GeneWatch Vol. 25 No. 5

GeneWatch THE MAGAZINE OF THE COUNCIL FOR RESPONSIBLE GENETICS | ADVANCING THE PUBLIC INTEREST IN BIOTECHNOLOGY SINCE 1983

Volume 25 Number 5 | Oct-Nov 2012

Featuring: Jeremy Lazarus, President of the American Medical Association Joanne Armstrong, Senior Medical Director at Aetna Anita Allen, Presidential Commission for the Study of Bioethical Issues ISSN 0740-9737

GeneWatch October-November 2012 Volume 25 Number 5

Editor and Designer: Samuel W. Anderson Editorial Committee: Jeremy Gruber, Sheldon Krimsky, Ruth Hubbard 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.

Address 5 Upland Road, Suite 3 Cambridge, MA 02140 Phone 617.868.0870 Fax 617.491.5344 www.councilforresponsiblegenetics.org

board of directors

Sheldon Krimsky, PhD, Board Chair Tufts University Evan Balaban, PhD McGill University Paul Billings, MD, PhD Life Technologies Corporation Sujatha Byravan, Phd Centre for Development Finance, India Robert DeSalle, Phd American Museum of Natural History Robert Green, MD, MPH Harvard University Jeremy Gruber, JD Council for Responsible Genetics Rayna Rapp, PhD New York University Patricia Williams, JD Columbia University staff

Jeremy Gruber, President and Executive Director Sheila Sinclair, Manager of Operations Samuel Anderson, Editor of GeneWatch Andrew Thibedeau, Senior Fellow Vani Kilakkathi, Fellow Editorial & Creative Consultant Grace Twesigye Unless otherwise noted, all material in this publication is protected by copyright by the Council for Responsible Genetics. All rights reserved. GeneWatch 25,5 0740-973

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Editor’s Note

Samuel W. Anderson

You can get your entire genome sequenced for a few thousand dollars, but the information you get back will be worthless.

All right, “worthless” may be a bit misleading. Your whole genome sequence has the potential to bring you real, tangible benefits—even, in some cases, the life-saving sort—but it’s going to take some additional work beyond just getting the code. Quite a lot of additional work, it turns out.

If you’ve seen The Matrix, you might remember the characters watching those green strings of code trickling down their computer screens. The code is essentially a readout of the inner workings— the genome, if you will—of “the matrix” (a virtual cyber-world where everyone does kung fu, for those of you who haven’t seen the movie). A few of the characters are savvy enough to know in great detail what’s going on in the matrix just by reading those bits of raw code on a computer screen.

The human genome isn’t like that. You’re never going to be able to eyeball your raw genomic code—over three billion pairs of A’s and T’s and G’s and C’s—and have any idea what the heck it says about you. You’re going to need some help with this.

Because we tend to talk about whole genome sequencing casually or conceptually, it’s easy to forget just how big the human genome is. I did it in just the last paragraph, in fact. There it is, quietly nestled between hyphens: three billion base pairs.

How big is that, really? If you are so enthralled by this issue of GeneWatch that you find yourself reading it from cover to cover, you will have read around 135,000 letters, numbers, and punctuation marks. In order to get to three billion characters, you would need to read another 22,222 issues, or about 800,000 pages.

Now let’s say this magazine is published in Slovak (and let’s assume you don’t speak Slovak). In order to make sense of those three billion characters, you’ll need some sort of key, like an English-Slovak dictionary. Better yet, you could just plug the whole thing into Google Translate. There will be a few minor errors, but you’ll get the gist of it.

Once again, though, the human genome doesn’t really work this way. Its alphabet may only be four letters, but Genomese is an immense and terribly complex language. The dictionary is still in development and may never actually be complete. We can identify nearly all of the letters on those 800,000 pages with impressive accuracy, and we know where to find certain scraps of important information; the rest is still Slovak to us. nnn

comments and submissions GeneWatch welcomes article submissions, comments and letters to the editor. Please email anderson@gene-watch.org if you would like to submit a letter or any other comments or queries, including proposals for article submissions.

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 October-November 2012

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Vol. 25 No. 5

4 In Memoriam: A Tribute to Barry Commoner Called the “father of grassroots environmentalism,” Barry Commoner was a scientist with an uncommon commitment to the public interest. By Sheldon Krimsky 6 More Science Than Art Next generation sequencing could be a revolution in the making, but as the pace of advances quickens, it’s easy to forget how far we have yet to go. By Paul Billings 8 Will Insurance Cover Genome Sequencing? It’s the million ... well, several-thousand dollar question; but there is still a bit of science to do before insurance coverage becomes a sticking point. Interview with Joanne Armstrong 10 Doctors (Cautiously) Onboard Genetic technologies offer promise, but many clinical challenges remain. By Jeremy Lazarus 12 Privacy in the Age of Revelation The Presidential Commission for the Study of Bioethical Issues hands the Obama Administration a report on genomics and privacy. Interview with Anita Allen 15 The Genome Sequencing and Privacy Report: A Missed Opportunity The Presidential Commission’s report on whole genome sequencing and privacy is helpful as a first step, but not as the final word. By Mark Rothstein 18 Computer Science A genome can be stored in just a gigabyte; studying and analyzing it is another matter. Interview with Steven Salzberg 21 Managing Your Genetic Portfolio Was it a wise investment to get your genome sequenced? That depends on what you do with it. By Maggie Curnutte and Melody Slashinski 23 Great Expectations, Modest Returns Personalized genetic medicine has received enormous hype from overconfident backers, but the evidence paints a humbler picture. By Donna Dickenson 26 Questioning the Utility of Whole Genome Sequencing Discussions about the impact of whole genome sequencing are too often built on the assumption that it will revolutionize medicine. By Helen Wallace *** 29 The Complicated Cost-Benefit Calculus of Newborn Screening When a program saves or improves the lives of thousands of infants each year, its potential disadvantages have a way of being overlooked. By Vani Kilakkathi 32 Notes From the Field: Forensic Genetics in India The Forensic Genetics Policy Initiative travels to Bangalore and New Delhi to help partners raise awareness about India’s pending DNA profiling bill. By Jeremy Gruber 33 Topic Update: GMO Labeling California Voters Reject Prop 37 34 Endnotes

In Memoriam: A Tribute to Barry Commoner Called the “father of grassroots environmentalism,” Barry Commoner was a scientist with an uncommon commitment to the public interest. By Sheldon Krimsky If there were a Nobel Prize awarded for public interest science, without a doubt Barry Commoner would have been one of its recipients. His work, spanning more than a half century, challenged the apathy of calcified government agencies and scientists who fed from their troughs and raised the consciousness of countless young scientists to understand that inaction in the face of moral crisis was itself immoral.

Commoner found his calling in science with a public purpose. He tackled the iconic environmental problems of the 20th century, including radioactive fallout, toxic pollution, air quality, the fossil fuel economy, hazardous waste, nuclear power, chemically intensive agriculture, climate change and the ecology of the planet.

In his pursuit of fundamental questions, he refused to be limited to the disciplines of his education, namely biochemistry and genetics.

He mastered the literature in other fields in order to create a more holistic view of the causes and solutions of environmental problems. On the celebration of Commoner’s 80th birthday one of his students, Danny Kohl, wrote: “Barry Commoner’s scientific career is best characterized by his insistent commitment to holistic (as opposed to reductionist) approaches to understanding how living things function and his alertness in bringing the most modern tools from physics and chemistry to bear on the 4 GeneWatch

properties of living systems.”

Activist Peter Montague spoke of him most aptly as the father of grassroots environmentalism. Commoner gave ordinary citizens more credit for their ability to assimilate technical information than most of his contemporaries. He introduced the concept of “right to know” decades before it became a cornerstone of legislation.

Commoner’s defiance against immoral authority began at a young age. While writing Science in the Private Interest, I interviewed Commoner for a profile I was preparing on a few public interest scientists. He told me that when he attended James Madison High School in Brooklyn, where he had been a high academic achiever spending considerable time in biology labs, his teachers prompted him to go to college to study biology. Commoner’s uncle, a Russianborn intellectual on the staff of the New York Public Library, advised his nephew that Jews had a difficult time getting positions in universities; if he wanted such a career, he should enroll in an elite college, specifically not City College, the default choice of most of the children of immigrant parents. He applied to Columbia and was rejected, according to Commoner, because of the Jewish quotas that many Ivy League schools had during that period. Columbia directed him to Seth Low Junior College, which it had established to accept ethnic and racial minorities.

Commoner refused to attend the “lesser school” and eventually one of his family members contested the decision and he was admitted to Columbia and thereafter Harvard.

The issue that jump started Commoner’s public role in science and on which he spent a dozen years was nuclear radiation from atomic testing.

In the mid-to-late 1950s the public was assured that there were no risks from the radiation released from atmospheric testing of nuclear weapons. So much of the information was classified that it was impossible to make an informed decision. Commoner argued that the decision about atmospheric testing should not rest with the scientists alone. He started the St. Louis Committee for Nuclear Information (CNI), which led to the magazine Scientist and Citizen.

Working through CNI, Commoner executed one of the most iconic citizen information campaigns in the 20th century. At Washington University, he collaborated with the Dental School and collected baby teeth to determine the levels of strontium 90 absorption from the radioactive fallout of atmospheric nuclear weapons testing. The citizens of St. Louis played a critical role in delivering biological information to scientists.

Commoner also made his scientific expertise available to occupational health and safety activists who lobbied for legislation protecting workers. CRG founding member Tony Mazzocchi, who served as vice October-November 2012

Volume 25 Number 5

Image: Oregon State University

president of the Oil, Chemical and Atomic Workers Union, wrote about Commoner: “Without [our] association with Barry we would never have changed the face of the workplace.”

Mazzocchi was also a participant in the Baby Tooth Survey while he was a member of SANE (the anti nuclear organization). Commoner was also a member of the advisory committee of the then nascent Council for Responsible Genetics.

Ralph Nader spoke of Commoner as one of the most complete scientists, a person who doesn’t just contribute to the technical details of a debate. He asked more fundamental questions, such as why we should have a fossil fuel economy in the 21st century, or how do we organize our economy so it is not dependent on high throughput material consumption and technologies that disrupt the biosphere?

While Commoner was widely known for his environmental activism and for applying science toward a public purpose, he was also a brilliant and creative scientist working across fields of biology and physics.

He began his career investigating the tobacco mosaic virus. He used electron spin resonance to study free radicals (molecules with one rather than two electrons in the outer shell which gave them unique chemical properties).

While researching the history of biology, I came across Commoner’s early writings in molecular genetics.

In 1964 and 1968 Commoner published articles in Nature where he questioned the Watson-Crick theory of DNA in inheritance and criticized the central dogma of molecular biology. Commoner contended that DNA was not self-replicating and that their theory failed to account for the role of proteins. He left that debate aside and came back to it many years later.

I came across a comment by Commoner in the media that stated that many of the new genetically modified products had already been tested in nature’s genetic exchanges. I wrote him and explained that the new biotechnology was similar to the rise of synthetic organic chemistry and could do things nature had not imagined or tried out. Moreover, I reminded him of his early work which was emblematic of an anti-reductionist approach to biotechnology.

Some time passed and I learned that Commoner was steeping himself in the newest studies of molecular biology. Then, in 2002 he published a widely distributed article in Harpers Magazine titled “Unraveling the DNA Myth: The Spurious Foundations of Genetic Engineering.” This took him full circle from his 1968 Nature paper “Failure of the WatsonCrick Theory as a Chemical Explanation of Inheritance.” In his essay he questioned the biological claims of the new agricultural biotechnology

enterprise.

When I began teaching a course on the political economy of the environment, I was drawn to Commoner’s work. He wrote compellingly about energy, population growth, industrial production, reductionism in science and the responsibility of scientists.

