Cell Circuitry || Science Teaches English || The Chicken Genome Is Hot || Magnets in Medicine SEPTEMBER 2002 www.hhmi.org/bulletin

Leading Doublea Life It’s a stretch, but doctors who work bench to bedside say they wouldn’t do it any other way. FEATURES

14 On Human Terms 24 The Evolutionary War A small—some say too small—group of Efforts to undermine evolution education have physician-scientists believes the best science evolved into a 21st-century marketing cam- requires patient contact. paign that relies on legal acumen, manipulation By Marlene Cimons of scientific literature and grassroots tactics. 20 Engineering the Cell By Trisha Gura Adam Arkin sees the cell as a mechanical system. He hopes to transform molecular 28 Call of the Wild biology into a kind of cellular engineering Could quirky, new animal models help scien- and in the process, learn how to move cells tists learn how to regenerate human limbs or from sickness to health. avert the debilitating effects of a stroke? By M. Mitchell Waldrop By Kathryn Brown

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In front of a crowd of 1,500, Ohio’s Board of Education heard testimony on whether students should learn about intelligent design in science class. DEPARTMENTS

2 NOTA BENE 33 PERSPECTIVE ulletin Intelligent Design Is a Cop-Out 4 LETTERS September 2002 || Volume 15 Number 3

NEWS AND NOTES HHMI TRUSTEES PRESIDENT’S LETTER 5 JAMES A. BAKER, III, ESQ. 34 Senior Partner, Baker & Botts A Creative Influence In from the Fields ALEXANDER G. BEARN, M.D. Executive Officer, American Philosophical Society 35 Lost on the Tip of the Tongue Adjunct Professor, The Rockefeller University UP FRONT Professor Emeritus of Medicine, Cornell University Medical College 36 Biology by Numbers FRANK WILLIAM GAY 6 Follow the Songbird Former President and Chief Executive Officer, SUMMA Corporation

JAMES H. GILLIAM, JR., ESQ. 8 Curriculum Congestion 37 Undergraduate Grants Foster Former Executive Vice President and General Counsel, Teaching, Interdisciplinary Beneficial Corporation HANNA H. GRAY, PH.D., C HAIRMAN 9 Learning from Their Elders Courses President Emeritus and Harry Pratt Judson Distinguished Service 11 Professor of History, The University of Chicago With a Little Help from 37 Students Love the Details GARNETT L. KEITH Chairman, SeaBridge Investment Advisors, L.L.C. Our Friends Former Vice Chairman and Chief Investment Officer, The Prudential 38 From Soybean Finding, Insurance Company of America 13 Q & A Genome Insider JEREMY R. KNOWLES, D.PHIL. a Career in Science Sprouts Dean of the Faculty of Arts and Sciences and Amory Houghton Professor of Chemistry and Biochemistry, Harvard University 39 WILLIAM R. LUMMIS, ESQ. HHMI Professors Promise Former Chairman of the Board of Directors to Break the Mold and Chief Executive Officer, The Howard Hughes Corporation ANNE M. TATLOCK Chairman and Chief Executive Officer Fiduciary Trust Company International 40 HHMI LAB BOOK HHMI OFFICERS THOMAS R. CECH, PH.D., President 42 HANDS ON PETER J. BRUNS, PH.D., Vice President for Animal Magnetism Grants and Special Programs DAVID A. CLAYTON, PH.D., Vice President and Chief Scientific Officer 44 INSIDE HHMI STEPHEN M. COHEN, Vice President and Chief Financial Officer International Scholars JOAN S. LEONARD, ESQ., Vice President and General Counsel AVICE A. MEEHAN, Vice President for Communications Down Under and Public Affairs

GERALD M. RUBIN, PH.D., Vice President and 45 On Stage and Off, This Director of Planning for Janelia Farm Lawyer Performs NESTOR V. SANTIAGO, Vice President and Chief Investment Officer

HHMI BULLETIN STAFF 14 On the Cover: Photographs by Kathleen Dooher. CORI VANCHIERI, Editor JIM KEELEY, Science Editor Jennifer Donovan, Education Editor 34 PATRICIA FOSTER, Manager of Publishing KIMBERLY BLANCHARD, Editorial Coordinator ELIZABETH COWLEY, Copy Editor

Maya Pines, Contributing Editor

KALYANI NARASIMHAN, fact checking STEVEN MARCUS, PETER TARR, story editing KATHY SAVORY, copy editing

David Herbick Design, Publication Design

Telephone (301) 215 8855 n Fax (301) 215 8863 n www.hhmi.org The Bulletin is published by the HHMI Office of Communications and Public Affairs. © 2002 Howard Hughes Medical Institute PRETE/AP (LEFT), DAVID GRAHAM (TOP RIGHT), TORSTEN KJELLSTRAND (BOTTOM RIGHT)

A The opinions, beliefs and viewpoints expressed by authors in the HHMI Bulletin do not necessarily reflect the opinions, beliefs and viewpoints or

