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Volume 28 Number 3 | Oct-Dec 2015

ISSN 0740-9737


GeneWatch October-December 2015 Volume 28 Number 3

Editor and Designer: Samuel Anderson Editorial Committee: Sheldon Krimsky

GeneWatch is published by the Council for Responsible Genetics (CRG), a national, nonprofit, taxexempt organization. Founded in 1983, CRG’s mission is to foster public debate on the social, ethical, and environmental implications of new genetic technologies. The views expressed herein do not necessarily represent the views of the staff or the CRG Board of Directors. Phone 617.868.0870 Fax 617.491.5344 www.councilforresponsiblegenetics.org

board of directors

Sheldon Krimsky, PhD, Board Chair Tufts University Paul Billings, MD, PhD Life Technologies Corporation Robert DeSalle, Phd American Museum of Natural History Robert Green, MD, MPH Harvard University Rayna Rapp, PhD New York University Patricia Williams, JD Columbia University

Editor’s Note

Samuel Anderson

Five years ago I stepped out of a party to take an unexpected call from Anne Wojcicki, co-founder and CEO of 23andMe. I had tried for a couple of months to land an interview with Anne. Her company was probably the best known consumer genetic testing company at the time, and remains so today – though it, and the consumer genomics landscape in general, has changed quite a bit since then. I knew she would be an ambitious target, given that she was probably pretty busy with the small matter of running a multimillion-dollar startup marketing a very new product in a regulatory environment with a very uncertain future. I had more or less given up on the interview when I got the call. The interview was very brief and didn’t make a particularly electrifying read, but I got another shot two years later, for our “Genetics in Twenty Years” issue (one of our best, by the way). I asked her: “Where do you see consumer genomics in 20 years?” Her answer was very much in line with how the other contributors had responded when asked to look two decades into the future: “Twenty years is an eternity in this business. I feel like it would be sci-fi even if we were talking three to five years.” Well, it has been three to five years, and consumer genomics really has not entered sci-fi territory. In fact, you might say it has stalled out. As Alexis Carere points out in this issue (page 4), the direct-to-consumer (DTC) genetic testing experience offered by 23andMe and a few other companies back in 2012 no longer exists. A year after our interview, FDA blocked 23andMe and other companies from returning health-related genetic testing results directly to consumers. Some companies shifted their model to offer their tests through doctors instead of directly with consumers. 23andMe turned its attention toward ancestry testing, and “many DTC genetic testing companies have since closed up shop altogether.” But things are heating up again. New gene-editing techniques like CRISPR bring us closer to the advent of human gene engineering (see Steven Salzberg’s article on page 10). The European continued on page 11

staff

Sheldon Krimsky, Acting Executive Director Sheila Sinclair, Manager of Operations Samuel Anderson, Editor of GeneWatch Martin Levin, Martin Levin, Senior Fellow Elizabeth Small, Associate Fellow Cover Design Samuel Anderson

Unless otherwise noted, all material in this publication is protected by copyright by the Council for Responsible Genetics. All rights reserved. GeneWatch 28,3 0740-973

2 GeneWatch

comments and submissions GeneWatch welcomes article submissions, comments and letters to the editor. Please email editor.genewatch@gmail.com if you would like to submit a letter or any other comments or queries, including proposals for article submissions. Student submissions welcome!

founding members of the council for responsible genetics Ruth Hubbard • Jonathan King • Sheldon Krimsky Philip Bereano • Stuart Newman • Claire Nader • Liebe Cavalieri Barbara Rosenberg • Anthony Mazzocchi • Susan Wright Colin Gracey • Martha Herbert • Terri Goldberg Oct-Dec 2015


GeneWatch Vol. 28 No. 3

4 Five Years Later: The Impact of Personal Genomics Study What we’ve learned from a cohort of direct-to-consumer genetic testing customers. By Deanna Alexis Carere 7 From the Lab to the Market Consumer understanding and direct-toconsumer genetic testing. By Andelka M. Phillips and Jan Charbonneau 10 Ready or Not, Human Bioenhancement Is Coming With the advent of powerful new technologies like CRISPR, gene editing has arrived. By Steven Salzberg 12 Gene Test Regulation in Europe The European Union is finally addressing its lack of regulation for genetic tests with health-related claims. By Helen Wallace 14 GE Salmon: Not Ready for Your Plate The FDA approved genetically engineered salmon for human consumption after insufficient food safety and environmental reviews. By Jaydee Hanson 16 Endnotes Volume 28 Number 3

Image: Sarah Kim. From GeneWatch Vol. 23, No. 4.

GeneWatch 3


Five Years Later: The Impact of Personal Genomics Study What we’ve learned from a cohort of direct-to-consumer genetic testing customers. By Deanna Alexis Carere

The state of the direct-to-consumer genetic testing industry has changed dramatically since it was last highlighted in GeneWatch in Fall 2010. At that time, direct-toconsumer (DTC) genetic testing had recently been named as the “Invention of the Year” by Time magazine, and DTC genetic testing companies were expanding both in number and in their offerings. At the same time, criticisms of the industry were growing, and the Food and Drug Administration and Government Accountability Office were each formally investigating these services. Little regulatory action had been taken, however, with the exception of the FDA blocking over-the-counter sales of DTC genetic tests from one company, Pathway Genomics. It was in this context that the Impact of Personal Genomics (PGen) Study was funded by the National Human Genome Research Institute (NHGRI) to provide the first “before and after” survey of DTC genetic testing customers. The PGen Study, a longitudinal survey of customers from two DTC genetic testing companies, was designed as a collaboration between academic researchers (at Brigham and Women’s Hospital / Harvard Medical School and the University of Michigan School of Public Health) and research scientists in the private sector (at 23andMe and Pathway Genomics). Other 4 GeneWatch

studies had previously investigated DTC-type genetic testing, but often lacked baseline (pre-testing) data and access to individual genetic results, were conducted in clinical settings with pre- and/or post-testing genetic counseling, or used test packages that did not reflect current commercial offerings. The PGen Study was designed to address these shortcomings. Participants were recruited from among actual customers of

