HHMI at 50 || MacKinnon’s Nobel || Breast Cancer Metastasis || Rare Eye Diseases DECEMBER 2003 www.hhmi.org/bulletin TheMysterious Centromere A Closer Look at “The Ultimate Black Box of Our Genome” FEATURES 12 The Genome’s Black Box 24 Field of Vision At the waistline of our chromosomes, the mysterious cen- Undeterred by bumps in their road to good intentions, tromere holds a key to cancer and birth defects—and two investigators remain determined to apply genetic may reveal a new code in DNA. By Maya Pines research to help patients in the ophthalmology clinic. By Steve Olson 18 Courage and Convictions When Roderick MacKinnon abruptly switched research 28 Catalyst for Discovery methods in midcareer, colleagues feared for his sanity. HHMI celebrates its 50th anniversary. Vindication came in the form of a Nobel Prize. By Richard Saltus 30 When Breast Cancer Spreads MEET THE PRESS News of Investigating how cancer reaches from breast to bone, Roderick MacKinnon’s Nobel researchers find insights on the mysteries of metastasis. Prize drew the media to his Rockefeller University lab. By Margaret A. Woodbury 18 BRUCE GILBERT 4 DEPARTMENTS 2 HHMI AT 50 3 PRESIDENT’S LETTER December 2003 || Volume 16 Number 4 High Risk, High Reward HHMI TRUSTEES JAMES A. BAKER, III, ESQ. Senior Partner, Baker & Botts UP FRONT ALEXANDER G. BEARN, M.D. Former Executive Officer, American Philosophical Society 4 Adult Stem Cell Plasticity Professor Emeritus of Medicine, Cornell University Medical College Now in Doubt FRANK WILLIAM GAY Former President and Chief Executive Officer, SUMMA Corporation 6 Yeast Is Yeast JOSEPH L GOLDSTEIN, M.D. Professor and Chairman, Department of Molecular Genetics, 8 Combine and Conquer University of Texas Southwestern Medical Center at Dallas HANNA H. GRAY, PH.D., CHAIRMAN President Emeritus and Harry Pratt Judson Distinguished Service 10 Science in the Circle of Life Professor of History, The University of Chicago GARNETT L. KEITH Chairman, SeaBridge Investment Advisors, L.L.C. Former Vice Chairman and Chief Investment Officer, The Prudential 35 INTERVIEW Insurance Company of America C-SPAN for Science JEREMY R. KNOWLES, D.PHIL. Dean Emeritus and Amory Houghton Professor of Chemistry and Biochemistry, Harvard University 36 PERSPECTIVE DONNA TEREK WILLIAM R. LUMMIS, ESQ. A Global Science Corps Former Chairman of the Board of Directors and Chief Executive Officer, The Howard Hughes Corporation 30 ANNE M. TATLOCK Chairman and Chief Executive Officer NEWS & NOTES Fiduciary Trust Company International 37 Spared Ribs HHMI OFFICERS 38 Science They Can’t Learn THOMAS R. CECH, PH.D., President MARK A. BARNARD, Managing Director, Private Investments from a Book and Acting Chief Investment Officer PETER J. BRUNS, PH.D., Vice President for 39 Aid in the Shade Grants and Special Programs DAVID A. CLAYTON, PH.D., Vice President and 40 The Exciting Dr. D Chief Scientific Officer 41 STEPHEN M. COHEN, Vice President and Chief Financial Officer Another Person’s Treasure JOAN S. LEONARD, ESQ., Vice President and General Counsel AVICE A. MEEHAN, Vice President for Communications 42 Field Work and Public Affairs GERALD M. RUBIN, Ph.D., Vice President and 43 Dual Major Director, Janelia Farm Research Campus 44 Embryonic Journey HHMI BULLETIN STAFF 45 Intellectual Traveler STEPHEN G. PELLETIER, Editor JIM KEELEY, Science Editor CHRIS PRIEST / PHOTO RESEARCHERS, INC. 46 JENNIFER DONOVAN, Education Editor Scientists on Ice PATRICIA FOSTER, Manager of Publishing 46 ELIZABETH COWLEY, Copy Editor 47 HHMI LAB BOOK MAYA PINES, Contributing Editor LAURA BONETTA, fact checking 49 INSIDE HHMI STEVEN MARCUS, story editing A Pivotal and Unique Role KATHY SAVORY, DEAN TRACKMAN, copy editing DAVID HERBICK DESIGN, publication design 50 NOTA BENE Telephone (301) 215 8855 n Fax (301) 215 8863 n www.hhmi.org The Bulletin is published by the HHMI Office of Communications 53 IN MEMORIAM and Public Affairs. © 2003 Howard Hughes Medical Institute James H. Gilliam Jr. The opinions, beliefs and viewpoints expressed by authors in the HHMI Bulletin do not necessarily reflect the opinions, beliefs and viewpoints or FRED MERTZ On the Cover: Illustration by Vito Aluia official policies of the Howard Hughes Medical Institute. HHMI AT 50 Looking Back, Looking Ahead When Howard R. Hughes recent advances, from founded the scientific the discovery of genes institution that bears his related to cancer, heart name, he created what is disease, and other dis- likely to be his most eases to new insights into enduring legacy. The how organisms develop, Howard Hughes Medical cells communicate, and Institute has become one learning occurs. of the world’s leaders in The Institute sup- biomedical research, with ports not only scientific hhmi investigators con- research but also the tributing prodigiously to training on which it scientific knowledge and depends. hhmi’s pro- to advances in human gram of grants to well-being. improve science educa- hhmi had the oppor- HHMI headquarters, tion, started