This commentary in the Genomics Law Report’s ongoing series What ELSI is New? is contributed by George Church, Harvard Medical School.

One of the recurring themes in this ELSI series has been the discussion of open-access vs. research-only models for genomic research (see Bobe, MacArthur, McCarty, Prainsack and Sweeney). Below I discuss the characteristics and advantages of, as well as obstacles to, an open-access data model for genomic research.

A. Self-access: Open-access and freedom of information are increasingly required by law. Medical research is increasingly holistic — integrating a variety of (identifiable) traits and molecular signatures. Genomics is just part of this, not particularly exceptional. Multi-purpose cohorts and biobanks are displacing single trait studies. Research volunteers are increasingly expecting to see their own data and what is being doing with it. So with respect to such desired transparency, projects can be classified as ranging from 1) “no access” (HapMap, 1000 Genomes, dbGAP), to 2) limited access and no vetting exam (ClinSeq, CPMC and REVEAL), to 3) full access based on obtaining a 100% score on an exam covering risks of data sharing and re-identification (PGP).

B. Sharing: Since individuals can now easily get their medical and genomic data in digital form (outside of their actual “medical records” or any research project), and since individuals can have motivations to share these data, we can let this happen with or without scientific / non-profit / IRB guidance. If we choose the “without” route, then we will likely see Facebook / for-profit / non-IRB “DTC genomic research” proliferate. Projects that choose the “with” route, such as PGP, aim to set higher standards for how much knowledge citizens demonstrate about genetics and research before they give or receive data. The risks for both individual and society of sharing data are likely lower than many occupations (e.g. police and taxi) and possibly lower than the risks of “not sharing,” but those risks still need to be communicated and appropriate guidance provided (pdf).

C. Science: Access to information can be restricted via fees, legal threats, technological censoring (e.g. GPS and encryption algorithms), and study design (eliminating useful data linkages). What has been the impact of such restrictions on science, on serendipity, collaboration, interdisciplinary research, etc. in the past? Will computer experts, (with artists, writers, etc.) create user interfaces, de-mystifying huge case-control studies in open-access systems or in closed? Will physicists and chemists make whole systems biology models if they can only see part of the data (or none of it)? Will social scientists (with ethicists and policy experts) discover alarming (or hopeful) trends in open-access systems or closed? Do we really know in advance who will contribute and who will not? Will we prioritize access based on willingness to jump through bureaucratic hoops? Is that likely to maximize the number of creative interdisciplinarians or produce the biggest out-of-the-box analytic breakthroughs? This is not about mere inconvenience, it is about a series of totally missed opportunities. The predictable positive impact of open-access is huge, and add to that impacts far beyond what we can currently predict.

D. Politics:

1) Retroactive activism: One could argue that current case-control cohorts and biobanks have enough momentum that nothing new can compete. But monuments do topple. If enough volunteers request / demand their data, then there may be pressure to give it to them, no matter what the original contract said. Any claim that the data or cells are de-identified will be untenable, since past volunteers can inexpensively provide DNA identifiers (say 100 SNPs).

2) Proactive: More importantly, going forward, larger biobanks and cohorts will likely be the most useful and new recruits may increasingly migrate to the most transparent and scientifically exciting projects.

3) Reactive: The press and the public will react to efforts that permit people to publicly share their own data; but any criticism is likely to be much less severe than the backlash following the accidental (or intentional) release of multiple volunteers without their permission. Keeping secret data about people that they cannot access will perpetuate distrust of science. In contrast, celebrating volunteers willing to become informed and share their medical information might inspire the public in a manner like astronauts in the 1960s.

This commentary in the Genomics Law Report’s ongoing series

As the era of personal genomics comes of age, genomic information will play an increasingly important role not only in medical decisions but also in reproductive decisions. Already, preimplantation genetic screening (“PGS”, also referred to as preimplantation genetic diagnosis or “PGD”) is being used to screen embryos prior to implantation to select those without known genetic diseases such as cystic fibrosis and Huntington’s disease. As the understanding of the genetic contribution to diseases and traits increases, and as the cost of full genome sequencing decreases, it will become feasible to use PGS to target the full spectrum of genetic diseases.