23andMe and Pathway Genomics, surveys were administered prior to customers’ receipt of results and in two post-testing follow-ups, and company collaboration enabled direct linking of complete genetic results with survey data. Although it was not anticipated at its initiation, the PGen Study – conducted between July 2012 and early 2013 – would provide a glimpse into a DTC genetic testing experience

Oct-Dec 2015


that no longer exists. In general, many DTC genetic testing companies have since closed up shop altogether. Pathway Genomics has shifted to a physician-mediated genetic testing model, and 23andMe launched a new health-related service in October 2015 (two years after being blocked by FDA from returning health-related results directly to consumers) that includes only carrier testing for recessive conditions. Nonetheless, insights from the PGen Study remain relevant to the future of this industry and the kind of testing that likely lies ahead. 23andMe has publicly stated its intentions to seek FDA approval for an expanded test menu, within a context of “direct-to-consumer healthcare,” and FDA regulation notwithstanding, DTC-GT offerings are expected only to grow.1 What, then, has the PGen Study

lower educational attainment, lower genetic literacy/numeracy, and older age were associated with lower comprehension of results, suggesting that comprehension may be improved by the tailoring of results reports to individual consumer characteristics or preferences. Consumer confidence was a different story: while understanding of genetics concepts was high both prior to and following testing, perceived self-efficacy with these concepts (i.e., confidence in one’s ability to apply one’s genetics knowledge) showed significant decreases 6 months after results were returned. Importantly, this decrease in selfefficacy post-testing was associated with lower probability of health-care provider consultation, lower perceived value of DTC genetic testing, and greater regret regarding the decision to pursue testing.

“new customer experience” recently launched by 23andMe: beyond revising the scope of testing available, the company created and evaluated new carrier testing reports in large, population-based samples across the United States to demonstrate user comprehension.4 These new reports (viewable at www.medical.23andme. org) feature less text and more white space, highlight the most important pieces of information including intended uses and limitations, and employ a logical step-by-step method of revealing increasingly complex details. What remains to be seen is how these changes will be translated to future reports for complex disease risks and pharmacogenomics results, where consumer comprehension of what actions ought or ought not to be taken in response to results (e.g., cancer screening, medication chang-

Although it was not anticipated at its initiation, the PGen Study would provide a glimpse into a DTC genetic testing experience that no longer exists. revealed so far, and how might its findings be instructive to the future of DTC genetic testing (and directto-consumer healthcare more generally)? The first substantive findings from the PGen Study pertained to consumer understanding of genetics, comprehension of their results, and confidence in making use of them.2,3 Here, the vast majority of DTC genetic testing customers (a self-selected, generally well-educated but still diverse group) showed good understanding of basic concepts in medical genetics, and comprehension was high across all types of results (i.e., pharmacogenomics, carrier screening, and disease risk). Nonetheless, Volume 28 Number 3

Lowered genetics self-efficacy following DTC genetic testing may reflect an appropriate reevaluation by consumers of their facility with genetic information in response to receiving complex reports, which span dozens of conditions with variable environmental contributions and modes of inheritance. Nonetheless, this finding suggests that DTC genetic testing companies have work to do in improving the consumer experience – and motivation to do so, given the observed relationship between self-efficacy, perceived genetic testing value, and decision regret. On this front, we have reason to be optimistic about the

es) is of greater clinical significance than in carrier testing. The absence of disease risk and pharmacogenomic results from 23andMe’s new service marks another important, post-regulation change: the company currently does not provide any genetic information that might be relevant to the immediate tester’s health. This means not only that disease risk is not provided, but also that consumers will not be told through carrier testing if they carry two recessive mutations for a condition (and are therefore, at least at the genetic level, “affected”). A notice added to carrier testing reports reads: “This test does not diagnose GeneWatch 5


any health conditions. Please talk to a healthcare professional if this condition runs in your family, [or] you think you might have this condition.” Exclusion of affected individuals and those with a relevant family history is significant, and addresses a frequent criticism of DTC genetic testing – namely, that consumers who should be getting a comprehensive clinical genetics evaluation (including a physical examination, assessment of family history and sequencing of relevant genes) may assume that DTC genetic testing services adequately serve their needs. For example, an adjusted lifetime risk estimate for breast cancer based on genotyping of multiple single nucleotide polymorphisms (SNPs) may (setting aside legitimate criticisms of how such estimates are obtained) be relevant to a woman with no personal or family history of breast cancer or related risk factors, but as soon as she has a moderate/high personal- or familyhistory-based risk of breast cancer, these SNP-based estimates become clinically inappropriate and potentially confusing. That consumers seek DTC genetic testing not only for its predictive abilities but also for its explanatory power is evidenced by findings from the PGen Study: across all conditions tested, both family medical history and personal medical diagnosis were strongly associated with interest in condition-specific results.5 Furthermore, an unpublished review of qualitative data on test satisfaction indicates that some consumers were disappointed or confused when their DTC-GT results did not confirm a medical diagnosis (e.g., Ehlers-Danlos), or indicated they were at low genetic risk of a condition present in a close relative (e.g., breast cancer in a sister). Finally, we know from a PGen Study analysis of perceived 6 GeneWatch

cancer risk before and after testing that DTC genetic information has a measurable and predictable effect on consumers’ perceptions of disease risk.6 How to responsibly address the fact that consumers with cancer, heart disease, or neurological conditions (or significant family histories of these conditions) will continue to order DTC genetic testing once disease risk estimates are reinstated is something that 23andMe and other companies will need to sort out in order to satisfy FDA. Preliminary PGen Study data can provide insight into the other component of 23andMe’s services halted by the FDA: pharmacogenomic testing. Pharmacogenetics represents one of the greatest opportunities in personalized medicine, with the promise of preventing adverse drug events and targeting medications to those who will benefit most. The potential clinical utility of pharmacogenomics, however, means it may also be one of the least ‘benign’ types of DTC genomic information, and the FDA detailed specific concerns in its initial Warning Letter about consumers changing their medications without clinician consultation. PGen Study data presented at the 2014 American College of Medical Genetics Annual Meeting revealed that, among 1,003 PGen Study participants, 54 (5%) changed a prescription medication and 70 (7%) changed a non-prescription medication on the basis of their DTC genetic testing results; of these, 8 (0.8% overall) and 28 (3%), respectively, did so without consulting their health care provider. The frequency of unsupervised and inappropriate medication changes thus appears to be quite low, and some of these changes may have been made regardless of the results of genetic testing. (Of course, people make unsupervised changes to their medications

