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Knowing thy genome: The science and ethics of personal genome sequencing

Until not too long ago, asking “Who am I?” of oneself often meant undertaking a voyage of self-discovery either through travel to a faraway land or through time-limited visits to a therapist’s couch. We now live in an era that offers a third, possibly cheaper armchair option.

For less than the price of a business-class trip from New York to Europe, all one needs to do is to spit into a vial, wait a few weeks and log in to an online portal to find out exactly who one is—by scrolling through about 98% of one’s genetic code, guided by annotations that explain things such as why it is that one’s chances of developing diabetes could be as high as 52%; or why one’s cholesterol levels are not likely to respond to statin drugs; or if one really is a descendant of French royalty, as claimed by a suspiciously vague family legend.

The revolution that helped push genome sequencing out of the academic lab space and into the healthcare marketplace was made possible by the rapid fall in the cost of sequencing all 3 billion base pairs of the human genome—from around $300 million in 2003 to “the price of a Bentley in 2007 and now to the price of a motorcycle,” according to Professor W. Richard McCombie of Cold Spring Harbor Laboratory. McCombie and three other researchers on the front lines of this revolution spoke to an eager and enthralled audience of more than 300 who gathered at Grace Auditorium one recent summer evening to learn not just about the science of personal genomics but also about the ethical considerations that factor into a decision to have one’s genome sequenced.

McCombie and fellow CSHL researcher Diane Esposito first brought the audience up to speed with some of the basic concepts, terminology and technological aspects of genome sequencing—not a trivial task considering that these topics are usually taught as a semester-long course to undergraduates! McCombie is a leading expert in developing and using sequencing technology to understand cognitive disorders such as schizophrenia, bipolar disorder and depression, and runs CSHL’s Woodbury Genome Center. He gave the audience a tantalizing glimpse into one of his ongoing research projects in which his team sequenced DNA from 180 subjects to identify genetic variations that indicate susceptibility to bipolar disorder.

Esposito is a cancer researcher who studies copy number variations (CNVs)—alterations or mutations in the DNA caused by duplications or deletions of large DNA chunks. These can result in abnormal copies of genes that are normally found within the affected regions, whose expression can trigger disease. Esposito explained how CNVs have been linked to diseases such as autism and schizophrenia by several research groups, including that of CSHL’s own Mike Wigler. In 2004, Wigler and colleagues were the first to show that CNVs are a significant cause of genetic variation within the human population. Three years later, his group discovered that spontaneously occurring CNVs (i.e., CNVs in a child that do not occur in his or her parents) are much more common in children with autism than in healthy children.

Wigler’s insights into the role played by spontaneous or de novo CNVs in autism and other cognitive disorders subsequently inspired others, such as Dr. Kenneth Offit, Chief of Clinical Genetics at Memorial Sloan Kettering Cancer Center, to ask whether these de novo or new CNVs could also be a cause of cancer.

Offit’s team, which studied cancer-afflicted families to answer this question, ran into an ethical dilemma in the course of their genome sequencing work. Dr. Offit has dubbed it the problem of the “Incidentalome.” Having sequenced the whole genomes of cancer patients and their cancer-free parents to answer cancer-related research questions, are the researchers obligated to share with the ostensibly healthy parents incidental findings that might impact their own future health, such as the presence of a gene mutation predictive of Alzheimer’s?

This question is one of many that scientists and policy experts are grappling with at the moment, according to Dr. Kasmintan Schrader, a research fellow at Sloan-Kettering who is using sequencing to identify genes involved in familial colon cancer. Dr. Schrader explained that policy and law to protect the rights of those who’ve had their genomes sequenced have a long way to go to catch up with the science, thanks to the speed with which genomic data is being generated.

But a framework to define ethical challenges and identify solutions is slowly being put into place, Dr. Schrader explained. For example, there is now a general consensus that incidental information researchers find in the course of their studies should be returned to the research participants. Of course, she added, such a step would trigger another challenge: the need to train the medical community to be able to counsel and help patients in interpreting potentially life-altering information.

As evening turned into night, the audience jumped in with questions of their own. Some in the audience expressed concerns about the right to privacy in the genome age and asked whether they might be discriminated against on the basis of their genomic information. Although laws like GINA (Genetic Information Nondiscrimination Act), passed in 2008, will provide federal protection against genetic discrimination by health insurance companies and employers, the scientists agreed that a broader discussion of the privacy issue is vital.

With the symposium being held two days before the Supreme Court’s historic decision on the Affordable Care Act, others in the audience were anxious to know what implications genome sequencing would have for healthcare and ongoing efforts to make it both accessible and affordable. The scientists listed several ways in which the entry of personal genome sequencing into medical practice could reduce the costs of healthcare. But this optimism was tempered by caution: economic benefits would manifest only if this process were carefully regulated and patient rights were firmly in place. The scientists emphasized the high-stakes nature of the national debates that are sure to spring up as we as a society move further into the personal genome era. As Dr. McCombie put it, “Everyone has a preexisting condition for something. They just don’t know it yet.”

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