Inside this issueCover storiesThe big questionsNew Kavli center for neuroscience research will untangle mysteries of the human brain Molecular gambleYale physiologist elected to National Academy of Sciences TrailblazerMagazine innovator celebrates 101 years with gifts for his medical school “family” PeopleLifelines: Expert on gene-swapping joined molecular biology at its very beginningsFor new deputy dean, focus is on top-notch care, service to patientsKidney researchers celebrate a banner yearUnconventional physician-filmmaker receives “genius” grantNew HHMI investigator says appointment liberates his scienceAwards & honorsScienceAnalysis of genome reveals clues to macular degenerationVaccinating wildlife suggests a new strategy in continuing battle against Lyme diseaseAdvances: Salmonella “syringe” ready for its close-up | Possible cancer inhibitor found in worm studyHealthA heart is repaired, the patient grows up: Program helps growing number of adult survivors of congenital diseaseMore integrated care for cancer patients, collaboration of scientists and clinicians are goals of proposed new YNHH buildingAdvances: New test easier for patients to swallow. | Study finds payoff in wider HIV testingPartnershipsPfizer and Yale join forces for research and educationA long, fruitful collaboration: Bristol-Myers Squibb and YaleDrive to cure blindness hits $5 millionClass of 1954 makes a lasting impact with scholarship giftGrants and contracts
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Analysis of genome reveals clues to macular degenerationBiomedical research into the genetic basis of disease has progressed at a rapid clip since the sequence of the human genome was announced in 2000, but March 10 saw the scientific equivalent of a triple play. Three research teams, including one led by Josephine J. Hoh, Ph.D., of Yale’s Department of Epidemiology and Public Health, simultaneously announced that they had identified a gene variant associated with a greatly increased risk of age-related macular degeneration (AMD), a progressive disease leading to blindness that affects more than 10 million elderly Americans (see related story, Drive to Cure Blindness Hits $5 Million). 
In this detail of the genome map of a person with macular degeneration, red and white squares mark strong matches with probes that find gene variants. The human genome can be thought of as a vast string of 3 billion letters in which each letter represents one of the four nucleotides that provide instructions to the body’s protein-building machinery. The genome is 99.8 percent identical among humans, but after every 100- to 300-letter stretch on average are single nucleotide polymorphisms, or SNPs (pronounced “snips”), sites where one letter is substituted for another. Scientists believe that these single-letter variations may help explain why some people are predisposed to certain diseases or respond differently to drug therapies. Remarkably, all three of the teams who published their findings in March independently zeroed in on precisely the same SNP, a spot on chromosome 1 that is home to a gene that codes for an immune system protein known as complement factor H (CFH). In its usual form, CFH acts as a brake on the complement system, a component of the body’s innate immune response. According to Hoh, whose group scanned the full genomes of 96 individuals with AMD and those of 50 controls, those who carry two copies of the newly identified variant in the CFH gene are nearly 7.5 times more likely than the rest of the population to develop AMD. “This is only an association,” Hoh emphasizes. “It doesn’t really tell you that this is the cause of the disease.” But a faulty version of CFH may indeed be a culprit in AMD, which has many features of an autoimmune disease. For example, yellowish deposits at the back of the eye known as drusen, the clinical hallmark of AMD, contain complement proteins. Hoh, an assistant professor, credits the Raymond and Beverly Sackler Fund for the Arts and Sciences for making the study possible. “This particular kind of study is expensive, not the normal thing a junior faculty member can perform,” she says. “I am extremely grateful for the support from the Sackler family.” Michael B. Bracken, Ph.D., M.P.H., the Susan Dwight Bliss Professor of Epidemiology and Hoh’s collaborator, adds that the work represents a wholly new way of doing epidemiology. “For the past 100 years, we’ve used a hypothesis-testing approach, where hypotheses were generated from animal studies or small human studies and then we did large epidemiology studies.”
By contrast, whole-genome searches for SNPs are “hypothesis-free”: “The association between a gene and disease is established first, and the biology is done after,” Bracken says. “This takes all that we’ve thought about doing science and turns it on its head, and it’s likely to have major payoffs in the future.”
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Medicine@Yale Magazine
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June/July 2005 Volume 1 Issue 1
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