all the time based on perceived side effects, unaffordability, or information gleaned from the internet). On the other hand, evidence of even a low rate of inappropriate medication changes may represent sufficient harm for FDA to continue to block such testing, particularly when frequencies of 0.8% and 3% are applied to the entire DTC genetic testing population, which currently numbers over 1 million through 23andMe alone. There is still much to be learned about the impact of direct-to-consumer genetic testing – in particular what burden (if any) it places on health care systems and its effects on clinical outcomes – and large-scale empirical studies will be essential to answering these questions. It is fortunate, then, that a likely downstream effect of FDA’s regulatory interest in the industry is a renewed focus on rigorous empirical research, both by DTC genetic testing companies in the process of bringing products to market, and by government and academic researchers in post-market evaluations. nnn Deanna Alexis Carere, ScD, CGC, is a genetic counselor and postdoctoral fellow in Epidemiology at McMaster University in Hamilton, Ontario. As a doctoral student, she studied the evidence for and application of genetic testing using common variants within the Genomes2People research group at Brigham and Women’s Hospital in Boston, Massachusetts. She currently researches the molecular connections between cardiovascular genetics and dementia.

Oct-Dec 2015


From the Lab to the Market Consumer understanding and direct-to-consumer genetic testing. By Andelka M. Phillips

and Jan

With traditional genetic testing, doctors collect DNA samples, explain test results and advise patients on treatment options. With directto-consumer (DTC) genetic testing, private companies provide genetic tests and results in commercial transactions. Consumers provide DNA samples directly to DTC genetic testing companies, with results provided back directly to consumers, typically online and usually without involving doctors.1 Direct-to-consumer genetic tests range from health-related tests with significant healthcare implications (e.g. disease predisposition) to the so-called recreational genomics with no discernible implications (e.g. earwax consistency).2 Of particular concern has been the offering of health-related tests outside the traditional medico-legal environment. Questions have been raised about the quality of healthrelated direct-to-consumer genetic tests and whether results are understandable by the average consumer. Concern has also been expressed about the appropriate regulation of the DTC genetic testing industry; at present DTC genetic testing purchases are normally governed by corporate contract and privacy policies. It is questionable whether consumers are giving valid consent for the tests and participation in DTC genetic testing research. Finally, there is a consensus that consumers often have insufficient understanding that the terms and conditions they agree to on DTC genetic testing websites Volume 28 Number 3

Charbonneau (when they click “I agree”) are legally binding agreements. While debatable, let’s assume health-related DTC genetic testing tests are accurate and valid, meaning laboratories conducting tests are accredited and tests identify genetic variations with scientifically established links to health-related conditions. For tests to provide personal utility – information someone can do something with – consumers must be able to first understand their test results. Direct-to-consumer genetic tests are not medical tests, with the industry emphasizing they are for ‘research, information and education’ only and not to be considered as a diagnosis. Interpretation of DTC genetic testing results, presented by companies in standardized numeric form, and their use in healthcare decision-making is left to consumers. While many companies actively suggest consumers consult their doctors or genetic counselors, that also is left to the consumer. DTC genetic testing results for disease predisposition are essentially two numbers: the consumer’s own personal lifetime risk of developing a given disease and the average person’s lifetime risk of developing that same disease. So … it seems that it should be straightforward for a consumer to compare two numbers objectively and determine if their lifetime risk is higher or lower than the average and then, based on this interpretation, make appropriate

healthcare decisions. In 2015, three thousand potential and actual DTC genetic testing consumers in the United States, Australia and the United Kingdom were asked to interpret sample DTC genetic testing disease pre-disposition results. Analysis revealed that for some consumers, interpretation of these two numbers is anything but objective. Some consumers presented with a personal lifetime risk numerically lower than the average person’s believed their risk was actually higher or much higher; some presented with numerically higher than average risk believed their risk was actually lower or much lower. Others presented with a personal lifetime risk GeneWatch 7


significantly higher than the average felt their risk was ‘about the same’ as the average person’s. This diversity of interpretation was driven by a range of factors, including the individual’s assessment of their own health and lifestyle, family disease history, general health numeracy skills and even their beliefs about the role genes play in disease.3 Does this matter? How the numbers are interpreted was found to have an impact on consumers’ emotional states and behavioral intentions. For example, worry and anxiety increased if personal risk was interpreted by the consumer as higher, with relief increasing if personal risk was interpreted as lower than the average – perfectly normal responses if tests and interpretation are accurate but capable of generating unnecessary stress or a false sense of security if not. With regard to what consumers might do, those interpreting their disease risk as higher than average, regardless of the actual numbers, were more likely to, for example, monitor their health more closely, change their diet and visit their doctors – all positive health behaviors regardless of actual results. Of course, those interpreting their risk as lower, again regardless of the actual numbers, were less likely to make such positive health-related changes. At its core, consumer genomics is about consumer empowerment – allowing consumers to access their own genetic information and use that information in health related decision-making. However, for DTC genetic testing offerings to deliver on this, consumers must be able to accurately interpret test results and make appropriate decisions. This research suggests that DTC genetic testing companies’ assumption of ‘objective interpretation’ of results may not be 8 GeneWatch

the case, suggesting the ‘one size’ approach to returning results may not ‘fit all.’ How should we regulate the industry? At present, DTC genetic testing sits outside existing regulation. Several areas of law have relevance (medical devices regulation, consumer protection, and privacy), but specific regulation is needed in the U.S., where many of these companies are based. The FDA’s renewed interest in DTC genetic testing as of November 2015 also may we hope lead to more specific industry guidance being developed.4 Moving DNA testing away from the clinic means that many of the traditional safeguards that might apply in a medical setting are not present in the DTC genetic testing context. With the direct-to-consumer model, genetic testing has moved outside the

often tend to click ‘I Agree’ without considering the legal implications of this. In the DTC genetic testing context this raises questions regarding the validity of consumers’ consent for genetic tests and for participation in research. Even ignoring the non-reading problem, there is an issue of whether a person can ever really agree to terms that are not available at the time of entering into a contract. For instance, many contracts include a unilateral change of terms clause. Such clauses often allow companies to change their terms without direct notice to the consumer. And these contracts often deem consent to altered terms through continued use or visiting of a website, which is often possible without ever encountering terms. This is problematic as it may impact upon the purposes for which