His book Science and Survival, published in 1963, is a classic. I also had access to audio lectures he made on ecology and survival. As a lecturer he had in his voice all the drama of a seasoned thespian. He used his stage presence as effectively as any speaker I have ever heard. And he was masterful at simplifying complex science to a general audience. I can still hear his resonant voice bellow out in the audio tapes: ”We use atomic energy to heat water to 3,000 degrees when all we need is steam that requires 212 degrees.”

nnn Sheldon Krimsky, PhD, is Chair of the Board of Directors of the Council for Responsible Genetics.

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More Science Than Art Next generation sequencing could be a revolution in the making, but as the pace of advances quickens, it’s easy to forget how far we have yet to go. By Paul Billings The improvement in efficiency of microprocessors has led to incredible changes in our lives. The amount of information we have at our fingertips and the new ways we can communicate with others in a multitude of environments have been substantially made possible as a result of improvements in these tiny electronic components. Their evolution has generated the formulation of Moore’s Law (after the Intel Founder) who noted that microprocessor chip capabilities were doubling in power and productivity approximately every 2 years.

This remarkable, transformative technical accomplishment may soon be eclipsed in some respects by the changes occurring in nucleic acid sequencing. Until the advent of the Human Genome Project, accomplished over the decade of the 1990’s, the field of DNA sequencing was dominated by the relatively slow, laborious but highly accurate methods developed by Fred Sanger and Walter Gilbert. In fact, these methods still dominate key areas of sequencing application today. But when faced with the daunting task of analyzing and assembling the content of 24 unique human chromosomes comprising roughly 3 billion individual DNA bases (the approximate size of a haploid human genome), researchers decided that approaches termed “shot-gun” were required in order to complete the project. The genome was fragmented into small pieces, those fragments were copied faithfully, and this library of copies was decoded using tagged nucleotides. The decoding occurred as part of normal DNA synthesis, and as this occurred, 6 GeneWatch

the incorporated nucleotides were identified by light sensitive cameras.

The induced fragment sequences were then mapped and reconstructed by bioinformatic computational tools into the original whole genome sequence. With the invention of this new form of sequencing, called next generation sequencing, a rough draft of the human genome was prepared in about 10 years at a cost of roughly $3 billion.

Within the next few months, a new sequencing method that does not rely on photographic determinations of base incorporation in templated DNA libraries will deliver a whole genome sequence with accuracy similar to or better than what the Human Genome Project provided. This sequencing will be done in about a day for a cost of less than $1,000.

Using learning derived from the microprocessor industry, nucleic acid sequencing is turning to sequencing chips, and the productivity of this innovation is surpassing the pace predicted by Moore’s Law—the output of these chips has risen exponentially every 6 months!

This incredible speed improvement and cost reduction opens up a whole array of potential biological and medical applications. Researchers across the globe can afford to analyze DNA or RNA (the methods can be used for all types of nucleic acid analysis and are highly quantifiable) in a broad array of experimental systems using a desktop sequencer purchasable with a low capital expenditure. Entrants in clinical trials can easily be sequencing before commencing protocols or in post

hoc analyses in order to tailor therapies better for specific clinical cases.

This development will likely speed more personalized or individualized care and reduce the burden of adverse drug reactions. Rapid analysis of infectious agents or disease states may identify causative agents more rapidly and lead to more precise (and less wasteful) clinical care. The overall goals of this new type of rapid measurement should be to expand knowledge in related sciences while addressing, in a high quality manner, meaningful unmet needs in human health, and reducing costs and eliminating waste in clinical delivery.

The new methods can be applied to the analysis of amplicons (strings of nucleic acids copied) or complete genes depending on their length.

They can be trained on panels of areas of genes that are known to vary in important ways (for instance, genetic “hotspots” important in cancer care) or on all a cell’s expressed genes (the exome) or on whole genomes, the gene “home” in our cells. There are at least two genomes in most of human cells. One resides in the nucleus of cells and the other exists in the mitochondria. There appears to be a sharing of information between our two cellular repositories of DNA information.

As noted, sensitive and quantitative analyses of RNA are also possible with next generation sequencing methods. Variation in mRNA level is now used in research and in some clinical settings. For instance, in breast and lung cancer treatment planning, analysis of mRNA patterns appears to allow better predictions October-November 2012

of which patients can forego sometimes toxic continued treatments for their cancers.

Next generation sequencing methods may make these analyses even more precise, comprehensive or less costly.

The older methods of sequencing analyzed the ends of strings of nucleic acids by first marking them with tags and then terminating the ends one nucleotide at a time (“chain termination” methods). Next generation sequencing methods use natural enzymes that synthesize or link nucleic acids (polymerases or ligases) and note the incorporation of known nucleotides. The most common form of next generation sequencing incorporates fluorescent DNA bases recorded by a camera. The microprocessor method simply monitors the PH (acidity) around the artificial synthesis of DNA library fragments, functioning as miniature PH meters.

When the correct base is inserted, an acidic hydrogen ion is released and the microprocessor registers this event.

In the future, single molecule strings of nucleic acids (bases) may be passed through pores, one base at a time (but very rapidly) and analyzed (nanopore methods). A variety of other sensitive single molecule approaches have also been proposed.

The sensitivity of these methods may improve the detection of minor nucleic acid species in mixtures within biological fluids. For instance, the blood of a pregnant woman contains a relatively small number of molecules derived from the fetus during gestation. Reviewing and counting them may help in the monitoring of fetal health. Cancers shed DNA and RNA as they grow and spread into a blood based sea of normal nucleic acid strings and fragments.

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Analyzing them may provide important cancer biology data.

There are many factors that impact the accuracy and utility of all sequencing techniques. First, can the target sequence be reliably purified and prepared for the analytic approach? Some areas of the genome, for biochemical and structural reasons, are hard to assess. Second, can the targeted fragment be copied and modified into libraries for processing? Then, does the sequence to be analyzed conform to those that can be done accurately with the method applied? Long strings of the same DNA base (known as homopolymers) often confound next generation methods and do exist in parts of the human genome. Finally, the bioinformatic transformation of input from the sequencer into imputed strings of DNA bases and the calling of base changes (mutations) can vary.

If a method produces accurate and long strings of output, the computational transformations of raw data may be generally more accurate.

At present, no one method of next generation sequencing allows for all the DNA of the human genome to be fully analyzed. Around 5 to 10% of the genome seems relatively inaccessible for the reasons noted above. In addition, even if the method applied in a laboratory is 99.99% accurate—a level that far exceeds most clinically

applied measurements now— this would appear to be inadequate for clinical genome work. Consider that genome sequencing has at least 3x109 targets. An error rate of 0.01% (99.99% accuracy) would produce up to 105 inaccurate calls and potentially false results. That would be unacceptable in many applications. The use of highly redundant applications of next generation sequencing methods or two differing methods on the same specimen may be ways of improving the accuracy of newer DNA methods and limiting errors.

In this issue of GeneWatch, authors explore how next generation sequencing and other views of the genome may alter our lives and environments. It is certain that sequencing of genomes by methods including those described as “next generation” will not provide all the answers to our biology or address all our unmet clinical needs, but the use of these methods and resulting data will be a relatively quantifiable and reliable component of ongoing approaches to medical understanding and care.

It is hopeful that we will be building an analytic system using a rapidly improving series of methods with the characteristics of next generation sequencing. “Art” has dominated many measures of human variation so far.

The evolution of next generation sequencing promises the application of more “science” to important issues, likely a salubrious change. nnn Paul Billings, MD, PhD, is Vice Chair of the Board of Directors of the Council for Responsible Genetics and Chief Medical Officer of Life Technologies, Corp. This article represents Dr. Billings’ own views rather than those of Life Technologies.

GeneWatch 7

Will Insurance Cover Genome Sequencing?

It’s the million ... well, several-thousand dollar question; but there is still a bit of science to do before insurance coverage becomes a sticking point.

Interview with Joanne Armstrong

Joanne Armstrong, MD, MPH, is a senior medical director for Aetna, where she heads the Department of Women’s Health and is the clinical and strategic lead for genetics.

GeneWatch: There is a common assumption among many people that personalized genomics is going to revolutionize medicine—but ultimately, do you think it will be up to health insurers to decide if and when this happens?

Joanne Armstrong: I actually think that this is an evolution, not a revolution. I think we’re still in the early stages, but there are plenty—hundreds—of these technologies that are in clinical care. There has been an acceleration over the last five years or so, and I expect that as technology platforms improve and the science continues to be established around the validity, we’ll see more and more of these technologies in clinical care.

So I don’t think health insurance is what’s standing in the way of the “revolution.” I think that an evolution is occurring because the science is establishing the value of it, and I think that will continue.

How do health insurers figure out what genomic technologies they will cover?

I would say that with genomic technology, the principles of what gets covered are the same as the principles for non-genomic technologies.

In other words, it’s

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not exceptional; it’s the same process.

So as an overview, the services that are covered are those related to the prevention, diagnosis or treatment of an illness. The information that you get from the covered service has to affect the course of treatment; the care or treatment should be likely to improve the outcome, and that improvement should be attainable outside investigational settings—meaning it’s not just a research project, but in broad clinical practice you can see improvements; and finally, the service has to be consistent with the plan design, meaning that the customers who are buying the insurance have to have included this in their plan.

Those are the broad principles of coverage for genetic technologies, and it’s the same for everything else.

When you get down to the next level there are more specific standards for what gets covered. The technology you’re talking about must have evidence published in the scientific, peer-reviewed literature that permits conclusions about the performance effect of those technologies on health outcomes. I think this is where a lot of genetic technologies are still sitting, at various stages in this technology evaluation pipeline. The test needs to meet three standards: it needs to have analytic validity; it needs to be clinically valid; and it needs to have clinical utility.

For some of them it’s pretty straightforward: There’s a mutation that is known to be associated with a certain disease, and there is a test that October-November 2012

has been well studied and validated which identifies the gene associated with the disease; and when this gene is identified, you can act on it.

For something like whole genome sequencing, for example, I think that some of it is still in the analytic validity stages. The technology platforms are developing very quickly, and we don’t really have technical guidelines yet around those platforms—what quality controls are needed, for example. There is still a need to define standards to analyze the data that comes out of it. What are the standards to assess the quality of the sequence that you’ve read? What are the standards for measuring false positives and false negatives? Are these standards the same from one technology platform to another?

Then you ask the next level: What’s the standard against which this genome is being compared? What is it being benchmarked against? What gets reported, what does not? How do you know when you have enough data that it goes from a variant of uncertain significance to one of significance, to one that should be reported, to one that should be acted on?

All of this stuff is really at the early stages of analytic validity and clinical validity.

And then there’s this final step, which is clinical utility. What do you actually do with the results? Does the information translate into a measured improved health outcome?

So the challenges span both sequencing and analysis—do you see those two pieces, whole genome sequencing and the analysis of the sequence, being treated similarly from an insurance standpoint?

If you’re asking from the point of view of whether they are covered, definitely they are related. The sequencing is just the method by which you get all Volume 25 Number 5

the billion units. The critical thing is: What do you do with it? How does it translate into a measured improved health outcome for a population or for groups or individuals? That requires that you understand what that alphabet means, what’s significant and what’s not. The exercise of building that understanding is in progress, but it’s a big job. It means building libraries of data, maintaining them, understanding when something moves from a variant of uncertain significance to one of significance to one that gets reported. Then, when

results into clinical care. There is a legitimate question about who is going to be translating this information for the patient, and given the rate of information that’s coming out on these mutations and how it interacts with other clinical or genetic information, a very high level of sophistication is required to understand it. That’s just for the physician to understand it, and then you’ve got the next hurdle of having patients understand it. This will be a challenge for all of us, for all clinicians, for probably decades to come.