JAY L official policies of the Howard Hughes Medical Institute. NOTA BENE

tinction Award. The awards are given by ■ James P. Allison, hhmi investigator at the ■ hhmi President Emeritus Purnell W. panels of producers and other communica- University of California, Berkeley, won the Choppin received an honorary doctorate of tions professionals. 2002 Public Service Award from the Ameri- humane letters from The Johns Hopkins can Society of Immunologists and the 2001 University at its 2002 commencement. ■ H. Robert Horvitz, an hhmi investigator Centeon Award for Innovative Break- at the Massachusetts Institute of Technolo- throughs in Immunology. ■ The Royal Society, the United Kingdom’s gy,received the 2001 Genetics Society of national academy of science, named Roger J. America Medal. ■ Five hhmi investigators have been named Davis, an hhmi investigator at the Universi- fellows of the American Academy of Arts and ty of Massachusetts Medical School, one of ■ Andrzej Jerzmanowski, an hhmi interna- Sciences: David J. Anderson,California Insti- its 2002 fellows. Peter H. Raven, director of tional research scholar at Warsaw Univer- tute of Technology; Cornelia I. Bargmann, the Missouri Botanical Garden and pro- sity, has been elected to the Polish Academy Ronald D. Vale and Peter Walter,University of gram director of an hhmi precollege sci- of Sciences. California, San Francisco; and A. James Hud- ence education grant there, was elected a ■ speth,The Rockefeller University. foreign member of the society. Saulius Klimas˘auskas and Virginijus Siksnys, hhmi international research scholars in ■ ■ Three hhmi investigators and two of the Stephen J. Elledge, an hhmi investigator Lithuania, received the 2002 National Sci- Institute’s leaders were named as “Biotech at Baylor College of Medicine, won the 2002 ence Prize from the government of the Geniuses to Watch” in the June issue of National Academy of Sciences Award in Republic of Lithuania. Molecular Biology. The award recognizes a Discover magazine: David Baker,University young scientist who has made a recent ■ Louis M. Kunkel, an investigator at of Washington; Elaine Fuchs,who recently hhmi notable discovery in the field. Children’s Hospital, Boston, won the 2002 moved to The Rockefeller University; Stuart LIFE International Research Award for sci- L. Schreiber,Harvard University; Thomas R. ■ David Ginsburg, an hhmi investigator at entists whose research has led to clinical Cech, hhmi president; and Gerald M. Rubin, the University of Michigan Medical School, applications. The award is presented annu- vice president and director of planning for won the 2002 ISFP Prize from the Interna- ally by the Lois Pope LIFE Foundation. Janelia Farm. tional Society for Fibrinolysis and Proteolysis. ■ Two hhmi international research schol- ■ Nine hhmi investigators were elected to ■ Philip Green, an hhmi investigator at the ars, Pedro Labarca of Chile and Raúl A. Padrón the National Academy of Sciences. New University of Washington, was a winner of of Venezuela, have been elected to the members are Philip A. Beachy,The Johns the 2002 Gairdner Foundation International Academia de Ciencias de América Latina, Hopkins University School of Medicine; Award. The award recognizes individuals for the Latin American Academy of Sciences. Patrick O. Brown, Stanford University; their achievement in the field of medical Carlos J. Bustamante,University of Califor- science. He received the award, according to Robert J. Lefkowitz, an hhmi investigator at nia, Berkeley; Constance L. Cepko,Harvard the Foundation, for “his contributions to Duke University Medical Center, received Medical School; Jennifer A. Doudna,who development of the computational tools the 2002 Pasarow Award for Cardiovascular recently moved to the University of Cali- essential for sequencing of the human Research from the Robert J. and Claire fornia, Berkeley; Charles T. Esmon, Okla- genome. Further, he provided compelling Pasarow Foundation. homa Medical Research Foundation; early evidence for a dramatically reduced Richard A. Flavell,Yale University School of number of human genes.” ■ Richard P. Lifton, an hhmi investigator at Medicine; and Thomas Südhof,University of Yale University School of Medicine, won the Texas Southwestern Medical Center at Dal- ■ hhmi’s Holiday Lectures on Science,an American Society of Hypertension’s 2002 las. Thomas M. Jessell,Columbia University annual Webcast educational program pre- Richard Bright Award. College of Physicians and Surgeons, is a sented by hhmi investigators for high new foreign associate. school students, won two national awards ■ Richard M. Locksley, an hhmi investiga- for the 2001 lectures by hhmi investigators tor at the University of California, San ■ Three hhmi investigators, Pamela Bjork- David C. Page,Whitehead Institute for Bio- Francisco, is one of five new members man,California Institute of Technology, medical Research at the Massachusetts named to the National Advisory Allergy Judith Kimble,University of Wisconsin– Institute of Technology, and Barbara J. and Infectious Diseases Council, the prin- Madison, and Stanley J. Korsmeyer, Dana- Meyer,University of California, Berkeley. cipal advisory board for the National Farber Cancer Institute, were elected to the The program received the 2002 Bronze Telly Institute of Allergy and Infectious Diseases American Philosophical Society. Award and the 2002 Videographer of Dis- of the National Institutes of Health.

2 hhmi bulletin | september 2002 ■ Mario R. Capecchi,an Contribution Award from the American hhmi investigator at the Psychological Association. He was recog- University of Utah School nized for his neuroscience research. of Medicine, received the National Medal of ■ Peter H. St. George-Hyslop, an hhmi Science from President international research scholar at the Univer- George W. Bush at a sity of Toronto, Canada, won the Richard- White House ceremony son Lectureship Award from the Canadian in June. Capecchi accept- Neurological Society for contributions to ed this award—the neurological research. nation’s highest scientific honor—with 14 other ■ hhmi investigators Christine E. Seidman, scientists and engineers, Brigham and Women’s Hospital, Boston, and all of whom have made Jonathan G. Seidman,Harvard Medical School, lasting contributions to were joint recipients of the 2002 Bristol- scientific research. Capec- Myers Squibb Award for Distinguished chi was honored for Achievement in Cardiovascular Research. developing gene-targeting technology, which has ■ Jonathan S. Stamler, an hhmi investigator been used to generate DOUG MILLS/AP at Duke University Medical Center, won the mouse models of human diseases. Researchers worldwide use the technique to deter- 2002 Saul J. Horowitz, Jr., Memorial Award mine the function of individual genes. His previous honors include the 2001 Albert from the Mount Sinai School of Medicine Lasker Award, the Bristol-Myers Squibb Award, the Gairdner Foundation International for contributions as a medical investigator. Award, the General Motors Corporation’s Alfred P. Sloan Jr. Prize and the Kyoto Prize. The award also went to Harold Varmus,a member of the hhmi Medical Advisory Board ■ Joan A. Steitz, an hhmi investigator at Yale and president of Memorial Sloan-Kettering Cancer Center in New York City, for his dis- University, received the 2002 Lewis S. Rosen- covery with J. Michael Bishop, University of California, San Francisco, that normal stiel Award for Distinguished Work in Basic human and animal cells contain genes capable of becoming cancer genes. Medical Research from Brandeis University.