At its core, consumer genomics is about consumer empowerment ... doctor-patient relationship to that of a relationship between a consumer and company. In lieu of specific regulation, companies rely on the terms of service, terms of use and privacy policies that appear on their websites to govern transactions. An in-depth review was conducted of the contracts of DTC genetic testing companies providing health testing as well as the existing regulatory landscape.5 As with many webbased industries, DTC genetic testing contracts are often lengthy, complex documents. And the behavior of consumers in this context resembles their behavior regarding online contracting more generally. That is, it seems that consumers may not actually read the documents they have ‘agreed’ to when active online. We

stored genetic data may be used. For example, an individual might agree to participate in research conducted by the DTC genetic testing company for certain purposes, but those purposes might change if the terms were subsequently altered. These contracts often include broad indemnity and exemption clauses which consumers are not likely to expect or understand. For instance, it is common to include a clause disclaiming liability for fitness for purpose. It is possible that some of these terms could be deemed ‘unfair terms’ and unenforceable under UK and EU law. It may also be possible to challenge some of the terms under American or Australian law. For health related testing, tests really ought to be fit for their claimed Oct-Dec 2015


purpose and there ought not to be a discrepancy between website claims and contract content. DTC genetic testing contracts are also generally not industry specific, meaning that they resemble the wrap contracts used more generally by many online industries and large Internet Service Providers. Briefly, a wrap contract can be defined as ‘a unilaterally imposed set of terms which the drafter purports to be legally binding.’6 The two most common forms used on the Internet are clickwrap and browsewrap. Clickwrap contracts are presented in a form where a person can scroll through terms and click “I Agree” at the end, while browsewrap normally have terms available on a hyperlink, so that it is possible to click “I Agree” without viewing the terms at all.7,8 In online contracting more generally, companies frequently borrow terms from each other, which means there is much uniformity amongst them.9 Why does this matter? It matters because DTC genetic testing companies are often not tailoring their contracts and privacy policies to address the specific issues raised by this industry. The two most pressing issues here are the related issues of privacy and information security. Consumers need to be more aware that their stored sequenced DNA can be used to identify them and also their families. For example, an individual’s sequenced genetic data can serve as a unique identifier for that individual and stored data will remain inherently identifiable. And as families share much of their DNA, an

individual’s stored data poses potential risks for their family, as it is possible to re-identify quite large family groups. Several studies have now indicated that complete anonymization is not possible – even if data is “de-identified,” it is re-identifiable.10 Some sites offer social networking functions and consumers may also choose to engage with other online platforms that allow sharing of genetic test results and health information, such as CureTogether, owned by DTC genetic testing company 23andMe.11 When consumers engage with either social networking on a company’s website or on a sharing platform, they may also be agreeing to give the company a license to use user generated content. This is concerning, as in this context this content may include personal, lifestyle, and medical data that might normally be considered to be sensitive. Genetics is a rapidly evolving field with each day bringing new insight into the role genes and their interaction with environmental factors play in disease predisposition and progression and the impact of the microbiome on human health. Even in clinical research there is debate over the role of particular genes and their association with disease. Health-related genetic testing is complex in nature, even for medical professionals. DTC genetic testing adds additional layers of complexity. At present, many tests offered by companies have not been standardized and standards are not harmonized across the DTC genetic testing industry. The net result is that

... but to deliver on this, consumers must be able to accurately interpret test results and make appropriate decisions. Volume 28 Number 3

consumers choosing to purchase tests for the same conditions from different companies may get contradictory results. Even assuming the tests are accurate, consumers are left to interpret results themselves and then decide what to do with that information, information that might have serious personal and family implications. Consumers may choose to take their DTC genetic testing results to their physicians; however, many general practitioners have indicated they are not yet confident in interpreting genetic tests. Consequently, if consumers are going to benefit from these services, it is vital that physicians have sufficient information to assist them in interpreting DTC genetic testing results. Ultimately, when engaging with DTC genetic testing companies, consumers have to realize they are entering into legally binding contracts and agreeing to privacy policies involving the most intimate of personal and family information: their DNA. It appears that with DTC genetic testing it is still very much a case of ‘caveat emptor’ – let the buyer beware. nnn Andelka M. Phillips, has recently passed her viva for the degree of doctor of philosophy in law in the Faculty of Law at the University of Oxford. Her research focuses on regulation of DTC genetic testing and the protection of consumers’ rights in their genetic information in the context of DTC genetic testing. Jan Charbonneau is a PhD candidate in Law at the Centre for Law and Genetics, Faculty of Law, University of Tasmania, Australia. Her research takes an evidence-based approach to consumer protection in DTC genetic testing, with a particular focus on the potential for consumer detriment. GeneWatch 9


Ready or Not, Human Bioenhancement Is Coming With the advent of powerful new technologies like CRISPR, gene editing has arrived By Steven Salzberg

that HIV needs to infect immune cells.1 If successful, the improved CCR5 gene could prevent and even cure infection. Zinc fingers work, but they are tricky and expensive. A much-improved technology is based on an invention due to bacteria: Transcription activator-like effector nucleases, or TALENs. These genes are used by certain bacteria to help them infect plants. I led a bacterial genome project about a decade ago in which we sequenced several species of a plant pathogen called Xanthomonas oryzae, which is one of the primary sources of TAL genes. It turns out that TALENs can be used to edit DNA too, just like zinc

fingers. TALEN technology is much faster and cheaper, and many scientists quickly adopted it because of these advantages. It’s available in a kit from Life Technologies, allowing scientists to edit the genomes of yeast, plants, insects, and mammals (including humans).2 The latest and hottest technology is called CRISPR, another bacterial invention. In the early 2000’s, a variety of genome scientists noticed that some bacterial genomes contained long stretches of repetitive DNA interspersed with bits of viral DNA. This was a mystery until scientists determined, in 2007, that the bacteria were using the viral DNA as an immune system: after capturing a