The cost is not the issue that’s hanging up coverage policy around it. There are massive technology issues and clinical utility issues, but it’s not a cost issue.” do you report it? So there are lots of challenges. It certainly is moving quickly, and it’s exciting, but it definitely is in the early stages in terms of getting this to the bedside.

Although the price is coming down, it still costs thousands of dollars to get your genome sequenced. Is that issue of cost one of the things that we’re waiting on?

The cost is not the issue that’s hanging up coverage policy around it.

There are massive technology issues and clinical utility issues, but it’s not a cost issue.

Even if a genomic technology is shown to have clinical utility, what about the translation of that raw information into something that doctors and patients can understand and use?

I think there is a lot of concern that has been expressed today about the translation of genetic tests and

Is genetic counseling very often covered in health insurance plans?

We cover it broadly for people with, or at risk for, a range of known genetic conditions. I think, though, it’s a little simplistic to believe that a genetic counselor today is going to be able to interpret the results of a whole genome or exome sequence.

With that much information—today we have challenges meeting the storage and computational needs just to keep this information archived. So the need for training is across all levels of the medical workforce. Even if the technology were available today, it’s not like we have the trained workforce to understand what this means.

Some of this is because we don’t really have the evidence of what this information means right now. That’s why the biggest challenge, in my view, is not coverage—it’s evidence standards. What does this information mean, and what does it mean for the patient?

nnn GeneWatch 9

Doctors (Cautiously) Onboard Genetic technologies offer promise, but many clinical challenges remain.

By Jeremy Lazarus

Whole genome sequencing and whole exome sequencing are becoming more common in the clinical setting and offer promise for improving health outcomes. These techniques are becoming more commonly used in complex cases in which a patient’s disease appears to be genetic, but examination of individual candidate genes has not yielded a diagnosis.

However, significant hurdles must be overcome before the benefits 10 GeneWatch

offered by next-generation sequencing can be fully realized.

Of significant concern for physicians are the work-related demands required to guide patients through WGS or WES. Prior to sequencing, patients must undergo extensive genetic counseling covering such issues as medical history, inheritance patterns, false-positive and falsenegative results, privacy and informed consent. In medical centers

with WGS programs, it takes about 6-8 hours to fully counsel patients prior to sequencing. Some question whether the current system is equipped to deliver such intensive care, especially as the nation experiences a shortage of medical geneticists and genetic counselors. Left unaddressed, these shortages will place an incredible strain on genetics professionals. Will other physicians or health care providers be October-November 2012

capable of stepping in? Research shows that a genetics educational gap exists among non-geneticist physicians. To address this gap, undergraduate and residency training programs must work to better educate students about the underlying role of genetics in disease. The creation of certificate-like programs for practicing non-geneticist physicians who wish to undergo additional genetic-specific training has also been suggested.

Once a patient completes genetic counseling, the actual genetic sequencing can occur. These tests generate large amounts of extremely complex data. Typically, WGS will detect more than 3 million variants in an individual’s genome, but only a small percentage of those variants are causal of disease. Software programs sort through these variants and pick out those that are clinically meaningful, but even then, hundreds may remain. Physicians, genetic counselors and other health care professionals must spend a significant amount of time examining each variation to determine its potential role in a patient’s disease. As research identifies new variants associated with the patient’s disease, software programs that identify clinically meaningful variants will require updating.

Thus, a patient’s genome may need to be reanalyzed to detect variants that are newly classified as clinically meaningful. At this point, no guidelines exist on whose responsibility it is to direct the re-analysis or how often it should be done.

Next-generation sequencing has been most successful in identifying genetic causes of disease where standard diagnostic procedures have failed. However, whole genome sequencing will yield many clinically meaningful variants unrelated Volume 25 Number 5

to the disease being targeted. One of the most important decisions a patient undergoing WGS will make is whether to receive results on all variants that are clinically meaningful, or only those that are pertinent to the disease under consideration.

For example, a patient may want to know if she carries a mutation in the BRCA1 gene since this genetic variation dramatically increases her risk for breast and ovarian cancers. If patients choose to receive results on all variants that are clinically meaningful, physicians will spend many hours fully explaining all of these variants to patients.

Meanwhile, physicians must also decide what “clinically meaningful” means in the context of each patient’s clinical situation and wishes.

The most common definition of this term applies to genetic variants that will lead to a change in care. Some medical specialty societies have examined the issue of incidental findings from WGS, and one organization has undertaken an effort to identify variations and diseases that, even if found incidentally, would meet criteria for a physicians’ duty to inform. These include diseases that are well understood and that have associated treatments. While WGS may end the diagnostic odyssey for the disease a patient and their physician are seeking to diagnose and treat, incidental findings almost always lead to follow-up confirmatory testing and additional diagnostic procedures.

Whole genome sequencing offers promise for improving health outcomes, particularly for patients with rare genetic diseases, diseases that cannot be identified by a candidate gene approach, and cancers in which genetic tumor variations can be profiled. Though cost and time

barriers have been largely reduced, work remains to streamline and address clinical application concerns.

Important practice, payment, and regulatory issues, including how to compensate physicians and other health care professionals for the considerable work-related demands required, must also be considered.

Privacy protections must also be in place to protect a patient’s genetic information from misuse. Attention to these and clinical application challenges will help ensure that patients and physicians benefit from rapidly advancing genetic technologies so that these new advances can realize their full potential in improving health outcomes. nnn Jeremy A. Lazarus, MD, is President of the American Medical Association.

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Privacy in the Age of Revelation The Presidential Commission for the Study of Bioethical Issues hands the Obama Administration a report on genomics and privacy.

Interview with Anita Allen

In October, the Presidential Commission for the Study of Bioethical Issues released a report titled Privacy and Progress in Whole Genome Sequencing, addressing individual privacy concerns arising from whole genome sequencing in clinical care. The full report is available at www. bioethics.gov/cms/sites/default/files/ PrivacyProgress508.pdf Anita Allen, JD, PhD, is an appointee to the Presidential Commission for the Study of Bioethical Issues, and Henry R. Silverman Professor of Law at the University of Pennsylvania Law School.

GeneWatch: There is a lot of focus in the report on surreptitious testing—is there any particular reason to emphasize that rather than other issues like, say, biobanking?

Anita Allen: I think the examples of surreptitious testing that we mentioned in our work are so interesting that people often focus on them, even though they were just a part of what we were trying to bring to the public’s attention. As you point out, surreptitious testing is one problem that makes it so important to have a good system of rules and ethics; but we are, I would say, more concerned or motivated by the problem of testing that’s done in an orderly, lawful way for either clinical or research purposes, which nonetheless raise questions about data. What happens to the whole genome sequencing data that’s produced from research or clinical care? Who has access to it, 12 GeneWatch

under what conditions and with what grounds of consent?

the response you’ve received since the report came out?

Obviously the report is addressed to the Administration, but beyond that, who else do you hope reads it?

Well, the overwhelming response to the report has been extremely positive, from just about every sector.

Not everyone is happy. In an unofficial capacity, as an advisor to an organization called the Electronic Privacy Information Center, I became aware that Deborah Peel, who is a very prominent patient rights advocate, is a little bit concerned that the report doesn’t strike the right balance between protecting privacy and granting access to third parties. I think that from her point of view, the welcoming attitude that the report takes toward a collaborative research community working in tandem with the public to further medicine—that this might not be the most privacyprotective point of view.

That aside, I’ve been impressed by the large number of official communications that we’ve received from all kind of people, journalists like yourself and various agencies and so forth, praising the report for its proactive examination of this very difficult issue.

As you say, the Commission’s report was presented to President Obama, and that’s our primary audience, the President and his advisors. But we have been very interested in being in a dialogue with various branches of government—the National Institutes of Health, the Department of Health

“Some people say privacy impedes research, or national security, or law enforcement.

I’m of the opinion that the opposite is true.” and Human Services, and other agencies that may be involved in biomedical work and research. So the entire biomedical community, government and private, is really our audience. We think everybody should be mindful of the consequences of the new challenge of whole genome sequencing data collection, storage and sharing.

Have you been surprised by any of

These aren’t issues that you hear politicians bring up very much …

Right—it’s not stem cell research, it’s not abortion. I think that’s a good point, because it reveals a problem with our society which, in my view, is that a small number of highly contentious ethical issues command a disproportionate amount of the October-November 2012

attention of the public; whereas we are soon to be a society in which, because of genetic testing in research and clinical care, and electronic medical records, we are facing a huge question: Who is going to have access to all of this information? What about medical information stored in the cloud? What about medical information that’s subject to data breaches?

One of the strengths of our report is that it addresses the question of whole genome sequencing in a context which understands that not only are we engaging in whole genome sequencing, but we’re also storing medical data in the cloud—third party entrustment is now the name of the game, we’re not all just keeping medical data on our office computers or office servers. There’s the problem that medical breaches are happening, so even if you don’t want data to be exposed, sometimes by accident, or because of hacking, data gets exposed. The Commission, I think, properly recognized that among the reasons that we have to worry about whole genome sequencing is that the total information environment right now is one in which there’s a lot of social networking, a lot of cloud storage, a lot of data breaches—but also a lot of technological capability to provide secure and safe management of very sensitive data.

Some of the examples of privacy breaches that come up—hypothetical or reallife—can be startling to think about.

Was there anything that came up during the process of putting Volume 25 Number 5

together this report that was startling even to you?

Well, I have been writing and teaching about privacy and data protection since before the Internet, so there’s very little I find truly surprising! The kinds of things that are hap-

“It’s not good enough that people who are attractive to researchers ‘get’ to have their genome sequenced.” pening around the country are often stunning—everything from employees of hospitals who post to MySpace pages condemning a patient because she has an STD, to nursing students publishing pictures of themselves with placentas on Facebook, to billionaires surreptitiously testing their

wives’ lovers—some amazing things are happening out there. There’s so much going on out there that’s pretty stunning, even if I wasn’t personally stunned or surprised.

I was just glad—glad that the Commission had the foresight to address a very cutting edge privacy issue that allows us to reflect more broadly on why we still hear about privacy in the age of revelation.

The Commission did not learn about any startling whole genome sequencing privacy breach. This report is a proactive look by the Commission. The Commission searched for a specific example of a grievous privacy breach of one’s whole genome sequencing information and fortunately did not find it. However, given how quickly the scientific community is working to bring down the cost of whole genome sequencing, the Commission recognizes that whole genome sequencing and its increased use in research and the clinic will raise such ethical dilemmas if the proper privacy protections are not put into place.

The promise of whole genome sequencing is dependent upon widespread public participation and individual willingness to share genomic data and relevant medical information. Researchers need genomic data and corresponding health information from many people to determine what genetic variations mean. However, the Commission concluded that without respecting and securing interests in privacy, individuals will be less likely to voluntarily supply the data that have the potential to benefit us all with life-saving GeneWatch 13

treatments for genetic diseases. The Commission recognizes that confusion and uncertainty tend to erode trust, and that trust is the key to amassing the large number of genomic data sets needed to make powerful life-saving discoveries. Without the appropriate privacy protections, progress will be slowed.

One of the recommendations in the report that I was pleasantly surprised to see was the one stating that all citizens should benefit from the advances of whole genome sequencing.

Yes, that’s an important point. It’s not good enough that people who are attractive to researchers “get” to have their genome sequenced, and it’s not good enough that people who have the insurance and the capacity to have genetic data used in their clinical care have that benefit. Think about it: If people are being encouraged to share their genomic data with researchers, yet the benefits of that research are not broadly distributed across all classes of people, all ethnicities, all regions of the country—that’s an inequity. Among the most important bioethical principles is the principle of justice. So we thought it was important to emphasize that with all this data sharing going on, the benefits should be distributed broadly to include all classes of people.

