The Obedient Stem Cell |||| Marriages at Work |||| Cancer Drugs with Precision |||| Crime Scene Science DECEMBER 2002 www.hhmi.org/bulletin

TenaciousTenaciousAA FoeFoe HIV has outmaneuvered every new drug designed to stop it. FEATURES 12 Is HIV Smarter 18 A More 22 Healing Than We Are? Perfect Union Connections With each victory against HIV—and Scientists who have found partners Researchers are making progress there have been many in the last two in the lab dissect their relationships with mouse embryonic stem cells— decades—the virus reinvents itself and find that good marriages make connecting nerves to muscles and better science. improving mobility in animals. and evades total defeat. By Marlene Cimons By Dorothy Foltz-Gray By Maya Pines

12 18 22 DEPARTMENTS

2 NOTA BENE 28 PERSPECTIVE

4 LETTERS Transcending the Status Quo December 2002 || Volume 15 Number 4

5 PRESIDENT’S LETTER NEWS AND NOTES HHMI TRUSTEES A Sustainable Future James A. Baker, III, Esq. 30 A Chink in Melanoma’s Senior Partner, Baker & Botts Alexander G. Bearn, M.D. UP FRONT Genetic Armor Executive Officer, American Philosophical Society Adjunct Professor, The Rockefeller University 6 In Pursuit of the Next Gleevec Professor Emeritus of Medicine, Cornell University Medical College 31 Baseball’s Biochemist Frank William Gay 8 In Argentina, a Life of Contrasts Former President and Chief Executive Officer, summa Corporation 32 Aquariums Teach Ecology and James H. Gilliam, Jr., Esq. 10 In Synch with the Sun Former Executive Vice President and General Counsel, Local History Beneficial Corporation Joseph L Goldstein, M.D. 6 Professor and Chairman, Department of Molecular Genetics, 33 EPA Agrees to Smarter Waste University of Texas Southwestern Medical Center at Dallas Management Hanna H. Gray, Ph.D., CHAIRMAN President Emeritus and Harry Pratt Judson Distinguished Service Professor of History, The University of Chicago 34 Boosting Brain Repair Garnett L. Keith Chairman, SeaBridge Investment Advisors, L.L.C. Former Vice Chairman and Chief Investment Officer, The Prudential 35 Keeping Up with the Revolution Insurance Company of America Jeremy R. Knowles, D.Phil. Dean of the Faculty of Arts and Sciences and Amory Houghton 35 Report Urges Changes in Professor of Chemistry and Biochemistry, Harvard University William R. Lummis, Esq. College Biology Former Chairman of the Board of Directors and Chief Executive Officer, The Howard Hughes Corporation 36 Young Scientists Learn the Anne M. Tatlock Chairman and Chief Executive Officer Management Ropes Fiduciary Trust Company International

HHMI OFFICERS INTERVIEW Thomas R. Cech, Ph.D., President 37 Peter J. Bruns, Ph.D., Vice President for Israeli Scientist Soldiers On Grants and Special Programs David A. Clayton, Ph.D., Vice President and Chief Scientific Officer 38 HHMI LAB BOOK Stephen M. Cohen, Vice President and Chief Financial Officer Joan S. Leonard, Esq., Vice President and General Counsel Avice A. Meehan, Vice President for Communications 40 HANDS ON and Public Affairs Investigating Murders in Gerald M. Rubin, Ph.D., Vice President and Director of Planning for Janelia Farm Miniature Nestor V. Santiago, Vice President and Chief Investment Officer

42 FROM THE TOOLBOX HHMI BULLETIN STAFF Cori Vanchieri, Editor Slipping Past a Cancer Cell’s Jim Keeley, Science Editor Defenses Jennifer Donovan, Education Editor Patricia Foster, Manager of Publishing Kimberly Blanchard, Editorial Coordinator 44 INSIDE HHMI Elizabeth Cowley, Copy Editor His Brave Father’s Example Maya Pines, Contributing Editor APPRECIATION Kalyani Narasimhan, fact checking 45 Steven Marcus, Blair Burns Potter, Peter Tarr, story editing W. Maxwell Cowan Kathy Savory, copy editing

David Herbick Design, Publication Design On the Cover: Small HIV particles (blue) on the Telephone (301) 215 8855 n Fax (301) 215 8863 n www.hhmi.org surface of a T lymphocyte (orange) are budding The Bulletin is published by the HHMI Office of Communications and Public Affairs. away from the cell membrane. They will enter © 2002 Howard Hughes Medical Institute the bloodstream and infect more immune system cells. Photograph by Eye of Science/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. NOTA BENE

at the University of Pennsylvania School received a 2001 National Award for ■ Five hhmi investigators have been of Medicine, received the 2002 Stanley N. Museum and Library Service, given by the elected to membership in the American Cohen Biomedical Research Award, given National Institute of Libraries and Muse- Academy of Arts and Sciences: David J. by the School of Medicine for basic science ums, for its hhmi-supported BioSITE Anderson,California Institute of Technology; research. program. The award was given to three A. James Hudspeth,The Rockefeller Universi- museums and three libraries in the United ty: and Cornelia I. Bargmann, Ronald D. Vale ■ Patrick O. Brown, an hhmi investigator States for innovative programs and active and Peter Walter, all at University of Califor- at Stanford University School of Medi- partnerships that demonstrate a commit- nia, San Francisco. cine, received the 2002 Takeda Award in ment to diverse communities. the life sciences from the Takeda Founda- ■ David Baker, an hhmi investigator at tion. The award recognizes outstanding ■ Roger J. Davis, an hhmi investigator at the University of Washington School of achievement in creating and applying new the University of Massachusetts Medical Medicine, won the 2002 Overton Prize from technologies. Brown also was one of five School, was elected to membership in the the International Society for Computational scientists who received a 2002 Innovation Royal Society, the British academy of the Biology for applying computational science Award from Discover magazine. Both natural and applied sciences. to drug design. awards recognize him for inventing the DNA microarray. ■ Aaron DiAntonio,Washington University ■ Graeme I. Bell, an hhmi investigator at School of Medicine, and Phillip D. Zamore, The University of Chicago, was one of three ■ Carlos Bustamante, an hhmi investigator University of Massachusetts School of scientists to receive the 2002 J. Allyn Taylor at the University of California, Berkeley, Medicine, were among five scientists named International Prize in Medicine. The award won the American Physical Society’s 2002 2002 W.M. Keck Foundation Distinguished recognizes his contributions to diabetes Biological Physics Prize for his pioneering Young Scholars in Medical Research. Both research. work in single-molecule biophysics. researchers received support from hhmi biomedical research resources grants to their ■ Morris J. Birnbaum, an hhmi investigator ■ Children’s Discovery Museum of San Jose institutions.

■ Goldstein Becomes HHMI Trustee

Joseph L. Goldstein,a noted scientist who shared returned to ut Southwestern in 1972 to head the 1985 Nobel Prize in Physiology or Medicine its new division of medical genetics. for discoveries related to cholesterol metabolism, There, the two scientists began working has been elected a trustee of hhmi. together to research a human genetic disease— Goldstein, chairman of the department of familial hypercholesterolemia. This collaboration molecular genetics at the University of Texas led them to unravel the mechanisms of regulated (ut) Southwestern Medical Center at Dallas, cholesterol import into human cells, discoveries has been a member of hhmi’s Medical Adviso- that became the basis of their 1985 Nobel Prize. ry Board (mab) since 1985, becoming its chair From his own experience melding laboratory and in 1995. He was also a member of hhmi’s Sci- clinical research, Goldstein has been an advo- entific Review Board from 1978 to 1984. cate for increasing support for physician-scien- Named to succeed Goldstein as mab chair tists who conduct patient-oriented research. is Craig B. Thompson,a cancer biologist who Thompson, 49, the incoming mab chair, serves as scientific director of the Abramson also has a long association with hhmi,both as Family Cancer Research Institute at the Univer- OF UT SOUTHWESTERN COURTESY a scientist and member of the mab.Thompson sity of Pennsylvania. was first appointed an hhmi associate investigator in 1987 while at Goldstein, 62, received his medical degree in 1966 from ut the University of Michigan. He became director of the Knapp Cen- Southwestern, where he first became interested in genetics and ter at The University of Chicago and an hhmi investigator in 1993, research. After periods at the National Institutes of Health and leaving six years later to assume the directorship of the Abramson Massachusetts General Hospital—where he met Michael S. Brown, Institute. Thompson’s lab focuses on the role of genes that regulate a scientist who became his long-term collaborator—Goldstein programmed cell death and their potential use in treating cancer.

2 hhmi bulletin | december 2002 ■ Horvitz Shares Nobel Prize H. Robert Horvitz, an hhmi investigator at the Massachusetts Institute of Technology, was awarded with two other scientists the 2002 Nobel Prize in Physiology or Medicine ington Association for Biomedical Research. for discoveries concerning the genetic regulation of organ development and pro- grammed cell death. He shared the prize with Sydney Brenner of the Molecular Sciences ■ Two hhmi investigators, Thomas M. Institute in Berkeley, California, and John E. Sulston of the Sanger Centre in Cambridge, Jessell, at the Columbia University College England. The three scientists were honored for their studies of the nematode worm of Physicians and Surgeons, and Anna Marie Caenorhabditis elegans to Pyle,now at Yale University Medical identify key genes that School, shared the 2002 New York City regulate organ develop- Mayor’s Award for Excellence in Science ment and programmed and Technology. cell death and for showing that corresponding genes ■ Eric R. Kandel, an hhmi investigator at exist in higher species, Columbia University College of Physicians including humans. and Surgeons, was named an honorary Horvitz identified the fellow of the Collegium Internationale first two “death genes,” ced- Neuro-psychopharmacologicum, an 3 and ced-4, and showed honorary member of the Discipline of that these genes are neces- Mathematics and Natural Science of the sary for cell death to be Austrian Academy of Sciences and a executed. Later, Horvitz Companion of the Royal Society of Canada. showed that another gene, He also shared with Arvid Carlsson and ced-9,protects against cell Paul Greengard the 2002 Julius Axelrod death by interacting with Neuroscience Award from the National ced-3 and ced-4.He also Alliance for Research on Schizophrenia identified several genes and Depression. that direct how the dead cell is eliminated. Finally, ■ Richard P. Lifton, an hhmi investigator he showed that the human at Yale University School of Medicine, has genome contains a ced-3- been named winner of the 2003 Roy O. like gene. In 2002, Horvitz Greep Award from the Endocrine Society also received the Peter for outstanding contributions to research Gruber Foundation’s in endocrinology. Lifton also won the 2002 Genetics Prize. Basic Research Prize from the American IA KEPKA

AS Heart Association.

■ Three hhmi investigators were among National Academies’ Institute of Medicine. ■ William T. Newsome, an hhmi investiga- five winners nationally of the 2002 City of Recognized for their contributions to medi- tor at Stanford University School of Medicine awards. Brian J. Druker,Oregon cine were David Eisenberg,University of Cali- Medicine, received the 2002 Distinguished Health and Science University; Ronald M. fornia, Los Angeles; Stanley J. Korsmeyer, Scientific Contribution Award from the Evans,The Salk Institute; and Stanley J. Dana-Farber Cancer Institute; Richard P. American Psychological Association. Korsmeyer, Dana-Farber Cancer Institute Lifton,Yale University School of Medicine; and Harvard Medical School, were hon- David L. Valle,The Johns Hopkins University ■ Anthony Pawson, an hhmi international ored by Durham Health Partners of School of Medicine; Gerald M. Rubin,vice research scholar at the Samuel Lunenfeld Durham, North Carolina, for their contri- president and director of planning for Janelia Research Institute in Toronto, Canada, was butions to medicine in the public interest. Farm; and Craig B. Thompson,Abramson one of two recipients of the 2002 Premier’s Druker also received the American Cancer Family Cancer Research Institute. Platinum Medal for Research Excellence. Society’s highest award, the 2002 Medal of Honor for clinical research. ■ Paula Fraser, an elementary school teacher ■ Michael F. Summers, an hhmi investigator in Bellevue, Washington, who is active in at the University of Maryland, Baltimore ■ Four hhmi investigators, an Institute the hhmi-supported Science Education County, has been named winner of the 2003 vice president and the incoming chair of Partnership of the Fred Hutchinson Cancer Emily M. Gray Award from the Biophysical the Medical Advisory Board were among 65 Research Center, won the 2002 Outstanding Society for the programs he established for scientists elected to membership in the Partner in Education Award from the Wash- minority undergraduate training.

hhmi bulletin | december 2002 3 NOTA BENE ■ 2002 Lasker Award Randy W. Schekman, an hhmi investi- gator at the University of California, ■ Matthew K. Waldor, an hhmi investigator Berkeley, shared the 2002 Albert Lasker at Tufts University School of Medicine, Award for Basic Medical Science with received the 2002 Squibb Award from the James E. Rothman of the Memorial Infectious Diseases Society of America for Sloan-Kettering Cancer Center. The research contributions to knowledge of award “honors two scientists who dis- infectious diseases. covered the universal molecular machinery that orchestrates the bud- ■ Paul H. Williams,former hhmi program ding and fusion of membrane vesicles, director at the University of Wisconsin– a process that cells use to organize Madison, received a special education their activities,” according to the foun- award in 2002 from the American Society dation announcement. The cellular of Plant Biologists, for his Wisconsin Fast trafficking system they elucidated Plants and Bottle Biology projects, which, underlies numerous vital processes, over 15 years, reached an estimated 100 including how pancreatic cells release million students through 1 million teachers insulin, how nerve cells communicate

worldwide. RIES BARBARA and how viruses infect. H

LETTERS TO THE EDITOR

Teaching Intelligent Design sion of a field) instead of more science edu- Intelligent design is not just an alternative I am bothered by the tone of “The Evolu- cation (inclusion of all reasonable fields). to evolution; it is an alternative to science. tionary War” (hhmi Bulletin,September Randy Scott Suppose for a moment that a scientifically 2002)—it felt like scientists of a different Gainesville, Florida trained person were to accept that an intel- era defending their “flat earth” theory: Not ligent-design event had occurred in nature. only must you accept our theory, but you I find the reactions of people like author After saying a quick “aha,” this scientist should forbid consideration of all others. Trisha Gura to be so ironic. From their would immediately begin asking such ques- I understand the scientific objection to point of view, those who challenge the sci- tions as, How was it done? How could we literal creationism—the evidence over- entific establishment to give open-minded reproduce this experiment? What were the whelmingly disputes it. This is not the case consideration to alternative explanations critical parameters? Can we have a look at with the intelligent-design theory. While are being emotional, unscientific and the failures? probably impossible to prove directly, there biased. But in reality, it is clearly quite the In science, each discovery leads to new is also no proof that contradicts it. Nor is opposite. I’m often impressed with the pas- questions: The questions build on past there conclusive proof of the alternative sions that are generated by this debate— results, and they never stop. Intelligent theory (in this case, evolution—which is passions that reveal, I believe, a heartfelt design, by contrast, lacks a method for pro- why it’s still called a “theory,” after all). In commitment to something much deeper gressively expanding on its findings and fact, the two theories are not necessarily than scientific facts. William Dembski was leads only to abrupt boundaries, clearly dis- even incompatible. quite right when he wrote that “Naturalism qualifying it as a subject for science educa- I agree that evolution should be taught is the intellectual pathology of our age.” I’m tion. This is not to say intelligent design in our schools, but legitimate alternatives to sorry to see that many hhmi investigators doesn’t have the power to persuade and current theory—whether they be scientific, are committed so strongly to such an stimulate the mind, for right or wrong. If it political, economic or whatever—should unscientific philosophy. The only scientist must be taught in schools, there’s surely a also be presented whenever possible. Objec- cited in the article who seemed to recognize place for it in rhetoric or philosophy. tively considering alternative hypotheses is a the true situation was Sean B. Carroll, who Douglas W. Raymond critical part of thinking like a scientist. If a described the establishment’s backwards Orinda, California single theory is presented without the con- view when he said, “Evolution is a large text of alternatives, then we are teaching body of scientific fact that is supported by a Send your letters: Via e-mail to [email protected] or to Let- dogma, not science. large body of theory.” ters, Office of Communications, Howard Hughes Medical Insti- tute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789. I am surprised to see your publication Tom Fletcher Letters will be edited for space and clarity. Please include your advocating for less science education (exclu- Costa Mesa, California name, address (e-mail or postal) and phone number.

4 hhmi bulletin | december 2002 PRESIDENT’S LETTER

A Sustainable Future KAY CHERNUSH KAY

t is not unusual that scientists associated research, grants and headquarters operations, the Institute has with hhmi get professional recognition, but announcements begun taking more substantial steps to bring spending in line with over the past few months are especially noteworthy. H. Robert our decreased endowment level. Horvitz, a 14-year hhmi investigator at the Massachusetts Biomedical research is hhmi’s core mission, and that is reflected Institute of Technology, shared the Nobel Prize in Physiology in the way we allocate our resources—for the 2003 fiscal year the or Medicine with Sydney Brenner of the Molecular Sciences investigator budget of $442 million represents 71 percent of the IInstitute in Berkeley, California, and John Sulston of the Sanger Institute’s total budget. But this level is higher than our current Centre in Cambridge, England. endowment can sustain over time. Because some budget categories In November, President Bush invited Bob Horvitz and the other will not be decreased—for example, salaries and benefits for investiga- American winners for an informal reception at the White House, and I tors, as well as occupancy payments made to host institutions for labo- had the opportunity to attend as well. Bob and Jimmy Carter, the Peace ratory space—savings must come from investigator-controlled por- Prize winner, had an animated conversation about river blindness, a tions of the budget. Reductions of up to 10 percent will be required in disease endemic to parts of Africa caused by a parasitic worm. Bob each of the next two years in the budgets of individual investigators. knew the biology of the worm, and Carter described the challenges We would like to have avoided this reduction in spending for bio- he’d encountered obtaining and distributing lifesaving medicine. medical research, but it is prudent for the future of the Institute. The work for which Bob won the prize concerns the embryonic Success in managing our spending will permit another nationwide development of the nonpathogenic nematode worm C. elegans. competition for new hhmi investigators several years from now. The Mutations in the human counterparts to the worm’s cell-death genes resulting reinvigoration of our cadre of biomedical scientists is surely contribute to human cancers by preventing the tumor cells from dying important to the health and vibrancy of our research program. a natural death and allowing the cancer to proliferate. Horvitz’s work We have reduced headquarters spending as well, and have institut- represents a paradigm for the research endeavors that hhmi sup- ed a moratorium on most new hires. The budget for the grants pro- ports: innovative, rigorous investigations of simpler biological systems gram is also being downsized. After this year, for example, the Institute that often throw open the door to understanding human disease. will discontinue the Research Resources program ($22 million annual- Randy Schekman, an hhmi investigator at the University of ly) that has helped fund laboratory improvements at medical schools. California, Berkeley, shared this year’s Lasker Award for Basic Meanwhile, we are proceeding carefully with the Janelia Farm Medical Research for elucidating the machinery that orchestrates Research Campus in Loudoun County, Virginia. The project has the budding and fusion of membrane vesicles. The process is essen- passed several significant milestones—including approval for the tial to organelle formation, nutrient uptake and secretion of hor- tax-exempt bonds that will finance construction. We are now in a mones and neurotransmitters. position to proceed while evaluating cost-effective approaches to hhmi investigator Philip Green, at the University of Washington, construction and program administration. Site work will com- accepted the 2002 Gairdner Foundation International Award in mence by the end of 2003. Toronto in October. His computational tools were essential for the By bringing hhmi’s spending to a sustainable level, we ensure the sequencing of the human genome. Institute’s long-term vitality and leadership in biomedical research. Finally, when the Institute of Medicine of the National Academies This judicious accommodation to reality allows us to preserve the very announced its newly elected members, we were pleased to see hhmi attributes that make hhmi unique—our support of pathbreaking Vice President Gerald Rubin and hhmi investigators David Eisenberg, research, our dedication to enhancing biology education and our Stanley Korsmeyer, Richard Lifton and David Valle on the list. Also commitment to creating a new kind of research community. elected was Craig Thompson, who will assume Joseph Goldstein’s posi- tion as chairman of the Medical Advisory Board on January 1, 2003, so that Joe can move into his new role as an Institute trustee. Along with this good news, hhmi faces significant challenges. Our endowment—like those of most nonprofit organizations—has Thomas R. Cech been reduced by fluctuations in the investment markets. Although President we have been exercising control over expenditures for biomedical Howard Hughes Medical Institute

hhmi bulletin | december 2002 5 Up Front In Pursuit of the Next Gleevec Researchers are trying new targeted drugs to combat a deadly leukemia.