Image: Samuel Anderson

Humans are on the verge of developing the technology to rewrite our own genetic code. It’s now a question of “when,” not “if.” Over the past decade, three new technologies for DNA editing have been developed. First there was a method based on genes known as zinc finger nucleases (ZFNs), which can cut DNA and allow a scientist to insert a new piece of genetic material. The patent on zinc finger technology is owned by Sangamo BioSciences, which licenses it out and is also using it to develop novel treatments. For example, Sangamo is developing a treatment for HIV/AIDs, already in Phase 2 trials, that uses ZFNs to edit the gene CCR5, a critical receptor

10 GeneWatch

Oct-Dec 2015


bit of the virus’s DNA, the bacteria was protected from infection by that virus.3 Bacteria use the CRISPR system to recognize a virus and chop it up, thereby preventing it from killing them. In 2012, two teams of scientists including Jennifer Doudna, Emmanuelle Charpentier, and Feng Zhang figured out how to use CRISPRs to edit genomes. (Within the scientific community, there is a fierce battle going on over who first invented this technology. Suffice it to say that the original inventors were microbes, not people.) CRISPRs are even better than TALENs: according to one recent review, they are “simple, inexpensive, easily programmed and ridiculously efficient.”4 The scientific community has mapped the human genome and determined the functions of many of our

(an egg or a sperm cell). This technology too is rapidly maturing: scientists have already cloned mammals using adult cells that they turned back into stem cells. Thus the two main pieces are in place: we can create germline cells, and we can edit our genome. It won’t be long before someone puts the two together. History teaches us that once a technology appears, we can’t put it back in the box. Genome editing is here, and it has tremendous potential to cure diseases and reduce human suffering. It also offers us the opportunity to improve our own genetic code. Given the choice to throw away our glasses and acquire the visual acuity of an eagle, how many people would say no? How about genes that will keep our arteries free of cholesterol until past the age of 100? Or genes that will prevent dementia and Alzheimer’s, the greatest

It’s only a matter of time before we find ways to adjust our genes to improve our vision, hearing, physical endurance, and other traits. genes. This enterprise still has a long way to go, but we know our genetic code, and we’re developing the methods to figure out how to alter genes to correct genetic defects, to help our immune systems fight disease, and to prevent cells from becoming cancerous. It’s only a matter of time before we find ways to adjust our genes to improve our vision, hearing, physical endurance, and other traits. One more critical piece of the puzzle, before we can custom-design humans, is the ability to turn a human cell into a pluripotent stem cell, one that can turn into a germline cell Volume 28 Number 3

scourges of advanced old age? No doubt many people are disturbed at the thought of editing our own DNA. Clearly we need to be careful how we employ this powerful new technology, but denying or ignoring it is not the answer. Genome editing is here, and human bioenhancement will not be far behind. nnn

Editor’s Note continued from page 2

Union is discussing new regulation of DTC genetic testing (see Helen Wallace’s article on page 12). And just a couple of months ago, 23andMe announced that they will begin offering health-related genetic testing again – more limited than before, but with FDA’s blessing. “Part of what we tried to do over the last two years is take advantage of being off the market to redesign the entire experience,” Anne Wojcicki told the New York Times. What they’ve also been doing in that time: Building a new business plan. The company had been sitting on the genetic information of over a million customers, most of whom had agreed to participate in research – and in doing so, automatically consented to having their genome sequenced. All the time 23andMe was marketing direct-to-consumer genetic tests for health and ancestry, they were amassing a database far more valuable than the $99 or $199 each customer had paid. This year 23andMe made big deals with Pfizer, Genentech, and other companies to start using that mountain of data to develop new drugs. The Forbes headline on the Genentech deal begins: “Surprise!” It’s hard to imagine what we will be talking about the next time GeneWatch publishes an issue focusing on consumer genomics. A lot can change in three to five years. nnn

Steven Salzberg, PhD, is Bloomberg Distinguished Professor of Biomedical Engineering, Computer Science, and Biostatistics at Johns Hopkins University.

GeneWatch 11


Gene Test Regulation in Europe The European Union is finally addressing its lack of regulation for genetic tests with health-related claims. By Helen Wallace

In the United States, action by the Food and Drug Administration (FDA) against companies selling health-related genetic tests online, such as the Google-funded company 23andMe, has made headline news. But few people realize that 23andMe began marketing their tests in Europe after the FDA imposed its ban, taking advantage of a lack of regulation.1,2 In the UK, the high street store Superdrug is selling unregulated genetic tests which have been banned in the U.S., and the tests are also available online.3 23andMe has been encouraging families to test their children, contrary to ethical advice.4 23andMe’s actions have been widely criticized by doctors, particularly because new European gene test regulations are close to being finalized, following recognition that assessment of health claims is essential to protect consumers. Likely to be adopted in 2016, this regulation is expected to have a five year leadin time, but will ultimately require companies to provide evidence of the scientific validity of the tests they sell. Direct to Consumer (DTC) sales of health-related genetic tests have been contentious in the UK since the UK company Sciona began selling gene tests with dietary advice in high street stores in 2001.5 GeneWatch UK conducted investigations into the scientific validity of Sciona’s tests and those of other companies and found 12 GeneWatch

most health claims could not be substantiated. Our findings were subsequently reinforced by investigations by the US Government Accountability Office (GAO)6,7 and academic researchers.8 In 2008, a Sunday Times journalist exposed how different companies selling gene tests in the UK would give consumers contradictory interpretations of their genetic code, a problem that was exposed again in the USA in 2013 by the New York Times.9,10 Regulators were slow to act, though, given that commentators first highlighted a need for regulation in the 1990s.11,12 After more than a decade of the debate, Europe’s new In Vitro Diagnostics (IVD) Regulation will finally regulate software and algorithms used for health diagnoses or predictions, including genetic and genomic tests, in the European Union. The IVD Regulation has now entered so-called “trilogue” negotiations between the European Parliament, the Council (which represents the Governments of EU member states) and the Commission (the EU’s civil service, which wrote the first draft of the new law).13 The final outcome will be a compromise between the three versions of the text, which will then be accepted or rejected by the European Parliament, probably next year. This means some issues have been settled, while others will be decided during the negotiations. Oct-Dec 2015


