HHMI Bulletin September 2003
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Neat Feats of Science |||| Genes Seen |||| Y’s Guy |||| Holiday Lectures SEPTEMBER 2003 www.hhmi.org/bulletin Cholesterol Up Close It’s necessary for life but can also do us harm. So how does the body process cholesterol? FEATURES 10 CHOLESTEROL UP CLOSE 20 Y’s Guy David Page says the Y chromosome has a few surprises 11 Signal to Signal Cholesterol molecules shed up its sleeve. By Richard Saltus light on how cells communicate. By Karyn Hede 13 Floppy Loops and Flexible Tails 24 Neat Feats Exploring the gateway that processes “bad” cholesterol. To get where you want to go in science, sometimes you By Renee Twombly have to build your own road. By Steve Mirsky 14 A New Angle on Cholesterol Researchers have their eye on a protein called LXR that 28 Genes Seen may be a master switch for cholesterol. By Robert Kuska A computer scientist builds a picture window on the 17 Searching for the Fat Switch Can we human genome. By Jeff Miller control fat by controlling metabolism? By Karen F. Schmidt David C. Page (center) and colleagues, announcing the sequencing of the Y chromosome at a June press conference. Accompanying Page were Richard K. Wilson (left), director of the Genome Sequencing Center at Washington 18 Cholesterol: A Century of Research University School of Medicine, and Francis S. Collins, director of the National By Joseph L. Goldstein and Michael S. Brown Human Genome Research Institute at the National Institutes of Health. 20 MAGGIE BARTLETT/NHGRI 4 DEPARTMENTS 2 HOLIDAY LECTURES 3 PRESIDENT’S LETTER September 2003 || Volume 16 Number 3 A Farewell to Friends HHMI TRUSTEES JAMES A. BAKER, III, ESQ. Senior Partner, Baker & Botts ALEXANDER G. BEARN, M.D. Former Executive Officer, American Philosophical Society UP FRONT Professor Emeritus of Medicine, Cornell University Medical College FRANK WILLIAM GAY 4 Translational Science Former President and Chief Executive Officer, SUMMA Corporation JOSEPH L GOLDSTEIN, M.D. 6 Killing the Messenger Professor and Chairman, Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas HANNA H. GRAY, PH.D., CHAIRMAN 8 Walking the Jungles and President Emeritus and Harry Pratt Judson Distinguished Service Professor of History, The University of Chicago Deserts of Chromosome 7 GARNETT L. KEITH Chairman, SeaBridge Investment Advisors, L.L.C. Former Vice Chairman and Chief Investment Officer, The Prudential Insurance Company of America 32 PERSPECTIVE JEREMY R. KNOWLES, D.PHIL. Dean Emeritus and Amory Houghton Professor of Chemistry and How to Talk to the Public Biochemistry, Harvard University About Genes WILLIAM R. LUMMIS, ESQ. Former Chairman of the Board of Directors and Chief Executive Officer, The Howard Hughes Corporation D.A. PETERSON ANNE M. TATLOCK NEWS & NOTES Chairman and Chief Executive Officer 24 33 Have Nobel, Will Mentor Fiduciary Trust Company International 34 Work Those Cells HHMI OFFICERS THOMAS R. CECH, PH.D., President PETER J. BRUNS, PH.D., Vice President for 35 New Grants Support Grants and Special Programs International Collaboration DAVID A. CLAYTON, PH.D., Vice President and Chief Scientific Officer 36 A Key in Search of a Lock STEPHEN M. COHEN, Vice President and Chief Financial Officer JOAN S. LEONARD, ESQ., Vice President and General Counsel 37 Getting an Early Read AVICE A. MEEHAN, Vice President for Communications on Dyslexia and Public Affairs RICHARD A. PENDER, Managing Director, U.S. Equities & Acting Chief Investment Officer 38 Bacteria Hijacks Pathway GERALD M. RUBIN, PH.D., Vice President and Director, Janelia Farm Research Campus 39 Free Thinking HHMI BULLETIN STAFF STEPHEN G. PELLETIER, Editor JIM KEELEY, Science Editor BRYAN LEISTER 40 HHMI LAB BOOK JENNIFER DONOVAN, Education Editor PATRICIA FOSTER, Manager of Publishing 33 42 NOTA BENE ELIZABETH COWLEY, Copy Editor MAYA PINES, Contributing Editor 44 INSIDE HHMI LAURA BONETTA, fact checking STEVEN MARCUS, story editing Betting on the Individual KATHY SAVORY, copy editing DAVID HERBICK DESIGN, publication design 45 IN MEMORIAM Telephone (301) 215 8855 n Fax (301) 215 8863 n www.hhmi.org The Bulletin is published by the HHMI Office of Communications Nestor Santiago and Public Affairs. © 2003 Howard Hughes Medical Institute On the Cover: Computer graphic of part of a choles- terol molecule. Image © Alfred Pasieka/Photo The opinions, beliefs and viewpoints expressed by authors in the HHMI Bulletin do not necessarily reflect the opinions, beliefs and viewpoints or Researchers, Inc. official policies of the Howard Hughes Medical Institute. PAUL MUHLRAD HOLIDAY LECTURES first patients was a four-year-old child with The Science of Medicine leukemia. “Here was this little girl with this disease that we knew almost nothing about, he girl had been a perfectly healthy been titled “Learning from Patients: The Sci- like a disease from outer space,” he