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The Azores Islands

n a wooden bookshelf in the laboratory that Carlos N. and Michele T. Pato run on the ground floor of Farber Hall, hard by two years' worth of the American Journal of Psychiatry, is a glossy coffee-table book: Cultural Atlas of Spain & Portugal.
     It's not what you'd expect in the Laboratory of Psychiatric and Molecular Genetics ... until, that is, you get to know this husband-and-wife team of psychiatrists. For the Patos, the genetics of psychiatric maladies-most recently bipolar disorder-and the country of Portugal-specifically its island group called the Azores, a thousand miles into the Atlantic off the Portuguese coast-are intimately tied together.
     The doctors are celebrating a $4.2 million grant from the National Institute of Mental Health (NIMH), announced in November. It will enable their research team to search methodically, in the Azores and at other sites, for the gene or genes responsible for bipolar disorder, commonly known as manic-depressive illness. The disorder is a cruel one, afflicting the sufferer with cycles of uncontrollable energy punctuated by severe and debilitating periods of depression. Those affected may be talking incessantly and acting out bizarre, egotistical fantasies one week, and the next be unable to climb out of bed because they're paralyzed by hope lessness and self-loathing. The condition affects about seven of every 1,000 people-imagine 560 sufferers in a sold-out Ralph Wilson Stadium, and you get an idea of its prevalence.
     Current treatments involve mood-stabilizing drugs like lithium carbonate and depakoate for the manic (high) phase, and antidepressants for the bottom of the roller coaster. But the treatments aren't 100 percent effective, come with serious side effects, and certainly are not a cure.
     Enter gene therapy, which offers the distant but tantalizing possibility of alleviating the group of conditions known as bipolar disorder.
     "We're pretty sure these disorders don't have a single genetic factor, like cystic fibrosis does," says Michele Pato. "It's probably the case that there is more than one gene interacting that allows the disorder to be expressed. It's not sweet peas, like [early geneticist Gregor] Mendel."
     "It's a very complex interaction that we're looking for," says Carlos Pato. "In each family (of subjects) we are asking the question, ‘Are there any single genes or groups of genes that seem to be inherited in a way that can cause this illness?'"

photo by: Tim Stegner

     And the Azores? Setting their study on the subtropical island group was a happy accident of genetics and heritage. Carlos Pato was born in Portugal, and the couple has visited there many times. On one of those visits they became more aware of the Azores, which were first settled in the 15th century by the Portuguese. That's where genetics comes into play: Because they're so remote, the island population has seen very little intermarriage with "outsiders." Thus the genetic code of the inhabitants shows much less variability than it would in, say, New York City. It's like looking for an imperfection in a roll of wallpaper-much easier to thumb through roll after roll of the same pattern, rather than an assortment of patterns that just obscure the target.
     "There's some benefit to studying an ethnically similar population," says Michele Pato. "We can eliminate a whole bunch of the genome [an individual's genetic material], because we know that the whole culture shares that part of the genome."
     The study itself is at once tedious and thrilling. Researchers-including all of the islands' psychiatrists-are identifying individuals among the islands' 250,000 people who have some variety of bipolar disorder. They now have close to 2,000 subjects and family members, and may end up with 5,000. The researchers collect very detailed psychiatric histories from those individuals-in interviews that can take up to six hours per patient-and identify other family members with the disorder and interview them, as well.
     The researchers also draw blood samples from the subjects, then culture and multiply the white blood cells and extract the DNA from their nuclei to begin the exacting process of searching for chromosomal "markers" for manic depression. It's not the A-G-C-T sequencing done in, for example, the Human Genome Project; rather, the researchers will scan the samples for segments, maybe 100 genes long, that seem to have been passed from parent to offspring with bipolar disorder. Once those "marker" segments are identified-no easy task in itself-the goal becomes to narrow the focus until the specific genes responsible for the disorder are identified.
     Complicating the process is that bipolar disorders, like many men tal illnesses, are not entirely a genetic condition: Having the gene doesn't mean that a person will definitely develop the disorder; it merely predisposes him or her to developing it. Stressful life events and childhood traumas have been identified as "triggers" that can increase a genetically predisposed person's probability of developing a bipolar disorder in adulthood.



enetics holds the possibility of teasing out what's nature and what's nurture," says Michele Pato. "There has been some suspicion of this kind of research, because some people worry that it could be used against people by insurance companies, for example. But I'm of the ‘knowledge-is-good' school. The more we know, the more we can be preventative."
     The Patos' study of bipolar disorder comes even as they continue another massive project along similar lines, searching among the Azores population for genetic markers for schizophrenia. That $2.6 million project, also funded by the NIMH, is in its third year. Michele Pato also has a major research interest in obsessive-compulsive disorders.
     These projects are the latest in a productive personal and professional collaboration that began when the doctors met as undergraduate students at Brown University. She was studying cognitive psychology; he was majoring in biochemistry and comparative literature. The Patos were the first residents accepted as a couple for psychiatry residencies at Massachusetts General Hospital; this was followed by fellowships-hers in obsessive-compulsive disorder, his in schizophrenia.
     "We both came to the realization that we loved psychiatry, and what we loved most about it was that so much was undiscovered," Michele Pato says.
     When they came to the University at Buffalo in 1996, that happy intersection of family and science happened again. They have two adolescent children, and Carlos Pato's parents happen to live in nearby Fredonia. Professionally, Michele Pato notes, the university was willing to invest in their work by building the Laboratory of Psychiatric and Molecular Genetics-an investment that has paid off handsomely in grant money that employs a team of six people in Buffalo and about 50 worldwide. (The bipolar disorders study also includes collaborative research teams in Toronto, Brazil, Portugal and Fall River, Massachusetts-all locations where significant populations of Portuguese emigrants have settled.)
     That grant money also supports their research-related travels. There are two ways to get from Buffalo to the Azores by air: a weekly direct flight out of Boston, or a longer route that goes from Newark to Lisbon and then on to the islands. The Patos make three or four quick trips per year; they also take their children for a longer stay in the summer.
     All this in addition to their teaching (both are associate professors), scholarly writing and other professional responsibilities. Carlos Pato serves as associate dean for clinical affairs in the School of Medicine and Biomedical Sciences, working on programs within UB's affiliated clinical sites, including clinical research and space-allocation issues in the university's health-care affiliates; he also heads the Division of Psychiatry for Kaleida Health. Michele Pato directs UB's psychiatry residency program. She also has a special interest in mentoring young investigators, and teaches a course for young residents on how to enter the research field.
     "Carlos and Michele Pato have made major contributions to undergraduate and postgraduate education during their relatively short tenure at the UB medical school," says medical school dean John Wright. "We are all very proud of their accomplishments."



Scott Thomas is copyediting coordinator of the Buffalo News.