In the EU, powers for prior premarket assessment of genetic tests are weaker than those exercised by the FDA, and it is expected that most oversight will remain with “notified bodies” which act as consultants to the companies making applications to sell tests on the EU market. This has led to some doubts about the quality of scrutiny of the evidence that companies provide. Nevertheless, for the first time companies will be required to collect and submit evidence about the scientific validity of genetic tests they place on the EU market, including their predictive value. Clauses which ban direct-to-consumer (DTC) sales of health-related genetic tests and make counselling

about the potential for scarce healthcare resources to be misdirected towards follow-up of poorly predictive tests or algorithms bought without advice from doctors. Another proposal in the European Parliament’s version of the Regulation is that tests marketed with a recommendation to take a particular drug depending on the outcome of the test (known as “companion diagnostics”) should require companies to supply evidence that the combination of the test and the drug improves health outcomes (i.e. shows “clinical utility”). However, this proposal is not included in either the Council or the Commission versions of the text. Strict regulation would restrict the market for genetic tests and other

For the first time companies will be required to collect and submit evidence about the scientific validity of genetic tests they place on the EU market.

Stem Cell Dialogues

A Philosophical and Scientific Inquiry Into Medical Frontiers By Sheldon Krimsky

mandatory appear only in the European Parliament’s version of the draft regulation, and remain contentious. EU member states disagree on the substance of a DTC ban, and the Council also argues that counselling provisions are an issue for each member state, not a decision that should be made at the European level. However, these clauses reflect widespread concerns about DTC genetic tests and their impacts on both individual patients and European health services. Universal health coverage in European countries, funded directly by taxpayers or by social insurance, means there is concern not only about the impacts of misleading tests directly on consumers but also Volume 28 Number 3

health-related algorithms to those that genuinely showed some benefit to health and would prevent companies from making unsupported and misleading claims. It is too early to say exactly what requirements will appear in the final version of the EU’s new IVD Regulation. However, it is clear that the days when companies could market genetic tests to European consumers with entirely unsubstantiated health claims are drawing to an end. nnn Helen Wallace, PhD, is Director of GeneWatch UK.

“Stem cells” have become linked with both new frontiers in medical science and political and ethical controversy. Addressing the moral and ethical issues of stem cell research while also educating readers about the biological function and medical applications of these cells, this book features fictional characters engaging in compelling inquiry and debate. Educational, entertaining, and rigorously researched, Stem Cell Dialogues should be included in any effort to help the public understand the science, ethics, and policy concerns of this promising field. “Krimsky’s use of the dialogue method identifies, sharpens and advances both key points of debate and the breadth of issues being addressed.” — Ronald M. Green, Dartmouth College AVAILABLE NOW from Columbia University Press

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GE Salmon: Not Ready for Your Plate The FDA approved genetically engineered salmon for human consumption after insufficient food safety and environmental reviews. By Jaydee Hanson

On November 19, 2015, the Food and Drug Administration approved the first genetically engineered animal intended to be eaten as a food, an Atlantic salmon (Salmo salar) engineered to express the growth hormone from the huge Chinook salmon (Oncorhynchus tsawytscha) continuously. This could be the first of many such approvals. Worldwide, more than 50 fish have been engineered. The company, AquaBounty, has announced that it also has genetically engineered trout and tilapia for which it may seek FDA approval. FDA used the wrong law FDA announced in 2009 that it would review genetically engineered animals as “new animal drugs.” That is, they decided to review this fish as though the genetically engineered DNA construct was a new drug for the animal, not reviewing the animal as a new food for people. The agency could have used its various food authorities or sought new legislation from Congress on reviewing “novel” foods, as other countries have done. The Center for Veterinary Medicine is one of the only parts of the FDA that lacks expertise in reviewing human trials for either food or drugs. Also, by choosing to review the animal as a drug, the agency must keep its review confidential. Had AquaBounty not advertised that it had submitted the fish for FDA review, the public would not have known 14 GeneWatch

that FDA was reviewing the fish. Food safety review was inadequate FDA did not require the AquaBounty company to conduct any human or animal feed studies that would examine the safety of humans or animals eating the fish, but several problems are likely. Routine use of antibiotics such as the ones used by the company in its research facilities is known to cause human health problems and diminish the effectiveness of related human antibiotics. The fish has also been sterilized by the insertion of an extra X chromosome into the eggs. This process, known as triploidy, causes skeletal and gill problems in fish, and these problems seem exacerbated in the AquaBounty fish, probably due to the excess hormone levels. The fish also may pose higher allergenicity problems than ordinary salmon. Even in the small number of fish (6 fertile and 6 sterile fish) tested by the company, the fertile fish were found to have an increased likelihood of causing an acute allergic reaction in humans. The sample size is too small to say that the sterilized fish won’t show an increased risk, too. In 2009, a study commissioned by the EU raised several food safety concerns about GE fish, including their higher levels of growth hormones and their higher tolerance of environmental toxins. The data released by the FDA shows that the