With time, it will also become possible to preferentially select for beneficial genetically-influenced traits such as athletic talents or high intelligence. Aside from the ethical and religious concerns with such a technology, one of the main social concerns is the potential for increased socioeconomic stratification. If access to PGS were limited to only those prospective parents with the financial means to pay for it, their progeny could gain a perpetual advantage over those whose parents could not afford it. Reactionary fear of this possibility has led to a backlash against PGS, with various groups calling for restrictions or outright bans on its use. This backlash is likely to increase with the number of traits that can be screened for, which could result in diminished access to those families who could most benefit from this technology. In order to ensure continued access to PGS while mitigating the risk of increased socioeconomic inequality, a new policy of universal access will be needed.

To-date, most of the debate surrounding PGS has been focused on whether and how to restrict access. Religious groups such as the Catholic Church have come out against it. In the UK, its use is governed and limited by the HFEA. In a few other countries such as Germany, Ireland and Switzerland, PGS is banned. This approach of limiting reproductive freedom denies parents the opportunity to avoid passing on deleterious mutations to their offspring and can result in unnecessary abortions with parents forced to choose after pregnancy has commenced rather than at the less destructive pre-implantation stage. These limitations also deny future generations the opportunity for improved health and quality of life and would result in many children born with diseases that could otherwise have been avoided. Furthermore, this policy could have the unintended effect of exacerbating one of the very problems it is intended to solve: by limiting access, it promotes increased reproductive tourism by affluent potential parents who can afford to travel to more favorable jurisdictions in order to gain access, thereby creating an even greater financial hurdle and increasing socioeconomic stratification.

A better approach would be focusing on how to make the option of PGS accessible to all those who wish to use it. With equal access, parental financial differences would become irrelevant and the playing field would be leveled across socioeconomic groups. While the choice of whether to use PGS should remain a personal one made by the parents, its widespread use could also result in public health benefits with the potential for numerous heritable diseases to be eliminated in much the same way as the widespread use of vaccines has eradicated many major infectious diseases in the developed world. Although some may argue that providing increased access is unaffordable, the costs of PGS could be more than offset by the lifetime healthcare cost savings of its beneficiaries. These benefits and the opportunity to minimize socioeconomic divergence all point to the need for policies that promote increased access for all groups, in direct opposition to those policies of restriction that have been pursued so far.

The future promise of personalized medicine rests precariously on the care with which we pursue genomic research in the current moment. While a focus on legal protections and open access are important, we must also attend to fundamental questions about the constitution of human diversity at the genomic and social level.

This is clearly evident in the recent collision of open source genomics with privacy rights. While calls for unfettered data sharing have formed the ground for much biomedical research, the achievement of a genomic commons may create its own kind of blockages. For example, although it is finally against the law to use genomic information to discriminate in healthcare or employment, the Genetic Information Non-Discrimination Act does not protect against misuses related to long term care coverage, life insurance, membership in federally-recognized groups, or immigration. For these and related reasons many people remain wary of involvement in genomic research. “Open access,” in other words, may inadvertently close the door for many.

Does this form of genomics, one that may not work for some, mean a genomics that will not work for all? Answering this question requires addressing questions about the ordering of human beings that are at once scientific and social. Scientifically, the limited ability of GWAS to explain trait variation has called into question the predominant role of common variation in disease risk. This has placed a renewed premium on the identification of rare variants. Only significant effort will achieve the participation of the broader and more diverse range of human beings required for such research. Understanding why some people participate, and many do not, will demand understanding the specific ways in which genomic ideas and practices form from and re-form social practices of racism and inequality–issues that remain with us despite the last decade of proclamations about the anti-racist and equalitarian features of genomics.

If the subjects of genomic research remain primarily those categorized as “white” or “European,” and those who have the means to afford genetic testing, then genomics will fall short of its goals to be a human science that meets human needs. To avoid this future requires that scientists more carefully attend and respond to questions about the ordering of nature and society that their field poses.

This commentary in the Genomics Law Report’s ongoing series What ELSI is New? is contributed by

Each year, about 60,000 pregnant women undergo prenatal genetic testing in the United States, out of more than 4.2 million live births. Within five years, new testing methods, made possible by the rise of cheap forms of genomic analysis, will be able to test cell-free fetal DNA from the pregnant woman’s blood. These tests, feasible as early as the fifth week of pregnancy, will require a simple 10 milliliter blood draw, avoiding the invasive procedures of amniocentesis or chorionic villi sampling, with their attendant high costs, discomfort, and miscarriage risks.