The informed consent recommendation is also very important. It’s really important to think about informed consent here in a new way, because when you are sharing genetic information, you are sharing information not just about yourself, but about your genetic family. People need to understand that, and to understand the consequences that can befall themselves and others if they choose to share that information. We need to have an informed consent 14 GeneWatch

process that takes into account not just whether an individual wants to partake in a particular research protocol or clinical opportunity and to share the data, but also whether they understand that it means facts about other people will inevitably be disclosed as well.

much more effective way than we do today.

Is there an underlying assumption in the report that whole genome sequencing will be transformative in medical care?

You know, there are people who will say things like “privacy impedes progress.” Some people say privacy impedes research, or national security, or law enforcement. I’m of the opinion that the opposite is true; that because our society respects privacy through both law and through medical and research ethics, we have an environment where people are more willing to participate and to trust. In the health care field, trust is absolutely essential. People won’t go to their doctors or engage in research if they think that sensitive information about them is going to be passed along to third parties without their consent. By promising confidentiality and privacy, and by sticking to those promises through rigorous programs of data security, we are actually securing the bases for medical advances. Far from standing in the way, privacy actually provides a context in which people can comfortably utilize the health care system and comfortably participate in health research. I mean, who would take part in health research if they thought that everything about them is going to wind up in some public database on the Internet? Privacy, anonymity, the whole process of anonymizing research records, the process of providing for confidentiality in faceto-face encounters—these are conditions that make it socially possible for us to utilize the health care system and participate in research. nnn

Well, I believe it will be transformative—not just another tool, but transformative. I see this as the future, where a number of important decisions about clinical care—whether to have surgery, whether to have chemotherapy, whether to use drug X or drug Y—will be based on precise genetic information and not on guessing or overkill. It will save the health care system money in the long run, it will save patients unnecessary treatment, and we’ll all stand to benefit.

We talked to a number of experts in the field about the promise of whole genome sequencing, and every single person believed that this technology will help us to eventually uncover and predict and treat conditions in a

Some people worry that if the privacy concerns are overblown, it will get in the way of progress. Was that idea taken into account in the way this report was developed?

October-November 2012

The Genome Sequencing and Privacy Report: A Missed Opportunity The Presidential Commission’s report on whole genome sequencing and privacy is helpful as a first step, but not as the final word. By Mark Rothstein It has been over 10 years since the first human genome sequence was completed and, since then, the holy grail of genomics has been the ability to perform fast, cheap, and accurate whole genome sequencing. For researchers, whole genome sequencing (WGS) provides important insights into the role of genes in disease. For clinicians, among other things, WGS is an essential part of the emerging field of personalized medicine.

Today, as scientists are on the verge of WGS for $1,000, it is especially important to consider the ethical, legal, and social implications of widespread sequencing. The Presidential Commission for the Study of Bioethical Issues entered this fray with the October 2012 release of its report, Privacy and Progress in Whole Genome Sequencing. The Commission, comprised of 13 distinguished scientists, clinicians, scholars, and citizens, is chaired by Dr. Amy Guttmann, President of the University of Pennsylvania; the vice chair is Dr. James W. Wagner, President of Emory University. The Commission held a series of hearings around the country and developed 12 recommendations.

There are certainly positive aspects to the report, but overall the document is disappointing. It lacks the necessary boldness, sense of urgency, and healthy skepticism needed to evaluate claims of current clinical utility of WGS. This review of the report is divided into three sections, which deal with the report’s strengths, weaknesses, and omissions.

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Strengths Among the strengths of the report are the following four recommendations. First, the report declared that privacy protections should not depend on the status of the individuals and entities that acquire, store, or use whole genome sequence information - in contrast with the HIPAA Privacy Rule, which only applies to “covered entities” in the payment chain. The Commission’s recommendation that privacy protections should follow the information wherever it goes and however it is used is an important insight that should be the basis of future health privacy legislation. Second, the Commission stated its opposition to researchers’ de-identification of genomic data as a means of avoiding regulation under the Common Rule, thereby reiterating the praiseworthy position previously taken by a prior presidential commission. Third, the Commission recognized the importance of studying incidental findings of WGS, but rather than addressing the issue in this report, it announced plans to study the issue separately in the future. Fourth, the Commission

recommended prohibiting nonconsensual or unauthorized DNA testing (although the recommendation is to prohibit nonconsensual “sequencing”) of biological materials on commonly used or discarded items, such as straws and glasses. The United Kingdom’s Human Tissue Act of 2004 prohibits nonconsensual analysis of human specimens, but there are no comparable laws in the United States. The Commission’s support of legislation on this matter is most welcome.

Weaknesses The report places too much emphasis on research and not enough on clinical applications. The research issues are relatively uncontroversial, because there is widespread societal recognition of the desirability of research utilizing WGS, so long as there is informed consent, data security, and other traditional protections. The clinical applications are less easily resolved. Certain uses of WGS are undoubtedly valuable, including for analyzing rare disorders, performing tumor genome sequencing, and determining pharmacogenomically appropriate medications.

For other uses, however, such as predictive risk assessment for common, complex disorders in asymptomatic individuals, there is little current clinical utility and therefore WGS is difficult to justify.

Another weakness of the report is that it underestimates the potential harms that individuals may suffer as a result of WGS. Except for observing GeneWatch 15

the burden of knowing about a condition for which there is no effective treatment, the report focuses solely on tangible harms, such as discrimination. Nevertheless, many individuals currently experience various psychological and social harms from traditional genetic testing (e.g., depression, anxiety), and the massive scope of WGS is likely to increase the number and severity of these intangible problems.

The discussion of privacy, the main focus of the report, is incomplete. By emphasizing the risk of unauthorized uses of genomic information the report overlooks the substantial issue of lawful uses of information pursuant to compelled authorizations. This occurs when individuals are required to sign a broad authorization (releasing substantially all of their health records) as a condition of applying for a job, various forms of insurance, government benefits, or other matters. Each year in the U.S. individuals sign at least 25 million compelled authorizations, and the adoption of interoperable, comprehensive, and longitudinal electronic health records greatly increases the scope of disclosure and therefore the privacy risks.

Unless these risks are addressed it is impossible to protect genetic privacy -- or more broadly, informational health privacy.

The report also contains an inadequate (and, in places, incorrect) discussion of applicable laws. For example, it states (on pages 66-67) that GINA “does not address the use of or access to genetic data. In other words, GINA is an anti-discrimination law; it does not provide comprehensive privacy protections.” This statement is incorrect. Section 202 of GINA prohibits an employer from requiring or requesting an individual to undergo genetic testing or disclose genetic information as a condition of employment. In theory, an employer 16 GeneWatch

cannot discriminate if it does not have genetic information; also, individuals will be more willing to undergo beneficial testing if the results will not be available to employers. The problem is that there is no practical way for custodians of health records to comply with a request to disclose everything except genetic information (which, under GINA, includes family health information). By calling attention to this problem, the Commission could have helped to hasten the development of necessary privacy-enhancing technologies.

Omissions Although the report is limited to broadly defined “privacy” issues, it is impossible to study privacy concerns without understanding the context in which WGS will be used. The adoption of WGS technology has the capacity to overturn numerous established practices in clinical genetics, and the report’s failure even to mention these applications is unfortunate. Three examples follow.

First, genetic screening of newborns and children is now limited to conditions for which medical intervention in childhood is necessary and potentially beneficial. The rationale for limited testing in childhood is that for adult-onset disorders that cannot be ameliorated in childhood (e.g., Huntington disease, Alzheimer’s disease), the child should be able to decide upon reaching maturity whether to undergo genetic testing.

Routine, population-wide WGS of newborns and children would fundamentally alter this established policy.

Such a change could have significant psycho-social implications, including privacy implications, and therefore requires thoughtful analysis.

Second, as the cost difference between a single genetic test and WGS is reduced to nominal levels, there will be pressure to undergo WGS in

every situation where only a single test is needed initially. This “might as well” sequencing could be promoted by public or private payers as being more efficient than multiple tests, as well as by clinicians who believe the additional genomic information has clinical value. WGS will generate numerous incidental findings that would necessitate genetic counseling, surveillance, and privacy controls. It also could lead to a significant psychological burden that needs to be considered.

Third, the report does not address direct-to-consumer WGS. In addition to numerous regulatory issues, direct-to-consumer WGS raises such fundamental ethical issues as the conflict between autonomy and paternalism, nonmaleficence, justice, and privacy.

Conclusion By failing to evaluate whether the widespread clinical application of WGS for asymptomatic individuals is medically and ethically appropriate, the Commission’s report may be viewed as tacitly endorsing unconstrained WGS. Consequently, the Commission’s sensible, but limited, recommendations on privacy will be overshadowed by the unresolved ethical, legal, and social implications of expansive WGS. If the report is the first of many efforts by this or other distinguished bodies to analyze the issues associated with WGS and recommend policy development, it will be a helpful step forward. The Commission report, however, is not – and should not be – the last word on this subject.

nnn Mark A. Rothstein, JD, is Director of the Institute for Bioethics, Health Policy and Law at the University of Louisville School of Medicine and President of the American Society of Law, Medicine and Ethics.

October-November 2012

Race and the Genetic Revolution

Science, Myth, and Culture

Edited by Sheldon Krimsky and Kathleen Sloan

“I can hardly wait for this book to begin circulation. It should be read and taught as widely as possible.” —Adolph Reed, Jr., University of Pennsylvania Divided into six major categories, the collection begins with the historical origins and current uses of the concept of “race” in science. It follows with an analysis of the role of race in DNA databanks and its reflection of racial disparities in the criminal justice system. Essays then consider the rise of recreational genetics in the form of for-profit testing of genetic ancestry and the introduction of racialized medicine, specifically through an FDA-approved heart drug called BiDil, marketed to African American men.

Concluding sections discuss the contradictions between our scientific and cultural understandings of race and the continuing significance of race in educational and criminal justice policy, not to mention the ongoing project of a society that has no use for racial stereotypes.

SHELDON KRIMSKY is professor of urban and environmental policy and planning and adjunct professor of public health and community medicine at Tufts University. He is the author of Science in the Private Interest: Has the Lure of Profit Corrupted Biomedical Research?

KATHLEEN SLOAN is a human rights advocate specializing in global feminism. She has run nonprofit organizations for more than twenty years and has directed communications and public relations functions for multinational corporations and nonprofits.

CO LU M B I A U NIVE R S ITY PRE S S Tel: 800-343-4499 Fax: 800-351-5073 cup.columbia.edu

$35.00 / £24.00 paper 978-0-231-15697-4 $105.00 / £72.50 cloth 978-0-231-15696-7 304 pages, 1 line drawings, 4 tables A PROJECT OF THE COUNCIL FOR RESPONSIBLE GENETICS

“Novel and forward thinking, this book will be a valuable addition to a literature that needs to be brought up to speed.” —David Rosner, Columbia University and Mailman School of Public Health

ORDER ONLINE AND SAVE 30% To order online: www.cup.columbia.edu Enter Code: RACKR for 30% discount Race and the Genetic Revolution Edited by Krimsky Sloan (304 pages) paper ISBN 978-0-231-15697-4 regular price $35.00, now $24.50 Regular shipping and handling costs apply.

Computer Science A genome can be stored in just a gigabyte; studying and analyzing it is another matter.

Interview with Steven Salzberg

Steven Salzberg, PhD, is a Professor of Medicine in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University.

GeneWatch: Are there any particular bioinformatics or computational challenges standing in the way of whole genome sequencing becoming widely adopted in clinical care?

Steven Salzberg: I don’t think that we’re that far away from having the technical ability to use sequencing in the clinic. I think we’re somewhat further away from having knowledge of genetic variants that are actionable, that you can really do something about. That’s really where the problem is.

Right now a lot of sequencing is focusing on just doing exons, or the exome, which is only about two percent of the genome. Even if you restrict your attention to the exome,

“The actual costs of analysis are going to dominate the cost of sequencing.”

