Getting Serious About Personal Genomics’ Risks

After several months of public drama, the University of California, Berkeley’s ambitious program to introduce its incoming freshmen to personalized medicine reached its denouement in late August.

As part of its program, Berkeley offered students the option to participate in genetic testing for three common genetic variants relevant to the body’s ability to metabolize milk products, alcohol and folic acid. The University’s original plan was to allow students to elect to receive the results of their tests as part of the program. Two weeks ago, however, the California Department of Public Health (CDPH) ruled that if Berkeley wanted to return personalized genetic data to some of its freshmen, the testing must be conducted at the direction of a physician and performed by a licensed clinical laboratory. The significant logistical burden and cost of complying with the CDPH’s ruling forced Berkeley to modify its program. While some aspects of the program will go forward, no student will be able to access any personalized genetic information.

(CDPH’s ruling was unexpected. Berkeley’s Dean of Biological Sciences, Mark Schlissel, noted that the department’s ruling “relies on an interpretation of legal statutes that is entirely different from the interpretation of the same statutes by UC’s top lawyers.” The ruling itself has potentially significant implications for genetic research across the country, although that topic is the subject for a future post.)

The focus of this post is the rapid mobilization of critics of the Berkeley program and the power of public controversy to spur regulatory action and, ultimately, to force the University to adopt a fundamentally different approach to personal genomics education than originally intended. This in spite of a detailed internal review process that consumed substantial resources and required Berkeley’s Institutional Review Board (IRB) to approve the project. Examining how and why this happened is instructive for evaluating the future prospects of personal genomics research and innovation.

A Controversy Emerges. From the outset, a handful of bioethicists and public interest groups voiced hypothetical concerns about the risks of offering genetic testing to Berkeley’s freshmen. The Council for Responsible Genetics greeted the program’s launch with a letter to the University (pdf) that warned that genetic information “has the risk of being used out of context in ways that are contrary to the interests of the individual, perhaps even discriminatory and certainly privacy invasive.” Similarly, an article in The New York Times featured Boston University bioethicist George Annas, who posed the following hypothetical:

What if someone tests negative [for alcohol metabolization], and they don’t have the marker, so they think that means they can drink more? Like all genetic information, it’s potentially harmful.

Finally, the Center for Genetics and Society linked the Berkeley program to contemporaneous developments in direct-to-consumer (DTC) genetic testing, and warned that “students might think, ‘Berkeley gave it to us. It must be good. UC Berkeley would never be giving its incoming students anything bad or controversial.’”

In short order, what began as an innovative approach to introduce incoming students to genetics and personalized medicine by offering those students the opportunity to personalize their experience quickly became a controversy.

From Controversy to Regulation. Controversial educational initiatives are hardly new. Indeed, they are part of the mission of many institutions of higher education, including Berkeley. In responding to initial criticisms of the program (pdf), the University emphasized that “provoking a free and open discussion about issues surrounding genetic testing is an important aspect of educating our students to be informed citizens.”

Unquestionably, there is considerable value in subjecting all forms of innovation to close scrutiny. In fact, in any Common Rule-governed human subjects research, this is a requirement. Among the many criteria for IRB approval of a human subjects research project is the requirement that “risks to subjects are reasonable in relation to anticipated benefits.” The provision of informed consent is a separate, and similarly important, prerequisite to approval. Berkeley’s own IRB reviewed the University’s project, applied these and other statutory criteria, and ultimately approved the project.

Despite not being legally required to do so, Berkeley actively engaged with the program’s critics from the outset. A program that was vetted internally was now being vetted by the public, with the University’s active participation. In response to public feedback the University modified the project to clarify the project’s voluntary nature, the informed consent process and its separation from actual or perceived industry conflicts of interest.

Critics of the Berkeley program, however, were not satisfied. They continued to urge first the University and then California legislators to much more dramatically alter the program, or even to discontinue it entirely. The constant stream of criticism had an impact. Over the course of the summer, legislation was introduced that would have halted the program. That was followed by legislative hearings to debate the program’s merits and, ultimately, by the CDPH ruling that effectively ended the program in its originally-proposed form.

The rapid reaction of regulators to a debate that was largely driven, especially initially, by media reports, “expert” commentary and social media discourse was strikingly reminiscent of another mid-May personal genomics development.

The week before Berkeley’s program was announced, DTC genetic testing company Pathway Genomics and drugstore giant Walgreens announced a partnership that would have made Pathway’s consumer genetic test available through Walgreens’ stores. In Pathway’s case, the leap to controversy was even swifter: the initial story in The Washington Post describing the agreement warned of a “Pandora’s box of confusion, privacy violations, genetic discrimination and other issues.” Nonetheless, the end result was the same as regulators quickly stepped in and demanded changes. Rather than the CPDH demanding physician intervention and a clinical lab, in Pathway’s case it was the FDA declaring the product in question a medical device in need of a time-consuming and expensive medical device clearance or approval. In both cases, swift regulatory action effectively quashed the proposed activity.

Why Debating Personal Genomics is Difficult. Recent developments suggest that innovation in personal genomics is an increasingly difficult undertaking. In addition to the Berkeley and Pathway cases, examples include the FDA’s increased oversight of DTC genetic testing companies (in addition to Pathway), the GAO’s report on the perils of DTC genetic testing and, most recently, criticism of the University of Minnesota’s attempt to bring genetic research to the State Fair. Collectively, this suggests the emergence of a disturbing trend: developments in the area of personal genomics that deserve serious public debate are shaped from the outset by commentators, policymakers and lawmakers more concerned with making a point than with advancing the conversation.