he unexplained bruising, bleed- Gilliland’s group are like smart bombs that ing, fatigue and infections of home in on signal receptors on the surface of acute myelogenous leukemia leukemia cells, shutting down the cancer. The signal a malignant explosion of drugs block the tyrosine kinase signal at its immature blood stem cells in receptor site on the surface of cancer cells, pre- Tthe bone marrow. This cellular population venting it from being relayed to the cell’s boom rapidly crowds out normal compo- nucleus, where it would activate the growth nents of the blood such as red and white cells program. The errant growth signals are found and platelets. only in tumor cells, minimizing toxic side Chemotherapy can turn back the cancer, effects to normal cells and tissues. Scientists referred to as AML, for a while, but relapse is envision a time when cancers such as AML common, and only 2 in 10 patients survive for might be cured using these approaches, or at five years. Researchers are aiming new treat- least be treated as chronic diseases, held in ments at the very heart of this cancer—a single check by routine doses of highly specific drugs mutation in the DNA of the cancer cell that that patients can easily tolerate. drives the cell’s relentless reproduction in near- The first of this class of drug, Gleevec, is ly one-third of AML cases. already on pharmacists’ shelves. It blocks A biochemical signal triggered by the growth signals in two types of hard-to-treat mutation of the FLT3 gene “is the engine, or cancers—chronic myelogenous leukemia the gas pedal, for the cancer,”says D. Gary (CML) and gastrointestinal stromal tumor Gilliland, an hhmi investigator at Brigham (GIST)—and in both cases has been aston- and Women’s Hospital and Harvard Medical ishingly effective (see hhmi Bulletin, School. “It renders the cancer cells complete- December 2001). ly self-sufficient for proliferation.” Most patients who have taken Gleevec use other inhibitors of this type to treat The FLT3 mutation is a cancer trigger, have had at least a temporary positive other leukemias.”This conjecture took him but it may also be an Achilles’ heel. It pro- response. It is an oral drug that has few of to AML and its mutant FLT3 trigger—and to duces a receptor tyrosine kinase on the sur- the side effects cancer patients dread, such as a search for the next Gleevec. face of the blood cell that is constantly severe nausea and hair loss. Initial data indi- active, serving as a maverick signal for cate that it will help patients live longer; Bringing Drug Companies on Board uncontrolled growth. That signal is however, that question is still under study. In 2000, Gilliland took his quest for a tyro- Gilliland’s target, and with the success of the Gilliland’s interest in leukemia began sine kinase inhibitor for FLT3 from the lab much-publicized drug Gleevec, which acts with his hematology fellowship at Brigham bench to COR Therapeutics, a pharmaceuti- against another overactive tyrosine kinase in and Women’s Hospital. Originally trained in cal company in South San Francisco. COR, a different form of leukemia, Gilliland and microbiology (he has a Ph.D. in the field), he which has since merged with Millennium his colleagues have high hopes of achieving went on to earn his M.D. at the University of Pharmaceuticals of Cambridge, Massachu- similar victory against AML. California, San Francisco. Now an attending setts, was developing tyrosine kinase blockers Gilliland leads an academic-industry physician at Brigham and Women’s Hospital for heart disease. After screening hundreds of collaboration that in June 2002 published and at the Dana-Farber Cancer Institute, compounds using Gilliland’s mutant FLT3 two papers showing that a pair of inhibitor Gilliland collaborated with scientists cell lines, company scientists discovered a drugs blocked the FLT3 signal, dramatically involved in the development of Gleevec in promising one, called CT53518, that was very lengthening survival of laboratory mice with the mid-1990s. Impressed with the response effective at blocking FLT3 signals. leukemia induced by mutant FLT3. of so many CML patients, he recalls, “We Around the same time, one of Gilliland’s Drugs such as Gleevec and those tested by and others had the idea that maybe we could collaborators, James Griffin, a Dana-Farber

6 hhmi bulletin | december 2002 FLT3 genes. After a dividing, as one might think. According to month, the mice Gilliland, the cells have already become were given CT53518 “addicted” to the nonstop growth signal, and by mouth. Com- when the inhibitor blocks that signal, the pared with untreated tumor cells “crash and die.” In human control mice—all patients, the impact can be dramatic, says Grif- dead at the end of fin. With Gleevec,“it’s really impressive to see the experiment—the patients’ responses—they can have kilograms animals given the of leukemia cells melt away in a week or two.” drug were much less Now the crucial question is whether either affected by disease: of the new anti-AML drugs will work as effec- Ninety percent sur- tively in humans as they did in the preliminary vived and showed mouse tests. In two separate clinical trials, the significant improve- inhibitors are being given to patients who have ment, Kelly says. relapsed AML or who are not able to tolerate A second group, intensive chemotherapy. In the meantime, at headed by Ellen least three other FLT3 blockers are being or Weisberg, a Harvard will soon be tested in humans. One com- instructor in medi- pound is from Cephalon of West Chester, cine at Dana-Farber, Pennsylvania; two others are being developed demonstrated simi- at sugen of South San Francisco. lar results with Judging by the experience with Gleevec, PKC412 in mice. The Gilliland won’t be surprised if the anti-AML drug killed malig- inhibitor drugs—assuming they are effec- nant cells while caus- tive—will fail in some cases because cancer ing no apparent toxi- cells figure out a way to get around the city in the animals. growth signal blockade. Such resistance has The two groups were been seen in some of the CML and GIST then paired with col- patients taking Gleevec, so scientists are pur- laborators at Novar- suing ways of hitting the target with two or tis and Millennium more drugs at once. to carry develop- “We expect resistance is going to be an ment forward. issue with FLT3,” Gilliland says. “But we have Kelly, who a backup plan: multiple agents. If we can IA KEPKA

AS joined Gilliland’s lab bring two compounds with different chemi- If resistance becomes an issue with drugs that inhibit FLT3 signals, Gary just before the FLT3 cal structures to bear on the same enzyme, Gilliland is ready to hit the damaging enzyme with two or more drugs at once. experiments began, we have a good chance of neutralizing the developed the mouse resistance.” physician-researcher who specializes in can- model of AML used to prove the inhibitor’s If the drugs do even moderately well in cers of the blood, approached Novartis AG, effectiveness. “Initially, I was skeptical,”she treating this stubborn disease, the story could the maker of Gleevec. This company, too, had says. The logistics looked forbidding: Squirt- have a poignant coda, albeit a few years down a compound that shut off FLT3 signals, called ing the drug into the throats of so many the road. Watching from the wings is a group PKC412. Gilliland geared up his teams to mice “morning, noon and night” required a of doctors at Dana-Farber who are eager to begin testing the Millennium and Novartis large team of researchers and technicians. try anti-AML drugs in a small number of drugs in laboratory cancer cell lines with “But Gary really got everyone motivated and children who are at great risk of death in the mutant FLT3 genes, and then in mice. In the set off all these collaborations and kept them first year or two of life. The children have a June 2002 issue of Cancer Cell,two papers rolling, and kept everyone excited about it, form of acute lymphoblastic leukemia that from Gilliland’s lab described how both com- which isn’t easy to do.”The project was all the Dana-Farber scientists have determined is pounds inhibited the FLT3 tyrosine kinase the more intense, says Kelly, because they caused by mutant FLT3. signal in laboratory experiments with cell were racing against other scientific groups “We are working desperately to get these cultures and in mouse models of leukemia. working on FLT3 inhibitors. into kids,”says Gilliland. But, because the A group headed by Louise Kelly, a children are in their early stages of growth research fellow in Gilliland’s lab, created a But Will It Work in Humans? and development, toxicity and efficacy of the mouse version of AML by giving the mice When the tyrosine kinase inhibitors interact drugs need to be evaluated in adults first. bone marrow transplants of cells with mutant with leukemia cells, the cells don’t simply stop —RICHARD SALTUS

hhmi bulletin | december 2002 7 Up Front the University of Buenos Aires dropped by more than a third. Graduate students are flocking overseas. “In my generation, people would go abroad for training, with the clear In Argentina, a Life of Contrasts idea of coming back soon after,”says Fernan- do A. Goldbaum, an hhmi international During an economic crisis, foreign funding shields some scientists, research scholar at Campomar who is engi- who contend that science can only help the country. neering proteins to develop new vaccines against brucellosis, a bacterial disease that afflicts both animals and people in many lberto R. Korn- decades, the financial impact countries. “Now, more young people are . . . blihtt gazes hit hard this year as the coun- staying [away] longer or even for life.” around his Uni- try defaulted on international But not all stay abroad. Ceriani returned versity of debt, froze bank accounts and to a different Argentina in April after a five- Buenos Aires devalued the peso—which year postdoctoral position at the Scripps Aclassroom and his eyes linger promptly lost 70 percent of its Research Institute in La Jolla, California. on the empty desks. Since last value. “It used to be that one “The contrast is huge, but I don’t regret spring, at least a dozen stu- peso equaled one dollar,” moving back,”Ceriani says. She does add dents have dropped Korn- explains Maria Fernanda that setting up a new lab would have been blihtt’s introductory biology Ceriani, an hhmi interna- impossible without hhmi.“When you are class. These kids don’t lack tional research scholar at the starting from scratch, you need a million ambition, or even good grades. KORNBLIHTT Leloir Institute of Biochem- things—chemical reagents, plasticware, What they lack is bus fare. istry Research, Campomar equipment. This is one of the ways hhmi For Kornblihtt, an hhmi internation- Foundation, in Buenos Aires who is working funding has had a major impact on our sci- al research scholar, this is a unique time to identify the genes behind neurodegenera- ence.” hhmi supports 16 scientists in marked by both privilege and pain. tive disorders such as Parkinson’s and Argentina. Their Argentina, long recognized as Latin Amer- Alzheimer’s. “Now it takes almost four pesos five-year grants ica’s scientific star—boasting top academic to equal one dollar, so the amount of money range from just labs and three Nobel prizes—has collapsed in your hand is one-quarter of what you had under $267,000 to into a deep economic depression. One out before.”In the United States, that would be $450,000. of every two Argentines cannot buy basic the equivalent of spending $6 for a gallon of These researchers food and clothes. “Whole families, with gas, $8 for bread and $200 for ordinary ten- estimate that fewer

small children, wander along Buenos Aires nis shoes—without any increase in salary. than a third of AP WIDE WORLD streets every evening, collecting paper and The shortfall threatens Argentina’s sto- Argentine scientists cardboard from the rubbish to sell,” Korn- ried scientific establishment, as supplies run have funding from blihtt says. short, government funds dry up and gradu- outside the country. Yet he heads to work each morning, ate students scramble for positions abroad. The Wellcome Trust, CERIANI preparing novel experiments on regulation For Argentine scientists, lab supplies—all for instance, awards of messenger RNA in mammalian cells. His purchased from U.S. and European compa- grants to Argentine researchers working lab is well stocked. He sets aside time to nies—have become prohibitively expensive. with colleagues in the United Kingdom. Sim- write journal articles and travels to interna- “If you don’t have a grant from abroad that ilarly, the National Institutes of Health (nih) tional meetings. All of this makes Korn- is in dollars or euros, you are basically with- offers Fogarty International Research Collab- blihtt—and 15 other Argentines who are out money to do science,”says Ana Belén oration Awards to Argentine researchers hhmi international research Elgoyhen, an hhmi interna- working with U.S. scientists. Other coveted scholars—a distinct minori- tional research scholar at awards come from Italy, Japan and the Euro- ty. “I am one of the lucky conicet,a science funding pean Union. ones,” he says. Living a life of agency in Buenos Aires. After Researchers with outside funds are quick contrasts, these researchers a six-month freeze on to share lab resources. “I am collaborating find themselves in a position research grants, some money with other scientists, and I offer them things to help others—and raise has begun to flow again. But like petri dishes and Eppendorf tubes awareness about the role of the grants buy considerably because I know they don’t have them, and science in building a stronger less than before. we just can’t do collaborative experiments economy. Scientists fear the tumult without them,”says Goldbaum, who also Although political insta- will lead to a brain drain. In received a $32,000 nih grant this year for ELGOYHEN bility has racked Argentina for 2002, science enrollment at his work on vaccines. Kornblihtt remembers (4) CREEK PICTURES CHAPLIN/PINE DOMINIC

8 hhmi bulletin | december 2002 One of every two Argentines cannot buy food and clothing. Whole families dig through rubble for objects to sell on street corners and subway stations. tight times earlier in his career, when he had fight for independence,”he says. “If we want ports scientists in Brazil, Chile, Mexico, to sterilize and reuse plastic petri dishes at to get out of this crisis, we should be more Uruguay and Venezuela—several of these least once or twice. “I’m afraid that some independent, both politically and economi- countries are facing economic downturns groups, if they want to keep working, will cally—and in that picture, science is key.” as well. soon have to go back to these methods.” Kornblihtt suggests that the government “Our problem is not that we are a poor Argentina’s hhmi research scholars see increase the national science budget to at least country but that we are a rich country that science as a way forward, and as the country’s one percent of the gross national product and has been badly managed,”says Argentina’s crisis deepens, they are sounding the call for require private companies to invest in local Goldbaum. “To see young people doing sci- stronger investment in research and development, ence at an international level could have a research. “One could argue which, he says, would create big impact by showing that this kind of that it’s nonsense to support new jobs. effort, in the long term, can bring success.” science when you have to feed “I think our real impact Still, everyone feels the emotional hungry people,”Kornblihtt may be as an example in the drain of a country where banks refuse to concedes. But he contends that middle of this disaster,” says cash checks and political leaders change science and technology will be Goldbaum, noting that even like the shifting sands. “Even if you have the cornerstone of a stronger now Argentina has more an hhmi grant,” says Elgoyhen, “you still country, and he has joined hhmi research scholars have to live this disturbing life where you others in drafting proposals than any other Latin Ameri- don’t know what’s going to happen in the for improved state policies. “I can country. Within Latin future. The only way to survive, I guess, is GOLDBAUM link my fight for science with a America, hhmi also sup- to keep going.” —KATHRYN BROWN

hhmi bulletin | december 2002 9 UP FRONT In Synch with the Sun The system that keeps us on a 24-hour clock may have evolved alongside behaviors that protected primitive creatures from the sun.

esearchers are discovering that tions; they tell us when to rise, when to eat and humans and other creatures when to go to bed. possess a “second-sight” system that helps them maintain an Blind mice keep time accurate biological clock, or cir- It seemed a matter of common sense that the Rcadian rhythm. Their findings are leading standard visual system—the eyes’ rods and HARTLOVE CHRIS some to suspect that second sight and circadi- cones—supplied information about environ- King-Wai Yau mapped the neural circuitry of the light- an behavior may have evolved in tandem, mental light to calibrate the circadian clock. sensing system that controls the biological clock. independently of “primary vision.” In laboratory rats whose eyes had been In people totally deprived of cues from removed, the internal biological clock could Rather than produce sharp, photorealistic the outside world—not only light, but all not synchronize with the solar light/dark images, this second light-sensitive system yields social and environmental cues—it takes a bit cycle. This proved that photoentrainment was information about whether it’s daytime, night- less than 25 hours for the natural human impossible without the eyes. Yet the story time or twilight. Yau and other scientists refer clock to complete one full cycle. Many other changed in the late 1990s when a group under to this as “nonvisual photoreception.” species also have natural cycles close, but not Russell Foster at the University of Virginia Whatever one calls it, this system’s exis- exactly equal, to the length of a solar day. Yet began experimenting with mice whose eyes tence raised new questions about a process all creatures are able to stay in synch with the were genetically engineered to lack function- scientists thought they understood. If photo- 24-hour cycle. This is possible because bio- ing rods and cones. These blind mice were entrainment involved the eyes but was not logical clocks reset themselves daily in a able to keep their normal circadian rhythm. dependent upon rods and cones, there was an process called photoentrainment. This same “This was big news,”Yau recalls. “It was important mammalian photoreceptor that process helps jet-lagged travelers adjust to both alarming and interesting. It meant had not yet been identified. The likely sus- new time zones within a few days. there must be other cells in the eye that ‘see’ pects included several forms of the protein Light collected by the eyes supplies the environmental light. They respond to light, opsin related to pigments in the retina. One internal clock with information about ambi- but they’re not rods and cones. Someone of these, called melanopsin, was cloned in ent light, setting the entrainment process in came up with a cute term to describe this 1998 by Ignacio Provencio at the Uniformed motion.“The assumption for many years was phenomenon—they called it ‘second sight.’” Services University of the Health Sciences in that the standard visual pathway does the job,” Yau isn’t entirely happy with the nick- Bethesda, Maryland. says hhmi investigator King-Wai Yau, at The name. Environmental light levels registered by Melanopsin was found in Xenopus,an Johns Hopkins University School of Medicine. the second-sight system do not constitute sight African frog with skin that changes color In the visual pathway, light-sensitive pig- in the conventional visual sense, he notes.“You according to the level of ambient light. When ments in the retina’s rods and cones absorb can’t use it to recognize your grandmother.” the search was extended to other animals, the incoming photons, whose energy is convert- molecule was promptly found ed into electrochemical signals. These signals Michael Rosbash links DNA repair, survival and biological clocks. in the retinas of both mice and are carried from retinal ganglion cells humans. Early in 2002, Yau (rgcs) down the optic nerve and into a part and David Berson at Brown of the brain called the lateral geniculate University published back-to- nucleus. Finally, the impulses are dispatched back papers in Science,which to the visual cortex for image processing. indicated melanopsin’s pres- “But it’s also well known that a small per- ence in the previously identi- centage of rgcs send impulses to a region of fied subset of retinal ganglion the hypothalamus called the suprachiasmatic cells that project to the scn. nucleus (scn),”Yau explains. The scn is the No one has conclusively home of the master circadian pacemaker. It demonstrated that melanopsin provides the equivalent of a timing signal, is a photopigment, performing enabling organs throughout the body to syn- the same function in the sec- chronize. These signals regulate our body tem- ond-sight system as light-sen- ANLEY ROWIN ANLEY