18 GeneWatch

you’ll still find a very large number of variants, of sequence differences, in anybody that you sequence. Typically you’ll get 50,000 to 100,000 differences in the exomes alone.

Many of them are just private mutations that belong to that person and people closely related to that person which have no effect on health, nothing clinically relevant. So one challenge—and this is mostly computational—is winnowing the list down to a smaller number. We have computational ways of getting that list down to, say, less than 100 variants that are likely to have some biological effect.

But then you start to come up against the limitations on our knowledge. We don’t know that much about how mutations will affect the function of a gene; and even when

we do know that, at a molecular level, we don’t know how those changes in function would affect the person’s health. We’re pretty far away from being able to say, “Oh, you have this mutation? Eat more spinach.”

We need a lot more knowledge about how you link those small changes in someone’s genetics to the way their body responds to the environment, to nutrition, or to a drug.

There are a few variants we know about that make you more or less sensitive to certain drugs or certain infections, but we don’t know that many of them.

So the sequencing technology is less key right now than the genefinding technology?

The sequencing technology, because October-November 2012

it’s gotten so much better so quickly—it certainly was a barrier, a few years ago, but now we’re at the point where it’s feasible to do a good bit of sequencing for any person who needs health care, and it’s not that expensive. I think we’re not that far away from the day when we’ll do sequencing routinely for people as part of their workup, their general physical. I think within ten years we’ll see lots of sequencing done routinely.

We’re working on it, but we need to get a lot more information. As a scientific community, we need to gather much more precise information—not about what the genes are, but what their functions are and how those functions translate into higher-level phenotypes.

When you talk about genome sequencing happening in the near future, are you talking about whole genome or exome sequencing, or something else?

Sort of both … it depends on what the time scale is. Today you can sequence an exome for something like $1,200, but there’s a lot of overhead that’s present in exome sequencing that’s not present in genome sequencing.

Doing a whole genome might cost something like $4,000, but it’s about fifty times as much DNA—instead of 2% of the genome, you get all of it. As the sequencing gets a little bit cheaper, it will cost about the same to do the whole genome as the whole exome, so you’ll just do the whole genome at that point. That’s probably only two or three years away.

At that point it becomes more of a computational problem. The actual costs of analysis are going to dominate the cost of sequencing.

Storing and analyzing the data is going to cost more than capturing the data. Maybe people won’t want to do Volume 25 Number 5

whole genome sequencing because it’s just so much data, because it’s overwhelming—but it won’t be because we can’t do it.

You hear all this talk about the “thousand-dollar genome”—a couple of people even mention “the hundred-dollar genome”…

That’s premature!

Still, whether it’s a thousand dollars or a hundred dollars, is this the wrong way to be thinking about it? Are we focusing on the wrong thing when we fixate on the cost of sequencing?

“We’re pretty far away from being able to say, ‘Oh, you have this mutation? Eat more spinach.’”

The analysis is going to be the sticking point. It’s going to be what’s difficult to do. Right now the sequencing is difficult to do, and it’s still out of reach for most of us, but it already looks like companies are emerging to try to provide some value added to your sequence. Direct-to-consumer genetic testing companies, for example, like 23andMe—they are not doing whole genome sequencing right now, they’re doing SNP chips, so they’re just interrogating your genome at a million locations. There’s a lot they can tell you from that. Not very much of it is actually going to have an effect on your health, but at

least it’s interesting, and it’s correct.

The more data we produce, the more we’re going to see—I hope— entrepreneurs trying to figure out: How do we use that data to tell you something that’s medically relevant and useful? But there’s a lot of basic research yet to be done. We simply don’t know that much about what most variants mean for you.

The analysis end of it is still a work in progress.

Right—but the good thing is that once you sequence your DNA, that’s not going to change. You can use that forever, and as we learn new things, as new mutations are discovered and studied, you would be able to go back periodically and look up whether there’s anything new that’s relevant to your genome. We don’t have any such service today, but I can see a point in the future where we would.

You mentioned that one of the big costs is the storage of data. How much space does it take on a hard drive to store a whole genome sequence right now?

The genome itself doesn’t take up that much space. You can store all 3 billion base pairs in a gigabyte, which is not much these days. If you want to have all the reads, however, it’s a much bigger dataset. Even if you compress it, you’re looking at more like 100 to 200 gigabytes of data.

That starts to be a problem. It’s not easy to move around files, today, that are a couple hundred gigabytes. Networks don’t have enough bandwidth.

Everybody has enough space on their own home computers to store their own genome; but if you’re doing research and you’re looking at hundreds of genomes, it’s a real problem.

You need many, many terabytes. And GeneWatch 19

moving it around is even more difficult than storing it. These days, with the kind of research many of us are doing, we collaborate with a lot of different people, so we need to move the data around.

A lot of research now is being focused on gene expression, which is even more complex. When you’re looking at someone’s genome for information, you’re really asking: Is there anything this person was born with that could affect their health? Does it tell them anything about how to eat, or things to avoid? But there’s much more information contained in your tissues themselves. Today we do a lot more than just look at the inherited variants; we also look at variations between tissues. Every one of your cells has the same DNA in it, and yet the cells obviously don’t behave the same.

20 GeneWatch

To understand a disease specific to one type of tissue—the liver, for example—just getting your genome might not tell us anything. We may need to actually look at the genes that are being turned on and off in the tissue that is affected. Our understanding of that kind of data is not as far along as it is for the genome itself, but we’re working on it very actively. That’s not where the direct-to-consumer testing is going to happen—it’s very complicated.

Where do you think genome sequencing can be most useful in medicine?

I think we’ll continue to see personalized medicine happening in very specific cases for a while, and that will start to convince people of the value of it.

Cancer is one of those cases. There

are many treatments for cancer, but they are effective for some types of tumors and not others. That’s the kind of thing I’d expect to see earlier, because cancer is such a devastating disease … and because people spend so much money treating it, if you’re looking at sequencing a genome, it doesn’t add that much to the total costs.

I think we’ll see that sort of thing first, as opposed to walking into your internist’s office when you have a cough … they’re not going to sequence your genome. Even if you have the flu, you’re not going to sequence your genome; it’s the flu, it’s not you. Probably the most value will be the very expensive types of medical treatments where we might be able to afford doing medical genome sequencing without really changing the cost, and maybe end up saving someone’s life. nnn October-November 2012

Managing Your Genetic Portfolio Was it a wise investment to get your genome sequenced? That depends on what you do with it. By Maggie Curnutte and Melody Slashinski “I’d rather spend my money on my genome than a Bentley or an airplane,” said Mr. Stoicescu, 56, a biotechnology entrepreneur who retired two years ago after selling his company. He says he will check discoveries about genetic disease risk against his own genome sequence daily, “like a stock portfolio.”1 At the time this statement was printed in March 2008, Mr. Stoicescu was the first person to have his entire genome sequenced by the Cambridge, Massachusetts private company Knome. With a price tag of $350,000, in the same ballpark as that of a Bentley or an airplane, entire genome sequencing was first offered by Knome in November 2007.

In comparison to the Human Genome Project, which cost $3 billion,

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this was a relative bargain—if not exactly cheap. By 2010 the cost had dropped to $50,000. Today, Knome— co-founded by Harvard’s pioneering human geneticist George Church, who helped to initiate the Human Genome project—caters its whole genome services and interpretation tools to researchers, not consumers.

Mr. Stoicescu’s comparison of his genomic profile to a stock portfolio immediately captures how whole genome sequencing has been sold. It was and continues to be advertised as a long-term investment. As we gain more knowledge about how genes correspond to and influence disease, one’s personal genomic information will become more valuable, or meaningful. Whereas in the case of

the stock portfolio, risk assessment is used as a tool for managing economic investments, the value of the genomic profile is knowledge of one’s risk for certain genetic conditions.

When thinking about the value of genetic information specifically in the medical context, clinicians speak of utility—the likelihood that genetic information will lead to an improved health outcome. An assessment of utility often includes determining whether there are preventive measures or effective treatments available. This model makes sense for classical genetic testing, which can include anything from one’s susceptibility for developing colon cancer to a diagnostic test for Huntington’s disease. How might we think about

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utility, though, with whole genome sequencing? Currently very little of the human genome is understood, thus much of the data produced from whole genome sequencing does not yet have significance, or meaning.

Raw, un-interpreted data do not have utility.

Investing in a complete genetic profile in a clinical setting, however, implies future utility, or direct utility for clinical purposes in light of new research findings. To achieve this predicted future utility, we anticipate that one of the greatest challenges to the integration of whole genome sequencing in the clinic will be developing new mechanisms to revisit people’s genetic data in light of new research findings. While not exhaustive, we would like to explore three guiding questions that highlight some ways in which the future utility of whole genome sequencing challenges current clinical practices.

How often will a patient’s complete genome be revisited?

Eventually whole genome sequencing will become a standard tool of clinical practice. What we currently see as non-significant, noninterpretable, raw data will have clinical significance—identification of genetic markers for disease susceptibility and development of targeted therapies, for example. The pace of integrating an individual’s genetic profile into clinical care goes hand in hand with the question of how often the patient’s genome will be revisited. Health care providers could update a patient’s genetic profile during the annual medical exam, but this introduces several issues. First, a potential lack of genetic knowledge on the part of the physician suggests that the physician would need access to training to make use of the genetic information. On a broader level, it requires us to think about current 22 GeneWatch

medical school curricula and whether doctors are sufficiently trained in genetics. Second, in lieu of additional training, the influx of genetic information into the clinic will place a greater demand on genetic counselors who are able to review patients’ complete sequence data and make recommendations based on current research. Lastly, physician-patient communication to review and respond to a patient’s complete genomic profile may be compromised by the limited time the physician is currently allotted to each patient.

How will we balance the rights of patients to know/not know their genetic information with the physicians’ responsibility to treat?

If we develop a model in which, for example, patients’ whole genomes are revisited on an annual basis in light of current research findings, we must also develop a framework that respects patient autonomy and preferences in light of physician responsibility. One consideration centers on who will be responsible for determining the clinical significance of an individual’s genetic information – who will decide what is relevant, or worth knowing? We must consider how to balance the rights of patients to decide which pieces of genetic information they want to know with physicians’ ability to treat. On the one hand, physicians might have difficulty not disclosing all information, such as genetic markers for debilitating conditions or carrier status for diseases, given this might inhibit their ability to treat their patients. On the other hand, patients might have good reasons for wanting to know some genetic information, such as susceptibility for heart disease, because there are measures to reduce risk and outcome, while not wanting to know other types of information, such as one’s susceptibility for

Alzheimer’s disease, for which there are no preventive measures. Choosing a model of shared decision-making between physician and patient will facilitate communication and protect physicians from potential liability associated with full disclosure or withholding of information.

How should we think about whole genome sequencing coverage?

Should it follow from a cost-benefit analysis and should insurers pay?

The concerns we’ve posed above for the future utility of whole genome sequencing makes it difficult to assess at this point whether insurers currently should pay for clinical whole genome sequencing. A somewhat unsatisfying truism, context matters. As the cost of whole genome sequencing goes down, however, and it becomes more readily available, there will likely be a demand for physicians to integrate this information into clinical care. There will be many who want whole genome sequencing to be covered by insurance. Again, we are still unsure whether all of this data is currently useful, as integrating it into clinical practice is still under investigation. Genetic information is unique from other types of clinical information. For example, measuring one’s blood pressure or platelet counts are time-dependent snapshots of one’s health. In contrast, genetic information is (relatively) static—yet the clinical significance is emerging. nnn Maggie Curnutte, PhD, is a Post Doctoral Fellow at Baylor College of Medicine’s Center for Medical Ethics and Health Policy.

Melody Slashinski, MPH, PhD, is an Instructor at Baylor College of Medicine.

October-November 2012

Great Expectations, Modest Returns Personalized genetic medicine has received enormous hype from overconfident backers, but the evidence paints a humbler picture. By Donna Dickenson

“We are in a new era of the life sciences, but in no area of research is the promise greater than in personalized medicine.”