Cell-free fetal DNA testing will be able to reveal aneuoploidies, single gene diseases, broad disease risks, and some non-disease traits: certainly sex and probably skin, eye, and hair color; hair type; likely height; and male pattern baldness, among others. The price of this analysis should be $1000 or less. At that price, insurers will likely find this testing cost-effective for every pregnancy, not just high-risk pregnancies. Safe, early, comfortable, broad, and fully insured fetal genetic testing is likely to be used by far more than the current 1.5 percent of pregnant women – probably fifty to eighty percent. As a result, abortions for serious genetic conditions will increase substantially and children born with such conditions are likely to be concentrated in populations particularly opposed to genetic testing or abortion.

How should our society react? Should we encourage, discourage, or view as neutral this kind of testing? What kind of quality regulation should we impose on this testing? Should we – can we – impose other, non-quality regulation, aimed either at preventing prospective parents from terminating pregnancies based on some genetic characteristics or at preventing testing (or communication of test results) for some kinds of genetic risks? We all will soon have to answer these questions, but we are only beginning to pose them.

This commentary in the Genomics Law Report’s ongoing series What ELSI is New? is contributed by Patrice M. Milos,

I’ve had a fascinating time reading these posts and it has taken me awhile to articulate a question I imagine many of you might, or will, have. I believe the above question will be front and foremost on people’s minds in the next two to three years. As genome sequencing costs continue to fall dramatically, we will arrive at our end goal of the $1000 genome… or perhaps even $100… shortly.

Yet it is just this one question which raises many more ELSI questions.

First and foremost – do I have a right to my genome sequence?

I have a fundamental belief that the answer is a resounding yes. Why should I have to worry about whether I can obtain the sequence of genes that may actually prove important for key decisions for me as well as my family?

Once this question is answered a key question on my mind is how can I ensure my sequence is accurate? What is the standard that I am to accept if I am to make sense of my sequence? Who will be responsible for ensuring the level of acceptable accuracy?

In all honesty I am still grappling with this question – is one in a million, one in a billion error rate acceptable? What if my one error suggests a mutation in a cardiovascular gene which predisposes to myocardial infarction? What if the error is in a drug metabolism gene resulting in the inactivation one of the genes? What if the error is in BRCA1? If there were an area where regulations could actually prove important, the ability to ensure your sequence is accurate is key.

Let’s assume we obtain near flawless consensus accuracy – what decisions will I be able to make based on my individual genome variation?

We are at an early stage of making sense of the sequence of human genomes but the pace of knowledge is rapidly escalating. I remain confident as we accurately sequence hundreds to thousands of genomes that we will have a much better understanding of the unfolding story of our genome. This will come as the technological revolution around us continues.

Finally, how will I and my doctor use my genome to make my healthcare better?

This to me is the hardest question – sure we have examples but they haven’t touched me yet. Is our healthcare system ready to fully realize the value of our genome – not today, but let’s hope all our efforts will pave the way to the era of personalized healthcare.

I must say, I have not made my own decision whether or not I will sequence my genome and I am just not sure why I remain guarded. Perhaps those of you who know me might imagine that I would not want anyone to understand what secrets my genome holds and what it is that makes me unique… although as our technology matures at the same pace as our science I may just have to find out why as a female I am colorblind and why I have a funny toe and why I remain an eternal optimist. After all you still can’t fully understand a person by their genome sequence alone.

Good luck to each of you in making your personal decision in the years ahead. I’ll let you know when I am ready.

This commentary in the Genomics Law Report’s ongoing series

At the frontiers of science and engineering, promising new technologies are becoming available that will help us address pressing problems in human health and well-being. As the recent history of personal computing has shown, technology is often the easy part. Once into the world, technologies tend to go careening down the well-beaten path toward “better, faster, and cheaper” on a journey that leads ultimately to everyone’s front door. Personal genomic technologies are no different. If you don’t have any DNA sequence of your own yet, you will soon and so will many of your family, friends, and neighbors (and pets too).

