Oncology: Unleashing One Human Scourge Against Another Pathology: CMV Stealth Tactics Health Policy: Report Redefines Medicare Payments Cancer Prevention: Seizing a Teachable Moment to Decrease Patient's Colorectal Cancer Risk Toxicology: Chip Data Show Genetic Ups and Downs Missing Piece in Biological Clock Discovered Cancer Trigger Must Remain Pulled for Melanoma to Develop Asthma Clues from the Mouths of Babes Bosnian War Refugees Disabled by Psychiatric Disorders Local Hospitals Fare Well in U.S. News and World Report Poll Best-Kept Secret of the Lab: Few Things Go as Planned Front Page

Missing Piece in Biological Clock Discovered A team of Massachusetts General Hospital researchers has identified a protein that could be the missing cog in the mammalian biological clock. The discovery by Steven Reppert, HMS professor of pediatrics at MGH, and his colleagues appears in the July 26 Cell. Over the past two years, scientists have uncovered many of the molecular components--the genes and proteins--of the biological clock, which resides in a tiny cluster of neurons located just behind the eyes. But while they knew that the clock works by turning on and off a central clock gene, per, how that gene is turned off in the mammalian clock was something of a mystery. In flies, per is turned off by two proteins--the protein it produces, PER, and another protein, TIM. As PER accumulates in the cytoplasm, it pairs with TIM; together they enter the nucleus and turn off the per gene. Yet in mammals, PER and TIM do not pair up. Some thought PER might be pairing up with itself and entering the nucleus to turn off the gene. But experiments by Reppert and his colleagues showed that the PER protein alone cannot shut off the per gene completely. There had to be another partner. Meanwhile, researchers elsewhere had shown that mice lacking the genes for two cryptochrome proteins (mCRY1 and mCRY2) showed no clock activity. To see if the CRY proteins might play a role in the core clock, Kazuhiko Kume, a visiting scientist from the University of Tokyo, put the two mouse cry genes into cultured mammalian cells. The clock shut down almost completely. "The data were pretty stunning," says David Weaver, HMS associate professor of pediatrics at MGH, and a co-author on the study. Further experiments showed that CRY does, in fact, bind PER and that once in the nucleus, the pair turns off not just per but the cry genes. "Our discovery of the functions of mCRY1 and mCRY2 within the clock feedback loop provides a sharper view of the molecular workings of the mammalian clockwork," the authors write. Cancer Trigger Must Remain Pulled for Melanoma to Develop As the ozone layer wanes--and as the benefits of sunscreen are called into question--it may come as no surprise that skin cancer is the second-fastest rising cancer. Skin cancer is not only potentially deadly but also very difficult to study. In most animal models, cancer-causing mutations are introduced before birth, in the embryo. But in people, skin cancer is due to the accumulation of multiple mutations in skin cells over a lifetime. Lynda Chin, assistant professor of dermatology; Ron DePinho, professor of medicine (genetics); and their colleagues at the Dana­Farber Cancer Institute report in the July 29 Nature that they have developed a mouse model that enables them to turn on skin cancer­causing mutations after birth--and then turn them off. What is more, they have used the model to answer a longstanding question in cancer biology: must the genes that trigger cancer remain activated to keep the cancer growing? The answer, at least in the case of melanoma, appears to be yes. Using their inducible mouse model, Chin and her colleagues turned on the melanoma trigger gene, Ras, in adult mice and waited 60 days for other mutations to accumulate. Twenty-five percent of the mice developed melanomas. The researchers then switched off the Ras gene in those mice. "To our surprise, the cancers completely regressed. They went away," says Chin. Upon closer examination, it appeared the blood vessel cells surrounding the tumor were dying. "Tumor cells tell the host to provide a blood supply. But when we turned off Ras, the host was no longer listening to the tumor cells," says Chin, who, with visiting fellow in oncology Alice Tam, is lead author of the study. "There is a big effort in pharmaceutical companies to make an anti-Ras molecule," Chin says. But she believes that deciphering the signal sent by Ras to the host could lead to alternative therapies for cancer. For example, it may be possible to design small molecules that interfere with that signal at various points, thereby halting blood vessel growth and, with it, the growth of tumors. Asthma Clues from The Mouths of Babes Every breath is labored during a flare of asthma, as if the patient is breathing through a small straw with the weight of bricks on his chest. In otherwise rambunctious children, asthma is particularly debilitating. However, predicting asthma is difficult, and there have only been a few studies that point out possible predictors--studies that link allergen exposure in the first year of life or a repeated or persistent wheeze with asthma later. In a prospective study on repeated wheeze, Diane Gold, assistant professor of medicine, and colleagues at Brigham and Women's Hospital, HSPH, and HMS give insight into what might cause wheeze in infants. Their work, published in the July American Journal of Respiratory and Critical Care Medicine, confirms previous work showing that low birthweight, acute respiratory disease, maternal smoking, and poverty are predictors of wheeze. And they present new evidence that cockroach allergens also may cause an increase in wheeze. Unlike allergens of cats and dust mites, cockroach and dog allergens have previously been statistically linked to an increase in wheeze. Gold's study shows that children in homes with high cockroach allergen levels are twice as likely to wheeze, and since cockroaches infest homes of the wealthy and impoverished alike, this trend occurs across the economic spectrum. Though these data are intriguing, Gold cautions that "not all children who wheeze in their first year of life continue to wheeze as they grow up, nor do they automatically become allergic or asthmatic." --Brief by Justin Yarrow Bosnian War Refugees Disabled by Psychiatric Disorders One in four Bosnian adults who fled the Bosnia and Herzegovina war may be functionally disabled due to psychiatric disorders, according to a study from HMS and the Harvard Program in Refugee Trauma. The findings go well beyond simple depression and anxiety and, the researchers suggest, underline the need to address mental health issues when creating and implementing redevelopment programs in war-torn countries. The study is published in the August 4 Journal of the American Medical Association. The researchers surveyed 534 adults aged 18 years or older who were randomly selected from families living in a refugee camp in Varazdin, Croatia. The survey was conducted in 1996, nearly a year after the Dayton Peace Accord ended the war. The researchers found that 25.5 percent of the respondents were functionally disabled. Refugees who reported symptoms for both major depression and posttraumatic stress disorder were five times more likely to report a disability than those who reported no psychiatric symptoms. After controlling for demographic characteristics and personal risk factors, such as age and exposure to traumatic events, those who reported symptoms for both major depression and posttraumatic stress disorder were two times more likely to report a disability than those who reported no psychiatric symptoms at all. "War and civil strife obviously affect people physically, but our study shows that there is also a mental toll that requires immediate medical treatment," says Richard Mollica, HMS associate professor of psychiatry and director of the program in refugee trauma.