-Barack Obama, as a Senator introducing the bill that became the Genomics and Personalized Medicine Act 2007

The soaring promises made by personalized genetic medicine advocates are probably loftier than those in any other medical or scientific realm today. Francis Collins, former co-director of the Human Genome Project, wrote: “We are on the leading edge of a true revolution in medicine, one that promises to transform the traditional ‘one size fits all’ approach into a much more powerful strategy that considers each individual as unique and as having special characteristics that should guide an approach to staying healthy…You have to be ready to embrace this new world.”1 Certainly vast sums are pouring into personalized medicine; plans to spend $416 million on a four-year plan were announced in December 2011 by the National Institutes of Health, and private sector interest is also intense.

But does the science bear out the claim that there’s a genuine paradigm shift toward personalized genetic medicine? It has been said that ten years after the completion of the Human Genome Project, geneticists are almost back to square one in knowing where to look for the roots of common disease.2 As of March 2012, current genetic tests and molecular diagnostics have only been applied to about two per cent Volume 25 Number 5

of the US population.3 A Harris poll of 2,760 patients and physicians in January and February 2012 indicated that doctors had only recommended personal genetic tests for four percent of their patients, hardly the stuff of a paradigm shift—at least not yet.

It has been asserted that a baby could have her genome fully sequenced at birth, revealing her susceptibility to particular diseases.

She could then enjoy the benefits of made-to-order diagnostic tools and drugs throughout her lifetime. That really is the “Holy Grail” of personalized genetic medicine, but it makes

huge and currently unfounded assumptions about how much we are actually able to predict. Most major diseases are caused by the interplay of many genes rather than one, and they arise from both environmental and genetic causes.

The most recent policy update from the American Society of Clinical Oncology accepts that genetic testing for personal cancer susceptibility is now a routine part of clinical care, especially for high-penetrance mutations like the alleles (variants) of the BRCA1 and BRCA2 genes implicated in some breast and ovarian GeneWatch 23

cancers. However, the Society also notes that such cancers are comparatively uncommon. The Society believes that there is little clinical value in testing for the 100 or more relatively common single nucleotide polymorphisms (SNPs) linked to parts of the genome that are associated with cancer in a yet undetermined way, because the risk from each individual SNP variation is generally too small to serve as the basis for clinical decision-making. By contrast, a family history of breast and ovarian cancer could alert a clinician to order a direct and specific test for the BRCA1 and BRCA2 genes implicated in some such tumors. But BRCA 1 and 2 testing may be restricted by monopoly patent protection on those genes, leading to prices of up to $3,500 for the diagnostic tests. Although these patents were challenged in a recent court case,4 they still stand at present.

In pharmacogenetics or pharmacogenomics, clinical genetic typing is used to determine a patient’s probable response to drugs such as cancer treatments and to tailor the pharmaceutical regime personally.

It might be possible, for example, to identify patients who are genetically programmed to respond more quickly to chemotherapy and to give them lighter dosages, so as to avoid the worst side effects. Pharmacogenetics is not confined to oncology, but there the goal is also to adjust treatment to the sequenced genome of the cancer, which differs from the patient’s normal cells. This double approach is crucial because cancer is so heterogeneous, even in patients with the same diagnosis. After sequencing the entire genomes of fifty patients’ breast cancers, researchers found that only ten percent of the tumors had more than three mutations in common.5 24 GeneWatch

Outside oncology, there has also been progress in pharmacogenetics.

For example, the drug warfarin is an oral anticoagulant commonly used to prevent or manage venous thrombosis. It is sometimes difficult to determine the correct dosage for an individual patient, and thinning the blood excessively can be an unwanted side effect, carrying its own risks.

This is the largely ignored economic reality of personalized genetic medicine: The more personalized it becomes, the more its range of customers narrows— and therefore the less incentive there is for firms to produce the drugs.

But now warfarin dosage can be tailored to identify particular patients at increased risk of bleeding, by sequencing two genes that account for most of the variation in how people react to the drug. In public health, a major study—the five-year “Human Heredity and Health in Africa” (H3) study, jointly funded by the National Institutes of Health and the Wellcome Trust—aims to apply genome scanning and sequencing techniques to major communicable diseases such as HIV/AIDS, tuberculosis and malaria, as well as to non-communicable conditions such as cancer, stroke, heart disease and diabetes. The hope is that the project

will finally bring some of the benefits of advanced genetics research to the world’s poorest continent.

These and other developments give reason to be hopeful about pharmacogenetics, certainly more so than about direct-to-consumer retail genetic testing. However, a genome-wide analysis of biopsies done on four kidney cancer patients showed that a single tumor can have many different genetic mutations at various locations. Two-thirds of the genetic faults identified were not repeated in the same tumor, let alone in any other metastasized tumors in the body.6 That is quite discouraging, because if a pharmacogenetic drug targets one mutation in the tumor, it may not work on other mutations.

The former head of the American Society of Clinical Oncology, George Sledge, has gone so far as to declare that the only cancers that have been outwitted so far by pharmacogenetics are the “stupid” ones—the minority of cancers caused by mutations in only one or two genes. “One danger of stupid cancer is that it makes us feel smarter than we are,” Sledge concedes ruefully.7 That overconfidence is obvious in many of the more exaggerated paeans to personalized medicine.

Trials in cancer pharmacogenetics additionally have to contend with an inherent paradox of personalization: The more unique or specific the proposed drug is to particular genetic sub-groups of patients, the harder it becomes to find enough patients for statistically significant results.

This profound problem makes some commentators skeptical that individualized drug therapy will be possible for most conditions any time in the foreseeable future.

The continuous discoveries of new surprises about the genome call into

October-November 2012

question the claim that personalized medicine is almost here, or that individualized drug therapy will soon be a reality. In fact, it probably never will be, or at least not by DNA testing alone, because most genotype- phenotype associated studies are hampered by limited size and therefore decrease in statistical power.8

If the scientific evidence alone fails to bear out the bigger claims for personalized medicine, why is there such great interest? We need to look to social and economic factors as well as scientific ones. For a pharmaceutical industry facing the expiry of patent protection on many of its best-selling drugs, new markets have to be found. By breaking an existing medication down into different “size ranges,” and by persuading customers that they cannot simply rely on a “one-size-fits-all product,” pharmaceutical companies can create new niche markets.

It would be even more advantageous for the pharmaceutical industry if the individual patient could be persuaded to pay for genetic typing out of her own pocket, so that she would then know which of the niche pharmaceuticals is her “size.” Now that the $1,000 whole-genome test is approaching reality, retail genetics may well extend its reach from subsets of SNPs to offering wholegenome mapping. Customers could thus have all their personalized genetic information ready for access when needed, so that prescribing on a pharmacogenetic model could become much more commonplace. In that event, diagnostic costs would be transferred from the public health system or insurers to the private individual, while some individuals might find themselves excluded from coverage on the basis of their genetic profile.

Patients’ enthusiasm for Volume 25 Number 5

pharmacogenetics would take quite a dent if they saw it as a rationale for denying them therapy, but in an era of cost-cutting, that could well happen. Cancers driven by a number of different genetic pathways may require different regimes of drug combinations for different patients. With drugs required by smaller-size patient groups, it may not be economical for drug companies to produce every drug required for the regimen of any particular patient. From the drug companies’ point of view, big

Most major diseases are caused by the interplay of many genes rather than one, and they arise from both environmental and genetic causes. blockbuster drugs have traditionally been the money-spinners. Unless a stratified patient group is large (or wealthy) enough to constitute a niche market, it would not necessarily be in drug companies’ interests to tailor medicines too narrowly. This is the largely ignored economic reality of personalized genetic medicine: The more personalized it becomes, the more its range of customers narrows—and therefore the less incentive there is for firms to produce the drugs.

Alternatively, pharmaceutical firms might pursue a strategy of high price increases for personalized cancer drugs. The pricing of a group of oral oncolytic (anti-tumor) drugs, including Gleevec, has gone up by over 76 per cent since 2006.9 The drug Xalkori, which was developed with

a small group of patients whose lung cancers had a particular mutation, is being made available at a price of $9,600 per month.10 This high price is driven by the small size of the potential market; the total target population for the drug is expected to be fewer than 10,000 patients.11 Against the trend of genetic personalized medicine, some of the most promising research in cancer prevention actually comes not from the complexities and costs of individually tailored drugs, but from simple, cheap and comparatively safe “one size fits all” drugs, even for genetically caused conditions. In October 2011, a UK team found that a daily 600 mg dose of aspirin resulted in a 63 percent reduction in the number of colorectal cancers in patients with a hereditary disease called Lynch syndrome. This genetic condition increases the risk of colorectal and uterine cancer in about 2 to 7 percent of the population by affecting genes responsible for detecting and repairing DNA damage.12 Every one of the 861 people with this syndrome in the trial got the same dosage of the same simple drug against the same threat. It worked. nnn Donna Dickenson, MSc, PhD, is a fellow of the Ethox Centre in Oxford, Emeritus Professor of Medical Ethics and Humanities at the University of London, and honorary senior research fellow at the Centre for Ethics in Medicine at the University of Bristol.

GeneWatch 25

Questioning the Utility of Whole Genome Sequencing Discussions about the impact of whole genome sequencing are too often built on the assumption that it will revolutionize medicine. By Helen Wallace

Companies are competing to sequence your genome as quickly and as cheaply as they can. We are promised this will usher in a new era of “personalized medicine” which takes account of individual genetic differences. In this vision of the future, both the prevention and treatment of disease will be tailored to the individual and we will all live longer, healthier lives.

Against this vision is set a series of concerns about the potential for surveillance and categorization of ordinary citizens to an extent that is currently unprecedented. If everyone has their genetic sequence stored in a database, this allows them to be tracked using the sequence as a unique identifier which is left on coffee cups and wine glasses wherever they go. It also allows their relatives to be identified and non-paternity to be exposed. Genetic categories could also lead to stigma or discrimination.

Most debates try to weigh the pros and cons of better health versus possible misuse, and either propose safeguards such as high standards for data protection and antidiscrimination legislation, or simply claim the benefits will outweigh the harms. Too little attention, however, has been paid to the claims that genetic differences are important to an individual’s health and whether 26 GeneWatch

“personalized medicine” really can deliver what is claimed. These claims are rooted in the history of the Human Genome Project and the role of corporate interests in promoting this worldview.

Back in 2000, the draft of the human genome was announced to great fanfare by President Bill Clinton and UK Prime Minister Tony Blair.

Their claims were based on a major speech – the 1999 Shattuck lecture – in which Francis Collins, then head of the Human Genome Project in

the U.S., described a hypothetical future in which, by 2010, a healthy 23-year-old college graduate gives a cheek-swab of DNA to his doctor and receives a battery of genetic tests to assess his genetic risk of colon, lung and prostate cancer, heart disease and Alzheimer’s disease, leading to a regime of new prophylactic drugs, annual colonoscopy and the motivation to quit smoking. These claims have underpinned billions of dollars of investment in genetic research, sequencing technology, and in building vast databases and biobanks intended to deliver these predictions.

However, this idea does not stand up to scrutiny. Most geneticists now admit that the predictive value of individual differences between people’s genomes is low for most diseases in most people. While there are many genetic disorders caused by a single mutation, and many common diseases have relatively rare familial forms in which mutations can play a major part, the claim that useful genetic risk predictions can be made for most diseases in most people has turned out to be flawed.

How did we get into a situation where erroneous claims have underpinned so much public spending and R&D investment?