Making personal genomes useful is a much more formidable challenge. In medicine, we want to employ personal genomics in the development of therapies that eliminate disease and diagnostics that reduce illness through early detection or prevention. In our personal and family affairs, we want knowledge that enables us to lead fuller lives, to know how our own personal biology interacts with the varied environments and lifestyle choices that makes us who we are and connects us with others.

Low-cost sequencing technologies take us one small step toward achieving such translational goals, but a giant leap remains: connecting personal genomes with personal phenomes. And that, as David Houle reminded us recently, is why we got into this business in the first place:

“We did not begin to study genomes because we care about genotypes; we study genomes because we care about phenotypes, the health and well-being of humans and the diversity of life on Earth. Now is the time to begin to take the study of the phenotype as seriously as we take the study of the genotype. We must number, locate, and measure even the hairs of our heads, the details of the phenotype, so that we can understand which of those details matter.”

To get beyond databases comprised solely of disembodied DNA sequences, we will need the help of individuals who are willing to open up their personal lives and to share the details of their medical histories, physical traits, behaviors, and other phenotypes.

These individuals are the astronauts of our era. By sharing their genomes and phenomes and making them broadly available through participation in public genomics research studies like the Personal Genome Project (PGP), these pioneers will radically accelerate our ability to explore new frontiers of human knowledge. In doing so, they face potential risks. They are putting it on the line for our benefit and for the benefit of future generations. They deserve our support. To the moon!

This commentary in the Genomics Law Report’s ongoing series

A prescription drug’s labeling is the primary vehicle used by drug manufacturers to inform providers of the conditions under which a drug is safe and effective for use, and must be approved by FDA at the time the drug is approved. Post-market labeling changes may also require FDA approval depending on the type of change. Pharmacogenetics is a relatively new and complex field that regulators and drug sponsors alike are trying to navigate. In recent post-market labeling changes to include pharmacogenetic information, FDA has been inconsistent in the type and amount of data it has required to support the new claim. A clearer regulatory path is critical to encourage drug sponsors to invest in pharmacogenetic research and to ensure that health care providers get the information they need to get patients the right drug at the right dose at the right time.

FDA encourages sponsors to include pharmacogenetic information as part of new drug applications. In 2005 the agency issued a guidance document titled “Pharmacogenomic Data Submissions”, which explains when and how pharmacogenomic data should be submitted during drug review. However, there are several hurdles to the incorporation of this information post market, especially when the efficacy of the drug is affected thus narrowing the patient population. Although FDA appears to be willing to permit pharmacogenetic claims relating to safety that are supported by a modest level of evidence, data from randomized controlled trials are usually required for claims of reduced or increased efficacy. However, conducting a randomized controlled trial for every potential predictive genetic variant would be costly and risks hampering innovation. On the other hand, absent appropriate data collection and analytical methods, retrospective analyses of data from completed clinical trials run the risk of creating biased results.

The recent debate between FDA and sponsors of the colon cancer drugs Erbitux (cetuximab) and Vectibix (panitumumab) over whether the drugs’ labeling should include KRAS mutant status as predictive of drug efficacy highlights FDA’s discomfort with using retrospective data to support efficacy claims. However, the rapid pace of genomics research means that genetic effects on drug response will frequently be identified post market. Therefore, clear guidelines on when retrospective analyses will be adequate and what criteria such data must meet are necessary to facilitate incorporation of pharmacogenetic information into drug labeling. This position echoes the recent comments of Larry Lesko, director of the Office of Clinical Pharmacology at FDA, during the National Conference on Personalized Healthcare in early October 2009. He commented that the KRAS experience could be used to set a framework to inform other drug sponsors on how to utilize retrospective analyses of genomic biomarkers and drug response.

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*The views expressed in this article are exclusively those of the author and do not necessarily reflect those of Sidley Austin LLP and its partners.

This commentary in the Genomics Law Report’s ongoing series What ELSI is New? is contributed by

Over the last decade, our acquisition of genetic knowledge has gathered pace; whole human genome sequencing is now within reach, as accessibility increases and prices tumble. One consequence has been to challenge existing conceptions of what the term ‘genetic’ actually implies. The popular perception that a person is shaped solely by their genes has been undermined by the sheer volume, complexity and mundane nature of much genomic information. Whilst genomics and personalised medicine have the potential to unlock copious biological secrets and yield enormous medical benefits, other forms of information (such as family history, medical imaging or other biomarkers) may be equally useful, predictive and personally sensitive.