■ Roger Y. Tsien, an hhmi investigator at ■ John B. Lowe, an hhmi investigator at the tion Association of Washington. The Utah the University of California, San Diego, won University of Michigan Medical School, was Society for Environmental Education chose the 2002 Dr. H.P. Heineken Prize for Bio- elected a 2002 fellow of the American Asso- the Red Butte Connection for its 2001 Pro- chemistry and Biophysics from the Royal ciation for the Advancement of Science. gram of the Year Award. Netherlands Academy of Arts and Sciences and the 2002 American Chemical Society Roderick MacKinnon, an hhmi investigator ■ Nancy P. Moreno, hhmi precollege science Award for Creative Invention. at The Rockefeller University, received the education program director at Baylor Col- 2001 Perl-UNC Neuroscience Prize for solv- lege of Medicine, received the 2002 Full- ■ High school students participating in a Uni- ing the crystal structure of the potassium bright & Jaworski LLP Faculty Excellence versity of California, San Diego, science educa- ion channel. Award for achievement in education and tion program supported by an hhmi grant development of educational materials. placed first in a 2002 regional competition of ■ Joan Massagué, an hhmi investigator at the National Organization of Black Chemists Memorial Sloan-Kettering Cancer Center, ■ Sean J. Morrison, an hhmi investigator at and Chemical Engineers (nobcche) and won the 2002 Howard Taylor Ricketts the University of Michigan Medical School, second in the senior division at nobcche’s Award, the highest honor given by the Uni- was named to Technology Review’s 2002 2002 national competition in New Orleans. versity of Chicago Division of Biological TR100, the magazine’s annual list of top Sciences and Pritzker School of Medicine. young innovators in business and technolo- ■ Thomas J. Wenzel,a chemistry professor at gy.A native of Canada, he was also named a Bates College, Lewiston, Maine, was one of ■ Two K–12 science education programs top young scientist in Time magazine’s two educators in the United States to receive supported by grants from hhmi have won Canada edition. a 2002 Council on Undergraduate Research state environmental education awards. The Fellows Award. Wenzel provides research Mercer Slough Environmental Education Center ■ William T. Newsome, an hhmi investigator opportunities to students in a program sup- received the 2001–2002 Community Cata- at Stanford University School of Medicine, ported by an hhmi undergraduate biologi- lyst Award from the Environmental Educa- received the 2002 Distinguished Scientific cal sciences education grant. H

hhmi bulletin | september 2002 3 LETTERS TO THE EDITOR

Women Scientists in Training should see that women’s contributions the confidence that if she wants to do sci- I was pleased to see “Accomplished Women” can rank with those of men. ence, she can do it. (June 2002, p. 20). As you pointed out, and Carolyn S. Stahl my recent discussions with female students We need to view work/family balance Norwood, Massachusetts suggest (Nature Medicine 2002 May; 8: •as an issue for young scientists of both 439–41), we still have a long way to go sexes. We must escape a system that dis- Gleevec Brings Hope before women are proportionately repre- courages men from choosing to be equal Iread “Gleevec’s Glory Days” (December sented in science. Young women worry participants in parenting. 2001, p. 10) with great interest because my about balancing a demanding career with 23-year-old son, Andy, has chronic myel- raising children. They feel they must accom- Nancy C. Andrews ogenous leukemia (CML). It’s a well-writ- plish more than their male counterparts to hhmi Investigator, Children’s Hospital, Boston ten, informative article that provided me be viewed as equals. They are directed away and Director, Harvard-mit M.D., Ph.D. Program with the names of the people who’ve made from physician-scientist careers—being told such a huge difference in Andy’s life: Owen they can’t do it all—often by well-meaning While exploring your Web site today, I came Witte, whose work led to the development but misinformed undergraduate advisers. across “Accomplished Women.” As a woman of Gleevec, and Brian Druker, who perse- Finally, most young women have little direct who is considering returning to graduate vered in getting the drug on Novartis’ radar exposure to women who have achieved school for a science degree in the next few screen. When Andy was first diagnosed a lit- stature in the scientific community. Impor- years, I found the article helpful, uplifting tle over a year ago, Gleevec had not yet been tant steps must be taken: and insightful. approved by the fda.He was put on As a mother with two daughters, I hydroxyurea, a debilitating temporary treat- We need to change the culture of aca- have copied the article for their future. My ment to reduce his white-cell count, which •demia to encourage teamwork and dis- eldest daughter, age 10, is extremely inter- had spiked to 500,000. He has achieved courage competition at the expense of ested in science. She has taken a science remission on Gleevec, with only minor side others. This will make science more enrichment class through our local school. effects, and is thus far able to lead a relative- appealing to young women who are dis- She enjoyed the classroom experiments ly normal life. Hope and optimism have heartened by the aggressive behavior but wanted to do more. She convinced us replaced our fear. they view as “part of the job.” to buy a hamster so that she could build a Mirinda Kossoff maze and run the hamster through it. She Burroughs Wellcome Fund We need to sustain an effort to place made observations about the hamster’s Research Triangle Park, North Carolina •women in respected positions in our sci- babies in a notebook. My husband and I entific institutions. Female students want to continue to foster her interest in Send your letters: Via e-mail to [email protected] or to Let- should have female role models and science. We both know that she will face ters, Office of Communications, Howard Hughes Medical Insti- tute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789. mentors with the clout to help them possible obstacles in school. I plan to Letters will be edited for space and clarity. Please include your develop their careers. And all students share this article with her and instill in her name, address (e-mail or postal) and phone number.