perature, cardiac output and hormonal secre- ST sitive rod and cone pigments

10 hhmi bulletin | december 2002 do in the primary visual system. Berson’s independently, determined how the fly genes ter J. Gehring of the University of Basel sug- experiments have, however, shown that reti- dubbed period and timeless and their protein gest how second sight may have emerged. nal ganglion cells containing melanopsin are products form a self-regulating feedback loop They propose that evolution long ago select- intrinsically light sensitive, and Yau’s work has that rises and falls on a 24-hour timetable, con- ed for creatures that either lived away from yielded a map of the second-sight system’s trolling the fly’s circadian rhythm. gene-damaging ultraviolet (uv) light from neural circuitry. “The system projects to all Hints for second sight, it turns out, were the sun or could learn to sense it and flee. In the right places” in the brain, Yau says. These manifest in Rosbash’s fruit fly work. His lab, in the oceans, such a scenario would have include, besides the scn,a part of the brain collaboration with his Brandeis colleague Jeff favored creatures that dove to the depths in that governs contraction of the pupils in Hall, developed a mutant fly variety called cryb daylight and surfaced only at night. response to bright light. whose clock remained steady even when the Rosbash and Gehring think a light- The existence of light-sensitive fly was subjected to uninterrupted light. Nor- sensing protein, perhaps a precursor to melanopsin-containing cells does not rule out mally, organisms exposed to constant illumi- cryptochromes or the opsins found in the the existence of yet another system in the eye nation “go wacko,”Rosbash says, raising the modern retina, set off a warning signal in engaged in nonvisual photoreception. How- question of how the cryb flies managed to creatures whose DNA was subject to dam- ever, recent collaborative experiments by Yau’s remain rhythmic. Their distinguishing feature age by uv rays. Cryptochromes are relatives group and Robert Lucas of Imperial College, is a mutation in a gene called dcry that codes of photolyases, DNA-repair enzymes pres- London, on mice genetically engineered to for cryptochrome, a protein believed to be ent in most contemporary organisms. lack melanopsin, indicate that this possibility Drosophila’s principal circadian light receptor. Cryptochromes and photolyases are struc- is unlikely, according to Yau. Regardless of “If there were other major photoreceptors turally similar, and both are sensitive to melanopsin’s status, the work of Yau and col- involved in entrainment, they would have pro- blue light, the only wavelength in the visible leagues suggests that photoreception in mam- duced arrhythmia in the cryb flies subjected to spectrum that penetrates to any substantial mals has a range of applications unrelated to constant light,”Rosbash says. depth in the oceans. For organisms that the formation of visual images. Yet there must be another system that is made the sea their home, the ability to sensitive to light, because these mutant flies are detect blue light would have enhanced their Cryptic flies still rhythmic and can entrain to different light chances of survival. Evidence of a second light-processing system cycles. Rosbash and Yau agree that most or all Rosbash and former postdoc Ravi Alla- in the mammalian eye did not shock organisms have some kind of nonvisual light- da, now at Northwestern University, point to researchers in the lab of hhmi investigator processing system. And both believe this a second possible evolutionary link between Michael Rosbash at Brandeis University. For ‘second’ system probably evolved independent- DNA repair and biological clocks. This link years they have been trying to determine, at the ly of what we think of as primary vision— is casein kinase II, a molecule also involved molecular level, how the circadian rhythm of although it’s impossible to say which came first. in signaling the presence of DNA damage in the fruit fly, Drosophila, is established and how the circadian systems of contemporary genetic mutations in clock-related genes affect Evolutionary scenarios plants, animals and Neurosopora fungi. fly behavior. In 1996, Rosbash and Michael In a paper soon to be published in the Jour- In their evolutionary scenario, Rosbash Young of The Rockefeller University, working nal of Molecular Evolution,Rosbash and Wal- and Gehring propose that a second-sight system—sensitive to blue light—emerged Two Different Paths For vision (left), pigments in the retina's rods and cones in complex organisms and functioned as absorb light and send signals through retinal ganglion cells (RGCs) to the optic nerve and into an avoidance mechanism, enabling crea- the lateral geniculate nucleus. Impulses then reach the visual cortex for image production. For tures to avoid damage from harmful uv second sight (right), light is absorbed by rod and cone pigments, but also by a pigment found in a rays. A precursor of sophisticated circadian group of intrinsically photosensitive RGCs. These RGCs convey the light signals to the suprachi- clockworks? Perhaps. The theory helps sci- asmatic nucleus (SCN). The SCN processes information about day length and sends messages to entists think about a critical moment in the pineal gland, which triggers various endocrine responses. evolutionary history called the Cambrian explosion, when organisms of considerable complexity began to proliferate in the lateral geniculate nucleus hypothalamus suprachiasmatic earth’s oceans. nucleus (SCN) “Life that evolved in the seas had to be able to perceive light,”Rosbash reasons. primary visual pineal cortex gland While it’s widely believed that accurate vision systems emerged in Cambrian times, the Rosbash-Gehring thesis—which they light light admit is speculative—suggests an early stage retina retina in this process, and one that also helps optic nerve optic nerve account for the origins of biological clocks. ANIEL FAZER

D — JOEL N. SHURKIN AND PETER TARR

hhmi bulletin | december 2002 11 With each large and small victory against HIV—and there have been many in the last two decades— the virus reinvents itself and evades total defeat. By Marlene Cimons Is HIV Smarter Than We Are ? AMES KING-HOLMES/PHOTO RESEARCHERS, INC. RESEARCHERS, AMES KING-HOLMES/PHOTO J

12 hhmi bulletin | december 2002 A masked technician uses a centrifuge to separate virus- es such as HIV or hepatitis from blood cells. A high- speed spin causes the higher density blood cells (red) to separate from the virus, seen as an opaque layer within the less dense, clear fluid.

hhmi bulletin | december 2002 13 hat Robert F. Siliciano saw when he entered his lab five years ago triggered conflicting emotions. He was elated because the clear substrate in the plates had turned blue, confirming his W hypothesis. But he also felt a deep sadness because it meant bad news for those aids patients who had been enjoying remark- able clinical benefits from new protease inhibitor drugs. His tests showed that the human immunodeficiency virus (hiv) was still in their bodies, despite tantalizing hope that the drugs could eradicate hiv. “That was a moment that really shook us up,” says Siliciano, an hhmi investigator who conducts aids research at The Johns Hopkins University School of Medicine.“It was the realization that this virus will remain in their bodies forever.” In the more than 20 years since the earliest aids cases were doc- umented, hiv has proved a formidable foe, thwarting some of the sharpest scientific minds in the world. The National Institutes of Health has poured $24.3 billion into hiv research since 1982, including $2.77 billion this year alone, with impressive results that have often translat- ed into widespread benefits reaching far beyond the boundaries of aids (see sidebar, page 15).Yet for each hurdle scientists have overcome, hiv, in maddening fashion, seems to devise another to throw in their path. Each new promising drug, for example, has brought elation with its efficacy, only to be followed by despair as the virus developed resistance to it. “We know so much more about hiv than any other virus,” says hhmi investigator Bruce D. Walker, director of the Harvard Medical School’s Division of aids.“But hiv is a very tough nut to crack. It ulti- mately gets the upper hand.” Is hiv truly smarter than we are? To be sure,a virus has no innate intel- ligence; it’s just a bit of genetic material surrounded by a protein coat, try-

ing to stay alive. “It may look like it’s smart, but it’s doing what it is pro- BILL DENISON grammed to do, which is to replicate and adapt,” says Anthony S. Fauci, Robert Siliciano has seen HIV held in check, but the drugs are still too toxic. director of the National Institute of Allergy and Infectious Diseases (niaid). Certainly, other viruses do that too, but hiv,a retrovirus, has the insidi- immune-system cells.For example,hhmi investigator Dan R.Littman at ous habit of permanently integrating itself into the host’s cells, unlike flu New York University School of Medicine and colleagues have focused on viruses,for example,which wreak their temporary havoc and leave.Because how hiv invades helper T lymphocytes,the cells that are destroyed by hiv. hiv is a retrovirus, it contains RNA rather than DNA, and uses an enzyme Elimination of helper T cells leaves the body vulnerable to life-threaten- known as reverse transcriptase to convert its RNA into DNA as it integrates, ing infections.Most recently,in a paper published January 2002 in the jour- turning the body’s own cells into little virus factories. nal Immunity,the researchers showed that for potent infectivity,hiv must One reason the virus is so difficult to fight, says Robert C. Gallo, be taken up by the dendritic cells on mucosal surfaces.“The virus hops onto director of the Institute of Human Virology at the University of the dendritic cell to hitch a ride to the lymphatic tissues, where the T cells Maryland in Baltimore (and hiv’s co-discoverer, along with France’s are,and then infects these cells very effectively,”Littman explains.However, Luc Montagnier), is that “the ability of hiv to replicate itself is tremen- at this point,he adds,“I’m not aware of any approaches to exploit the den- dously greater than that of other retroviruses.And it’s a newer infection dritic cell work to develop therapies or vaccines.” in mankind, so we are less adapted to it.” “Every time the virus replicates, it is capable of changing,”Fauci says. PROGRESS AMID PROBLEMS “And every time the virus mutates, it has the potential of assuming a Despite the roller-coaster nature of progress against aids,researchers form that can avoid destruction” by drugs or a vaccine. Also, the virus point to great advances in drug development during the past 15 years. does not exist as one universal strain. There are subtypes, and people The growing arsenal of drugs has transformed an aids diagnosis from can become infected with more than one. New subtypes could present an automatic death sentence; patients now expect to manage the dis- “an even bigger problem for an aids vaccine than the simple mutation ease as a chronic illness. problems people talk about now,”says June E. Osborn, a virologist who The first anti-aids drug,AZT,was approved by the Food and Drug chaired the U.S. National Commission on aids and now runs the Josiah Administration in 1987 with much fanfare. Until then, antiviral drugs Macy Jr. Foundation in New York City. “When I want to worry late at were nearly nonexistent, so the rapid development and licensing of AZT night, that’s what I worry about.” was regarded as a triumph. It prolonged survival and improved quali- Still, a tremendous amount of understanding has accumulated about ty of life. But AZT,like every aids drug that would follow, proved prob- the behavior of hiv,including the various ways in which the virus infects lematic, bringing nasty side effects and eventual viral resistance. It did,

14 hhmi bulletin | december 2002 however, offer an important lesson—that viruses could be attacked and are rare, one in a million, and they are not making any RNA or protein. controlled, even if the effect was only temporary. They are indistinguishable from the rest.” With that hopeful note, pharmaceutical companies pumped more money, time and energy into studying other compounds, while clini- BLOCKING ENTRANCE cians tried innovative ways to use them, going beyond single-drug ther- Although no one has any illusions at present that some particular drug apy to the approach that is practiced today—cocktails of different com- combination will be a panacea, researchers remain convinced that newer pounds that hit the virus in multiple ways. and better drugs are still the best chance of helping those who are already Today,16 drugs in four different classes are licensed to treat hiv.Three infected, so the work on new drugs continues. In July, researchers at the of the classes block reverse transcriptase; the fourth, which blocks another International aids Conference in Barcelona heard encouraging news enzyme,called protease,dramatically changed the landscape of aids treat- about the first new aids drug in six years—T-20, the first member of ment when it was introduced in 1995.Used in cocktail combinations known a long-anticipated family called fusion inhibitors. Unlike current drugs, as “highly active antiretroviral therapy”(haart), the protease-inhibiting which block enzymes needed for replication, fusion inhibitors keep hiv drugs proved much more potent than the earlier drugs; the annual num- from entering cells. bers of U.S. deaths plunged 60 percent—from 38,100 in 1996 to 15,300 in The drug, developed by Trimeris of Durham, North Carolina, and 2000, according to the Centers for Disease Control and Prevention. to be marketed as Fuzeon by Hoffmann-La Roche, was tested in patients The early impact of the protease inhibitors led some researchers, who no longer responded to other aids drugs. It reduced their blood- including David D. Ho, director of the Aaron Diamond aids Research borne virus levels by three-quarters, and doubled the percentage of Center in New York City, to suggest for a time that haart might be patients in whom the virus fell to undetectable levels. able to completely eliminate hiv from the body. Researchers are also trying to improve existing drugs by changing Not so. The research of Siliciano and other groups revealed hidden their formulation to encourage compliance; regimens of at least 3 to at reservoirs of hiv. Later, Ho’s work showed that low-level viral replica- most 20 pills per day have sometimes been difficult to follow. Depending tion continues, even when patients are on haart.Today Ho says:“It on the regimen and the patient population, anywhere from 5 to 35 per- is clear that eradication is going to be very, very difficult.”Siliciano agrees. cent of patients abandon multidrug therapy. “I don’t think it will be possible to hit the resting cells,” he says. “They “With some of these drugs formulated in the same capsule,we can sup-

Lessons Learned–and Shared

he early burst of activity in support of AIDS sary for viral replication. And hepatitis B makes an For hepatitis C, the combination of interferon research occurred against a backdrop of enzyme that is similar to HIV’s reverse transcriptase. and ribavirin—also originally an HIV drug—has pro- resentment among advocates for research “We are learning in hepatitis C treatment, as we duced a better sustained viral response than single- on other diseases. Many complained that learned with HIV, that hitting multiple metabolic path- drug therapy. T AIDS afflicted far fewer people than their ways of the virus using multiple drugs is effective,” says “Before HIV, many drug companies were scared own conditions of interest, yet it received far Lawrence Deyton, who directs HIV and hepatitis C of researching antiviral drugs,” says Vicki L. Sato, pres- more research funding. programs for the U.S. Department of Veterans Affairs. ident of Vertex Pharmaceuticals in Cambridge, Mass- In recent years, however, such criticism has been Moreover, “the knowledge gained in understanding achusetts. But lessons learned from HIV “gave us the muted by the growing applications of AIDS research virology and the viral/immune-system interactions— confidence to try.” The company has a protease to other medical areas. Despite the dogged inclination everything we didn’t know before HIV—will really help inhibitor candidate against hepatitis C, called VX-950, of HIV to elude scientists’ best efforts, their work has us leapfrog in [hepatitis C research],” Deyton says. “We which could go into clinical trials sometime next year. produced a wealth of knowledge that goes well are just taking all our cards off the HIV table.” Researchers also are looking to other areas to beyond the scope of AIDS; in particular, it has pro- The same goes for hepatitis B. Patients who apply AIDS advances. Among those considered the vided models for fighting other chronic viral infections, suffer from chronic hepatitis B have a new drug, most promising: blood disorders, autoimmune dis- historically among the toughest to treat. adefovir dipivoxil, made by Gilead Sciences of Foster eases and cancer. For example, in cervical cancer, non- As researchers began to better understand how City, California. The Food and Drug Administration Hodgkin’s lymphoma and Kaposi’s sarcoma, both virus- HIV worked, they discovered that the more hits a virus recently approved the drug to help treat this life- es and the immune system are believed to play a role. took during different stages of replication, the more threatening infection. Adefovir was initially tried in Similarly, research into HIV vaccines, however effective the result. This led to the development of pro- AIDS patients but was rejected as too toxic for the frustrating, may open the door to developing vac- tease inhibitors and other drugs that could deliver kidneys. In lower and safer doses, however, it is cines against other infections. “All sorts of novel one-two punches at different phases in HIV’s cycle. effective against hepatitis B. strategies are being pursued in HIV vaccine Scientists are now applying that same approach The other major hepatitis B drug, lamivudine research,” says David D. Ho, director of the Aaron to other viral diseases. Both hepatitis C and hepati- (also known as 3TC and epivir), made by the U.K.- Diamond AIDS Research Center in New York City. tis B, which together infect an estimated 600 million based GlaxoSmithKline, also got its start as an AIDS “If this ultimately results in a protective vaccine, the persons worldwide, are prime candidates. Like HIV, treatment. In fact, it is still used against HIV in com- lessons will be most useful for other vaccines, par- hepatitis C makes a protease enzyme that is neces- bination with other drugs. ticularly for malaria and tuberculosis.” —M.C.

hhmi bulletin | december 2002 15 press viral replication for years with two pills a day,with very few side effects,” tions, which offer a reprieve from drug toxicities, save on drug costs and, says Robert T. Schooley, an aids specialist who heads the infectious dis- in some cases, even train the body’s immune system to kick in and gain eases division of the University of Colorado Health Sciences Center.“If they control of the virus. are used the way we prescribe them, resistance will be a rare event because Researchers at niaid have been experimenting with a seven-day- the virus won’t be replicating fast enough to develop mutations.” on/seven-day-off cycle in which patients go off treatment but then And some patients continue to do well on existing haart.In these return to it before the virus starts to bounce back. Fauci and niaid col- individuals, Siliciano has seen viral evolution stop. “Those who can league Mark Dybul have followed 10 patients for two years on this rou- maintain below 50 copies [of viral RNA] per milliliter of plasma have tine, and “they are still doing very well,”Fauci says. The researchers are halted replication and resistance,”he says.“This means, at least in prin- doing an expanded study of a similar protocol now in the United States ciple, that it is possible to permanently hold the virus in check.”Still, the and, soon to start, in Uganda. drugs are toxic. But “if we can develop nontoxic drugs, it should be pos- Walker and colleagues at Massachusetts General Hospital have also sible for a patient to have a normal life,”he says. tried a novel interruption approach. They’ve been studying 14 patients who started haart within weeks of learning they were infected. After TIMING IS EVERYTHING about 18 months of continuous treatment, they stopped the drugs, One way researchers are trying to make the drug regimens more toler- returning to treatment only when the virus began to rebound. Over able and reduce side effects is through carefully timed drug interrup- the course of three years, the researchers found that the time between

Turning the Tide

reatment is important, and Jr. Foundation in New York City. She we should take care of cites Thailand, Uganda, Senegal, people who are sick,” Ivory Coast and Brazil as examples of says Barry R. Bloom, nations that have been able to turn “T dean of the Harvard the tide. School of Public Health and In Thailand, for example, “where HHMI Medical Advisory Board mem- young men in the military have a long ber. “But if we don’t prevent trans- tradition with sexual commerce, the mission, there will be even more peo- yearly new-infection rate among mil- ple sick. The challenge is to get the itary recruits was 20 percent,” Osborn most effective balance.” The global says. “The government did a turn- fight against AIDS is not about treat- around on preventive messages about ment or prevention, but about both. safe sex, and the rate dropped to 3 Indeed, a report released last percent almost instantly.” July in Barcelona by UNAIDS (the In Brazil, the world’s fifth- Joint United Nations Programme on largest country, aggressive preven- HIV/AIDS) recommended a mini- tion messages and access to free

mum of $10 billion annually, largely JOE/AFPALEXANDER PHOTO drugs have resulted in a drop of HIV- subsidized by the world’s wealthier Children who lost their parents to AIDS gather at the Tithanizane Orphan Care related hospital admissions by 75 nations, to achieve two critical goals: Center in Ndirane Township, Malawi. HIV infects 13 percent of Malawi’s population. percent since 1997 and a decline in more affordable drugs and beefed- AIDS deaths of 50 percent, accord- up prevention programs. Otherwise, it warned, more Also, infections are soaring among pregnant ing to a 2002 Ford Foundation report. than 68 million people worldwide could die from women. In Botswana, for example, HIV prevalence in “Curtailing HIV is in our grasp,” Osborn says. “In AIDS over the next 20 years. this group was 45 percent in 2001. those countries where they realize it’s a matter of life While the rate of new infections and mortali- However, public health experts say that isolated and death, the simple messages that we have had ty has been leveling off in the United States and success stories prove that sustained prevention from the beginning have worked.” Europe—thanks to prevention and the availability efforts—including the willingness to publicly talk Bloom agrees. “As primitive as the tools for pre- of therapy—the same cannot be said of the epi- about unprotected sex and other unsafe practices— vention may be—condoms and exhortation—we demic in developing nations. In sub-Saharan Africa, and antiviral drug programs can have an impact. know they are working in places like Senegal, Thai- for example, 28.5 million people are living with “There are countries that have made marvelous land and Uganda,” he says. “HIV never rose in Sene- HIV, but fewer than 30,000 are getting AIDS progress, and in every instance, it relates to the gov- gal, and dropped dramatically in Thailand and Ugan- drugs. The disease is decimating the adult popula- ernment getting past its prudery,” says June E. da. As nontechnical, unsophisticated and unappealing tion, having already orphaned an estimated 11 mil- Osborn, a virologist who chaired the U.S. National as it sounds, prevention can work. But it takes a lion children in the region. Commission on AIDS and now runs the Josiah Macy huge effort.” —M.C.