AquaBounty salmon may have a 40% higher level of a hormone called IGF-1 (insulin-like growth hormone factor 1), which has been shown to increase the risk of certain cancers, including breast cancer. These GE salmon also have lower levels of the beneficial omega fats that wild salmon provide. They even have, according the company’s own data, lower ratios of healthy Omega 3 fats to unhealthy Omega 6 fats than do farmed salmon. Inadequate environmental review The FDA approved this GE fish without fully reviewing the potential environmental impacts of the fish escaping into the wild. The only fisheries scientist on the FDA Advisory Committee that reviewed the fish called on the FDA to develop a full environmental impact statement. Geneticists working for the U.S. Fish and Wildlife Service warned that the FDA Environmental Analysis is overly simplistic and does not adequately capture the actual risk of environmental damages to wild Atlantic salmon or the ecosystem as a whole. The FDA failed to require studies of the potential for interbreeding with wild salmon, studies of the incorporation of genes from the GE salmon into the gene pool of wild salmon, or studies on the likelihood of hybridization with the closely related brown trout, a fish that is found throughout many parts of the U.S. and Canada. Oct-Dec 2015


Further studies are needed that look at the likelihood that escaped GE salmon would disturb the habitat of endangered populations of wild salmon, as the GE salmon would compete for resources with the wild salmon. Even unsuccessful attempts to mate with the GE fish would reduce the likelihood of subsequent successful matings of the wild salmon. Moreover, the GE salmon could spread disease to wild salmon and other species. Escapes of GE salmon from Prince Edward Island, where AquaBounty is raising the fertile GE salmon, could affect wild salmon throughout the entire range of wild Atlantic salmon. Atlantic salmon are known to travel extensively from the areas where they have spawned; tagged salmon from Maine have been caught off the coast of Greenland. The ecological impacts associated with the effects of the GE salmon, the likelihood of their persisting in the ecosystem, and the likely dispersal of the GE fish throughout the waters of the Atlantic should have been studied before the Volume 28 Number 3

approval of this fish. A plan for monitoring the AquaBounty company’s procedures to prevent escapes and to assure that the production facility’s employees do not take eggs or fry from the facility and grown them out in unapproved locations needs to be in place. The company has been fined for failing to comply with Panamanian environmental laws in its Panama location. The company failed to report in its submission of data to the FDA in 2010 that its Prince Edward Island facility had a major outbreak of ISA, a fish flu that can devastate fish populations. Canadian, Panamanian, and U.S. authorities will have to closely monitor this company’s production facilities to assure that it does not cause serious environmental problems that spread beyond the production sites. In mid-December, AquaBounty announced that it planned to sell eggs to fish farmers in other countries and for growth in other locations in the U.S. This makes it even more likely that the genetically engineered salmon will escape

confinement and cause great ecological problems. Pushback – labeling and lawsuit The FDA decided not to require this new GE salmon to be labeled. Nonetheless, a bi-partisan effort in the Senate headed by Senators Murkowski (R-AK) and Cantwell (D-WA) inserted a provision into the Omnibus government financing bill requiring that FDA develop a labeling program that will indicate to consumers whether the salmon they are buying is GE or not. The provision prohibits sale of the fish in the U.S. until they are labeled. Finally, a coalition of consumer and environmental groups headed by the Center for Food Safety and Earth Justice has announced that they are suing to stop the approval of the fish. nnn Jaydee Hanson is Senior Policy Analyst at the Center for Food Safety.

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Endnotes Carere, p. 4 1. Steinmetz, K. “23andMe’s CEO says the company will win FDA approval for more tests.” Fortune. Accessed online, December 1 2015: http://fortune. com/2015/12/01/23andme-genetic-tests/ 2. Ostergren JE, et al. “How well do customers of direct-to-consumer personal genomic testing services comprehend genetic test results? Findings from the Impact of Personal Genomics Study.” Public Health Genomics. 2015;18(4):216-24. 3. Carere DA, et al. “Consumers report lower confidence in their genetics knowledge following direct-toconsumer personal genomic testing.” Genet Med. 2015; Epub ahead of print. 4. FDA. “FDA news release: FDA permits marking of first direct-to-consumer genetic carrier test for Bloom syndrome.” Accessed online, December 1 2015: http:// www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm435003.htm 5. Meisel, SF et al. “Explaining, not just predicting, drives interest in personal genomics. Genome Med. 2015;7:74. 6. Carere, DA et al. “The impact of direct-toconsumer personal genomic testing on perceived risk of breast, prostate, colorectal, and lung cancer: findings from the PGen Study.” BMC Med Genomics. 2015;8:63.

Phillips & Charbonneau, p. 7 1. The DTCGT industry has been evolving in terms of business models and modes of distribution. Some companies now require, or offer the option, of return of results to consumers’ healthcare professionals. 23andMe’s UK branch also supplies tests through Superdrug, a pharmaceutical chain. 2. For information on the range of nonhealth related DTCGT tests on offer, especially some of the more questionable types of testing, see A. Phillips, ‘Only a Click Away – DTC Genetics for Ancestry, Health, Love…and More: A View of the Business and Regulatory Landscape’ in Applied & Translational Genomics – forthcoming 2016. 3. Jan Charbonneau, (2015), Doctoral research ‘Think before you spit: Regulatory requirements for consumer protection in Direct-to-Consumer Genetic Testing’, University of Tasmania. 4. GenomeWeb Staff Reporter, ‘FDA Sends DNA4Life Untitled Letter Regarding Pharmacogenetic Report Product’ (GenomeWeb, 9 November 2015) <https://www.genomeweb.com/