HOWARD HUGHES MEDICAL INSTITUTE Presents the 2002 Holiday Lectures on Science Scanning Life's Matrix Genes, Proteins and Small Molecules

THE LECTURERS Eric S. Lander, Ph.D. Director, Whitehead Institute/MIT Center for Genome Research Stuart L. Schreiber, Ph.D. HHMI Investigator, Harvard University

DECEMBER 5 AND 6, 2002 For more information: www.holidaylectures.org

4 hhmi bulletin | september 2002 PRESIDENT’S LETTER

A Creative Influence KAY CHERNUSH KAY

n chemistry, equilibrium describes a set of Altering the steady state in undergraduate education is, in many reactions that are internally dynamic but stable overall. Once respects, an even more daunting task. Yet, speaking from the per- a steady state is achieved, no net change will occur without spective of someone who taught undergraduate chemistry and bio- outside influence. chemistry for two decades, the opportunities are substantial. I am I like to think of the Howard Hughes Medical Institute as delighted with the 20 hhmi professors we have selected—they are Iproviding that outside influence, when the equilibrium of science and highly regarded scientists who will bring creativity and ingenuity to of the teaching of science could benefit from net change. Part of our the endeavor (see page 39). It was also a pleasure to work with Alice mission, as I see it, is to use our resources to introduce new elements Huang of the California Institute of Technology, who chaired the that will alter the steady state in creative directions. Two hhmi ini- selection committee, and her panel of scientist-educators; our meet- tiatives—a competition for investigators who conduct patient-orient- ings were lively and thought provoking. ed research and grants for topflight scientists committed to under- As a group, the successful candidates more than answered our graduate education—are certainly in that spirit. challenge to create new models for teaching biology and related sci- Both of these initiatives direct our support to individuals who ences. The array of ideas they plan to pursue is breathtaking: are well placed in the nation’s research institutions and universities enriched opportunities for promising students, new courses in and who have the skills and motivation to shift the equilibrium. chemical biology, lectures for non-science majors that focus on the Both groups of scientists welcome the opportunity to meet the ethical and social issues raised by current research, development of demands of equally important and often-conflicting endeavors—in Internet-based teaching materials and many others. I am struck by one “reaction,” laboratory research and patient care; in the other, the fact that each proposal seeks, in one way or another, to create a scientific exploration and undergraduate teaching. By empowering community of scholars at the undergraduate level by giving stu- them with resources and recognition, we hope to make a difference. dents a window on the way science is practiced today. The goals are to enhance translational research and provide new Our own community of scholars has been diminished by the models for what it means to teach biology. recent death of W. Maxwell Cowan, who retired two years ago as the This issue of the Bulletin features the winners of the new investi- Institute’s vice president and chief scientific officer. Max had already gator competition (see page 14). We selected 12 outstanding physi- made significant contributions to neuroscience—as both a practicing cian-scientists from 138 candidates nominated by medical schools scientist and a leader in the world of academic research—when and hospitals throughout the country. These professionals are Purnell Choppin recruited him to hhmi in 1987. At the Institute, extraordinarily accomplished, and they will bolster our existing Max worked to establish the high standards for which our science pro- cadre of investigators who derive their inspiration from the patients gram is known and helped identify promising new areas of research. they treat and then move the problems into their laboratories, where His willingness to support bold moves had an impact on my own they ferret out a detailed understanding of the disease process. The research, when he approved a request for equipment to determine eventual goal is to return to the bedside with new clinical treatments. crystal structures of large RNA molecules and in the process showed Joseph Goldstein, from the University of Texas Southwestern his enthusiasm for the work. And certainly Max’s encyclopedic knowl- Medical Center at Dallas, who chairs our Medical Advisory Board edge of the research occurring in every hhmi laboratory set him (mab), and David Nathan, at Dana-Farber Cancer Institute, also a apart. The work of our investigators frequently delighted and some- member of the mab,deserve credit for encouraging hhmi to times frustrated him, but it always engaged his scientific curiosity and expand the number of investigators who conduct patient-oriented his intellect. We shall miss him. research. As scientists whose own work has helped solve significant clinical problems, Goldstein and Nathan understand the value of research that combines clinical expertise with the powerful tools of molecular biology. As research administrators, they also understand how daunting it can be for physician-scientists to work on the boundary between science and medicine. After all, as the equilibri- Thomas R. Cech um exists today, only 11 percent of all medical school graduates President plan careers that include a substantial commitment to research. Howard Hughes Medical Institute