The answer, to those who delve into its history, is October-November 2012

shocking, although not totally surprising. Collins’ story that genetic screening individuals for their risk of lung cancer would motivate them to quit smoking comes straight from the tobacco industry.1 In the run up to the Human Genome Project, the project’s scientific advocates struggled to convince governments in Britain and the USA that it would have industrial applicability, a new requirement for scientific research being emphasised by the Thatcher and Reagan governments. They overcame this by shifting the aim of the research away from the original proposal (which was based on looking for genetic damage caused by radiation) back to an old idea: that inherited genetic risk, rather than environmental factors or genetic damage, was the key to understanding diseases such as lung cancer. Known as the “constitutional hypothesis,” this idea was first promoted by the eugenicist Ronald Fisher, who became a tobacco industry consultant in the 1950s. He argued that genes existed which made a person both more likely to smoke and more likely to get lung cancer, thus making the statistical link between smoking and lung cancer a mere coincidence. The tobacco industry also used Fisher’s theory to lay the foundations of behavioral genetics: funding the hunt for the genes for smoking behavior as well as for lung cancer.2 Over time, as it became more and more difficult to deny tobacco smoke as a causal factor for lung cancer, the aim became to use genetic screening as a means to target smoking cessation measures at a “genetically susceptible” minority. The story was that “only” one in ten smokers gets lung cancer, therefore there must be a gene or genes which would enable these individuals to be identified in advance, allowing the rest of the Volume 25 Number 5

population to “smoke with impunity.” When senior researchers at the U.S. National Institutes of Health endorsed this theory in the New York Times, the industry’s research body, Council for Tobacco Research, was ecstatic, claiming this was “vindication” of their multi-million dollar research strategy. In Britain, Sydney Brenner, who later won a Nobel Prize, set up the Human Genome Organisation (HUGO) to lobby for the funding for the Human Genome Project straight after a secret meeting with British American Tobacco (BAT). Brenner used his position at the Medical Research Council (MRC) to jointly fund work with BAT hunting for the genes for lung cancer, which published numerous spurious results.

This was the beginning of a major shift in the role of epidemiology, away from seeking to identify causal environmental factors which might be reduced or removed, towards seeking genetic factors which could not be removed but which could be used instead for a different aim: individual risk prediction. The tobacco industry’s research agenda pleased a lot of other corporate interests too, including the nuclear and chemical industries which preferred the idea of targeted measures based on individual genetic susceptibility to controls on exposures to hazardous chemicals or radiation. The food industry leapt on the idea, and used it to start a race to find genes for hypertension and type 2 diabetes, arguing that only a minority of people needed to eat less salt or sugar, so prevention should be personalized, not focused on their products.3 Following the success of statins – a lucrative mass market drug largely prescribed to people who are not ill – the idea that everyone could be classed as at high genetic risk of one or more big killer

diseases was backed by Big Pharma too. Some predictions suggest the drug market could double if everyone has their genome sequenced.

New markets are also expected to open up for so-called functional foods (such as cholesterol-lowering margarines), supplements and other medical tests and treatments sold to healthy people to ‘treat’ their genetic risks.

Thus, preventive health has become about creating lucrative new markets, rather than about restrictions on unhealthy products or pollution. Whether these markets will be created in practice will depend on whether individuals choose to allow their genomes to be used for personalized marketing, or whether sequencing can be brought in through the backdoor using public subsidies, for example by using babies’ blood spots taken at birth.

Should health policy and R&D investments really be determined by the eugenicists who went to work for the tobacco industry all those years ago and by the long string of commercial interests endorsing this approach? Or does preventing cancer, obesity and other illnesses need a renewed focus on environmental clean-up, tackling inequalities and improving diets? The bottom line is that the major differences in life expectancy around the world have little to do with biology at all, let alone genetics. But that’s not something those with vested interests want to hear about. nnn Helen Wallace is Director of GeneWatch UK.

GeneWatch 27

CHANGE EVERYTHING YOU KNOW ABOUT AUTISM. In this paradigm-changing book, prominent Harvard researcher and clinician Dr. Martha Herbert offers a revolutionary and transformative strategy for living with autism.

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The Complicated Cost-Benefit Calculus of Newborn Screening When a program saves or improves the lives of thousands of infants each year, its potential disadvantages have a way of being overlooked. By Vani Kilakkathi In their first days of life, 98 percent of the 4.3 million babies born annually in the United States undergo a form of genetic screening.1 Doctors in all fifty states and the District of Columbia collect blood samples from these infants and send the specimens to laboratories to be tested for a variety of metabolic conditions. Unlike many medical tests, the information from newborn screening tests are obtained and maintained by the state.

To date, studies have not offered an explanation accounting for this difference, but perhaps one can look to the history of newborn screening for an answer. Modern newborn screening programs can trace

Volume 25 Number 5

their roots back to the 1960s. In 1961, Robert Guthrie developed a simple test to screen for phenylketonuria (PKU), a metabolic condition, which, if left untreated, can lead to mental retardation.2 A few years later, disability activists successfully persuaded states to mandate newborn screening for this condition.3 Because these tests were originally conducted by the states, it is possible that modern newborn screening occurs at the state level purely through happenstance.

Since the 1960s, screening for newborn conditions has expanded greatly. To respond to the variance among the states regarding the number and

list of conditions tested, in 2005 the American College of Medical Genetics (ACMG) proposed a “uniform screening panel”4—in other words, a standard list of metabolic conditions that newborns should or could be screened for. The ACMG assessed the screening potential of eighty-four conditions and ultimately grouped them into three categories: “core panel” conditions, “secondary panel” conditions, and conditions deemed to be “inappropriate for screening.”5 From this category construction, it appears that conditions on the core panel and the secondary panel are appropriate screening targets, since they are set apart from the group of

GeneWatch 29

conditions that the ACMG determined was “inappropriate for screening.” As further support for this idea, in its report, the ACMG stated: “The expert group recommends that State newborn screening programs: 1.

Mandate screening for all core panel conditions defined by this report; [and] 2. Mandate reporting of all secondary target conditions defined by this report and of any abnormal results that may be associated with clinically significant conditions.”6 When asked about this report, ACMG Executive Director Michael S. Watson responded that “we never recommend screening for secondary conditions.”7 This is technically true; the report does recommend “reporting,” rather than “screening,” of secondary conditions. However, this semantic distinction is not particularly meaningful if one considers how the secondary conditions are identified.

The ACMG core panel consists of twenty-nine conditions that should be primary screening targets, and the secondary panel consists of twentyfive conditions that, while not initial screening targets, may still be diagnosed and disclosed to patients if they are identified while screening for a core panel condition.8 Watson provided the following analogy: The secondary panel conditions “are secondary to the targets of screening as is a tumor found in a chest x-ray that is done to evaluate the victim of a car accident.”9 Just as the cancer would be reported to the accident victim, so too would a secondary condition that appeared during the screening for a core panel condition. However, it is important to note that both the cancer and the secondary condition would still be diagnosed as a result of some form of screening, despite the fact that they were not the initial targets of the X-ray or metabolic assay. Thus, if the ACMG mandates reporting of secondary conditions, 30 GeneWatch

they necessarily mandate some form of screening as well to identify these conditions.

This distinction between screening and reporting may indeed have been too nuanced, because after the ACMG published its report, jurisdictions increasingly began screening for conditions listed on the ACMG secondary panel as well as those on the core panel.10 Although the expansion of screening seems like a relatively benign or even beneficial development, there are a few reasons why such expansion should give pause. For one, the ACMG report departs from the traditional Wilson

One professor of pediatrics estimated that only about “one in fifty of every ‘positive’ newborn screening test detects actual disease.” and Jungner criteria for screening, which emphasize the importance of treatment: “Of all the criteria that a screening test should fulfill, the ability to treat the condition adequately, when discovered, is perhaps the most important.”11 Instead, the ACMG effectively loosened the screening requirements, as the report states that secondary panel conditions may “lack . . . proven efficacious treatment,” or may have natural histories that are “not sufficiently well understood.”12 This move by the ACMG may have propelled some states to go beyond screening for the core and secondary panel conditions and begin including other conditions, like Krabbe.13 Krabbe illustrates the dangers of

adopting looser screening requirements: Of the twenty-four children who were screened for and “found to have genetic markers associated with the disease” in the state of New York, “only four . . . have developed Krabbe symptoms, whereas the other 20 continue to appear healthy.”14 This is not to say that newborn screening should be abandoned, or that these screening programs do not have benefits. It has been estimated that “[e]very year, between 4,000 and 5,000 infants are correctly identified as having serious genetic disorders, including some that would result in disability or death if they weren’t flagged so treatment could begin.”15 But even this number cannot capture the value of screening to the individual parents whose children have been able to lead normal, healthy lives because of early identification.

While this social value should not be diminished, it is possible that the benefits of screening have been somewhat overstated. One reason why the benefits of screening may be exaggerated is that the rarity of the conditions is often underemphasized. George Annas noted that “[a] t the observed rate [of screening], it would take 500 years before one case [of PKU] was missed because of parental refusal.” He also predicted that the same would be true of other conditions subsequently added to the newborn screening panels.16 Another reason why the benefits of screening are overstated is that many initial positives are actually false positives.

One professor of pediatrics estimated that only about “one in fifty of every ‘positive’ newborn screening test detects actual disease” and stated that the average rate of false positives “can vary widely” between the conditions tested. As an additional complication, state-to-state differences in skill and resource availability may lead to situations where “parents in one state October-November 2012

might find that false positive rates are as low as 0.01 percent of all newborn tests, while parents a few states over may find as many as 1.52 percent of those tests are false alarms.”17 An additional reason why the value of newborn screening may be exaggerated is that the public health benefits of screening may not live up to their promise. In its 2005 report, the ACMG stated that newborn screening offers the opportunity to “better [understand] disease history and characteristics” and provides hope for “earlier medical interventions” to be developed in the future.18 However, according to officials administering the screening programs in New York, Massachusetts, and North Carolina, newborn screening is mostly used to ensure that existing tests meet quality control standards, and, in certain cases, used to formulate new screening tests.19 While these are certainly beneficial applications

of newborn screening, they seem to fall short of the stated promises of elucidating disease characteristics and generating earlier interventions.

When asked about other applications of newborn screening, none of these public health officials could offer examples of research projects that had yielded results aligned with the promises stated in the ACMG paper; a survey of the available medical literature also failed to turn up any studies reflecting the benefits promised by the ACMG.20 Thus, it appears that the cost-benefit calculus of newborn screening is more complicated than one might expect.

When analyzing newborn screening programs, it is important to critically consider all of the potential benefits, as well as any associated disadvantages. The current systems for screening appear to have evolved organically, instead of developing through critical, strategic planning.

As a result, the disadvantages of the current screening system may be overlooked or dismissed.

For this reason, it is important to stimulate a national discussion about newborn screening that involves multiple perspectives, so that the full complexity of the issue is represented and considered. nnn Vani Kilakkathi is a Fellow of the Council for Responsible Genetics and a second year student at Harvard Law School.

This article is based on the CRG report “Newborn Screening in America: Problems and Policies,” also by the author. For the full report, visit www.councilforresponsiblegenetics.org or http://v.gd/ P7TX0b.

GeneWatch Multimedia CRG is excited to announce that GeneWatch magazine has launched its new Youtube video channel: GeneWatch TV. Each new issue of GeneWatch magazine will have a video component highlighting the key people and hot topics in its pages.

www.youtube.com/thecrgchannel2

Volume 25 Number 5

GeneWatch 31

notes from the field

Forensic Genetics in India The Forensic Genetics Policy Initiative travels to Bangalore and New Delhi to help partners raise awareness about India’s pending DNA profiling bill. By Jeremy Gruber The Forensic Genetics Policy Initiative, a project of the Council for Responsible Genetics, GeneWatch UK and Privacy International, is an international project to raise awareness of the privacy and human rights issues associated with the global growth of forensic DNA databases.

FGPI works with civil society organizations in countries around the world to build their capacity to engage in public policy on this issue.