16 hhmi bulletin | december 2002 stopping treatment and viral rebound had Structures Revealed lengthened. They theorize that early treat- ment helped preserve killer immune-sys- tem cells that recognize hiv and that each Two groups of HHMI investigators in 1997 inde- ▲ time the virus returned, those cells pendently revealed the structure of a protein increased in number. fragment, called gp41, from the surface of HIV that “It’s our hope that since we are dealing penetrates a cell’s membrane, allowing the virus to with a lifelong infection, we can get the gain access to the cell’s reproductive machinery. immune system to do a better job. If so, we Peter S. Kim, who was an HHMI investigator at the might be able to limit treatment and toxici- Whitehead Institute for Biomedical Research, ties,”Walker says. Despite promising results headed the first group. He is now at Merck. The late in boosting immunity for patients who Don C. Wiley and Stephen C. Harrison, both at receive therapy soon after they become Children’s Hospital in Boston and Harvard infected, this approach does not appear to University, were members of the second group. work in patients who have been infected for longer periods of time.

IN PURSUIT OF A VACCINE Most aids researchers acknowledge that advances in drug therapy have moved at a much faster pace than vaccine research. Nevertheless, no one is giving up the chase. More than two dozen candidate vaccines have undergone early (phase I and phase II) stud-

ies in humans for safety and efficacy,and some RESEARCH BIOMEDICAL FOR INSTITUTE WHITEHEAD KIM LABORATORY, have progressed to large, phase III studies. ▲ Farthest along of all experimental aids In 1998, Wayne A. Hendrickson, an vaccines is aidsvax,a product developed HHMI investigator at Columbia University, by VaxGen of Brisbane, California, and and colleagues solved the three- manufactured by Genentech. It was the first dimensional structure of the HIV-1 protein, to enter phase III trials—enrolling nearly gp120, that makes first contact with 8,000 volunteers in the United States, human cells. When this surface protein Canada, the Netherlands and Thailand— (red) encounters a lymphocyte that bears and early data are expected in 2003. the protein CD4 on its surface (yellow), aidsvax is based on the traditional the gp120 docks with the lymphocyte. The approach of trying to prevent the virus from virus also must bind to a chemokine recep- establishing an infection by generating anti- tor, discovered by Dan R. Littman and oth-

bodies that will immediately bind to the virus ers, in order to begin infection. UNIVERSITY AND ERIK MARTINEZ-HACKERT/COLUMBIA PETER KWONG and neutralize it. aidsvax uses hiv’s sur- face protein, gp120. Experts generally remain pessimistic, however, believing that a truly effective vaccine against hiv aidsvax.This is a process known as “prime boost,” in which patients needs to both prevent infection and provide what is known as cell-medi- are “primed”with one vaccine, then after a period of time, they are given ated immunity, which is the ability of immune-system cells to kill those a “boost” of either the same vaccine or a different one. cells that are already infected. Though the researchers behind such efforts are hopeful, they can’t Merck & Co. is testing two versions of its candidate vaccine in be too confident. hiv-vaccine research efforts, however creative, have humans: The first inserts an hiv gene called gag into a plasmid DNA all failed to produce broadly useful results. The same characteristics vector, and the second inserts gag into a modified adenovirus. The com- that enable this crafty virus to confound treatment—first and fore- pany is conducting studies in uninfected individuals, as well as hiv-pos- most, its ability to mutate—also make it highly adept at eluding an itive patients undergoing haart therapy. immune-system attack. A universally protective candidate has proved Also, the U.S. and Thai governments announced at the Barcelona con- difficult to achieve. ference that they are planning the largest vaccine trial yet, testing two prod- Public health experts insist that while the research continues, the sin- ucts on more than 16,000 subjects in Thailand. The test will first inocu- gle most effective way to thwart hiv is to return to the basics. And that late subjects with a vaccine designed to stimulate cell-mediated means prevention through behavior modification (see sidebar, page 16). immunity. Developed by the French company Aventis Pasteur, it is a live- niaid’s Fauci agrees. “The best way to stop hiv,quite simply, is virus vaccine that uses the canarypox virus engineered with the genes of to not allow it to spread from person to person,”he says.“Interrupt the several hiv proteins. This will be followed by the administration of chain of transmission. That’s the way you outsmart this virus.” H

hhmi bulletin | december 2002 17 Yuh Nung Jan and Lily Jan saw an obvious opportunity in working together. To most of us, “May I use your centrifuge?” hardly sounds like pillow talk. But for scientists who share both marriage and laboratory—who live She is very patient, and I’m a little the opposite. She is capable of focus- together, raise children together and work together—the language of love ing on one area and learning everything about it. I tend to come out with is often indistinguishable from the language of science. As one such sci- wild and crazy ideas, and occasionally there is a good one. So with our entist puts it,“My wife and I are so intimate professionally that we can dis- combination, we can turn some good ideas into useful work.” cuss science in shorthand.It’s wonderful.”Another is more cryptic:“Science As he speaks, Yuh Nung sits at his computer in a small office filled is the only bit of our marriage that has always worked 100 percent.” with piles of papers—papers written by postdoctoral fellows and grad- The success of such couples isn’t just luck. In fact, scientists who man- uate students, journal articles, graduate applica- age to share both pillows and pipettes generally have certain traits in tions—and a painting of fruit flies done by his common: mutual respect for each other’s work; separate, careful- daughter, Emily, when she was in high school. ly carved-out research niches; more (Down the hall, Lily’s office looks much the or less equal status and a feeling A same.) Lily looks at him, nodding occa- of shared success. They sionally. She waits for a few seconds until also have uncommonly she is certain he has finished speaking good marriages. Most and then tackles the same question.Yuh think their spouse the More Nung and Lily are calm, respectful and smartest person they complementary to each other. It is easy know and the person to imagine them working together. whose opinion matters It’s also easy to see that the Jans are not most. Their mutual Perfect joined at the hip. They have done what most delight in the wonders of successful collaborators do: They have each the lab deepens their rela- developed their own area of expertise. Yuh tionship: Stalking elusive Nung focuses on the development of the nervous science with someone you love Union system, Lily on its function. “Then we each have is serious fun. some independence in the lab and in the commu- Take Lily Y. Jan and Yuh Nung nity,”explains Lily.The arrangement is practical as well: Jan, one of several collaborating couples By Dorothy Yuh Nung goes to meetings related to development and within hhmi.The Jans, both hhmi inves- Foltz-Gray Lily to those about function, a division that proved espe- tigators at the University of California, San cially valuable when their daughter,now 25,was small.It was Francisco, have shared a marriage since 1971 and a lab during those years that teamwork mattered most.“We basically since 1979. Both study the nervous system of flies, searching worked on raising our daughter and collaborating on projects,” for themes common to other organisms, and most of the time they says Lily,recalling that each evening Yuh Nung would walk her home simply alternate authorship prominence on their publications. Their so she could relieve her mother, who watched Emily (Max, their 17- theory is that when two people work together, the whole of their work year-old son was not yet born.).“Then he would go back and stay with the is greater than the sum of the two separate parts. prep until 2 a.m. We had to work shifts on the same experiments.” “Inevitably you fight, and then you figure out how to Even as the two talk about the tough times, when both kids and avoid fighting,” says Lily. “But if you truly care about petri dishes needed tending, they seem unsur- a question, you want to find the right way. So you Scientists prised, almost unaware that they have argue until you figure out how to make it work.” who have found accomplished what many spouses would But harmony—not argument—seems to dom- partners in the find impossible. “It’s the only life we’ve inate the Jans’life. They met as physics students at the had,”says Yuh Nung, shrugging. National Taiwan University in Taipei and married as lab dissect their The Jans’ collaboration was made graduate students in biology at the California Institute relationships and easier by their simultaneous entry into of Technology in Pasadena. Their first mentor, the late find that good science. Neither was more advanced than molecular biologist Max Delbrück, who won the 1969 marriages the other. Not all couples share that advan- Nobel Prize in Medicine, kept their work separate, urging tage, however. When hhmi investigator and them to tackle problems independently. Still, the pair loved make better cancer biologist Charles J. Sherr met Martine F. talking science together, the way some people like arguing pol- science. Roussel, he was running a laboratory at the National itics or philosophy.As Lily puts it,“We’re both curious about the Institutes of Health (nih) in Bethesda, Maryland. Roussel, questions the other is addressing. It’s just simple curiosity.” six years his junior, was a Ph.D. student in cancer biology at Villejuif In 1974, when the Jans had to choose partners in a neurobiolo- Hospital in Paris and later at the Pasteur Institute in Lille, France. The gy course, they chose each other, taking advantage of what seemed to two maintained a long-distance relationship until 1980, when Roussel them an obvious opportunity. In essence, they began sharing fruit flies went to nih as a Fogarty Scholar. the way other couples share china and silver. Nothing seemed more nat- At first, Roussel and Sherr merged households but not beakers. “I

FRED MERTZ ural, says Yuh Nung.“In our case, working together works out very well. refused to work with him for three years,”says Roussel.“My concern was

hhmi bulletin | december 2002 19 that I wouldn’t get credit for what I did. But even though we were in two labs, we spent so much time thinking about science together. It was so clear that we were working together intellectually. So Chuck said,‘Do experiments with me. At least we will get something out of it.’And as soon as we started working togeth- er, our projects were successful.” Working together was one thing; building careers was another. What Roussel and Sherr understood about each other—that they were intellectual equals—wasn’t as easy for out- siders to grasp, since one scientist was junior to the other and a woman to boot. In 1983, St. Jude Children’s Research Hospital in Memphis, Tennessee, recruited Sherr to head Martine Roussel has worked its new department in tumor cell biology and hard to step out of husband

added his new wife as a junior faculty mem- TEVE JONES S ber. “There weren’t many women scientists then,”says Sherr.“Every time she did something, they would say it was Roussel faced other obstacles as well. She spoke little English when my work.There was an underlying prejudice because she was a woman.” the pair met, and writing, whether in English or in French, was never Roussel agrees that her path was a rocky one.“I was an appendage. her strong suit. While presentations about oncogenes were difficult in I was there because they wanted Chuck. I didn’t like it, but there was not French, they were terrifying in English. As Roussel struggled to master much I could do.”Sherr was also his wife’s department chair, which made these professional skills, she found that she would soon need to master decisions about promotions and raises tricky at best. “I was the worst a new skill, mothering. In 1985, she and Sherr had a son, Jonathan, and paid,”says Roussel,“and Chuck didn’t want to promote me because he Roussel took three weeks of maternity leave—with unexpected results. didn’t want people to think he was favoring me.” He’s still her depart- Other scientists in the lab had taken over Roussel’s experiments in her ment chair, but now she reports to someone else. absence, so she was forced to develop projects independent of Sherr’s. As Sherr puts it,“I was her greatest supporter and her greatest obsta- Soon she began to get her own funding, which, in turn, led to promo- cle. That ambiguity was always there. We’ve just handled it better than tion and independent recognition. most people.” Today, both Sherr and Roussel are full members (the equivalent of

Marriage Under a Microscope there’s opportunity for friction at almost any time.” —Jonathan G. Seidman, HHMI investigator, For a scientist married to another scientist, each sphere—work and home—inevitably affects, and Harvard Medical School, married to Christine E. sometimes instructs, the other. Below, some HHMI investigators and their spouses offer their observations: Seidman, HHMI investigator, Brigham and Women’s Hospital and Harvard Medical School Science Schooling Marriage Collaboration “You have to be rational in our profession, to see “If you collaborate with another scientist, on Shared Identities the other side of things. That carries over. I consid- occasion, things can happen that poison the “People who don’t know you have trouble er it a stroke of luck to have met a scientist.” relationship. But Helen and I have a large basket of separating you. They say, ‘Who’s the brains — Johann Deisenhofer, married to Kirsten Fischer trust a priori that facilitates collaboration.” there?’”— John W. Kappler Lindahl, both HHMI investigators at the University — David Piwnica-Worms, director of the of Texas Southwestern Medical Center “Someone always wants to know who did it. Molecular Imaging Center, Washington University, But science is not a solo act.” St. Louis, married to Helen M. Piwnica-Worms, Competition — Christine E. Seidman HHMI investigator, Washington University “We don’t nickel and dime who did what.” — Philippa Marrack, married to John W. Kappler, Boundaries Communication both HHMI investigators, National Jewish Medical “Our life is a seamless interface as we go back and “Every so often John and I have a fight, but the and Research Center, Denver forth from office to home. It all blends together as science trundles along.” — Philippa Marrack one big adventure.” — David Piwnica-Worms “People ask, ‘How do you feel when she wins so many awards?’ I say, ‘I feel great.’” — Thomas A. “The good news is that couples who work together Attraction Steitz, married to Joan A. Steitz, both HHMI are constantly communicating so issues can be “I don’t think it was the biochemistry that drew investigators, Yale University worked out immediately. The bad news is that me to her.”— Thomas A. Steitz

20 hhmi bulletin | december 2002 full professors) at St. Jude’s. Struggle is a verb they use in the past tense, although Roussel notes there is occasionally friction about who gets credit for what.“We have tough discussions. In science, you have to dis- cuss every fact, and the facts have to be right, and so you apply this to your relationship as well. You learn how to speak up, to say what you think, even if it’s not pleasant. But two strong people cannot be at the top simultaneously all the time. You have to give in at some point.” Sherr tells a revealing story. Roussel, a gardener, wanted a com- puterized watering system for their yard in East Memphis. Sherr balked at the expense, the inevitable complications. But Roussel persisted. Every day, says Sherr, she’d mention how nice a watering system would be. Finally, Sherr agreed to review some information, and Roussel called for quotes. Sherr grilled the contractors and settled on a system just high-tech enough to interest him. Suddenly he was a kid with a new toy, and she had a blossoming garden.With gardens or shared careers,“each person has to get something,”says Roussel. Not all married scientists choose to cultivate their garden togeth- er, or at least not the same patch. hhmi investigators Eric Wieschaus and Trudi Schüpbach, both molecular biologists at Princeton University, have drawn firmer lines between their careers than either the Jans or Sherr and Roussel. Wieschaus and Schüpbach met in Zurich in 1975, as Schüpbach was completing graduate work and Wieschaus a post- doctoral fellowship. Initially, they published a few papers together, but when they arrived at Princeton in 1981, he as an assistant professor and she as a nontenured research biologist, they set out on different research Eric Wieschaus paths.Wieschaus studied embryo development in flies, and Schüpbach does the cooking while studied oogenesis, or what happens in mother flies as eggs form. wife Trudi Schüpbach “The lines were pretty clear between our research programs early oversees homework. on,” says Wieschaus. “We had to keep them distinct initially, in part VID GRAHAM DA because she didn’t have a professorship. It would not have been good for her to be seen as just another member of my group.” to accept each other’s long hours in the lab and to share household tasks. By the mid-1980s, Schüpbach had funding for her own laboratory, Most days, Wieschaus rides home from the lab on his bicycle, thinking and, as their professional identities became more distinct, they began about what he’ll cook for dinner, while Schüpbach helps their 17-year- to tiptoe back together. Now Wieschaus’ lab is on the same floor as old daughter, Laura, with homework.Wieschaus likes to cook, Schüpbach’s; they hold joint lab meetings, and postdoctoral stu- mostly because he knows the work will result in success— dents float between the labs to exchange a prediction less certain in a lab. ideas and information. “We confer on “In science, When their three daughters (Ingrid, 27; Eleanor, 20 each other’s projects,”says Schüpbach. you have to discuss and Laura) were young, however, dreamy bike rides “That’s one of the pleasures of being were a luxury.“There was a lot of pressure on our time in the same field. You can share little every fact, and the trying to bring up the children, do the housework,”says daily triumphs—like when some- facts have to be right, Schüpbach.“It was really important that both partners thing works or when someone finds and so you apply equally respected each other’s work so that each one something out.And you can share your this to your would take on these other responsibilities. I never felt that depression when the experiments didn’t Eric saw his work as more important than mine. When our work—for the fifth time.” relationship children were sick, for instance, we would check with each When people have their own successes, they as well.” other about who was doing what and who could take off work. can gracefully share huge triumphs too, as Schüpbach In science, in the middle of an experiment, you have to be there did when Wieschaus won the 1995 Nobel Prize in or lose a lot of work.” Physiology or Medicine.“I knew how important the work was, Being there, being supportive, being forthright—these themes so it was really gratifying to see it honored in that way,”says Schüpbach. surface again and again as couples dissect their collaborations. The “A lot of people working with flies were very happy. It validated the work point is, good marriages make better science. The 19th-century we’re doing.And I’ve never felt that I was toiling away, with no one notic- Spanish scientist Santiago Ramón y Cajal put it slightly differently. The ing what I do. But I can imagine that if one were working very hard and perfect spouse for a scientist can be “the helium that propels him sky- no one was saying anything, it would be harder.” ward,”he wrote in his 1897 book Advice for a Young Investigator.“And Both Schüpbach and Wieschaus are quick to acknowledge their if fame should smile, its brilliance will surround the two foreheads with ambitions. Knowing what it takes to cross a scientific border helps them a single halo.” H

hhmi bulletin | december 2002 21 MUSCLE CONTROL A cross section of an embryonic chick’s spinal cord shows the nerve pathways taken by a chick’s own motor neurons (red) and by motor neurons derived from mouse embryonic stem cells (green). The transplanted mouse cells performed as well as the chick’s own cells. Healing Connections A handful of researchers are making progress with mouse embryonic stem cells—connecting nerves to muscles and improving mobility in animals. BY MAYA PINES

tem cells—the precious and finicky immature cells that can grow into specialized cells or renew themselves—are finally being harnessed. After years of research into how organisms develop from a fertilized egg into an adult and how the earliest cells differentiate, a few teams of scientists are finding ways to Smake stem cells do their bidding, at least in mice and other animals. One team of scientists has coaxed mouse embryonic stem (ES) cells to grow into motor neurons—the specialized nerve cells that control the movement of muscles. When the team inserted these newly made motor neurons into a chick embryo’s spinal cord, they found that the neurons grew long extensions called axons and made contact with muscle cells just as well as the embryo’s own motor neurons did. This extraordinary finding by hhmi investigator Thomas M. Jessell at Columbia University’s College of Physicians and Surgeons and his colleagues was given early publication online by Cell on July 17, 2002, and was published in the August 9 issue. It raised hopes that several incurable muscle diseases, including amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), as well as spinal cord injuries, might eventually be treated with such cells. Along similar lines, Ron McKay and his team at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, have successfully directed mouse ES cells to become neurons that release dopamine, the chemical lacking in Parkinson’s disease. The scientists also showed that these neurons restore some aspects of mobility in a rat model of Parkinson’s, a possible harbinger of more effective therapies for this common disease. All stem cells are immature, unspecialized cells with great potential, but some are more limited than others. ES cells—those derived from very early embryos—can become any type of cell in an organism and can renew themselves indefinitely. But adult stem cells have already started on a particular pathway of differentiation. They can still generate a variety of cell types, but the choices are restricted. hhmi investigators Allan C. Spradling, Sean J. Morrison and Mark T. Keating (see sidebar, page 26) and others are examining how adult stem cells might be made to treat diseases. The therapeutic potential of adult stem cells is particularly important because of current U.S. restrictions on research involving human ES cells.