hhmi bulletin | september 2002 5 The stable isotopes of elements such as carbon, hydrogen, sulfur and strontium form durable patterns in the soil that vary pre- Up Front dictably from place to place and can thus serve as tracers. Taken up by plants, isotope signatures are subsequently expressed in the insects that eat the plants and, ultimately, in the birds and other animals that eat the Follow the Songbird insects. “You are what you eat,”says Ruben- stein. In birds, these signatures manifest Isotopes tell a tale of bird migration and may help with themselves in the chemical makeup of the efforts to conserve natural habitats. feathers and thus can serve as natural markers for where a bird has been. By sampling a sin- ield biologists have long been try- for field biologists, says Rubenstein, an gle tail feather from a captured bird or even a ing to discover exactly where hhmi predoctoral fellow, has been over- museum specimen, scientists can identify migratory animals go on their sea- coming the “needle in the haystack” limita- where a bird lived. The isotopic signature sonal journeys. In a world of rap- tions of traditional capture-and-recover field reflects the latitude at which the bird has been idly vanishing habitats, such studies; thousands of birds may be captured living and where it grew new feathers. Finsight would help those trying to protect and fitted with leg bands, but only a few are As a Dartmouth undergraduate on an sensitive lands. With more than 20 percent of ever recovered once they complete their hhmi research internship, Rubenstein the world’s forests having disappeared in the migratory journeys. helped orchestrate one of the first compre- past 300 years, habitat loss ranks as one of the As an alternative, Rubenstein, 25, in col- hensive studies using stable isotopes to ferret biggest threats to wildlife, especially migratory laboration with Dartmouth College biologist out the closely held secrets of a particular birds, which rely on two locations—a winter Richard T. Holmes and Stanford University migratory songbird, the black-throated blue and a summer home—for shelter and food. geochemist C. Page Chamberlain, started warbler—a species that summers and breeds Dustin R. Rubenstein, currently a Cor- monitoring stable isotopes—alternative over a deep swath of eastern North America nell University graduate student in behav- forms of chemical elements—that exist nat- (from Ontario to Georgia) and winters in ioral ecology, concentrates on migratory urally in the environment. They capitalized the Caribbean. In the process, he and col- songbirds. These small, hard-to-observe on a technique, pioneered by Chamberlain, leagues discovered “the astonishing fact that creatures are especially vulnerable because that uses the “chemical signature” of stable warblers from different breeding regions many of them depend on large, uninterrupt- isotopes locked in birds’ feathers to tell have distinct migratory patterns”—a discov- ed tracts of forest to survive. The challenge where a bird has been spending its time. ery that not only revealed a previously unknown migratory behavior of the black-throated blue warbler in particular but, by extension, raised the possibili- ty that many other migratory songbirds might behave in the Summer same way. breeding grounds Their findings, published 500 km in the February 8, 2002, issue Winter of Science, showed that the habitat warblers that summer in northern sections of North Bahamas America tend to winter in the western Caribbean and those that summer in the southern Puerto Rico United States winter in the Cuba eastern Caribbean islands. Jamaica Haiti To learn where the Dominican Republic migrating birds were coming ANIEL FAZER (MAP), COURTESY OF LARRY MASTER/NATURESERVE OF LARRY COURTESY (MAP), ANIEL FAZER D from as they traveled south THERE IS A SEASON Black-throated blue warblers (right) that spend their summer breeding time for the winter, Rubenstein and further north, between Michigan and New Brunswick, Canada, tend to winter in the western Caribbean. Warblers that his colleagues first determined summer as far south as Georgia migrate to the eastern Caribbean islands for the winter. the isotopic pattern found in

6 hhmi bulletin | september 2002 Rico for the winter. The stable isotope method as used by Rubenstein “is a way to investigate in some detail where some birds are spending the win- ter,” according to Kevin J. McGowan, a researcher at Cornell University’s Laboratory of Ornithology. “It’s surprising what we don’t know about the wintering ranges. For a lot of birds, we just don’t know where they go. It’s impossible to watch these behaviors unfold across the sur- face of the globe, and when we get access to tools like this, it really helps us out.” Rubenstein, Cham- berlain and Holmes believe that their recent work sets a standard for other studies that seek to reveal the hidden lives of wild animals. And Rubenstein’s con- tribution, say his senior colleagues, notably transcended its original purpose as a senior the- sis at Dartmouth.

MICHAEL GREENLAR MICHAEL “When Dustin Dustin Rubenstein studied the isotope signatures in thousands of warbler feathers. He hopes his work came on board, he was will expose the impact of deforestation and habitat loss. facing a tremendous amount of work, much more than a traditional thesis would feathers of birds whose breeding locations mer populations to environmental change require,”says Chamberlain. “The number of were known. They then compared those sig- occurring where the birds spend their win- analyses on one species—numbering in the natures with the isotopic signatures extract- ters. “Variable rates of deforestation and thousands—is unprecedented, and without ed from birds of unknown breeding location habitat loss on the different Caribbean him pushing to do this, the study never caught in their wintering grounds. islands may affect some breeding popula- would have been done. It’s the kind of work “Isotopes have been used [before] to tions more than others,”says Rubenstein. that was Ph.D. quality.” study bird migration, butterfly migration The severe deforestation occurring in Haiti, To publish in Science as an undergradu- and fish migration,”says Rubenstein. “Our for example, is thought to be contributing to ate was testimony to the quality of the work, study, however, was the first really compre- the decline of the black-throated blue war- note both Holmes and Chamberlain. For hensive one that sampled birds from across a bler’s southernmost breeding populations Rubenstein, the achievement was a kick, he species’ entire breeding and wintering (those birds that spend their summers in says, but he adds, “It’s somewhat daunting range.”It illustrated the technique’s promise Georgia and North Carolina), which usually since this was my first paper. I hope I haven’t not only for field biology but also for conser- migrate to the more easterly islands of His- peaked this early in my career.” vation—by linking declines in regional sum- paniola—where Haiti is located—and Puerto —TERRY DEVITT