in 1987, has tunity to reflect on its past opened in 1993. grown from annual dis- and look into the future bursements of $40 mil- when it celebrated its 50th anniversary in employ more than 320 scientists who con- lion in 1988 to $107 million in 2003. More- November. The Institute was established in duct research in fields such as cell biology, over, the Institute has committed itself to Delaware on December 17, 1953. Its first computational biology, genetics, immunolo- exploring greater productivity in science years were marked largely by intellectual gy,neuroscience, and structural biology. through collaborative, interdisciplinary foundation-building—a select group of Using modern science’s powerful tools, mechanisms—in particular the bold new Hughes’s advisers charted the fields of bio- hhmi investigators seek to explain how the venture of an independent research campus medical research that it would support. In human body functions and why disease at Janelia Farm in Virginia, which is sched- the 1980s and thereafter, the Institute’s char- occurs. Their work has resulted in many uled to open in 2006. ter trustees brought vision and leadership to “The Howard Hughes Medical Institute what might be called hhmi’s modern era. is certainly [Hughes’s] greatest and most Their momentous decision to sell the Hughes lasting legacy—no question about it,” said Aircraft Company ultimately helped create a hhmi Charter Trustee William R. Lummis. diversified endowment that today is valued “The Institute has become something that at nearly $12 billion. he never could have imagined.” From the 47 original hhmi investiga- For more on ’s anniversary, see page 28. tors in 1957, the Institute has grown to hhmi Addressing the celebrants for hhmi’s 50th anniver- that look above all to attracting young people to the sary, Hanna H. Gray, (right) chairman of the Insti- excitement of scientific learning, to strengthening the tute’s Trustees, took a few moments for personal curricula and resources of science in undergraduate reflection. “It has been immensely satisfying to work education, to supporting graduate students and post- with the excellent leadership of the Institute and with doctoral scientists, to stimulating an interest in its dedicated executives and administrators,” she said. research on the part of clinicians. “It has been satisfying, too, to become acquainted with many of the Hughes “And we now see the development of the Janelia Farm campus as a critical investigators, to be introduced to their fields of inquiry, and to watch their ever- step in providing the next opportunities for hhmi to advance research and deepening accomplishments and contributions, which continue to sustain the training in emerging areas of the biomedical sciences.” Institute’s core program and shape the character and impact of the Institute’s All in all, Gray observed, “hhmi’s history spans a period of breathtaking place in the scientific community. development in the biomedical sciences, and our mission remains constant even “It has been equally rewarding to assist in the development of new programs while some areas of discovery take on new contours and possibilities.” WILLIAM K. GEIGER (HHMI), PAUL FETTERS (GRAY) (HHMI), PAUL WILLIAM K. GEIGER 2 hhmi bulletin | december 2003 PRESIDENT’S LETTER High Risk, High Reward KAY CHERNUSH KAY n december 17, 1903, wilbur and orville how to define the ideal life sciences curriculum, and the future direc- Wright achieved the first powered flight with a heav- tions of the Institute itself. ier-than-air machine. The Wright Flyer traversed What emerged was a mix of boldness and caution, as exempli- only 120 feet along the beach at Kitty Hawk, North fied by Roger Y. Tsien, an hhmi investigator at the University of Carolina, but that 12-second flight transformed the California, San Diego, who described the potential application of Ocentury. The disciplined and inspired experiments of two bicycle single-cell imaging and biochemistry to cancer treatment. “The manufacturers from Dayton, Ohio, spawned almost unimaginable dream, of course, is that in the morning [a patient has] the imaging technological innovations. Who could have dreamt that we would agent injected and if you see the bright contrast for the metastasis see regular missions of the space shuttle or that people would be against the normal tissue, then in the afternoon you put in the ther- transported at supersonic speeds on aircraft like the Concorde? apeutic agent that’s supposed to burn out the tumor,” said Tsien, Exactly 50 years after the Wright brothers’ flight, another avia- whose lab works with cultured cells. “I’m very well aware that 99 tion pioneer made the momentous decision to found the Howard percent of what works in tissue culture doesn’t work in vivo and Hughes Medical Institute. History doesn’t relate whether Howard then 99 percent of what worked in a mouse is not going to work in Hughes deliberately chose the anniversary of the pioneering flight people.