential challenge of the rapidly-growing field of genomic testing, and the question King is pressing all of us to contemplate: when are the data good enough to share with patients?

Set the bar too high, and it raises the ugly specter of paternalism (as King suggests), as well as the very real concern that regulators, with the best of intentions, may let the perfect be the enemy of the good, and make it more difficult (and more expensive) for patients to access important information that could impact their lives.

However, share too early (before analytic validity is established, for example), and you risk providing bad data to patients that could result in devastating, life-changing decisions; this is the logic behind the FDA’s drive to regulate high-risk laboratory developed tests, for example (nicely discussed on this Mendelspod podcast).

Similarly, if you share data you don’t understand (which is a fair characterization of many mutations that are found during genetic screening), you risk scaring patients without helping them.  King, according to the Times, feels “ women should not be told about other rare mutations whose significance is unknown.”  (Others feel even these data should be shared.)

As the molecular basis of cancer and other diseases becomes increasingly well-understood, and additional risk factors are identified and characterized, more and more genes are likely to enter the BRCA1 and BRCA2 category, and merit serious consideration for population screening.

Moreover, as the cost of sequencing plummets, and the amount of actionable data increases, we may start to ask (as some already have) whether it makes sense to offer newborn infants not a handful of biochemical tests, as we do today, but rather genetic screening – perhaps even sequencing of their complete genomes.

In an era where many parents already bank cord blood (as my wife and I did), based on the slight chance that it might be useful one day, is it such a stretch to imagine parents might want to obtain the complete genomic sequence of their kids, in hopes that over time, and with ever-increasing annotation, it might prove at least as beneficial as cord blood?  Such testing would raise a host of thorny issues, as a group from McGill University discussed thoughtfully in Science Translational Medicine earlier this year.

In contemplating the astonishing complexity around bleeding edge medical technologies, including the very real operational challenges, and the attendant ethical issues that are appropriately raised, you can certainly appreciate why an incumbent consumer electronics company might elect to steer clear of controversy, and opt instead for a watch that occasionally reminds you to stand up.

Towards Fulfilling The Promise Of Genomic Medicine

David ShaywitzI was in eleventh grade when I first discovered The Eighth Day of Creation, Horace Freeland Judson’s wonderful, eloquent, deeply inspiring account of the history of DNA and the origins of molecular medicine.  I’ve been hooked ever since.

My choice of college was driven by the opportunity to study with many of the key players in the story – and sealed when a biochemistry department tour guide pointed to what he said was the exact centrifuge used in the famous Meselson-Stahl experiment.

It was thrilling to learn about molecular biology, and even more exciting to become a molecular biologist, learning how to extract and recover DNA, how to splice it, and how to sequence it.

I spent my first year in graduate school studying tumor suppressor genes, then found myself seduced by the elegant power of yeast genetics, and chose this area for my thesis research.

When I returned to medical school and entered the clinic, I was surprised by what I discovered.  While medicine is often regarded as applied science, I was reminded every day just how limited and fragile our understanding of health and disease really is.  The molecular basis of illness often escapes us, and even in the relatively rare instances where the biology is well understood, a cure can be difficult to come by – consider sickle cell disease (considered the first illness defined at a molecular level), for instance, or cystic fibrosis.

Along with co-authors Dennis Ausiello and Joseph Martin, I wrote in 2000,

“Physicians and physician-scientists have become increasingly concerned with ensuring that the tremendous advances they have seen in basic science find expression in clinical practice.  While an understanding of the genetic basis of disease allows us to consider the development of molecular therapies, we have learned not to underestimate either the magnitude of this undertaking or the extent of preparation required.  Indeed, this endeavor is much more difficult than most have anticipated.

As Goldstein and Brown recently noted, paraphrasing Magritte, ‘a gene sequence is not a drug,’ and although the development of rational therapy for a disease may require an understanding of its molecular basis, the path from mechanistic understanding to clinical treatment is often difficult to define and hard to predict.  Proteins often behave differently in test tubes than in cells, and cells behave differently in culture than as part of a vital organism.  Finally, a patient’s experience of disease reflects more than simply an underlying biological defect.  It is, to quote Eric Cassell, ‘a process inextricably bound up with the unfolding story of this particular patient.’  Thus, the critical question we are now struggling with as physicians and physician-scientists is how to avail ourselves of the advances in molecular biology without losing sight of our primary goal – the care and treatment of our patients.”

In the fourteen years since this was written, our tools have changed, our computational power has improved exponentially, the volume and velocity of data have grown at almost unimaginable rates, yet the fundamental challenge remains the same: how can we translate promising science into improved patient care?

More generally, how can we harness large data flows to improve the human condition? I believe this represents the central scientific challenge — and greatest scientific opportunity — faced by our generation.

The starting and ending point for this vision must be patients.  Data collected from a patient belong to the patient.  With appropriate permissions and rigorous safeguards, these data can be shared in de-identified fashion, in effort to accelerate the sort of rapid knowledge turns Andy Grove has insightfully discussed, and that Josh Sommer of the Chordoma Foundation so poignantly described at the first Sage Bionetworks Congress.

Progress will require brave exploration — memorably championed by Pixar’s Ed Catmull — combined with seamless collaboration, so that, as Cloudera’s Jeff Hammerbacher says, everyone can “party on the data.”

Genomic sequencing data represent a natural foundation, not only providing an essential “parts list” (as Eric Lander has nicely described it), a sense of what you are starting with, but increasingly providing dynamic visibility into important clinical pathophysiology, such as the evolving molecular characteristics of circulating tumor cells, or treatment-resistant bacteria or virions.

I’m especially excited by the opportunities at the intersections of large data streams, loci that, like overlapping academic disciplines, promise to be especially rich sources of novelty and insight.

DNAnexus represents a natural home for these aspiration, offering a compelling, secure, cloud-based data management platform, an enabling tool for any healthcare organization – academic medical center, healthcare system, biopharma company, payor – who recognizes that getting a handle on large healthcare data flows is rapidly becoming table stakes, and that figuring out how to manage and leverage genomic data is a wise place to start.

I’m excited – and feel inordinately privileged – to join the DNAnexus team, and to work with passionate colleagues from throughout the healthcare system, in both the private and the public sector, and explore together how we can move from genome to value, from data to impact, from information to cure.


David Shaywitz, MD, PhD is the Chief Medical Officer of DNAnexus, and the co-author, with Lisa Suennen, of Tech Tonics: Can Passionate Entrepreneurs Heal Healthcare With Technology? (Hyperink Press, 2013).  You can follow him on Twitter: @dshaywitz.