EFTA01140266.pdf

i CY; C9 i l,.r . tro )11•77 #4. Pt I Jf Secrets packed away in a family's genome are increasingly being found— and discussed by David Cameron legacy Joseph Thakuria was facing an impasse. ■ He stood at a whiteboard in a conference room where a group of patients, all members of an extended family, sat around a table. They had come to him out of desperation. For generations, seemingly healthy family members in the prime of life had, without warning, died of a thoracic aortic aneurysm. The indiscriminate nature of the affliction was shaking the psychological well-being of the family tree. No one knew where they stood. Doctors were out of ideas. As a last-ditch effort to find answers, this band of relatives had come to Thakuria, a medical geneticist at Massachusetts General Hospital. 18 HARVARD MEDICINE - AUTUMN 2013 HARVARD MEDICINE • AUTUMN 2013 19 EFTA01140266  handed down issues raise a host of medical, serial, ethical, and even psychological concerns. Take Thakuria's foray into family therapy. Decades ago, the majority of known genetic disorders were rare, and often chromosomal. Today researchers know of nearly 5,000 such disorders. Not more than a decade ago, medical geneticists relied on physical examinations and phenotypic clues, while genetic testing yielded only the crudest data, confined primarily to single gene analyses and to locating large structural rearrangements, such as the extra chromosome that causes Down syndrome or the string of nucleotide repeats associated with Huntington's rheeicr. But the clinical use of genetic testing has now caused an information surge that the medical establishment is struggling to manage. Today, a person can spit into a tube, send the sample to any number of direct-to- consumer companies and, for as little as one hundred dollars, receive a scan of genetic markers—known variations in DNA that can he used to identify a person, species, or disease—that indicates susceptibility to conditions such as Alzheimer's disease and prostate cancer. When We Talk About Genes Joan Stoler knows well the complexity described the diagnosis buried in their genes. of translating genetic information to the GOOD COUNSEL Medical geneticists like Joseph Then, he asked each of them the million-dollar layperson. For years, Stoler, an HMS Thakuria and Joan Stoler question: Do you want to know? assistant professor of pediatrics at Boston work with patients and their "Not everything in genetics is 100 percent Children's Hospital and program director families as they learn of heri• certain and predictive the way it was for this of the Harvard Medical School Genetics table conditions uncovered particular family," says Thakuria, who also is Training Program, has been working in analyses of the genetic information contained in their an instructor in pediatrics at Mass GeneraL with patients and families as they wrestle chromosomes. "But there really is no correct answer to this with the fact that they carry a potentially question? troublesome genetic mutation. One by one, members of the family One problem she and others in her XhivtrEA SARPAn (EAR LEFT) ADRIAN T SukthERtittENCE PHOTO LIBRARY agreed to be tested. Then one said "no." profession confront is that for many sing the investigatory skills that He preferred to continue receiving annual The clinical use A Change of Pace conditions there is no definitive test. The specialists like Thakuria are known for, part echocardiograms rather than knowing of genetic testing Over the past decade, the science of genetics binary precision of the genetic condition science and pan detective work, he and his which genetic cards he'd been dealt. has accelerated at a rate that makes Moore's found in the family Thakuria was counseling colleagues solved the mystery. Careful and His relatives thought he was nuts. Each of has caused an Law look like a slacker. Thanks to advances isn't the norm. What's more, if genomic intensive genome sequencing had fingered them took him to task, insisting that there information surge in technology platforms like microfluidics, information has been increasing by an the causative mutation. was only one sane answer to the question. that the medical printing out a patient's genetic code could order of magnitude each year, so has our While knowing the identity of the genetic Dodging the genetic test was simply not soon become as routine as taking blood for a appreciation of a gene's complexity. Sure, culprit would not point to a cure, it would rational. In the hope of breaking the tension, establishment cholesterol test. a gene may be turned on or off—but it may allow physicians to screen family members. Thakuria jumped in. is struggling to As Thakuria and his colleagues continue to also simply be dimmed. Or the gene itself Those in the clear could breathe easy, while "I tried to explain that this was like manage. incorporate more in-depth genomic sequencing might be fine but one of its regulators may those bearing the DNA signature could take deciding what to do with lottery money," he into the clink, researchers will need to grapple have gone rogue. For unknown reasons, preventive measures. says. "ft's different for everybody. There's no not only with a whirlwind of information, a genetic alteration that may result in a Thakuria ushered the family into a right or wrong." but also with patients and doctors who will calamitous deformity in one person might conference room to explain all this—and to The individual stuck to his decision, and, in struggle over how to interpret the results. cause a physiological blip in another. give each of them the option to be tested for the end, everyone was right. But what should In short, the world of genetics is undergoing In other words, as our knowledge the mutation. More than a dozen members of medicine do when the patient is a family and a revolution. But like all major cultural and increases, the one gene-one protein this extended family listened, rapt, as Thakuria the diagnosis implicates generations? technological insurgencies, the attendant pedagogy becomes almost quaint. 