hhmi bulletin | september 2002 7 Up Front old-style survey courses might make students mere “stamp collectors” of species, with no insight into molecular fundamentals, modern classes may lay out their own stamp collections Curriculum Congestion of molecules and biochemical pathways, with- out the context of actual, living organisms. The explosion in scientific knowledge is overloading undergraduate Lazarowitz points out that historical biology courses. What to take out is a thorny problem. details are often the first items sacrificed to make room for new material, again potential- magine a 17th-century Dutch natural- The needed changes will likely be driven ly removing context from biology education. ist given the privilege of looking not by committee but by individuals.“It’s “One answer to this dilemma has been to through Leeuwenhoek’s microscope at rare—but it does happen—that an entire create a one-credit ‘Readings in X’ seminar/ the previously unknown world of department will get together and decide to discussion course in a given area—for exam- microbial life. His first reaction must redesign their entire curriculum,”says Sondra ple, microbiology or genetics—in which stu- Ihave been, “How wonderful!” His second G. Lazarowitz, a professor of plant pathology at dents read and discuss landmark papers that reaction was probably, “How am I ever going Cornell University.“But the more common were truly groundbreaking in a particular to make room for this in my studies?” thing is that new people come This imagined example of an over- into an environment who have whelmed naturalist has a real, modern coun- strong ideas about the course- terpart: Today’s biology educators must work and decide they’re going to make tough decisions about what new infor- change it. Historically, universi- mation to make room for and, also, what to ties have relied on new faculty leave behind. “Contemporary biology has with new perspectives to invigor- seen a geometric progression in knowledge, ate courses. It’s more evolution breadth and impact,”says Peter J. Bruns, vice than revolution.” president for grants and special programs at For example, shortly after hhmi.Everything from Watson and Crick’s coming to Cornell four years DNA structure to the publication of the ago, she and Gary Whitaker of entire human genome has occurred within the university’s veterinary col- the past 50 years, and the undergraduate lege overhauled a course on the curriculum is straining under the load. Plus, principles of virology. “We basi- “modern biology brings in other, associated cally threw out the old curricu- sciences—chemistry, mathematics, physics, lum,”says Lazarowitz, who also computer science—that it didn’t so power- directs the hhmi Cornell Pro- fully in the past,”adds Bruns. gram in Undergraduate Biology Given that at least two major processes and Precollege Outreach. “The

are required to keep the curriculum cur- traditional approach would be GREENLAR MICHAEL rent—courses must be updated as well as to provide an overview of the Sondra Lazarowitz finds ways to keep historical context in biology lessons. made more interdisciplinary—one might features and replication of all assume that the biology curriculum is now in groups of animal viruses. We made the discipline,”she says. tremendous flux nationwide. Yet “it’s proba- course more interdisciplinary, using key Meanwhile, an obvious need in biology bly not in flux enough,”says Bruns. “New viruses to emphasize general principles of curricula is interdisciplinary education to things are not being added fast enough, and molecular virology and to explain the exper- accommodate the emerging fields of secondary information is not being cut. I imental basis for our current understanding genomics, proteomics and bioinformatics. think the response requires a big rethinking.” of how animal, plant and bacterial viruses To ultimately work in those areas—to Gabriele Wienhausen, a principal inves- interact with their hosts.” understand, and perhaps transcend, topics tigator of the HHMI Undergraduate Science One solution to the overcrowded-with- such as protein folding or statistical analyses Enrichment Program at the University of content curricula has been adopted just about in epidemiology—students need training in California, San Diego, acknowledges that this everywhere: The old introductory courses that biology, mathematics and computer science. process is difficult, daunting and deadly were basically surveys of the animal and plant Although much of the interdisciplinary slow. Faculty “do see the need for these kingdoms have disappeared.“There has been a melding takes place at the graduate level, changes, but actually making them can be tremendous movement to get away from those some campuses are attempting to foster painful,”she says. “Still, it has to happen. You survey classes and to focus more on cellular, undergraduate departmental crossbreeding really have to start arguing with people and molecular and biochemical issues,”Wien- as well. At Virginia’s College of William and work out the pros and cons.” hausen says.“But it comes at a price.”Whereas Mary, the mathematics and biology depart-

8 hhmi bulletin | september 2002 ments have modified courses so that stu- dents learn basics while also being able to move in both worlds. For example, they can learn calculus and differential equations as ways to address biological modeling prob- lems rather than as pure mathematics. Sometimes, modernizing the curriculum may require not cleaning out the attic but making room for new possessions. Accord- ing to an August, 2001, article in Science called “Information Overload Hampers Biol- ogy Reforms,”the biology department at Hope College in Michigan tried to update its introductory biology course in 1997. After duking it out, the faculty compromised, opt- ing to add a course that featured new con- cepts in biology while keeping in place the old course, which discussed nuts and bolts such as chloroplasts and mitochondria. hhmi has attempted to ease some of the difficulties in updating curricula: Since 1988, the Institute has awarded more than $556