THE RIGHT SIGNALS For his systematic, decade-long study of how the nervous system functions—“specifically, how different cell types in the vertebrate nervous system actually become different”— Jessell relied initially on stem cells from embryonic neural tissue. At first, he could not even tell these neural progenitor cells apart.“At the very early stages of development, it’s impossible to recognize a motor neuron or a sensory neuron by its appear- ance,”he explains. But each class of neurons turns on a different set of genes. These genes are

JESSELL LAB activated by different sets of transcription factors, proteins whose signals turn on specific

hhmi bulletin | december 2002 23 genes in a cell’s nucleus. Because these factors could be recognized by become a generic neural progenitor cell. The second is the decision to specific antibodies that were available to him, Jessell soon learned to become a spinal cord progenitor cell. The third is the decision to identify various types of neurons at their earliest stages. become a particular progenitor cell that gives rise to a motor neuron.” While studying the early developmental signals that normally The retinoids “are good at converting neural progenitor cells into produce motor neurons, Jessell decided to find out whether “naïve ES spinal progenitor cells, and then hedgehog is good at converting cells” could be converted into motor neurons by means of the same spinal progenitor cells into the kind of cells that are precursors of the signals. With great satisfaction, he now reports that the answer is motor neurons,”Jessell says.“Where we got lucky is with the first step. yes—at least in mice. Hynek Wichterle, a Czech postdoctoral fellow in For some reason, ES cells tend to become nerve cells almost by Jessell’s lab, recently proved it in an experiment that “demonstrates default, as first suggested by hhmi investigator Douglas Melton (at one can learn from embryonic development and apply it directly to Harvard University).” ES cells. Just by exposing the mouse ES cells to developmentally The third step was not so simple, however, because different relevant signals, we drove them to differentiate all the way to motor concentrations, or grades, of sonic hedgehog have different effects. neurons.” “Hedgehog’s graded actions normally produce at least five different Wichterle notes that he had “a huge chunk of luck”: He managed classes of neurons,”Jessell points out.“Typically, only 25–30 percent to produce all these changes by using only two signals. One is retinoic of the cells that emerge from exposure to sonic hedgehog are motor acid, a product of vitamin A that binds to receptors in the nucleus. neurons. I think it’s going to be essentially impossible, in the context The other is Sonic hedgehog, the product of a gene that was first of neural stem cells, ever to find situations where 100 percent of the identified in developing fruit flies and that Jessell found expressed in generated cells are of one particular neuronal subtype.” the mouse spinal cord, where it plays a critical role in the To get around this problem, he explains,“we used a genetic trick. differentiation of motor neurons. Wichterle, together with postdoctoral fellow Ivo Lieberam, marked “There are three main steps that an ES cell needs to take in order the motor neurons with green fluorescent protein. Then by putting to become a motor neuron,”says Jessell.“The first is the ‘decision’ to all the cells through a fluorescence-activated cell sorter, we could separate the fluorescent ones from the others and get DIRECTIVE SIGNALS Thomas Jessell can turn mouse ES cells into motor neurons. essentially 100 percent purity.”

RATIONAL DESIGN Ultimately, Jessell is seeking precision, control. He points to several clinical trials in which people with Parkinson’s disease were treated with human cells that produce dopamine,“not of ES cell origin but of fetal brain origin.”A few patients benefited from these attempts, but some actually got worse.“That may be because the cells introduced into those patients were a heterogeneous mixture,”Jessell says.“It’s not surprising that the clinical outcome is variable if you cannot control the precise number or proportion of dopamine-producing cells that you are putting in.” Such control would be even more important in dealing with other diseases, he believes.“In Parkinson’s, at least you know that you really need dopamine-producing neurons,”he says.“But in other diseases, it is not clear which cell type is needed to reconstruct a circuit or prevent neural degeneration. In the context of ALS, for instance, do you want to put in motor neurons or would you be better off with spinal interneurons or glial cells, which normally surround the motor neurons and may actually support the survival of the remaining ones?” Or, for that matter, should all classes of spinal cord cells be used? Having a way to purify the appropriate cells “puts you in a position now where you can ask such questions,”Jessell says. He is also pleased that “we have manipulated mouse ES cells simply by exposing them to different environmental sig- nals—we have not changed the genetic makeup of the ES cell itself,”he says. While some other scientists introduce genes directly into the ES cell,“we have just added factors that we know are involved in the normal developmental process and

MARC BRYAN-BROWN let the ES cell do the rest.”As a result, Jessell has gained a tool Massachusetts, has identified a small molecule that acti- vates the hedgehog pathway, so we can now direct ES cells to become motor neurons simply with small, synthetic chemicals. You don’t even need mystery factors anymore.” Eager to test whether the neurons they grew from mouse ES cells were functional motor neurons, Wichterle decided to put them into live chick embryos. Why chicks? “Because their embryos grow in eggs rather than wombs,” Jessell explains. This makes it much easier to gain access to the neural tube and “introduce the ES cell-derived motor neurons into the spinal cord at exactly the same EASY TRACKING time that the host motor neurons are being generated.”In After implantation into a sense, Jessell says,“we are giving the ES cell-derived the spinal cord of a chick motor neuron an even chance.” embryo, motor neurons that The scientists found that “even in this completely dif- JESSELL LAB were derived from mouse ferent host species, the ES cell-derived motor neurons ES cells can be recognized that might eventually be used with human settle in the right place in the spinal cord, extend axons out and form by their green ES cells as well. differentiated synapses with target muscle” over the same time course fluorescence. “If we wanted to apply this strategy now to as the chick’s own motor neurons. In fact, Jessell says,“it was a dead a human ES cell, we could simply take the same heat.”The fluorescent green markers continued to function, so he factors,”Jessell says. “It turns out that the two factors we use—Sonic could follow the path of the ES cell-derived motor neurons. hedgehog and retinoic acid—cross species barriers. Furthermore, His team has already started to explore whether human ES cells one of our collaborators, Jeff Porter at Curis, in Cambridge, will behave in the same way.“We are collaborating with a group of Discovering the Genes for “Stemness” ouglas A. Melton, an hhmi investi- involved in embryo development and in other than they are to their differentiated gator at Harvard University, is sperm development. The 12, of course, will counterparts … This fits with a ‘default’ model exploring what gives stem cells their now be studied with special interest. we proposed, which is that the default fate of Dspecial abilities—what accounts for Another surprise was that the stem cells embryonic stem cells is to become neurons.” their “stemness.”And he has found hundreds expressed unusually large numbers of The team’s studies are likely to aid the of genes likely to play a role. “expressed sequence tags,”which mark genes search for new types of stem cells, Melton Together with his colleague Richard C. of unknown function.“For young scientists, believes.“For example, nobody has yet been Mulligan and other Harvard associates, Melton this finding is especially exciting because it able to identify adult pancreatic stem cells—a compared the activity of the three best-known shows that … no one has a clue to what the central effort in our laboratory,”he says.“But types of stem cells—embryonic, neural and gene products do,”says Melton.“It’s easily a now we know that if we’re going to isolate hematopoietic (blood-forming)—with the decade’s worth of work just to define the such cells, we should look for those that activity of other types of mouse cells. The functions of the genes that we have defined express many of these ‘stemness’ genes.” researchers discovered that 216 genes were as characteristically active in these stem cells.” Melton is motivated by more than turned on at least three times more frequently Although all stem cells expressed the 216 scientific curiosity. Hoping to find a cure for in the stem cells than in other cells.“These 216 genes, they did so in varying his 10-year-old son, Sam, genes are likely to reveal core stem cell proportions.“The three and millions of others with properties, or ‘stemness,’that underlie self- types of stem cells were not type 1 (juvenile) diabetes, he renewal and the ability to generate differentiat- identical” in their activity, launched a major drive ed progeny,”they reported in the September Melton points out. The activ- about a decade ago to turn 12, 2002, issue of Science Express. ity of hematopoietic stem human embryonic stem cells When the scientists tried to find out cells was more similar to that into the special kind of where these 216 genes were located, they of other cells in the bone pancreatic cells, called beta were surprised to learn that only 60 of them marrow than to the activity cells, that supply the insulin had been mapped to any chromosome. An of any other samples, he says. diabetics lack. This effort has astounding fraction of these latter genes—12 By contrast,“embryonic stem been slow going, he reports, out of 60—sat on mouse chromosome 17, cells and neural stem cells are but it did lead him to his MELTON

which also contains genes known to be much more similar to each DOOHER KATHLEEN stemness discoveries. —M.P.

hhmi bulletin | december 2002 25 scientists in Israel [led by Nissim Benvenisty of the Hebrew interested in cell-based treatments of diseases like ALS,”he says, University in Jerusalem] who have experience in turning human ES “but one of the difficulties in comparing results is that most people cells into neurons,”Jessell says. The goal, he says, is “to find out have been using different cells in different systems. If we can whether you can efficiently convert human ES cells into human generate motor neurons under fairly standardized conditions, we motor neurons.” can provide them to anyone who is interested, and it will be easier If so,“one could really start to evaluate whether this would be a to compare their results.” sensible way of approaching ALS, spinal muscular atrophy or spinal Jessell is working particularly closely with Robert Brown, director cord injuries,”Jessell says. But he warns that there are big hurdles of the Neuromuscular Disorders Unit at Massachusetts General ahead.“The motor system relies heavily on the precision of Hospital.“Bob Brown is a world expert on ALS,”Jessell says,“and he connections and circuits. Simply having generated a motor neuron is has mouse models of ALS. It will be interesting to test whether not sufficient. I think the challenge will be to reconstruct appropriate introducing motor neurons derived from mouse ES cells in these circuits,”he declares. Partly for this reason, Jessell is now studying the models actually does any good.” next steps in the differentiation of motor neurons. The two research teams are also investigating the basic cause of To help develop new therapies, Jessell has also started to ALS. A gene whose mutation is known to result in ALS in humans is collaborate with neurologists who are doing research on ALS as well the gene for an enzyme called superoxide dismutase 1, or SOD1. as other spinal cord disorders and injuries. “There are many groups Brown uses a mouse model of ALS engineered with the same Will Humans Generate Replacement Parts? or the past six years, Mark T. Keating turns on in newts whenever these animals need start the process. has been trying to figure out why a replacement part. Mice have a similar msx-1 More recently, Keating and his associates humans and other mammals who gene, and the scientists found a way to turn on compared how zebrafish and mammals react Flose a limb or an organ can’t do what this gene at will in mouse muscle cells. to heart injury. They found that zebrafish salamanders, worms and fish do in such Next, Keating, who had moved to regenerate heart muscle with little scarring. cases: grow a new one. In mammals, cells that Children’s and Harvard Medical School by However, other vertebrates respond by try to repair an injury just form a layer of then, used a different stimulus—an extract of producing large connective-tissue scars. The useless scar tissue over it. But in newts, the regenerating limb tissue collected from newts researchers then proposed that “scarring and cells that swarm over a fresh wound rapidly after their forelimbs had been amputated. regeneration compete” and that the vigor of turn into a layer of stem cells that effect a This extract worked wonders on mouse mus- each process is critical. In normal zebrafish complete repair. cle cells, making about 18 percent of them with heart injury, for instance, a fibrin clot Keating, an hhmi investigator at dedifferentiate and reenter the cell cycle—not formed, but cardiac muscle fibers “invariably Children’s Hospital in Boston, now believes very much less than the 25 percent of newt penetrated the clot and constructed a bridge this is the standard way that many animals muscle cells that did the same. In their report of new muscle around the wound.”By regrow lost or damaged body parts. First, on this work, Christopher J. McGann and contrast, zebrafish with a mutation that the wounds stimulate some mature cells to Shannon J. Odelberg (both at the University impairs cell division produced fewer muscle revert to their infancy as primitive stem of Utah) and Keating wrote that these studies cells and ended up with big scars. The cells, or “dedifferentiate”; then these cells are “indicate that mammalian cells have retained researchers now believe that stimulating reprogrammed to form new tissue or the intracellular signaling pathways heart muscle cells to proliferate, in response organs. Certain genes are turned on required for dedifferentiation” to the proper genetic signals,“will reduce scar to start both operations. F OLLOW THE NEWT and that the primary formation and facilitate cardiac regeneration According to Keating, When a newt's limb is obstacle to regeneration in mammals as well.”Keating adds, however, “humans probably still have amputated, mature cells near in mammals may be that “it’ll be a while before anything of this the genes that enable other the injury dedifferentiate and the lack of signals to sort is tried in humans.” —M.P. animals to regenerate tissue, become stem cells. After forming Complete but these genes were a mound and multiplying, the regeneration silenced, turned off” during cells redifferentiate to rebuild the evolution. Therefore, they limb—all in about 40 days. might be turned on again, Mid Late Amputation Early Early differentiation differentiation given the right stimulus. and wound bud differentiation Keating and his colleagues identi- healing fied their first such gene, msx-1,several years ago while doing research on human heart disease at the University of Utah. They discovered that msx-1

SOURCE: DEPARTMENT OF ZOOLOGY, UNIVERSITY OF GUELPH, ONTARIO, CANADA 26 hhmi bulletin | december 2002 mutation, with resultant motor neuron degeneration. Yet “nobody knows why motor neurons are selectively vulnerable to death in ALS,”Jessell points out. He hopes to discover the answer by comparing motor neurons that are derived from normal ES cells to motor neu- rons derived from ES cells bearing the SOD1 mutation.“Then we can ask what has changed, biochemical- ly, that might be a predictor of the later degeneration of the motor neurons,”he says. Scientists who work with stem cells are finding it difficult to choose among the many different RIGHT CELL research paths now opening up— FOR THE JOB and finding it particularly Sean Morrison's team cultured challenging to work with human these smooth muscle cells from ES cells. Although all mouse ES neural crest stem cells of an adult rat. MORRISON LAB MORRISON cell lines “behave in a rather They found the activity of the stem uniform way, that may not be true in human ES cells differed depending on their of stem cells will have to be controlled with care cells,”Jessell says. Yet researchers may have a hard origin, pointing to the importance if one hopes to use them in some form of time finding out. Most of them rely on federal of matching the cell to the therapy. funds, which can be used to study only a limited therapeutic goal. More data on the complexity of using adult stem number of human ES cell lines. And as Jessell points cells comes from Sean J. Morrison, an hhmi investigator out, “human ES cell lines are so poorly characterized, at the University of Michigan, who found that the properties compared to many of their mouse counterparts, that nobody actual- of some adult stem cells were quite different from those of embryonic ly knows how much they vary and whether the full range of develop- or fetal stem cells. Morrison managed to isolate “neural crest” stem mental potentials is going to be offered in those lines that now have cells from the gut tissue of adult rats, even though such stem cells federal approval.” (which give rise to various tissues, including the peripheral nervous system) were supposed to exist only in the embryo and fetus. Then he WHAT ABOUT ADULT STEM CELLS? The researchers who have either cultured them or transplanted them into chick embryos to chosen to work with adult stem cells face other problems. In many study their activity. It turned out that these adult stem cells could do tissues, adult stem cells are relatively unexplored and still full of some of the same things as embryonic and fetal stem cells but not oth- surprises. They become most active when tissues wear out or are ers; for example, they could not differentiate into cells that make two damaged, yet they are often hard to find. Besides the nervous system, important neurotransmitters, serotonin and noradrenaline. researchers are looking at blood, skin, nails, hair, saliva and sperm Morrison also found that neural crest stem cells he had isolated cells—where the need for replacement is particularly obvious. from the gut of rat fetuses differed from those that came from the sci- Allan C. Spradling, an hhmi investigator at the Carnegie atic nerve. After transplanting cells from both sources into the Institution of Washington in Baltimore, Maryland, has focused on developing nerves of chick embryos, Morrison discovered that stem what he calls niches, special microenvironments in various organs cells from the gut produced mainly neurons, whereas those from the such as the skin, gut and gonads. Each niche houses one or more sciatic nerve made only glial cells, a type of supporting cell. This find- adult stem cells and regulates their activity. His team has identified ing, he says,“suggests that it’s really important to match the origin of three types of regulatory cells that form such niches and keep the the stem cell to the therapeutic job that you’re trying to do.” stem cells from differentiating prematurely. “There is a great debate in the field of regenerative medicine as to The strongest evidence for such regulation in mammalian whether one should start with ES cells or with adult stem cells,”Jessell tissue probably comes from studies of spermatogenesis, Spradling says.“Many groups are trying to get adult neural progenitors to says. Thousands of stem cell niches have been found lining the differentiate into particular cell types. Our study shows very clearly walls of the seminiferous tubules in which sperm develop. that a mouse ES cell can become a motor neuron in a very predictable Spradling has focused on the niches that surround germline stem way, but so far, no one has shown that an adult neural progenitor cell cells in fruit flies and on the signals they send to the stem cells. can become a motor neuron.” Such signals appear to have a powerful influence on the behavior of “I think the potential of adult progenitor cells is exciting,”Jessell adjacent stem cells, he says. By comparison, the stem cells “may adds,“but in my view, the evidence that they perform as well as their themselves be relatively unspecialized.” Therefore, the environment embryonic counterparts is not strong at the moment.” H

hhmi bulletin | december 2002 27 PERSPECTIVE

Transcending the Status Quo Scientists and school educators need to join forces to raise student proficiency in science. By Keith Verner

t is considered unacceptable for any adult American to be in title II of the act encourages the establishment of partnerships unable to read or to be ignorant of important political and between universities and public schools to improve math and sci- economic issues. But the same cannot be said of scientific lit- ence education, and provides funding to do so. eracy. In our society, even well-educated and productive citi- Within this new environment, two broad strategies promise sci- zens and policymakers often lack a basic understanding of entists opportunities for exerting the greatest influence: (1) playing science. Tens of millions of Americans do not grasp even funda- a role in integrating the “science experience” into teacher prepara- Imental scientific concepts—such as the difference between viruses tion, professional development and interactions with K–12 students and bacteria or between a protein and DNA— and (2) establishing working partnerships and too little is being done about it. with public school teachers and administra- I believe the scientific community has a tors in science curriculum development. responsibility—and an excellent opportuni- ty—to help improve K–12 science education, the science experience which is clearly in need of reform. Our respon- Thinking scientifically can be likened to driv- sibility lies not only in preparing high school ing a car. If we had to think about each indi- graduates to enter scientific careers but, more vidual step, it would be difficult to get any- broadly, in educating them to become scientif- where. Instead, through practice, we intuitive- ically literate citizens. ly and fluidly proceed through the steps of It is on the shoulders of primary and sec- driving. This “behind the wheel” experience is ondary schools to teach rudimentary scientific essential. Rules for driving are described in concepts, and rightfully so. Why should we manuals and tested by official written exams, expect our colleges to explain to entering but no state waives the road test. Similarly, freshmen the phases of the moon, basic prop- scientific facts are found in books, learned erties of matter or fundamental concepts of from lectures and tested by multiple-choice human physiology? These topics are well with- exams, but the ability to think scientifically

in the developmental capacity of young stu- KENNETH SMITH/PSU comes only through practice. The mission of dents and are best taught during early stages of science education ultimately should be to cognitive development, instilling a solid conceptual basis for under- instill, through actual experience, a working familiarity with the standing the physical and biological world. processes of scientific thinking and problem solving. Once that Unfortunately, the K–12 system as presently constituted is not familiarity is achieved, the understanding of scientific facts and always able to handle the challenge. Despite past setbacks, however, concepts becomes almost instinctive. I strongly believe that public schools are more than capable of pro- Because most educators, including many science educators, have viding their students with an excellent grounding in science, and I not themselves practiced science, it is difficult for them to teach their suggest that collaborations between professional educators and sci- students or other teachers to think scientifically. Reaching teachers in entists are an excellent way to begin helping them to succeed. this manner necessitates the direct involvement of scientists in the Many capable educators, and now the law itself, support the planning and delivery of teacher “in-service” training programs. establishment of direct and meaningful partnerships. Most states Scientists can begin by contacting the superintendent of their have implemented science standards, and the recently enacted No local school district to get involved. If established programs do not Child Left Behind Act of 2001 stipulates that by 2007 every state exist in the district to facilitate partnerships (which is likely to be include in its accountability reporting the results of student tests the case), then such a program must be initiated. Models of success- assessing proficiency in science. Just as important, specific language ful programs can be obtained through Internet searches. Look for Keith Verner is chief of developmental pediatrics and learning at The Pennsylvania contact information and communicate directly with the scientists State University College of Medicine, Hershey, Pennsylvania. involved in these programs.