16 GeneWatch

molecular-diagnostics/fda-sendsdna4life-untitled-letter-regardingpharmacogenetic-report-product> accessed 10 November 2015. 5. This involved compiling a list of the DNA testing companies with English language websites. 248 have been identified and there are 102 websites that have offered testing for health purposes in the last four years. Please also see Andelka M Phillips, ‘Genomic Privacy and Direct-to-Consumer Genetics - Big Consumer Genetic Data - What’s in that Contract?‘ (2015 IEEE CS Security and Privacy Workshops); and Andelka M Phillips, Think Before You Click ? Ordering a Genetic Test Online‘ (2015) 11 Scitech Lawyer 8. 6. Nancy S Kim, Wrap Contracts: Foundations and Ramifications (OUP 2014) 2. 7. Nancy S Kim, Wrap Contracts: Foundations and Ramifications (OUP 2014) 35; and Nancy S Kim, ‘Exploitation by Wrap Contracts-Click’ (2014) 39 California Bar IP Journal, New Matter 10. 8. Steve Hedley, The Law of Electronic Commerce and the Internet in the UK and Ireland (2nd edn, Cavendish Publishing Limited 2006) 249. 9. Nancy S Kim, Wrap Contracts: Foundations and Ramifications (OUP 2014) 60-1. 10. Melissa Gymrek et al, ‘Identifying personal genomes by surname inference’ (2013) 339 Science 321; Yaniv Erlich and Arvind Narayanan, ‘Routes for breaching and protecting genetic privacy’ (2014) 15 Nature Reviews Genetics 409. 11. 23andMe, ‘23andMe Acquires CureTogether, Inc.’ (Press Release, 12 July 2012),<https://www.23andme.com/ about/press/curetogether/> accessed 6 January 2013; CureTogether Inc., <https:// www.23andme.com/about/press/curetogether/> accessed 6 January 2013.

Salzberg, p. 10 1. http://www.sangamo.com/ pipeline/sb-728.html 2. http://www.thermofisher.com/us/ en/home/life-science/genomeediting/geneart-tals.html 3. http://www.sciencemag.org/ content/327/5962/167.full 4. http://www.biocompare.com/EditorialArticles/144186-Genome-Editingwith-CRISPRs-TALENs-and-ZFNs

Wallace, p. 12 1. The FDA won’t let 23andMe test your genes - so it may go to Europe. VOX. 12th May 2014. http://www. vox.com/2014/5/12/5709766/thefda-wont-let-23andme-test-your-

genes-so-it-may-go-to-europe 2. Controversial DNA test halted in the US comes to UK. BBC. 2nd December 2014. http://www.bbc.co.uk/news/ science-environment-30288939 3. Superdrug criticised by doctors for stocking genetic self-testing kits. The Guardian. 31st March 2015. http://www.theguardian. com/science/2015/mar/31/superdrugcriticised-doctors-genetic-self-testing-kits 4. Mrs Google’s DNA test for her unborn girl: Wife of internet tycoon has daughter tested for risk of cancer, Alzheimer’s and Parkinson’s in later life. Mail on Sunday. 24th January 2015. http://www.dailymail. co.uk/health/article-2924572/Mrs-Googles-DNA-test-unborn-girl-Wife-internettycoon-daughter-tested-risk-cancerAlzheimer-s-Parkinson-s-later-life.html 5. http://www.genewatch.org/sub-396520 6. US Government Accountability Office (2006) Nutrigenetic testing: tests from four websites mislead consumers. July 2006. http://www. gao.gov/products/GAO-06-977T 7. US Government Accountability Office (2010) Direct-To-Consumer Genetic Tests: Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionable Practices July 2010. http://www.gao.gov/products/gao-10-847t 8. Janssens ACJW, Gwinn M, Bradley LA, Oostra BA, van Duijn CM, Khoury MJ (2008) A Critical Appraisal of the Scientific Basis of Commercial Genomic Profiles Used to Assess Health Risks and Personalize Health Interventions. The American Journal of Human Genetics 82, 593–599. http://www.ajhg.org/AJHG/ fulltext/S0002-9297(08)00145-6 . 9. Rival genetic tests leave buyers confused. The Sunday Times. 7th September 2008. http://www.thesundaytimes.co.uk/sto/ news/uk_news/article234529.ece 10. I Had My DNA Picture Taken, With Varying Results. New York Times. 30th December 2013. http://www.nytimes. com/2013/12/31/science/i-had-mydna-picture-taken-with-varying-results. html?pagewanted=1&_r=3&hp 11. Hogarth S, Javitt G, Melzer D (2008): The current landscape for direct-to-consumer genetic testing: legal, ethical, and policy issues. Annu Rev Genomics Hum Genet 9:161–182. 12. Hogarth, S (2010) Myths, Misconceptions and Myopia: Searching for Clarity in the Debate about the Regulation of Consumer Genetics. ­13:322–326 13. European Council (2015) Medical devices: Council mandates presidency to start talks with EP. 23rd September 2015. http://www.consilium.europa.eu/en/press/ press-releases/2015/09/23-medical-devices/

Oct-Dec 2015


From the Council for Responsible Genetics

The GMO DecepTiOn What You Need to Know about the Food, Corporations, and Government Agencies Putting Our Families and Our Environment at Risk

edited by Sheldon Krimsky and Jeremy Gruber Foreword by Ralph nader

“If you do not understand why there is so much opposition to GMOs, nationally and internationally, this book is the place to start.” —Marion Nestle, professor of nutrition, food studies, and public health at New York University and author of Eat Drink Vote: An Illustrated Guide to Food Politics “The GMO Deception is the most comprehensive resource covering all areas of this complex topic.” —Ken Roseboro, editor and publisher, The Organic & Non-GMO Report

ON SALE NOW Volume 28 Number 3

GeneWatch 17


Council for Responsible Genetics www.councilforresponsiblegenetics.org

Support from people like you makes CRG’s work possible. Much of our income comes from individuals. Your support helps keep our programs free of the restrictions that come with funding from pharmaceutical and health care companies or government sources. We are the watchdogs for accurate and unbiased information about biotechnology, even when the truth doesn’t suit current political or commercial agendas. And we depend on you to be able to do what we do. There are many ways you can help CRG. You can become a donor: an annual gift in quarterly installments of $25, $50 or $100 gives us a wonderful and predictable support with a minimal shock to your budget. You may also be able to designate CRG through your workplace giving program, including the Combined Federal Campaign. Many companies will actually match or even double-match your donation. Check with your employer about its matching gift program. You might also consider making an investment in a future where biotechnology is properly used by remembering CRG in your will with a bequest or charitable trust gift. To learn more about helping CRG, please call us at 617.868.0870, or visit www. councilforresponsiblegenetics.org. ISSN 0740-9737

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GeneWatch Vol. 28 No. 3  

Consumer Genomics

GeneWatch Vol. 28 No. 3  

Consumer Genomics

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