million to 225 biology departments (includ- GARDEN OF FAIRCHILD COURTESY ing those at William and Mary and Hope Melissa Espino (right), interviews Justalina Prielo (left) about her use of plants as medicines. Rachael College) to redesign curricula and develop Johnson records the conversation so that the girls can plan a research project. interdisciplinary courses and laboratories. In addition, the Institute just launched a new tea for stomach aches. “We ate garlic so we initiative in which 20 research scientists will Learning from wouldn’t get sick,”she adds. Hoydee Lorreate- receive $1 million each over four years to gae, born in Ecuador in 1932, recommends devise ways to improve undergraduate edu- lemon grass for fever and cactus for a swollen cation (see page 39). Their Elders foot, to seventh-graders Tamara Trotz and hhmi grants aimed at course improve- Jordan Shockett. Much of what the teenagers ment are awarded with a hands-off attitude, Programs cross generations to hear is a revelation. “I just never thought trusting the individual departments and fac- bolster children’s curiosity. about the plants, how they grew and how they ulty to proceed as they think best. Such ad used them,”13-year-old Gonzales remarks. hoc course revisions, however, do not serve ixty-five years of living may sepa- From these discussions, the middle all biology undergraduate students. rate Marta Valdes from seventh- school students choose a plant to study, and Although change based on the particular graders Victoria Karr and during the rest of the school term, they talents of a department may benefit stu- Phoenix Gonzales, but a middle investigate their plant’s scientific name, fam- dents at one institution, students elsewhere school science project has ily, place of origin, ecology and distribution. may still be missing out on the vitality of brought them together. The two students They study the plant’s reproductive biology modern biology. Sfrom George Washington Carver Middle and compare its traditional uses to its mod- But as in scientific research, the first step School in Miami are interviewing 78-year-old ern applications as a food, medicine, fiber or toward curriculum reform is to clearly pose Valdes at a community senior center. Their component in industrial or manufacturing the question and then explore ways to immediate goal: to learn how Hispanic immi- processes. They look up scientific studies on answer it. For her part, Wienhausen believes grants like Valdes used plants in their native the useful properties of the plant, and they that the solution “requires almost systemic countries. Hers: to help the girls choose a design an experiment such as a test for sugar change and a comprehensive look at what we plant to research. or starch content. Aloe vera, anise, garlic, are doing.”This is not yet happening—at “Did you ever use foods or other plants as sour orange and a score of other edible or least, not sufficiently. “Some people say, ‘We medicine?” Karr asks. “In Cuba, where I was medicinal plants come under scrutiny. The don’t have the resources or time to even born, we used sábila (aloe vera) to lower cho- students ultimately present their findings to think about this.’ But we really have to,”says lesterol,”Valdes replies. Another Cuban immi- the seniors they interviewed at an intergen- Wienhausen. “With the publication of every grant, 80-year-old Matilde Merino, tells erational ethnobotany symposium at new research paper, the problem grows.” Katherine Lopez and Yadira Perez, both 13, Miami’s Fairchild Tropical Garden. —STEVE MIRSKY that her mother gave her mint or chamomile What can different generations gain from

hhmi bulletin | september 2002 9 Up Front with their own parents,”explains Anderson. with same’s preschool education program. “Yet some of the seniors are from the same “What happens in the early years is an essen- Caribbean island or town that the kids’ par- tial stepping stone to what they are going to studying science together? “They can enrich ents came from, and that makes a connec- achieve in the future. Parents and teachers are each other’s understanding,”says Patti J. tion; it stimulates the children’s curiosity the ones providing the foundation.” Anderson, former science-education coordi- about their own culture.” Janice Thompson, whose 4-year-old nator at the Fairchild Tropical Garden. With Interest in projects that pair “the book- daughter Janishia Calhoun attends preschool support from hhmi, the garden developed end generations”—children and seniors—is at Chicago’s Medill Elementary School, vol- this project that pairs middle school students growing in education and among those who unteers in the classroom and goes to parent with neighborhood seniors to study plants so work with the aging, says Donna Butts, exec- workshops. “Science was boring back when I that young and old alike will reap personal utive director of Generations United, a was in school. We just worked from a book. satisfaction from the experience. “For the national coalition of more than 100 organi- But every science project we do here is fun kids, it’s an opportunity to relate to people zations with intergenerational programs. for me and fun for the kids.”At home, she from a different generation without having to The federal Older Americans Act includes and Janishia have planted watermelon seeds provisions for intergenerational programs, and watched them germinate and grow. and several universities, including the Uni- They put mealworms in a jar of oatmeal and versity of Pittsburgh and Ohio’s University watched them turn into beetles. “My daugh- of Findlay, now offer degrees in intergenera- ter loves science, and now so do I,”she says. tional studies. Elsewhere, the older generation may not Sometimes when science crosses the gen- be directly related to the students, but they eration gap, it does so within families. In often share a cultural heritage. At a summer Chicago, preschoolers and their parents are science camp in Grand Forks, North Dakota, studying science together. One physics tribal elders kick off each day of camp and primer begins with a trip to see Disney’s Lit- later wrap it up, helping the Native Ameri- tle Mermaid on Ice. Afterward, back in can schoolchildren connect what they’re school, the children try “skating” across a car- learning with the tribe’s culture. “The elders pet on squares of slippery waxed paper, thus serve as the heart of the camp,”says Mary learning about friction and balance. They Beth Kelley-Lowe, director of the hhmi- discover the principles of density, viscosity supported program run by the Dakota Sci- and flow by filling bottles with baby oil, food ence Center. “They talk with the kids about