28 hhmi bulletin | december 2002 There are other opportunities. What better time to foster scien- tific thinking than during a future teacher’s university training, when he or she resides on the same campus as practicing scientists, postdocs and science graduate students? For the scientist whose institution includes a college of education, the first step is to contact the administrative office and initiate collaboration between the col- leges. In addition, scientists should instill in their own students the importance of excellent K–12 science education and discuss career choices that may lead them into the classroom. Scientists also can bring the experience of science directly to students by providing summer or after-school projects or employ- ment for talented high school science students. Such early opportu- nities have pointed both medical and graduate students I know toward science careers. Direct interaction with students in K–12 classrooms is also important, provided these occasions transcend familiar “show-and-tell” and “career day” formats and become inte- gral to the science curriculum. Meaningful collaborations must be based on national and state science standards and have clearly defined and measurable outcomes, such as performance on stan- dardized state science tests. theory and practice To design hands-on instruction that is properly integrated with the curriculum requires an interweaving of scientists’ deep content expertise with educators’ real-life classroom practice. This was the vision that guided us over the past decade in utilizing teams of sci- entists and public school educators at the College of Medicine to create the LabLion elementary school science program (lablion.org). LabLion is designed to address national and state science stan- dards and provide an overall framework for understanding broad

JOHN BIONDO/PSU scientific concepts. This comprehensive K–6 program includes the LabLion students at Harrisburg’s Marshall Elementary School study anatomy. establishment of a fully equipped lab in the elementary school, a completely “hands-on” curriculum, teacher professional develop- Partnership programs can be as simple as summer employment ment and creation of community outreach programs. All directly or sabbatical arrangements that involve individual teachers directly link scientists to the curriculum. LabLion reaches more than in research laboratory projects. More ambitious and comprehensive 25,000 elementary school students across Pennsylvania, and we planning can establish workshops and institutes involving large have recently made plans for its dissemination elsewhere in the numbers of teachers. The work should focus on scientific content country, where it will be known as LabLearner.We need such and concepts as well as hands-on experimentation—components blends of theory and classroom activity within every subdiscipline often unavailable to teachers in their classrooms and in other pro- and every level of science education. fessional development programs. Failing to educate our public school students in science has far- To this end, a group of us in Pennsylvania has worked to estab- reaching consequences, not the least of which includes risking our lish the Governor’s Institute for Life Science Educators. It is an ability to maintain a competitive edge in an ever-increasingly tech- intensive in-residence program at the Penn State College of nology-based economy. Medicine attended each summer by one hundred K–12 teachers. We do not have to stop being scientists in order to play a signifi- They spend their mornings in activity-based, content-rich group cant role in K–12 education. At the same time, the basic education lessons that begin on Monday with the dissection of a human community deserves much more than part-time partnerships and cadaver and become more “molecular” as the week progresses, inte- promises. We scientists cannot back away once the novelty or com- grating biochemistry and biophysics. Afternoon and evening ses- munity spirit wears off. sions are devoted to grade level-specific content and lesson plans, as The time is right. If we genuinely commit to educating our young well as effective teaching strategies. Teachers genuinely value this students, we stand to make a major and lasting contribution to the experience, and the testing of participants’ content knowledge future of science education—and, inevitably, to the future of science before and after the program has established its success. The key, we itself. If we do not, I believe we lose the right to criticize our system of find, is that if teachers clearly see how their students will benefit, early science education; we will have to live with the knowledge that they will become committed to the process. we failed to seize an opportunity for meaningful change. H

hhmi bulletin | december 2002 29 NEWS& NOTES

A Chink in Melanoma’s Genetic Armor

series of recent discoveries may explain why malignant melanoma is Amuch deadlier and harder to treat than many other cancers. The findings, published in the journal Cell by a team that includes several hhmi fellows and investi- gators, have important implications for the development of new drugs that might bring melanoma under control. Melanoma occurs when melanocytes, which are normally stable, begin to divide. Melanocytes provide fair-skinned people with defense against sun damage. When exposed to ultraviolet (UV) rays, melanocytes manufac- ture melanin, giving the skin a tanned appear-

ance. Repeated or prolonged UV exposure, ON GROW

however, can damage the genetic material of JAS melanocytes, causing them to divide uncon- A team including Gaël McGill (left) and David Fisher (right) has found a master switch for melanoma. trollably and give rise to malignant melanoma. Melanocytes that have become malig- particular resistance to apoptosis.” Gabriela Motyckova and postdoc Martin nant are notoriously difficult to kill. Statis- The aim of many cancer therapies is to Horstmann, the Cell paper’s co-lead author, tics from the American Cancer Society bear induce apoptosis in malignant cells; it has also performed experiments suggesting this out: While melanomas account for only stands to reason, therefore, that cells with novel ways of rendering malignant versions 4 percent of the 1 million new skin cancer special resistance to apoptosis will not of the cells susceptible to apoptosis. cases diagnosed in the United States annual- respond to these types of treatments. The researchers discovered that stimula- ly, they account for 80 percent of all skin According to David E. Fisher, a former tion of a transcription factor called MITF cancer deaths. hhmi postdoc who is now an associate upregulates the expression of the Bcl-2 gene. What makes melanoma so tough? The professor at Harvard Medical School and In a large body of earlier work, team mem- key, reasoned hhmi predoctoral fellow Gaël Dana-Farber Cancer Institute, “while a con- ber Stanley J. Korsmeyer, an hhmi investi- G. McGill at Dana-Farber Cancer Institute nection between pigmentation and survival gator then at Washington University in St. and a team of investigators, lies in what is probably beneficial for normal pigment Louis and now at Harvard and Dana-Far- makes melanocytes special in the first place. cell function, the flip side is that it may con- ber, and other scientists had demonstrated Over eons of evolutionary time, melanocytes fer super survival properties and impede that Bcl-2 is a potent cell-death suppressor. developed the ability to withstand and successful therapy” once a pigment cell Fisher and others had also characterized the respond to assaults such as exposure to UV becomes malignant. biochemical and functional properties of radiation that would cause other types of Fisher, McGill and a team in Fisher’s lab MITF, determining that it is a “master regu- cells to undergo genetically programmed cell have devoted themselves to discovering the lator” of the process by which melanocytes death, or apoptosis. “Triggers that kill other precise genetic processes within melanocytes develop. When either MITF or Bcl-2 are cells don’t kill melanocytes,”McGill explains. that confer their resistance to cell death. The mutated or missing, black mice turn gray “These are cells that must have evolved a team, which includes hhmi predoc due to the death of melanocytes.

30 hhmi bulletin | december 2002 In collaboration with Todd R. Golub, an hhmi investigator at the Whitehead/Massa- Baseball’s Biochemist chusetts Institute of Technology Center for Genome Research and Dana-Farber, the team n June 4, 2002, Matthew McCarthy, a The third author on The EMBO Jour- has used DNA microarrays to demonstrate new graduate of Yale University who nal paper reporting this effort was M.D.- that in human tumors, the expression of the Ohad majored in molecular biophysics Ph.D. student Abhijit A. Patel. “Joan and cell-death suppressor Bcl-2 is tightly linked to and biochemistry, was drafted by baseball’s Abhi were great,” McCarthy says. “Abhi MITF. These experiments reveal that the link Anaheim Angels for its farm-team system, made me feel at home and took the time to is present in both normal melanocytes and in step one for players with major-league explain how experiments worked. They malignant melanoma cells. Specifically, when promise. A month later, while the lefty didn’t treat me as a jock or a dim under- MITF is present, the researchers have pitcher was perfecting his curve ball in graduate—they treated me as a fellow observed a rise in the amount of BCL-2 pro- Provo, Utah, his first scientific paper was researcher.” Then again, McCarthy earned tein and suppression of apoptosis. published in The EMBO (European Molec- such treatment. “Never before in 31 years The results reported in the Cell paper also ular Biology Organization) Journal. of teaching at Yale have I had an under- describe attempts by McGill and his collabo- Baseball was McCarthy’s ticket to graduate work in the lab for as rators to inhibit the activity of MITF in nor- science. In 1998, the Orlando high mal and malignant cells. Blocking MITF by school pitching star visited New infecting the cells with genetically engineered Haven and was sold on Yale after adenoviruses, they succeeded in killing both meeting baseball coach John Stuper, healthy and cancerous melanocytes. At the who had pitched the St. Louis Car- same time, they demonstrated that the dinals to victory in game six of the process works in reverse; cells in which the 1982 World Series, enabling them Bcl-2 gene was naturally overexpressed were to play and win game seven able to survive the researchers’ attempts to against the Milwaukee Brewers. induce apoptosis by blocking MITF. McCarthy eventually took a Now that a link has been established biochemistry course taught by between MITF and Bcl-2,some researchers hhmi investigator Joan A. believe that a new chapter in melanoma Steitz. I didn’t have a passion for research—and skin biology in general—has science, or biochemistry, until I been opened. The team’s findings “really fill took Joan’s course,”McCarthy an important gap of knowledge,”says recalls. “It was the best course Meenhard Herlyn, a researcher at The Wis- I took at Yale. She’s top-notch tar Institute in Philadelphia who studies the as a professor and a mechanisms behind the transformation of researcher. And she was then melanocytes into melanoma. nice enough to give me a Earlier research showing that Bcl-2 is a chance in her lab.”When suppressor of cell death has already inspired McCarthy asked if he could drug developers to conduct clinical trials perform original research with agents that seek to shut down the gene in the summer of 2001, he in cancer cells. McGill points out, however, applied for and received an hhmi summer that because Bcl-2 is expressed in every cell undergraduate research fellowship. He start- of the body, drugs that inhibit it could give ed working in the Steitz lab immediately Matthew McCarthy’s baseball card lists his rise to unwanted side effects. MITF, howev- after the baseball season. earned run average, strikeouts and other stats, er, is present only in melanocytes and a very McCarthy studied gene expression as a but no mention of his published scientific paper. limited number of other cell types. function of two different entities that splice Researchers in the Fisher lab are working out portions of RNA so that it can get trans- short a period as six months and truly to find agents that block MITF or interfere lated into the correct proteins—the U2- deserve coauthorship,” says Steitz. with its interaction with Bcl-2 expression. dependent spliceosome and the U12- While such praise is heartfelt, Steitz These would have potential as targeted thera- dependent spliceosome. He helped show admits to having a soft spot for ballplayers. pies for malignant melanoma. The task, says that the U12 is much less efficient than the She and her husband, fellow Yale faculty Fisher, is to “understand where within the more common U2. The guess is that U2 member and hhmi investigator Thomas pathway [between MITF and Bcl-2] there probably gets sent up to bat when feedback A. Steitz, are the parents of another recent might be drugable targets.” loops in the cell determine that less protein Yale molecular biophysics and biochem- —CAMILLE MOJICA REY should be produced. istry graduate and pitcher, Jon, a top draft

hhmi bulletin | december 2002 31 NEWS& NOTES

pick by Milwaukee in 2001 and currently in the Brewers’ minor-league system. Craig Aquariums Teach Ecology Breslow, yet another student in the same program, also became a Brewers’ farm- hand. (Apparently, understanding the bio- and Local History chemistry of anabolic steroids actually beats taking them.) hristina Langbecker’s 3rd-grade social its various types of marine life and habitat Most people probably don’t think of studies class at the Side by Side Com- are intricately linked with the history of the Yale as a brimming source of baseball talent, Cmunity School of South Norwalk, people who live and work there. Oyster har- but 17 players have signed professional con- Connecticut, is preparing for a field trip to vesting, for example, is a centuries-old way tracts since Stuper took over the team in the nearby shore. But first, they have to find of life along the Connecticut coast. 1993. Going back further, major leaguers their way. “This is like the Berlitz Method of learn- from Yale include pitcher Ron Darling, a With compass and city map, the stu- ing science: total immersion,”says Marie Ian- member of the 1986 World Series-winning dents chart their course to the local beach, nazzi, interim director of the Side by Side New York Mets, and original 1962 Mets where each is responsible for finding an ani- school. After Langbecker’s 3rd-graders finish player Ken MacKenzie, who returned to Yale mal—a blue crab or an oyster, for exam- their marine-animal scavenger hunt, for to coach baseball in 1969. ple—in its natural environment. Some stu- example, they discuss the relationships Although fans may assume that profes- dents search the sandy shore while others between the plants and animals of the sound sional ballplayers are all millionaires travel- investigate a rock jetty or a salt marsh—the and their habitats, they compare animals in ing to games in private jets, the minor three major habitats of the Long Island the aquarium and those in their natural envi- leagues are called the “bus” leagues for a rea- Sound. They are trying to understand why ronments, they investigate the kinds of indus- son. “We traveled 17 hours to play a team in some animals prefer one kind of home and tries along the shore and how they might Canada and 14 hours to get to Billings others favor entirely different conditions. affect marine life and they design and carry [Montana],”McCarthy says. “We have 12- Why study marine science in a social out experiments. The students also paint hour days—running, lifting weights, playing studies class? Because, as the students dis- murals of the sound’s plants and animals. the games. It’s definitely not as glamorous as cover, the ecology of Long Island Sound and At the end of their projects, each 3rd- you’d think. We stay in lots of crummy motels. But we are playing baseball for a liv- Rick Sigmund, an educator at Norwalk, Connecticut’s Maritime Aquarium, helps 3rd graders from the ing, and that’s great.” Side by Side Community School explore local marine life at nearby Calf Pasture Park. While McCarthy is on the road, the Angels organization is focused on refining his talent. “They’re making mechanical adjustments in my delivery, so my velocity is down a bit and at times it’s hard to hit spots, especially when facing good competition like Prince Fielder.”Fielder’s dad is former major-league slugger Cecil Fielder, a genetic legacy McCarthy and his biochemistry bud- dies can no doubt appreciate more than most other minor leaguers. Despite McCarthy’s athletic promise, “I predict that Matt will leave his mark in the field of medicine,”Joan Steitz wrote in a ref- erence letter for McCarthy. The 22-year- old’s experiment with baseball, however, will make medicine wait. He’s put off apply- ing to medical schools. First, he hopes to move up the Angels’ minor-league ladder in 2003 and play for the Cedar Rapids Kernels. Dwight Gooden was called “Doc” when he pitched for the Mets. Perhaps pitcher Matthew McCarthy will take the mound one day having truly earned the nickname. —STEVE MIRSKY

32 hhmi bulletin | december 2002 grader produces a written report and pres- the epa to adopt the performance-based ents his or her findings to an audience of EPA Agrees to standards developed by the team and to peers and parents. “The students exhibit a “promote conformity and consistency firm grasp of marine science and its impli- Smarter Waste among epa regional offices and state envi- cations,”says Iannazzi. ronmental-protection agencies” in applying These Side by Side student activities are hazardous-waste regulations. part of a new program, called Project alta Management The August 2002 epa memo, while a (All Living Things Adapt), designed by sci- he U.S. Environmental Protection seemingly small step, will make a huge dif- ence educators at the school and at the Mar- Agency (epa) has endorsed two key ference in the day-to-day operations of itime Aquarium in Norwalk, with support Trecommendations of an hhmi-led university research laboratories, says W. from hhmi.Project alta weaves science— initiative to make the handling of hazardous Emmett Barkley, director of hhmi’s Office and the scientific method—into the school’s waste from university laboratories less bur- of Laboratory Safety. With overall disposal social studies curricula from kindergarten densome and more effective. The changes shifted to trained university waste-manage- through 8th grade. The goal is to show stu- should enable universities to reduce their vol- ment officers who handle the waste stream dents how science pervades their lives. ume of hazardous waste, increase recycling for the entire institution, each lab no Across the country, other aquariums and more efficiently handle waste removal. longer needs to do its own labeling and have helped develop similar projects with In an August 2002 memorandum to its classification of hazardous waste, nor navi- hhmi support. The National Aquarium in regional offices, the epa stated that central- gate the sea of paperwork necessary for Baltimore, Maryland, and 10 of the city’s ized university health and safety offices can epa compliance. It also means labs have public schools created “AquaPartners” for assume the responsibility of handling haz- more flexibility to adopt effective pro- 4th- and 5th-grade students and teachers to ardous wastes in accordance with epa regu- grams, such as trading in unused chemicals study the Chesapeake Bay and its marine life. lations. This approach would supplant rather than sending them to hazardous- The New Jersey State Aquarium aims to holding individual laboratories responsi- waste facilities. boost minority participation in the science ble—the standard in some regions of the “The memorandum validates what workforce by providing summer science country. The epa also stated that universi- some universities are already doing,”says camps, an after-school ecology club and a ties can treat some waste on-site to cut Barkley. “We expect that many of the high school “junior staff” program to local down on volume and toxicity. remainder of the large research universities students. Sound Science, a program devel- These changes address problems stem- will now adopt the performance-based oped by the Seattle Aquarium with ming from enforcement of hazardous-waste approach outlined in our report.”The epa Seattle Public Schools, uses the standards, in place since 1981, that were is considering additional actions to address marine life and habitats of the designed to regulate chemical manufactur- other recommendations made in the Puget Sound to teach science to ing plants that create large quantities of group’s report, Barkley added. school children. waste. These same rules also applied to uni- “The epa has enunciated an approach Each aquarium program pro- versity research laboratories, which tend to to regulating hazardous wastes in the uni- vides teachers with course materi- generate small quantities of waste, though versity laboratory that recognizes the als and exposure to the most from an ever-shifting panoply of chemicals. unique culture of an academic research recent discoveries, often through Inconsistent interpreta- organization,”says Robert hands-on participation in tion of epa rules from BEST PRACTICE PROJECT R. Rich, immediate past research. Teachers also participate region to region prompted PARTICIPANTS president of the Federation in workshops, laboratory studies hhmi’s Office of Laboratory Duke University Medical Center of American Societies for and field excursions. Safety in 1999 to assemble a Harvard University Experimental Biology, The programs, most of which team of environmental which had joined with began in 2001, are in the process health and safety directors Stanford University hhmi in urging changes in of being independently evaluated and regional and national The Rockefeller University waste handling. “This col- by experts in learning. But, Jack epa representatives to try to University of Colorado, Boulder laboration has proved that Schneider, director of education at effect change (see hhmi academia and government University of Pennsylvania the Maritime Aquarium in Nor- Bulletin,December 2001). can successfully and cre- walk, knows the programs work. The group formulated “best University of Texas Southwestern atively partner to increase He sees the excitement of learning, practices” for handling haz- Medical Center efficiency, environmental he says, by “the enthusiasm of the ardous waste and put its University of Washington health and safety.” students, the pride and compe- ideas into action at 10 partic- University of Wisconsin–Madison —KARYN HEDE tence of the teachers and the looks ipating universities. The HHMI report is available Washington University » on the parents’ faces.” In October 2001, the School of Medicine online at www.hhmi.org/