20 HARVARD MEDICINE - AUTUMN 2013 HARVARD MEDICINE • AUTUMN 2013 21 EFTA01140267  handed down Stoler, however, must explain the risk reported increasing their long-term care subtleties we do know about to her patients, insurance coverage. finding ways to bridge the knowledge gap, For another set of participants, however, and, often, a cultural gap. Green disclosed risk for heart disease "For a couple from China, who often have along with the Alzheimer's risk and found only one child, teaming of a genetic defect is that when people learned they were a tremendous blow," she says. "One mother, at risk for both conditions, they were, from Central America, thought the mutation counterintuitively, less distressed. her child carried occurred because when she "Our preliminary data suggest that was pregnant she wore red during an eclipse. learning about multiple risks, particularly if Some blame coffee. Part of my job is simply to one of them seems preventable, is actually educate patients about what this all means. I less distressing: he says. try to drive home that each of us has something In a separate study, Green and his group that we can pass down to our children." surveyed roughly 1,800 individuals who Stoler often finds herself trying to explain had received medically relevant genetic the basic concepts of cells, chromosomes, information through a direct-to-consumer genes, and proteins through an interpreter. company. When asked who they would In these situations, she goes visual, using present this information to, the respondents charts, drawings, tic-tac-toe boards, and indicated overwhelmingly that they planned whatever analogies she can to inform those on discussing it with friends, family, and she is working with. colleagues, and, in some cases, their family In a way, experts like Stoler play the doctor. But few planned to discuss their traditional role of gatekeeper. They collect results with a genetic specialist. and interpret the genetic data, and then "As genomics enters the mainstream of decide the best methods for educating the medicine and society, regular physicians will patient. But as genetic testing becomes have to learn to cope with this information increasingly democratized, how will the role about their patients," says Green. 'Genetics of gatekeepers shift? is becoming democratized in a big way." Green's newest studies are NIB- Green's Genes supported ones that will explore genomic Robert Green is an expert in moving genetic sequencing in the medical care of adults discoveries into genomic medicine. He has and in newborns. Ultimately, this work UPON REFLECTION:A investigated and deciphered the nuances of full sequencing of Robert anticipates a future where genomics data are many genomes, including his own. Green's genome revealed available for every clinical visit. Like Thakuria and Stoler, Green, an HMS 16 mutations that. Until then, medical geneticists are in associate professor of medicine at Brigham without the benefit of the trenches with families excavating and Women's Hospital and director of the clinical context. could be the uncertainties of inherited disease. considered alarming. G2P (genomes2people) research program, is Thakuria has continued to follow his a medical geneticist. In addition to treating family of patients. The good news is patients, he oversees a research program that, since availing themselves of genetic that can best be described as translational Each of these 16 mutations could be There is, in fact, a there are many questions to be answered receive information regarding their genetic testing, no one in the family has died from genomics. Green and his research colleagues alarming without clinical context. One before genomics is routine, particularly in susceptibility to Alzheimer's. the condition: screening and medical use sequencing technologies to diagnose of them, for example, is in the gene that great deal of angst healthy individuals. Can we validate the "The study was run just like a clinical intervention has fended off what once some of the more obscure conditions. But causes Treacher Collins syndrome, a in the medical interpretation of disease risks so that we trial, except the drug we dispensed was seemed certain. S3NIDOJOAM3N3.1153Vn13,dXn03tVilt13N3H013b0 Green's discipline is complicated by some dominant condition resulting in severe community about how know what the genome is telling us? Will genetic information," says Green. The kind of detailed sequencing that hazy intricacies. To illustrate this, he facial deformities at birth. But here's the an increasing glut of genetic information improve people's health? The group measured potential patient improved the family's options, however, is still references his own genetic blueprint. thing: Green doesn't exhibit a single feature How often is it misunderstood? Can it be harm in terms of anxiety, depression, and reserved for extreme abnormalities. Thakuria, A full sequence of Green's genes turns up of Treacher Collins. Which brings up yet genetic information dangerous?" distress, eventually publishing in the New however, thinks that one day genomic a few million variations, 109,000 of which another dilemma in the world of genetic will affect patient There is, in fact, a great deal of angst EnglandJournal of Medicine that participants sequencing will become a preventive measure, could initially be considered medically diagnosis: There is no clear consensus on behavior. in the medical community about how an experienced a minimal and temporary rise in like mammograms and colonoscopies. If relevant. Of these, computational analysis what defines a pathogenic mutation—and increasing glut of genetic information will distress when they learned they were at an that occurs, family discussions of the results predicts that approximately 11,900 have an the race to package and sell translational affect patient behavior, and that is precisely increased risk for Alzheimer's disease. Some of genetic testing may lose some of their effect on a protein. Further analysis to find software to patients and doctors may only what Green and his colleagues are studying. of their subsequent behaviors were positive, emotional freight. Then again, given family the variations that are uncommon, and thus add to the confusion. Over the past decade Green has been such as better diet and more exercise; dynamics, maybe not. • more predictive of disease, leaves only 1,800. "There's a powerful narrative in play the principal investigator for the REVEAL other behaviors were debatable, such as When this remnant is processed through a that genomics will reveal all of our medical study: Risk Evaluation and Education purchasing unregulated dietary supplements David Cameron is director of science communi- database of known genetic diseases, only 16 secrets, and that we all will benefit from for Alzheimer's Disease. For this project, online. One striking finding: participants cations in the HMS Office of Communications and rare mutations are left. genome sequencing," says Green. "But researchers randomized participants to who learned that they were at increased External Relations. 22 HARVARD MEDICINE - AUTUMN 2013 HARVARD MEDICINE - AUTUMN 2013 23 EFTA01140268