It therefore seems all the more perplexing that ‘genetic exceptionalism’ – namely the notion that genetic material is special and distinctive – remains an enduring belief amongst the general public and relevant professional disciplines. The concern that third parties, such as employers or insurers, who have access to this information could use it in ways that discriminate against the individual to his detriment has already prompted some jurisdictions to impose legislation banning ‘genetic discrimination’. Such legislation is aimed at preventing employers from excluding those susceptible to future disease from potential employment, or insurers from using the results of genetic tests to identify and exclude at-risk individuals, ultimately leading to the creation of an unemployable and uninsurable genetic underclass.

The spectre of genetic discrimination seems likely to restrict generalised access to new genomic technologies. Relegating personalised medicine to the monopoly of professional elites is, in our view, misguided, unenforceable and unnecessarily paternalistic. However, worries about genetic discrimination still cast a shadow over the development of proportionate regulation, which requires education of citizens and institutions alike. Concerns over genetic discrimination must therefore be addressed in a practical and appropriately nuanced manner before the full promise of genomics and personalised medicine can be realised.

This commentary in the Genomics Law Report’s ongoing series What ELSI is New? is contributed by

Anyone with $400 is now able to learn much about their own DNA. This door is already open, but we’ve not yet had time to determine where it leads. The first few steps are small, and seem to be within the bounds of what is broadly acceptable. Stepping further seems to go beyond what we can reliably know today.

A DNA variant named rs3892097 increases risk of Parkinson’s Disease when exposed to pesticides. Is my insurer/employer allowed/obligated to test for this genotype and to prevent me from working with materials which are particularly hazardous to me? Do I have the right to work around pesticides? Similarly rs1799807 increases sensitivity to nerve agents such as VX and Sarin, how should the military factor this into their planning?

Today’s grey market for performance enhancing drugs

• http://www.guardian.co.uk/science/2009/sep/20/neuroenhancers-us-brain-power-drugs

adopts tomorrow’s genetic engineering medicines. An injection restores normal vision to the color blind

• http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08401.html

Using a slightly different DNA pattern makes it just as easy to give

• http://en.wikipedia.org/wiki/Tetrachromacy

to those afflicted with merely normal vision. Adding fully functional gills to the human body becomes a safe and similar procedure. World hunger ends when we add chloroplasts.

This commentary in the Genomics Law Report’s ongoing series What ELSI is New? is contributed by

Leroy Hood recently predicted the emergence of ‘P4 medicine – predictive, personalized, preventive and participatory’.¹  Particularly the final P in ‘P4’ seems to hit a nerve: Craig Venter already hailed the ‘democratization of genomics’² as part of a participatory turn in medicine, and 23andMe launched a ‘Do-It-Yourself revolution’ in disease research.³

It is indeed a welcome development that growing numbers of people can access genetic and other health information (personalised and otherwise) relatively easily, and that specialised medical knowledge is no longer the prerogative of those with a professional education. (The blurring of the divide between ‘lay people’ and professional experts, which currently takes place in personal genomics, arguably accounts for some of the latter’s concern about this newly emerging market.) But the participatory turn in medicine is also indicative of an ongoing individualisation of responsibility in health care⁴: The more knowledge we can obtain, the more we will be expected to obtain, and to pay for.

If we get sick when we could have prevented it, social and financial costs are often the result. It is one of the most challenging, but also most crucial tasks of ELSI research to ensure that people’s gain in power and agency will not be outweighed by the ‘gain’ in responsibility, new health duties, and blame. Taking the tenets of ‘P4 medicine’ seriously means that we should learn from people’s experiences and expectations – and ‘people’ is not restricted here to those who already participate. Otherwise we might get R4 instead of P4: a kind of medicine which is limited to those of us who are responsible, resilient, rich, and RSS-fed.

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¹ Leroy Hood. A Doctor’s Vision of the Future of Medicine. Newsweek (July 13, 2009).

² Craig Venter in an interview with the San Francisco Chronicle, June 11, 2009, pE1.

³ 23andMe blog Spittoon on July 7, 2009.

⁴ Rose, N. The Politics of Life Itself: Biomedicine, Power, and Subjectivity in the Twenty-First Century. Princeton University Press (2006).