COURTESY OF MARITIME AQUARIUM COURTESY —TRENT STOCKTON group issued a report urging research/labsafe/

hhmi bulletin | december 2002 33 NEWS& NOTES Boosting Brain Repair fter former President Gerald R. Ford suffered a stroke at the 2000 Republi- Acan National Convention in Philadel- phia, neurologist S. Thomas Carmichael appeared on cnn as an expert in stroke treatment. His interviewer asked if the emer- gency room staff were at fault for not recog- nizing Ford’s symptoms on his first visit. But Carmichael, at the time an hhmi postdoc at the University of California, Los Angeles (ucla), pointed out that early symptoms of stroke are difficult to recognize, and, worse yet, when a stroke is suspected, treatment options are often limited. Now an assistant professor at ucla, Carmichael and his colleagues are trying to fill the treatment void with a new approach—tracking brain waves that coax OM KELLER

growth of new electrical connections in the T brain. Their most recent findings, reported S. Thomas Carmichael has coaxed neurons in rats to grow new axons after stroke-like injury. in the July 15, 2002, issue of the Journal of Neuroscience,suggest a similarity between tracking down the brain’s repair-promoting rons grew sprouts. Without it, no sprouts signals sent out in response to stroke and signals after seeing evidence established by appeared. signals known to stimulate the building of other researchers that such signals exist: “Relatively speaking, the [sprouting] neuronal circuits in developing brains. Nerve cells in the brain can produce new neurons were miles away,”Carmichael says. Carmichael is not trying to find drugs sprouts that grow into long offshoots called Prompted by the distress signals, axons that protect the brain against damage. axons to rewire important brain circuits established long-distance projections to the “We’ve seen 37 failed clinical trials of neuro- that are disrupted when the blood supply is precise site where connections had been lost. protective agents,”Carmichael says. “The cut off during a stroke-like injury. Carmichael and colleagues encoun- field is ripe for a new agent that works in a To find out how stroke damage sparks tered another surprise: The signaling different way.”He is instead attempting to the growth of these sprouts, Carmichael patterns found in stroke-damaged brains exploit the brain’s ability to repair itself after and colleagues monitored electrical activity mirrored patterns detected in developing the damage has occurred. in the brains of rats immediately after brains during periods of rapid growth. “All stroke patients recover to some choking off critical brain arteries by zap- The work on the original wiring of the degree,”Carmichael says. Ford, for example, ping them with a thermal probe. “We were brain was done independently by hhmi recovered almost completely from the bal- surprised at how interesting these signals investigator Lawrence C. Katz, at Duke ance and speech problems that prompted turned out to be,” Carmichael says. Rather University, and hhmi Medical Advisory his visit to the emergency room. Most often, than picking up an indiscernible jumble of Board member Carla J. Shatz, at Harvard however, patients do not fully recover. electrical activity, electrodes placed Medical School. Their results, Carmichael “They may go from 80 percent disabled to throughout the rat brains recorded distinct says, indicate that the signals found by his 30 percent within six months to a year,”he patterns that indicated the brains were get- group may be part of a general brain says. The remaining disabilities—often ting a tune-up. Bursts of discharges were growth-promoting system. involving slurred speech or various degrees first detected surrounding the stroke-dam- He plans to continue tracking these sig- of paralysis—overshadow the recovery. aged area within a day of injury. Two to nals to pinpoint the sites of repair-related Carmichael hopes that finding the brain three days later, a chorus of neurons in a electrical activity, with hopes of finding a signals that stimulate repair after a stroke distant part of the brain answered back chemical signal that could lead to drugs will lead to drugs that can boost recovery to with a slower, rhythmic electrical refrain. If designed to boost axon growth after stroke. near-normal levels of function. He began the distinct pattern was present, the neu- —JILL WAALEN

34 hhmi bulletin | december 2002 the mechanic can list the parts and deter- Keeping Up with the Revolution mine how they function as a system. Genomics and chemical genetics are tuart L. Schreiber hopes his ground- hhmi Holiday Lectures on December 5 “popping the hood” for biology, providing a breaking research in chemical genet- and 6, called “Scanning Life’s Matrix: Genes, comprehensive, yet finite, parts list and Sics, which identifies the chemicals Proteins and Small Molecules.”They point- instruction set that eliminates the unpre- that modulate cellular processes, will one ed to the power of Internet databanks of dictability of studying life systems, Lander day be so obvious that high school students genetic sequences, such as GenBank, and of says. GenBank is already indispensable for will shrug, “Of course, how could it be any chemical interactions, called ChemBank, as working biologists and will become impor- other way?” Eric S. Lander, a leader in tools for research and medicine. tant for students, too. Although students genomics, the identification of the genes Lander uses a car analogy. Studying tra- cannot sequence a genome or knock out a that program those processes, agrees. “The ditional biology, he says, is like being a car gene to study its effects, they can access goal of this extraordinary scientific revolu- mechanic who cannot look under the hood. GenBank to conduct “virtual” experiments. tion,”he says, “is to be taken for granted as The mechanic can listen to the engine or For example, they could study evolution quickly as possible.” examine pieces that fall off to hypothesize by downloading and comparing genes for cell Schreiber, an hhmi investigator at Har- how it works. Still, he has no way to know division, reproduction and sensory receptors vard University, and Lander, director of the how many parts there are or what they do. from human, mouse, fly and bacterium Whitehead Institute/mit Center for Then somebody pops the hood. At first, the genomes, Lander says. They might find that Genome Research, collaborated on the 2002 engine looks complicated, but eventually genes for cell division have changed little over millions of years, while those for reproduction changed Report Urges Changes in College Biology very differently from species to species as these organisms Undergraduate biology education is not keeping pace with the rapidly changing arena of biological evolved. For smell-receptor research, concludes a new report from the National Research Council of the National Academies. genes, they would find a pro- BIO2010: Transforming Undergraduate Education for Future Research Biologists is the culmination of liferation in mice, while many an 18-month examination of how best to prepare the next generation of life-sciences researchers. of the human versions have The study was sponsored by hhmi and the National Institutes of Health (nih). become nonfunctional. This “Biology has changed,”says Joan A. Steitz, an hhmi investigator at Yale University and a mem- would indicate that mice rely ber of the committee that wrote the report. “The frontiers are now on the interface with more on smell more than humans quantitative sciences, such as structure determination and bioinformatics. Therefore, biology stu- do and that unneeded genes dents need stronger backgrounds in mathematics, engineering, physics and computational science deteriorate. in order to succeed in future research.” ChemBank, though still a The committee, which was asked by hhmi and nih to make recommendations on undergrad- prototype, will provide similar uate biology-curriculum reform, proposed that biology majors should receive much broader expo- power by cross-referencing sure to the methods of the physical sciences and mathematics. At the same time, the committee rec- proteins, small molecules and ognized that students should receive a broad liberal education as well. experimental observations, After studying several approaches, the group recommended the incorporation of physical and says Schreiber. Students could, information-science content into existing biology courses. In addition, they suggested that labora- for example, demonstrate tory courses become as interdisciplinary as possible and provide exposure to real-world laboratories how a drug interacts with cel- that routinely use techniques from both the biological and physical sciences. lular signals in a way that In effect, the committee urged college and university faculty to retool their courses to include the causes unwanted side effects. new integrative biology. And to give some assurance and inspiration, the report highlights case studies Schreiber describes these of innovative teaching methods that have been successful both at large universities and small colleges; databases as “hypothesis- the report also lists links to Internet-based resources. generating engines” that are The just-implemented hhmi Professors program essentially affirms the report’s conclusions and great equalizers. High school puts some of its recommendations into action. In announcing the new program’s first 20 appointees, students can have the same Institute President Thomas R. Cech noted that “we wish to empower scientists at research universities access as scientists. “The only to become more involved in science education and come up with innovative ideas that break the mold limit,”Lander says, “is your and take a fresh look.” —KARYN HEDE imagination in thinking up questions” and in the com- » The full text of the BIO2010 report is available at www.nap.edu/catalog/10497.html. Print copies may be puter’s ability to recognize obtained by calling (888) 624-8373 or (202) 334-3313. patterns in the data. To realize such creativity,

hhmi bulletin | december 2002 35 NEWS& NOTES

student and scientist alike must cultivate eral science lectures, watch “nova,” read ies into usable classroom exercises. an interdisciplinary mind-set, says Scientific American”to become familiar Today, it takes a courageous teacher with Schreiber. “Life science is tackling complex with work in many different fields. advanced computer skills to incorporate problems that can only be solved through To make true progress, however, multi- these databases into classroom learning. multidisciplinary approaches.”He disciplinary approaches must be integrated One day, however, they predict that the acknowledges, however, that this is easier with information sciences, he says. “Our necessary tools will become ubiquitous. said than done. Teachers should focus on experiments generate staggering sheets of No one will be able to conceive how peo- underlying connecting principles that data that would run around the planet. We ple ever learned biology in the dark ages many fields have in common. To make that cannot easily make sense of that informa- before genomics and chemical genetics, job easier, he encourages using familiar, tion unaided, but with the help of comput- just as most scientists cannot imagine simple and precise language, devoid of the ers, amazing patterns emerge.” how anyone studied chemistry before the jargon that isolates scientists from other Thus it’s no surprise, Schreiber and periodic table. —CATHRYN M. DELUDE fields of research. In addition, Schreiber Lander note, that teachers need sophisti- » For more information, see www.hhmi.org/ urges teachers and students to “go to gen- cated tools for translating new discover- lectures/2002

attended from the United States and abroad. Young Scientists Learn the Karen M. Ottemann, a microbiologist in her third year as an assistant professor at the Management Ropes University of California, Santa Cruz, says the step from postdoc to PI requires not only a ohannes Walter faced shift in thinking but a whole unfamiliar challenges as reconstruction of one’s day: “You Jhe started up a molecular transition to being a PI, and you biology lab at Harvard Medical have all these new responsibili- School in 1999. At the Universi- ties. You have to mentor more ty of California, San Diego, he students and less-senior had excelled as a postdoc, pub- researchers, you have to attend lishing papers on DNA replica- faculty meetings, write your tion in prestigious journals such grants—and balance it all.” as Science and Molecular Cell. Some find managing their But running a laboratory as money to be the big challenge. principal investigator (PI), he That might explain why atten- soon realized, required more dees packed the session on UL FETTERS

than scientific smarts. PA applying for the coveted nih For one thing, assembling a Postdocs and new PIs attended a course to learn how to run a lab. RO1 grant—the gold standard top team of postdocs wasn’t in multiyear, federal grants.“The going to be easy. “You’re a new PI, nobody sors, however, the tasks of coordinating most surprising thing was cost,”says Bernar- knows who you are and you’re competing staff, budgets and grants often pose a harsh do L. Sabatini, a second-year PI at Harvard with the best in your field,”says Walter. He reality—they weren’t trained for this. Medical School, where he runs a five-person quickly learned the recruitment game— “Our energies are so focused on getting neurobiology lab.“I thought I was okay with sending inquiries by e-mail to colleagues in the job—then what?” asks E. Lynn three or four private foundation grants. But the field, flying in candidates from near Zechiedrich, a PI in molecular virology and I’m running through money like you would- and far, even hosting some of them at his microbiology at Baylor College of Medicine. n’t believe.”Average startup costs for new home in Boston—and the effort paid off. Answering that often-overlooked question labs in the life sciences can run from His Harvard lab now hosts a research was the goal of the first annual Course in $100,000 to $1 million, excluding salaries, group of eight, including postdocs, gradu- Scientific Management held at hhmi head- according to the Burroughs Wellcome Fund. ate students and a research assistant. quarters in Chevy Chase, Maryland, in July. Many saw the four-day course as an During years of graduate work and Sponsored by the Burroughs Wellcome especially welcome opportunity to speak postdoctoral fellowships, young scientists Fund and the Institute, the course included with others who were going through the focus on their research, with hopes that sessions on collaborations, writing National same process, and those who had survived strong papers will help them garner first- Institutes of Health (nih) grant proposals it. “It’s reassuring,”says Yashi Ahmed, a new rate faculty positions. When these same and time management and mentoring skills. PI at Dartmouth College, “that many people researchers land jobs as assistant profes- Postdocs and new faculty—127 in all— here have the same fears.” —ELI KINTISCH

36 hhmi bulletin | december 2002 INTERVIEW Israeli Scientist Soldiers On A conversation with Shulamit Michaeli

hulamit Michaeli, an hhmi inter- over another’s work or to take national research scholar at Bar- credit for it. Beyond the proj- Ilan University near Tel Aviv, stud- ect and the papers, it is the ies messenger RNA production students themselves I am con- and protein sorting in a family of cerned about. When one of Sparasites called tryapanosomatids—the them was doing military serv- causes of sleeping sickness, Chagas dis- ice, a bomb exploded and ease and leishmaniasis. The latter is injured him; bits of shrap- endemic in the Middle East, where it is Q nel are still coming out all spread by the bite of sand flies. The dis- over his body. One piece ease affects the spleen, liver and bone & hit very near his eye, and marrow and can be fatal. A he was lucky not to lose his In a country where suicide bombings eyesight. In the lab right and military skirmishes have become a way next to mine, a graduate stu- of life, Michaeli knows only too well the dent lost her husband on their meaning of “under the gun.” first anniversary.

Isn’t it difficult doing science in your Aren’t you afraid for your war-torn country? personal family? Michaeli: We live under pressure, but I like Michaeli: Of course. One of my work so much that it helps me cope. I the bombings was in Herzliya, concentrate on the science and try not to the town where my parents

think about the bombings. The university is live, in the shopping center KENT KALLBERG well guarded, so the safest place to be is in where they buy fish for the Shulamit Michaeli’s students call from the tanks to check experiments. the lab. Still, the war is everywhere. The sol- weekend. Right away I called, diers are on the tanks, but this is everyone’s but at first the phone lines were all occu- ty of California, Berkeley] and at ucsf war. The kid who goes to school, any of my pied, and I got really nervous before I [the University of California, San Francisco]. students, anyone who goes to a shopping found out that they were safe at home. I I am sure I could get a good job in the Unit- mall or gets on a bus is a soldier. This is not have three wonderful children, Ram, 7, ed States or Europe. But I went to the U.S. going to break our spirit. We see it as our Shai, 9, and Bar, 11, and I am always won- to train so that I could go back to Israel as mission to continue life as normally as we dering, where are the kids? When school a professor of microbiology. It was my can. I can contribute by continuing my vacation starts, my husband [Moshe Gold- life’s goal. I was born in Israel, and I’m active research and academic activities. berg, a chemist who works for the Israeli proud to be Israeli. We are only a small Ministry of Defense] and I become even country, but we are asking important ques- How does the situation affect the more nervous, because the kids want to go tions that are central to science. I am graduate students and postdoctoral fellows out everywhere. I’m not just concerned proud of my country’s achievements, and in your lab? about their physical well-being; I am con- I believe we must cherish and fight for Michaeli: All 13 of my students are in the cerned about their emotional well-being, what we have. My parents are here. My reserve forces, and 5 of them have been growing up under constant fear. heritage is here. I want my children to grow called to active duty since April [2002]. One When I go to other countries and hear up proud to be Israelis too. I do not think has been called up twice. Sometimes they people talking about their plans for summer about leaving. Also, not one of my stu- phone from the tanks to check on their vacations, I realize how different we are. I am dents plans to leave Israel. Even my two research; one of them called recently to make thinking about whether my family and my graduate students and a postdoc from sure his parasites were fine. We try to contin- students are going to be alive next summer. China haven’t left. In fact, one of them ue their work while they are away—our lab recently brought his wife and child to join is a family, and we all pull together to get the Have you ever considered leaving Israel? him here. job done—but I don’t allow anyone to take Michaeli: I trained at Berkeley [the Universi- —JENNIFER BOETH DONOVAN

hhmi bulletin | december 2002 37 HHMI LAB BOOK RESEARCH NEWS FROM HHMI SCIENTISTS

IN BRIEF New Take on a Malaria Vaccine Relief for Rett syndrome Scientists have designed a mouse model of Rett ew therapies for syndrome, the leading cause of mental malaria are in demand retardation in girls. Using the model, Nbecause the malaria they plan to probe how the MECP2 parasite, Plasmodium falci- gene, which is mutated in the disorder, parum—which affects some affects brain function. 5–10 percent of the world’s Researcher: Huda Y. Zoghbi population—is rapidly www.hhmi.org/news/zoghbi5.html becoming resistant to stan- dard drugs. Most vaccines When Gleevec fails The drug Gleevec under study have been made doesn’t work in some patients who have to target parasite proteins chronic myelogenous leukemia (CML), and have not proved effective. it turns out, because specific mutations hhmi international in a rogue gene render the drug ineffec- research scholar Louis tive. Screening for the mutations will Schofield has taken a differ- help determine the best therapy for each ent approach, with promis- patient. The discovery may also lead to ing results. He and his team better anti-CML drugs. at the Walter and Eliza Hall Researchers: Charles L. Sawyers and Institute of Medical Research John Kuriyan in Melbourne, Australia, had www.hhmi.org/news/gleevec.html previously shown that the main toxin produced by the When a vaccine fails A subtle abnor- parasite—a sugar called gly- mality in the immune system may pre- cosylphosphatidylinositol

vent certain people from responding well (GPI)—caused a strong AND ELIZA HALL INSTITUTE WALTER DREW BERRY/THE to a vaccine for Lyme disease. The dis- inflammation response in Target the Toxin Infected mosquitos inject malaria parasites covery of this abnormality, which other- cells in culture and in mice. into an animal’s bloodstream. The parasites invade red blood cells and wise appears to exert no ill effect, under- This meant that the immune multiply within. Diseased red blood cells burst open, releasing parasites scores the importance of exploring the system was aggressively and toxins. Schofield and colleagues are using part of the toxin to stim- immune system’s protective pathways combating the molecule. So ulate immunity against malaria. for fending off microorganisms. The stud- the researchers, together ies also suggest several ways to improve with Peter H. Seeberger at the Massachusetts against some of the severe complications of the Lyme disease vaccine. Institute of Technology, identified the specific malaria, including pulmonary edema. Researchers: Richard A. Flavell, Erol part of GPI that made it act as a toxin and “The study provided the first proof of the Fikrig and Ruslan Medzhitov cause such a reaction, and they fashioned a toxin’s role in malaria,”Schofield says. “It www.hhmi.org/news/flavell2.html pure version of this part of the GPI molecule. established the toxin as a cause.”Results of the To see if this GPI extract might work in a research appeared in the August 15, 2002, Structural problem Subtle defects vaccine, Schofield and his colleagues injected issue of Nature. in the processing of a single protein that mice with it (in combination with large carrier Next steps: “We want to develop the vac- provides structural integrity to muscle molecules that trigger recognition by the cine further and develop a program to simpli- cells can lead to muscular dystrophy. This immune system) in an attempt to immunize fy the synthesis, making it easier and cheaper,” finding will help improve diagnosis and the animals against malaria. They then Schofield says. Over the next few years, he and genetic counseling and should eventually exposed the mice to the malaria parasites and his colleagues plan to create a variety of anti- help doctors tailor their interventions. found in initial tests that the potential anti- GPI vaccines and test them in other animal Researcher: Kevin P. Campbell GPI vaccine indeed provoked a strong anti- models of malaria. www.hhmi.org/news/campbell4.html body response, protecting the mice in part » www.hhmi.org/news/schofield.html

38 hhmi bulletin | december 2002 IN BRIEF

Weed for cancer? A chemical isolated from a weed that grows in mountain meadows of the western United States kills the cells of an aggressive childhood brain cancer in mice. The compound, cyclopamine, blocks a signaling pathway that appears to be important for the sur-

, 297:365-69, FIGS. 3A&B, 2002 COPYRIGHT AAAS COPYRIGHT 2002 3A&B, FIGS. , 297:365-69, vival of medulloblastoma. Researcher: Philip A. Beachy SCIENCE www.hhmi.org/news/beachy2.html