recalls. “Her child, playing and singing and other- ence of Medicine.” father asked good questions, but I didn’t have Twise acting like a typical toddler—until Zoghbi will be joined by physician Bert any answers. It was very frustrating.” she turned two, when she stopped making eye Vogelstein, a cancer biologist and hhmi That feeling of helplessness sent Vogel- contact, shied away from social interactions, investigator at the Sidney Kimmel Compre- stein to the laboratory, where he began to ceased to communicate, and started obsessive- hensive Cancer Center at The Johns Hopkins study colorectal cancers. These types of cancer ly wringing her hands. University School of Medicine. Together provide an attractive target for investigation “She made a huge impression on me,” they’ll discuss how their patients have led because tumors in all stages of development says Huda Y. Zoghbi, an hhmi investigator at them to a deeper understanding of the genet- are common and can be easily removed for Baylor College of Medicine, who was in her ics and biology of human disease and have analysis. Colorectal tumors begin as benign second year of residency when she saw this brought them closer to new methods for early polyps—small outgrowths in the lining of the patient in 1983. What caused this sudden diagnosis, disease prevention, and treatment. colon. Then, as mutations occur in genes that neurological deterioration? Zoghbi wondered. The gene responsible for Rett syndrome, normally balance the relative rates of cell birth And why was she normal for so long? it turns out, encodes a protein whose activity and cell death, the tumors grow larger, their With the help of a handful of affected is critical for the normal functioning of cells eventually breaking away and colonizing children and their families, Zoghbi and her nerve cells in the brain. Mutations in this other tissues in the body. Genetic analysis of collaborating researchers sought answers, gene disrupt the activity of these neurons families with a hereditary predisposition to ultimately identifying the gene responsible early in life. the disease, Vogelstein says, “gets you to the for Rett syndrome, a disorder that occurs genes quicker.” almost exclusively in females. Girls with this “I thought it was important” Knowing which genes are involved in a rare neurodegenerative disorder develop nor- Finding the gene for such a sporadic disease disease can lead to better methods for early mally for about 6 to 18 months and then (it strikes 1 child in 15,000) was not easy, and diagnosis and improved treatments. Deaths start to regress, losing the ability to speak, Zoghbi didn’t have much support from her from colon cancer are almost entirely pre- walk, and use their hands to hold, lift, or scientific colleagues along the way. “A lot of ventable if the tumors are caught early. And even point at things. Zoghbi’s search took the people told me I was ridiculous, that I was in the case of Rett syndrome, identification better part of 16 years—an odyssey she will wasting my time,” she says. “After a while, I of susceptible children should allow them to describe in December at this year’s hhmi stopped telling anybody I was working on be treated with medications that might stave Holiday Lectures on Science, which have Rett.” But she never gave up. “I had more neg- off the worst of their symptoms—a possibili- ative data than you can imagine. But I ty that Zoghbi is testing in an animal model. thought it was important to stick with it.” She Similarly, cancer researchers hope the felt that she could better help her patients at identification of cancer genes will lead to the lab bench than in the clinic. “Seeing these novel molecular therapies that prove more girls was so depressing,” she says. “I couldn’t effective and less devastating than handle having to walk in, give the parents the chemotherapy and radiation. And much the bad news, and walk out.” same hope applies to genes that underlie Vogelstein turned to research for similar neurodegenerative diseases. reasons. As a physician in the 1970s, one of his Until then, researchers like Zoghbi and Vogelstein will keep working, remembering who it is they’re working for. “I used to pass through the radiation unit to get to my lab,” says Vogelstein. “It was filled with patients with incurable cancer. You can’t just walk through there every day and see these people and not want to find ways to help.” Zoghbi agrees. “When you see the plight of these patients and their families, how can you quit?” Fortunately for medical science, the interaction is a two-way street. “For me,” says Zoghbi, “I wouldn’t be where I am with- THERINE NEWTON/RAW SIENNA DIGITAL SIENNA THERINE NEWTON/RAW CA out my patients.” —KAREN HOPKIN 2 hhmi bulletin | september 2003 PRESIDENT’S LETTER A Farewell to Friends UL FETTERS PA ach issue of the hhmi bulletin gives me an the personal and professional level.