FGPI recently returned from a very successful trip to India which was hosted by The Center for Internet and Society, a partner based in Bangalore, to assist in raising awareness and reaching out to key stakeholders, civil society, the media, students, academics, and the public about India’s pending database legislation.

Originally drafted in 2007 and updated earlier this year, India’s Draft DNA Profiling Bill would create a massive database of the population, including individuals both arrested for and convicted of virtually any type of crime, and allow for permanent retention of their biological samples as well as the profiles derived from them. It contains no privacy protections but rather vests the authority to determine what, if any, privacy protections should be created in a government-appointed board that has sweeping oversight powers.

Perhaps most alarmingly, the draft bill would create additional repositories for DNA collected for everything from civil cases to missing persons and unidentified bodies, all of which would be linked without clearly defined limitations.

32 GeneWatch

During our visit to Bangalore and New Delhi, we spoke at twelve different meetings, including two public talks, one closed door meeting, two public lectures at universities, a national press conference, and six personal meetings. Our visit, which was covered by the Indian media, allowed us to connect to key stakeholders and raise public awareness. As a result of our visit we have connected with the Department of Biotechnology, which is piloting the bill; the National Crime Records Bureau, which is responsible for consolidating crime records at a national level; former directors of Indian intelligence agencies; members of the Indian Parliament; DNA forensic specialists; key activists and journalists; and concerned civil society organizations.

As a result of our visit, the legislation is dead in its tracks as a reevaluation is being undertaken at the

highest levels of Indian government and society. We are now seeing significant and critical attention to the bill in the press and policy forums and a real national conversation is beginning. Now a dozen grassroots organizations in India are monitoring the situation and advocating for reform. We will continue to work through our growing list of civil society partners in India to ensure that there is informed engagement in the discussions as the bill proceeds through Parliament. nnn Jeremy Gruber, JD, is President of the Council for Responsible Genetics.

To learn more about the Forensic Genetics Policy Initiative, visit www.dnapolicyinitiative.org

October-November 2012

TOPIC UPDATE: GMO Labeling

California Voters Reject Prop 37 Despite leading in the polls until shortly before the election, a California ballot initiative which would have required the labeling of genetically engineered foods in the state fell short, 53% to 47%.

Proponents of Proposition 37 relied on a grassroots campaign and strong early support, but were outspent 5 to 1. Monsanto Company, the largest contributor to “No on 37,” pitched in $8.1 million—almost singlehandedly matching the total amount raised by “Yes on 37.” Biotechnology and agrochemical companies made up six of the top 10 “No on 37” funders, including DuPont ($5.4 million), Bayer CropScience, Dow AgroSciences, BASF Plant Science, and Syngenta ($2 million each).

Support for GMO labeling has consistently been strong, both in California and nationally, and early

polls showed Prop 37 winning by a comfortable margin. The tables turned when opponents made a late push with, as the Center for Food Safety put it in their post-election press release, a “corporate cashfueled barrage of TV and radio ads.”

“Although a lot of biased ads about candidates didn’t seem to be effective, over $46 million of lies, fear tactics and distortions about food production carried the day for agribusiness,” said Phil Bereano, Professor Emeritus of Human Centered Design and Engineering at the University of Washington and co-founder of the Council for Responsible Genetics.

“But 4.2 million Californians voted for labeling and the issue is now really out in the open. I think we have to bring the issue to legislators in many states and make it a real topic for serious politics.” nnn

Genetic Justice: DNA Data Banks, Criminal Investigations, and Civil Liberties National DNA databanks were initially established to catalogue the identities of violent criminals and sex offenders. However, since the mid-1990s, forensic DNA databanks have in some cases expanded to include people merely arrested, regardless of whether they’ve been charged or convicted of a crime. The public is largely unaware of these changes and the advances that biotechnology and forensic DNA science have made possible.

Yet many citizens are beginning to realize that the unfettered collection of DNA profiles might compromise our basic freedoms and rights.

Two leading authors on medical ethics, science policy, and civil liberties take a hard look at how the United States has balanced the use of DNA technology, particularly the use of DNA databanks in criminal justice, with the privacy rights of its citizenry.

Sheldon Krimsky is a founding member of the CRG Board of Directors, Professor of urban and environmental policy and planning at Tufts University, and author of eight books and over 175 published essays and reviews.

Tania Simoncelli is a former member of the CRG Board of Directors and Science Advisor at the American Civil Liberties Union. She currently works for the U.S. Food and Drug Administration.

image: thefoodlabelmovement.org

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Endnotes Maggie Curnutte and Melody Slashinski, p. 21 1. Harmon, Amy., 2008. Gene Map Becomes Luxury Item. The New York Times Online, 4 March.

Available from: http://www.nytimes.com/2008/03/04/health/ research/04geno.html?ref=dnaage [Accessed 31 October 2012].

medicine in oncology: next generation. Nature Reviews Drug Discovery 10: 895-896, at 895.

10. Ibid.

11. Kwak, E.L., et al. 2010. Anaplastic lyphoma kinase inhibition in nonsmall-cell lung cancer. New England Journal of Medicine 363: 1695-1703.

12. Geddes, Linda. 2011. Daily aspirin cuts risk of colorectal cancer.

New Scientist, October 28.

Donna Dickenson, p. 23 1. Collins, Francis S. 2010. The Language of Life: DNA and the Revolution in Personalized Medicine. New York: Harper Collins, pp. xxiv-xxv.

2. Wade, Nicholas. 2010. A decade later, genetic map yields few cures.

New York Times, June 12th.

3. United Health Center for Health Reform and Modernization.

2012. Personalized Medicine: Trends and Prospects for the New Science of Genetic Testing and Molecular Diagnostics.

Working Paper 7, March, p. 3.

4. Association of Molecular Pathology et al. v United States Patent and Trade Office and Myriad Genetics Inc. 2010. 669 F Supp 2d 365.

5. Wadman, Meredith. 2011. Fifty genomes sequences reveal breast cancer’s complexity. Nature News, April 2, doi:10.1038/news.2011.203.

6. Gerlinger, Marco, Rowan, Andrew J., Horswell, Stuart, et al. 2012.

Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New England Journal of Medicne 366(10) 883-892.

7. Quoted in Harper, Matthew. 2011.

Cancer’s new era of promise and chaos. Forbes, June 5, http://www. forbes.com/sites/matthewherper/2011/06/05/cancers-new-eraof-promise-and-chaos/, p. 3 8. Nebert, Daniel W., Ge, Zhang, and Vessell, Elliott S. 2008. From human genetics and genomics to pharmacogenetics and pharmacogenomics: past lessons, future directions. Drug Metabolism Review 40(2): 187-224.

9. Chiang, Alex, and Milton, Ryan P. 2011. Personalized

34 GeneWatch

Helen Wallace, p. 26 1. Wallace HM (2009) Big Tobacco and the human genome: driving the scientific bandwagon? Genomics, Society and Policy, 5(1), 80-133. http://www.hss.ed.ac.uk/genomics/ V5N1/documents/Wallace.pdf 2. Gundle KR, Dingel MJ, Koenig BA (2010) ‘To prove this is the industry’s best hope’: big tobacco’s support of research on the genetics of nicotine addiction. Addiction, 105, 974–983.

3. GeneWatch UK (2010) History of the Human Genome. June 2010. http://www.genewatch.org/uploads/ f03c6d66a9b354535738483c1c3d49e4/ HGPhistory_2.pdf Vani Kilakkathi, p. 29 1. Janis L. Gonzales, Genetic Testing and Newborn Screening, ETHICS FOR THE PEDIATRICIAN, Nov. 2011, at 490, 490.

2. Lainie Friedman Ross, Mandatory versus Voluntary Consent for Newborn Screening?, KENNEDY INST. ETHICS J., Dec. 2010, at 299-301.

3. Id. at 302-303.

4. Id. at 310.

5. AMERICAN COLLEGE OF MEDICAL GENETICS, NEWBORN SCREENING: TOWARD A UNIFORM SCREENING PANEL AND SYSTEM 13S-14S (2005), available at http://www.acmg.net/ resources/policies/NBS/NBS_Main_Report_00.pdf.

6. Id. at 43S (emphasis added).

7. Email from Michael S. Watson, Executive Director, Am. Coll. of Med. Genetics, to Jeremy Gruber,

President, Council for Responsible Genetics (Oct. 4, 2012, 14:19 EST) (on file with author) (emphasis added).

8. See AMERICAN COLLEGE OF MEDICAL GENETICS, supra note 5.

9. Email from Michael S. Watson, supra note 7.

10. VANI KILAKKATHI, NEWBORN SCREENING IN AMERICA: PROBLEMS AND POLICIES app.

A (2012), available at http://www. councilforresponsiblegenetics.org/ pageDocuments/ WNMAKEPP1P.pdf.

11. J. M. G. WILSON & G. JUNGNER, PRINCIPLES AND PRACTICE OF SCREENING FOR DISEASE 27 (1968).

12. AMERICAN COLLEGE OF MEDICAL GENETICS, supra note 5, at 38S. 13. KILAKKATHI, supra note 10.

14. Ariel Bleicher, Perils of Newborn Screening, SCIENTIFIC AMERICAN, http://www.scientificamerican. com/article.cfm?id=perils-ofnewborn-screening&page=2 (last visited Nov. 7, 2012).

15. JoNel Aleccia, Babies’ blood tests can end in false-positive screening scares, TODAY HEALTH, http:// today.msnbc.msn.com/id/42829175/ ns/today-today_health/t/babiesblood-tests-can-end-false-positivescreening-scares/#.T_HoCr9Yv2g (last visited Nov. 8, 2012).

16. Ross, supra note 2, at 305.

17. Aleccia, supra note 15.

18. AMERICAN COLLEGE OF MEDICAL GENETICS, supra note 5, at 17S. 19. E.g., Telephone Interview with Newborn Screening Official, Massachusetts State Newborn Screening Program (July 26, 2012); Telephone Interview with Newborn Screening Official, New York State Newborn Screening Program (July 12, 2012); Telephone Interview with Newborn Screening Official, North Carolina State Newborn Screening Program (July 26, 2012). All sources asked to have their names withheld.

20. KILAKKATHI, supra note 10, at 11.

October-November 2012

GEnEtic ExplanationS Sense and Nonsense

Edited by ShEldon KrimSKy and JErEmy GrubEr Can genes determine which fifty-year-old will succumb to Alzheimer’s, which citizen will turn out on voting day, and which child will be marked for a life of crime? Yes, according to the Internet, a few scientific studies, and some in the biotechnology industry who should know better. Sheldon Krimsky and Jeremy Gruber gather a team of genetic experts to argue that treating genes as the holy grail of our physical being is a patently unscientific endeavor. Genetic Explanations urges us to replace our faith in genetic determinism with scientific knowledge about how DNA actually contributes to human development.

The concept of the gene has been steadily revised since Watson and Crick discovered the structure of the DNA molecule in 1953. No longer viewed by scientists as the cell’s fixed set of master molecules, genes and DNA are seen as a dynamic script that is ad-libbed at each stage of development.

Rather than an autonomous predictor of disease, the DNA we inherit interacts continuously with the environment and functions differently as we age. What our parents hand down to us is just the beginning. Emphasizing relatively new understandings of genetic plasticity and epigenetic inheritance, the authors put into a broad developmental context the role genes are known to play in disease, behavior, evolution, and cognition.

Rather than dismissing genetic reductionism out of hand, Krimsky and Gruber ask why it persists despite opposing scientific evidence, how it influences attitudes about human behavior, and how it figures in the politics of research funding.

Sheldon Krimsky is Professor of Urban & Environmental Policy & Planning in the School of Arts and Sciences and Adjunct Professor of Public Health and Community Medicine in the School of Medicine at Tufts University.

Jeremy Gruber is President and Executive Director of the Council for Responsible Genetics.

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