Of course, it is hardly news that emerging areas of science and controversy generate controversy. In recent weeks, the safety and desirability of human embryonic stem cell research has sparked a heated public debate, just as it has at regular intervals for the past decade. The new dynamic facing personal genomics is the rapidity and ease with which any initiative may be branded as “controversial,” combined with the willingness of lawmakers and regulators to intervene directly and rapidly in such “controversial” activities. This may be as much a function of new paradigms in media, politics and public discourse as it is a function of personal genomics itself, but whatever the reason the concern is that it is having a chilling effect on innovation throughout the field.

On the commercial side, the effects of increasing regulatory uncertainty are evident, as businesses and investors are considering abandoning personal genomics or moving their operations – and attendant jobs and capital – overseas. On the research side, similar confusion – particularly in light of the Berkeley program’s fate – continues to discourage researchers from exploring innovative approaches that might help to accelerate our attempts to decipher genetic complexity and, ultimately, provide us all with more effective, less expensive health care.

Whatever the context, there can be no substitute for careful, public and reasoned debate when it comes to evaluating the appropriateness of a new personal genomics proposal. Similarly, there is no substitute for fully informed consent; for ensuring that all individuals – whether they are students, patients or consumers – understand the full extent of the risks attached to a decision to participate in a personal genomics activity. Both are critical in assuring that personal genomics is conducted in a responsible fashion.

But public debate and informed consent require more than an ability to enumerate hypothetical risks. When it comes to evaluating innovative personal genomics proposals, all of us – participants, funders (including taxpayers), media and commentators and, especially, policymakers and regulators – owe a duty to be thoughtful and balanced in assessing their merits. To be blunt, it requires all of us to do more than throw darts at the easiest targets.

This means understanding that it is not enough to simply enable public debate between those with opposing views on the merits of a particular project. It means recognizing that all innovation – scientific, technological, commercial, research, educational, etc. – carries with it a measure of uncertainty, but that uncertainty alone is an insufficient reason to slam on the brakes. It means acknowledging the difference between hypothetical or low-probability risks and actual, documented harms, and recognizing that the first step should be determining which is which. And most importantly of all, it means considering the benefits of innovation in personal genomics that accrue in addition to – and often because of – its risks.

This is not an easy task. Particularly in a field such as personal genomics, which is driven by new and often untested scientific knowledge and technology, it is trivial to examine a new idea and find something that could conceivably go wrong. Is it possible that a freshman tested for a genetic variant associated with alcohol flush reaction could interpret a negative result as a license to consume alcohol in excess? Of course it is possible, for the bar of “possibility” is exceptionally low. It is much more difficult to convert hypothetical risks into actual data on behavior (i.e., do individuals act to their detriment as a result of non-clinical genetic testing in general, and specifically in the case of the alcohol flush variant?), and more difficult still to balance such risks against the benefits of the same activity.

Keeping Our Heads. Realizing the promise of personal genomics will be impossible unless our society is willing to accept some measure of uncertainty and, yes, risk-taking. Our challenge is to figure out not only when the benefits of personal genomics outweigh its risks, but also who should be permitted to make that frequently difficult and personal risk-benefit decision, and in what contexts.

For those who would place that decision in the hands of individuals, there can be no question that we must first provide those individuals with the necessary information and perspective to make an informed decision. But the process of informing personal genomics participants – of informed consent – no matter how thoughtful and comprehensive, can only take us so far. The information will never be complete, the perspective will never be perfect, and the decision will never be without risk.

It is true, too, that there are many situations where society examines the risks associated with a particular activity and decides that they are simply too high – whether to the individual or to society as a whole – to be assumed, even knowingly and voluntarily, by the individual. We do not, for instance, let teenagers consume alcohol. We place restrictions on the acquisition or use of all manner of technologies, from automobiles to firearms. We require regulatory approval and a doctor’s prescription for most pharmaceuticals.

But as a society we also evince a deep respect for autonomy, leaving many risky decisions in the hands of individuals. The decision to drink alcohol or drive a car in the first place (assuming one is of legal age), to become pregnant (and even to terminate a pregnancy) and to provide informed consent to participate in scientific research: all of these decisions we leave in the hands of individuals.

We have not yet determined whether personal genomics is more like the decision to conceive a child– a personal decision free from state intrusion – or the decision to undergo chemotherapy – a personal decision highly regulated by the state. In a field with a landscape as diverse and rapidly-changing as personal genomics, the answer will frequently depend on context. Some aspects of personal genomics (e.g., genetic testing to determine a proper therapeutic treatment) warrant a greater degree of societal intervention than others (e.g., genetic testing to determine geographic ancestry).

The challenge is knowing where to draw that line. The risks posed by automobiles, firearms and pharmaceuticals are well-documented whereas, at least for the moment, the risks of personal genomics remain largely hypothetical. In the absence of clear data, the recent trend to deemphasize the benefits of personal genomics while focusing on its risks, and to use those risks as  justifications to shift control away from the individual, should cause us all to question whether we are drawing that line in the proper place.

If personal genomics is ever to live up to its name, at some point we must allow individuals – including the future leaders of our society, as embodied by Berkeley’s incoming freshmen – to decide for themselves whether and how to participate. To do otherwise, and to continue to aggressively criticize and thereby discourage personal genomics innovation in our zeal to render it a riskless enterprise, would be a mistake.