Cancer cell wrecking ball Researchers have identified a compound

WITH PERMISSION FROM WITH PERMISSION that selectively kills tumor cells by Mindful Mouse The brain of the normal mouse embryo (left) is small, smooth and flat. In mice destroying their mitochondria, or meta- specially engineered to overexpress ß-catenin, the cerebral cortex or "gray matter" of the brain is bolic power plants. The compound, enlarged, with ridges more characteristic of human and primate brains. named F16, seems to be active at rela- tively low concentrations, which the sci- entists suggest will be important in ties—expanded much more than the rest of reducing any toxicity. Building a the brain. During an hhmi postdoctoral fel- Researchers: Philip Leder and lowship in Walsh’s lab, Chenn set out with Valeria R. Fantin Bigger Brain Walsh to learn how and why. www.hhmi.org/news/leder.html The cerebral cortex varies a great deal in esearchers have found a protein switch shape and size among animals. It is small, Trading places By determining how a that increases the growth rate of the smooth and flat in rodents, for example, and a form of lymphoma can develop in mice Rcerebral cortex in specially engineered large, wrinkled sheet made up of repeating when large pieces of chromosomes young mice. columns of cells in humans and other pri- exchange locations, researchers have “We saw [embryonic] mice with enor- mates. “The human expansion has occurred gained a fresh perspective on how can- mous brains,”says Anjen Chenn, an assistant largely in the surface area, making it 1,000-fold cers arise from an increased “dosage” of professor of pathology at the Northwestern larger than in the mouse,”says Walsh.“We specific genes or regions of the genome. University Institute for Neuroscience. The wanted to find out what factors controlled the The discoveries should lead to a better cerebral cortex of these transgenic mice grew expansion of neurons and other brain cells understanding of how deficiencies in dramatically, expanding horizontally in area and how that might be regulated.” DNA repair and in the cellular DNA dam- but not in thickness. These changes produced They had some clues. ß-catenin was one age-detection system can cause tumors. the characteristic ridges and grooves that candidate for regulating the proliferation of Researchers: Frederick W. Alt, Cheng- anatomically distinguish human brains from precursor brain cells because it is known to ming Zhu and Kevin D. Mills those of lower animals. control cell growth and has been implicated in www.hhmi.org/news/alt3.html The switch that’s responsible, called ß- some brain tumors. To see whether it regulat- catenin, appears to be “telling the precursor ed brain growth, the scientists created trans- Stocking up on stem cells cells to keep dividing, rather than stopping genic mice that overexpressed ß-catenin in the Researchers have discovered a protein in and making a mature differentiated neuron,” neural precursor cells. the roundworm Caenorhabditis elegans says Chenn. He and hhmi investigator The team plans to study ß-catenin’s role that maintains a reservoir of germline Christopher A. Walsh, at Beth Israel Deaconess in a variety of other species with different- stem cells—the cells that are the source Medical Center and Harvard Medical School, size cortexes. But they harbor no illusions of sperm and eggs. The protein, FBF, is reported their findings in the July 19, 2002, that it calls all the shots. “We are certain,” necessary for germline stem cells to issue of the journal Science. says Chenn, “that the increase in brain size develop into both sperm and egg; with- Scientists have known for quite some time over evolution is going to be more compli- out FBF, the stem cells mature into only that during human evolution, the size of the cated than just due to changes in one gene sperm. The finding helps bring together a cerebral cortex—the “gray matter” region and one protein.” growing body of evidence on how stem that’s responsible for higher intellectual abili- » www.hhmi.org/news/walsh.html cells are regulated at the molecular level. Researcher: Judith Kimble HHMI Lab Book written by Steven I. Benowitz www.hhmi.org/news/kimble2.html

hhmi bulletin | december 2002 39 HANDS ON Investigating Murders in Miniature Dollhouse crime scenes teach students how science can solve real-life problems.

orty high school students gathered at the University of Maryland’s College Park campus this summer to play with 1 Fdolls—all in the name of serious science. During a weeklong course on forensic science, they heard experts explain the fine points of DNA fingerprinting, microscopic analysis, crime-scene and evi- dence preservation and ink chromatography. But the capstone was a session with a special set of dollhouses that simulate crime scenes. By featuring forensic science, the hhmi-funded summer science program, called Jump Start, captures the interest of students enthralled with popular television programs such as CSI and Crossing Jordan,says Kaci Thompson, director of undergraduate research and internship programs at the university’s college of life sciences. It also happens to incorporate aspects of several scientific disciplines—including anthro- pology, biology, chemistry, criminology and psychology. After spending four days studying the techniques of the forensic scientist, students peer inside meticulously crafted dollhouse crime scenes depicting victims, locations and lines of evidence. They (5) ROBERTS MOLLY debate possible scenarios. “I don’t think he was whacked,” says one 1. Chinyere Okol, Timothy student. “He’s not in an awkward position at all.” Another adds, “I Simons, Prabu Selvam, June think if he was dragged, his arms would be stretched back.” Later, Streets, Taniesha Hunter and they assess their powers of deduction when instructors reveal what Benjamin Miller (from left to each scene actually represents. right) discuss a dollhouse crime scene. Based on evidence pre- Thomas P. Mauriello, a professor of forensic sciences in the uni- sented (blood stains, footprints versity’s department of criminology and criminal justice, conceived and possible murder weapons, for of the dollhouses 10 years ago after seeing a similar set at the State example), they exchange ideas of Maryland’s medical examiner’s office, where they are used for about the nature of the crime, the time at which it was commit- training. Mauriello designed and furnished the dollhouses, with the ted, the cause of death and help of graphic artists, to use as a teaching tool in his undergradu- whether or not the scene actually ate class, Introduction to Criminalistics. He says the structures help depicts a crime at all. him integrate the techniques of forensic science into a cohesive and realistic process. The Jump Start students, juniors and seniors hailing from the greater Washington, D.C., area, are selected on the basis of grades, teacher recommendations and essays. According to Thompson, the program doesn’t necessarily aim to encourage students to pursue the field of forensic science. Rather, it tries to show students how knowledge of a broad range of scientific meth- ods can be used to solve real-world problems. Katherine Beling, a senior at Baltimore’s Catholic High School, liked the approach. “This gave us a chance to use our own imaginations rather than just look at DNA samples under a microscope.” Now in its fourth year, the program also includes two additional one-week high school courses, one focused on biotechnology and the other on animal behavior and physiology. —EUGENE RUSSO

40 hhmi bulletin | december 2002 2. Evidence, including footprints, a broken table lamp, blood stains and marks from the burglar’s crowbar, help students piece together how this living room burglary took place. The position of the door and the lamp and the two different blood stains suggest that the perpetrator stood behind the door, struck and killed the homeown- er with the table lamp, cutting him- self in the process, and then fled.

3. Bullet casings, an open safe, a shotgun and splattered blood from a shotgun wound are clues used by stu- dents to solve this attempted conven- ience store robbery. When the masked suspect turned to flee, cash in hand, the clerk shot him with a semiauto- matic weapon retrieved from the safe. As he was shot, the thief returned fire with his shotgun. Both the suspect and the clerk are found dead.

4. Suicide or accidental death? After moving her car into the garage, the victim locks her keys in the car— perhaps by accident, perhaps deliber- ately. The key chain also holds the key to the house. The victim slips on dog feces and hits her head on a toolbox. She and her dog die from carbon monoxide poisoning. 2

4 3

hhmi bulletin | december 2002 41 FROM THE T OOLBOX Slipping Past a Cancer Cell’s Defenses Protein transduction carries therapeutic possibilities.

n at least one respect, mammalian cells smaller protein fragments, called peptides, are like homeowners in a high-crime and then slip the entire package through a Iurban neighborhood: They are extreme- target cell’s membrane. Once across this bar- ly careful about who they let through the rier, the shipped protein is always at least front door. Unlike houses, of course, cells partially akimbo. But the cell’s internal have many thousands of “doors”—channels machinery refolds the protein into its and receptors—dotting their exterior, and correct, therapeutic shape. In such a case, the among the more obvious criteria for passage cell’s aversion to big things is overcome by an 1 through any of these is size. Large, complex ingenious molecular sleight of hand, bad for molecules such as proteins usually don’t have the diseased cell but potentially good for the Protein transduction in a mouse model a chance. They’re much too bulky to well-being of the larger organism. Once of human metastatic ovarian cancer. Fifteen min- negotiate tiny channels or to slip through the inside a cancer cell, for instance, a refolded utes after injection of a peptide labeled with pores of the cell’s membrane. therapeutic protein might precipitate the green fluorescence, most cells in the abdominal Like the alert urban homeowner, the cell demise of the cancer cell, while other, healthy cavity, where ovarian cancer cells have invaded, has good reason for being vigilant. In nature, cells in the area would be unaffected. have taken up the peptide. observes Steven F. Dowdy, an hhmi investiga- Elaborating on the metaphor of the well- tor who studies cancer at the University of guarded house, Dowdy says imagine that you But the only way information can enter the California, San Diego,“large” typically means want to tell the residents (or, perhaps more house is through the mail slot, a tiny area rel- viruses and other pathogens—precisely the fittingly, the appliances) to do something. ative to the size of the house. A single sort of visitors that the body’s envelope that can fit through the slot immune system works hard to repel. contains a limited amount of information, Formidable cellular membranes are a Dowdy says.“Some [information] can be protective measure evolved by very specific—go to the corner, buy some multicelled organisms for the express milk.”But in general, the level of instructions purpose of keeping big, nasty things is tightly constricted. This is analogous to the out whenever possible. information load carried by the small- Not every large molecule is a molecule drugs that are currently available. predator, however; some, if they “What we’ve done with protein transduc- could be brought inside diseased tion is we’ve taken your computer, slipped it cells, might have therapeutic effects. through the same mail slot, reassembled it on That’s the premise driving the work the inside with all the information on the of Dowdy and his colleagues: They hard drive intact,”he says. Once a protein is have devised a method they hope smuggled past the membrane, basic cell will enable them to smuggle some biology takes over. Within the cell wall are very large molecules into molecules called heat shock proteins, or mammalian cells—specifically, can- HSPs. These elite repairmen cruise around in cer cells. Their technique is called search of damaged proteins to refold and protein transduction, the art of restore into good working order. Fortunately, convincing a resistant cell says Dowdy, HSPs are indiscriminate: They membrane to accept something VID KILPER don’t care how a misfolded protein falls on DA much larger than its liking. Steven Dowdy says that, in theory, transduction can be used their doorstep, only that it’s there. If they can Specifically, Dowdy seeks to to treat headaches, colds and genetic disorders. fix it without expending too much energy, piggyback large proteins onto they will do so; otherwise, they pack it off to

42 hhmi bulletin | december 2002 2 3 COURTESY OF DOWDY LAB OF DOWDY COURTESY the proteosome, a cellular demolition factory. Transduction can change the biology of human fibroblast cells in culture. Two types of the same “The really amazing part is that when protein—known to alter membrane architecture—were transduced into the cell membranes. In you introduce the proteins, they take on the panel 2, the protein contained an inactivating mutation and the cell surface remained smooth. properties of what’s inside the cell,”Dowdy In panel 3, using a version containing an activating mutation, spikes appeared within 10 minutes says. Most proteins that attempt to enter a cell in more than 95 percent of the cells. get chewed up into their constituent amino acids, he says. They become cellular food. In ogy to people.“Can we deliver large One company that has had some early protein transduction,“the proteins stay macromolecules into a cell? Yes.Enough to success in protein transduction is CellGate. intact. They can be taken to the nucleus, they make a difference in animals? Yes.”But in The Sunnyvale, California, biotech firm can assemble with other proteins in the cell, humans? “We don’t know yet,”he admits. recently completed a phase I safety study in 15 they can be cleaved by enzymes. While we Dowdy has long been fascinated by the people with an experimental therapy for psori- don’t know that they do everything, they minuscule. He landed in graduate school at asis, a skin condition affecting about 7 million certainly do a lot of things.” the University of California, Irvine, after Americans. CellGate isn’t using a large Preliminary studies in mice and rabbits, choosing biology over particle physics. molecule in this trial, but rather a small one including Dowdy’s work, show that protein Ironically, it was as an undergraduate on a (the immune-suppressing drug cyclosporine) transduction works. He’s shown that peptides date at California’s Yosemite National Park— hitched to a “passkey” molecule. But the can pass through the membrane of ovarian a place where scale tends toward the principle is the same, says Edward F. tumor cells in lab mice. As a result, the p53 enormous end of nature’s spectrum—that he Schnipper, the company’s president and chief tumor suppressor gene is switched on, and the caught the transduction bug.“We ended up executive officer. malignant cells halt their activity and destroy spending practically an entire hike discussing CellGate also has its sights set on more themselves in a process known as apoptosis. So the problem of introducing large molecules deadly diseases, including a variety of far Dowdy and colleagues have succeeded in into cells and trying to devise mechanisms to cancers. The firm has partnered with several extending the lives of such animals two- to break down that barrier.”The exchange must larger companies, including Johnson & threefold, as compared with a control group of have been stimulating—Dowdy’s Johnson, to commercialize the technology. similarly sick mice. Yet they haven’t been able companion, a budding computer scientist Dowdy says he’s encouraged by CellGate’s to push much further.“It’s moving in the right named Lisa Howard, married him. preliminary results—which only test safety, direction, but it has clearly taken more effort Dowdy’s group is focused on transducing not effectiveness, and don’t involve large pro- than I had naively expected,”Dowdy says. anticancer agents, such as enzymes and teins. He’s hoping to move his work into Dowdy first started serious work on trans- proteins, to kill tumors but not normal cells. human studies, but experience has taught duction in 1997 and published his first paper He points out, however,“In theory, you could him to remain cautious.“Humans are going on the mechanics of the method in 1999. His use this approach for headaches, the common to be much more complex and more initial experiments in animals were so promis- cold and potentially for genetic disorders, difficult” than lab animals, he predicts, and ing, he says, that he became overly optimistic too,”by adjusting the therapeutic protein in his view,“It’s better to be conservative.” about how quickly he could bring the technol- delivered into target cells. —ADAM MARCUS

hhmi bulletin | december 2002 43 INSIDE HHMI The distractions were too much, Collins says. He eventually transferred to Howard University in Washington, D.C., where he earned a bachelor’s degree in electrical engi- neering and a master’s degree in computer science. “Attending Howard allowed me to pursue my studies in an oustanding academic environment that also enabled me to emulate the social, political and moral examples set forth by my parents,” he says. Although he laughs at the notion, Collins’ career path was a straight shot into leadership within the technology field. After jobs at ibm and Exxon, he returned to his alma mater, taking on more and more responsibility. Before coming to hhmi,he was associate vice president for information systems and services at Howard University, responsible for all central information tech- nology (it) support, a $13 million annual budget and a staff of 100.

WILLIAM K. GEIGER “I wanted to go back to Howard after Joseph Collins’ group provides information technology support from headquarters and two field offices. earning experience in the field and offer what I could to the institution that gave me the opportunities,” he says. “Now I’m work- ing for an institution whose mission in bio- His Brave Father’s Example medical research is also making a difference, but on a much larger and different scale oseph D. Collins, hhmi’s new direc- ing the New Testament as they debated the than Howard University. The potential to tor of information technology, grew appropriateness of carrying weapons. King, of provide world-class technology support for Jup in segregated Mississippi. He says course, was against the use of force; mean- our investigators and other staff, who are he was attracted to hhmi because its mis- while, J.D. told Joe to sleep that night with his involved in world-class biomedical research sion suits his aspiration—born early from rifle beside his bed. “My father, although a and science education, is exciting for me.” his father’s example—to make a difference. minister, was not a pacifist,” he says. White His main goal for the Institute’s it Collins’ father, Reverend J.D. Collins, supremacists had burned crosses in the department is to tightly integrate every was a civil rights activist and one of the first Collins’ front yard and shot out the window application (such as human resources, blacks to register to vote in Leflore County. of his father’s shoe repair shop, and the rev- grants, purchasing and investments) so that He formed the Progressive Negro Voters erend meant to protect his family. users “can access what they need whenever League in the 1940s to help other blacks That night, Collins’ mother, Katie, col- they need it, all via the Web.” pass the mandatory written test that was lected the autographs of the civil rights Collins’ family situation has come a long barring them from the voting booths. leaders in her old, spiral-bound address way since his youth in Mississippi—to the At the height of the civil rights move- book. King wrote “Thank you for all of your point, he says, that his two children regard ment in 1966, Collins recalls, his father wonderful hospitality,” and Abernathy tales of the civil rights movement as ancient brought seven guests home with him after a added “Your contribution to freedom has history. “When my daughters were growing freedom meeting at his church. In those days, meant so much to all of us.” She gave the up, I didn’t talk about the past a lot. I shield- most hotels in the Deep South were unavail- book to her son a few years ago. ed them from it.” But before his father died in able to black people, so visiting activists often Inspired by his father’s determination, 1995, he interviewed his parents on tape stayed in local homes. That evening, the Collins applied to top-ranking colleges and about their lives. “I plan to give a copy to my guests included Martin Luther King, Jr., and chose the University of California, Berkeley. kids and grandson. I gave one to my sister fellow civil rights leaders Ralph Abernathy He stepped into a cultural whirlwind: Mario and she was blown away.” He hopes to pre- and C.T. Vivian. “It was a very interesting Savio advocating free speech; Haight- serve his mother’s old address book with night,” says Collins, who was 17 years old at Ashbury’s free-love movement; and Huey P. those notable autographs as well, to give his the time. Newton, Bobby Seale and the Black Panthers children a tangible and priceless remem- He remembers his father and King quot- holding meetings on the steps of Sproul Hall. brance of their heritage. —CORI VANCHIERI

44 hhmi bulletin | december 2002 APPRECIATION W. Maxwell Cowan

W. Maxwell Cowan, hhmi’s vice president and chief sci- first encounter with him after joining hhmi,I could barely entific officer from 1987 to 2000, died in June at age 70. contain my nerves, yet within minutes, I started to feel at ease. Cowan, an accomplished neuroscientist, structured the The calm cadences of his voice, his South African lilt and the Institute’s scientific program and took a personal interest in warmth of his praise were avuncular and disarming. I was identifying scientists around the country whose work merited astonished at how much he knew of me and my work. But hhmi support. Cowan had a lasting impact on many. beyond his legendary analytical ability, what struck me most was his genuine concern for me and my career. Over time, I Eric R. Kandel, hhmi investigator, Columbia University, and increasingly turned to him when I needed advice or a sounding Nobel Laureate board. Max Cowan truly cared and thereby helped shape my I had already heard a great deal about Max Cowan by the time career in profound ways. we met in 1974, and I knew he had a prodigious knowledge of brain anatomy. In our initial discussion, I was taken by his com- Carla J. Shatz,member,hhmi Medical Advisory Board and ment that anatomy had no interest for him except as it enlight- former hhmi investigator ened the study of function. With time, I came Max Cowan was one of my scientific to realize that this principle guided much of fathers—a real “fairy godfather.” In 1976, his thinking. I saw this again the next year at he served as external examiner for my Cold Spring Harbor, when he was explaining Ph.D. thesis. Over the years, I know that the topographic surface anatomy of the he worked on my behalf behind the human brain to a beginning class. Max held scenes and that I owe a good deal of the in his hand a brain rigidly fixed in formalde- professional recognition that has come hyde, yet he made this fixed brain come alive my way to his support. Without Max, in a functional way that was simply extraordi- many of us would not have had the nary. I later saw a similar demonstration at a opportunity to become hhmi investiga- Congressional hearing: Max was carrying a tors. He worked hard to establish compet- porcelain jug under his arm containing a fixed itive standards, opening the door, for human brain. At the door of the Senate, Max instance, to the appointment of many was asked by the guard what he was carrying women—myself among them. I treasure UL FETTERS

under his arm. He answered without cracking PA his role in my life. a smile, “A human brain. Whenever I testify before Congress I always carry a spare.” Thomas C. Südhof, hhmi investigator, University of Texas As neuroscience matured, Max emerged as a major force in Southwestern Medical Center at Dallas the effort to combine anatomy and function, a synthesis that led to Max’s biggest strength may have been his ability to see the the coherent discipline we now enjoy. He was among the first to big picture, in and out of science. Max taught me to see beyond appreciate the importance of studying development, not only as a an individual scientific result or a particular historical moment, key for understanding mature brain function but also as a bridge a short-lived scientific triumph or humiliation, toward the larg- to the rest of biology, especially molecular biology. His studies of er goal of building knowledge and understanding. neuron cell death and nerve process retraction are still classics. Max was a natural leader. He was recognized as such and was Corey S. Goodman,president and CEO, Renovis, Inc., and constantly sought out for important leadership positions. His lead- former hhmi investigator ership role reached new heights at the Hughes. He loved the I first met Max in the summer of 1977 at a conference in hhmi and his various roles in it. Until his last few days Max Boulder. I had just finished graduate school, a shy student in remained productive. He could not have asked for a more success- awe of “Dr. Cowan,” but found the courage to ask him to look ful and rewarding career as a scientist and as a leader of science. at a manuscript. He listened, congratulated me, gave great advice and a lot of encouragement—something that would Marc Tessier-Lavigne, hhmi investigator, Stanford University continue for decades. Max was a mentor, and as I got older, he As a starting assistant professor, I only knew Max by repu- also became a good friend. Neuroscience lost a great champion, tation, and that reputation was profoundly intimidating. In my scholar and leader with Max’s death. H

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