COURTESY OF FAIRCHILD GARDEN OF FAIRCHILD COURTESY coloring and water and then agitating them. how they can be good scientists, yet respect Kurt Durnberg (left) and Erika Batlle present their Together they examine shells and sponges traditional knowledge and ancient ways.” first-prize results on bitter orange to local seniors. under a magnifying glass and hunt with In remote villages of rural Alaska, with magnets for metal objects hidden in sand. support from an hhmi grant, an Anchor- deal with the dynamics of family relation- The preschoolers and their relatives are age science museum called The Imaginari- ships,”Anderson says. “They enjoy the role of part of a hands-on science-education pro- um is working with elders and local experts interviewer and researcher, and they seem to gram—the Science and Math Excellence Net- familiar with cultural traditions to develop take the job seriously. The seniors enjoy talk- work (same)—run at 18 Chicago schools by science programs that incorporate examples ing with younger people, and the ones who Rush-Presbyterian-St. Luke’s Medical Center relevant to the children’s lives and culture— do have some knowledge of their native in collaboration with the Chicago public the speed of a kayak paddled with or against plants feel appreciated for what they know.” schools, independent schools and businesses. the current, for example, or the life cycle of There are cultural benefits as well. same is supported in part by hhmi.Par- a familiar bird or fish. Community science Caribbean immigrants make up a significant ents are an integral part of the program and festivals put on by the museum enable eld- segment of Miami’s population and cultural are encouraged to participate in workshops ers to share their knowledge, bringing tradi- heritage. But while many of the students at to help reinforce for the children the excite- tional and modern science to village resi- Carver Middle School have an immigrant ment and importance of learning. “Parents dents of all ages. parent or grandparents, more than a few con- are kids’ first teachers,”says Kati Gilson, an “We work with local elders to integrate fess little knowledge of their families’ native early-childhood science-education specialist traditional native knowledge,”explains lands. Interviews with the seniors Christopher Cable, The Imaginari- seem to awaken for many of the FOR MORE INFORMATION: um’s executive director. “It helps teenagers a new interest in, and Fairchild Tropical Garden, www.ftg.org make the content of our programs respect for, the places where their Science and Math Excellence Network, fisheredu.com/SAME relevant and meaningful to the entire parents or grandparents were born. Dakota Science Center, www.dakota-science.org community.” “Sometimes kids are simply more The Imaginarium, www.imaginarium.org —JENNIFER BOETH DONOVAN open to talking with strangers than and CATHERINE KRISTIANSEN

10 hhmi bulletin | september 2002 With a Little Help from Our Friends The genomes of chimps, chickens, bees and others may tell us much about ourselves.

hmi researcher A. James Hudspeth, who studies the causes of human deafness, can barely wait to get hold of the genome sequences of two Hsmall animals that seem quite remote from COOK TIMOTHY humans—zebrafish and chickens. “Nearly all human hearing problems are This is just the start of a flood of new served on the panel (see Q&A, page 13).“We due to the loss of hair cells in the cochlea,” genome sequences that are expected within took only one minute to decide.”The chicken, Hudspeth explains. Such losses are perma- the next few years. he explains, is a model system for studies of nent in mammals but not in other verte- Comparative genomics, in which the embryonic development, which is easier to brates. “If you expose a chicken to loud nois- DNA sequences of two or more species are observe in an egg than in a uterus. In addition, es or otherwise injure its delicate hair cells, it closely compared, is becoming a key tool for although the chicken genome is only about will lose its ability to hear, as a human would. scientists who want to understand the func- one-third the size of mammalian genomes, But within a few days, the chicken’s hair cells tions of human genes. Dozens of research there is a remarkable level of conservation will begin to regenerate,”he says. “Within a groups have been clamoring to get their between the two. few weeks, the cells have grown to maturity favorite animal’s genome sequenced ever since Scientists throughout the world are await- and reconnected to nerve fibers, and the the first draft of the human genome was ing this sequence for a variety of surprising chicken has largely recovered its hearing.” announced two years ago. The cat, dog, cow reasons. While Hudspeth looks forward to Hudspeth, who heads the Laboratory of and other familiar species have their partisans, finding the genes and proteins involved in Sensory Neuroscience at The Rockefeller while other scientists support the rhesus mon- deafness, David C. Page, an hhmi investiga- University in New York City, hopes to identi- key, the platypus or various strange birds, fish tor at the Massachusetts Institute of Technol- fy the chicken and fish genes that control this or fungi. To bring some order to this free-for- ogy, expects the chicken genome to help him regeneration. Having them in hand might all, nhgri drew up guidelines for setting pri- search for the causes of infertility in humans. lead to ways of stimulating the correspon- orities and asked some questions: How valu- “We could do a tremendous amount ding genes in human ears, he says, thereby able would the new genome sequence be to with this sequence,”Page says. “I’d be espe- improving the hearing of deaf people. His lab researchers? How would it be used, and how cially interested in the sex chromosomes has painstakingly cloned some of the genes soon? How would it advance human health? because in the chicken, the female has two related to hearing in zebrafish, which are eco- In the first round of replies, 13 groups different sex chromosomes, a W and a Z, nomical to work with. But if the zebrafish submitted “white papers” backing their par- while the male has two Zs. Given that we’ve genome were already sequenced, he says, “we ticular organisms, and a panel of scientists learned a great deal about sperm production could do in weeks what now takes us a year.” chose six organisms that varied enormously and male infertility from studying the human in size, type and evolutionary distance from Y [chromosome], one might speculate that And the winners are . . . humans. Approved in May by the nhgri’s the best way to study infertility in women is Hudspeth may soon have his wish. England’s advisory council, the winners were the chick- to sequence the chicken’s sex chromosomes.” Wellcome Trust Sanger Institute is sequenc- en, the chimpanzee, a group of fungi, the ing the zebrafish genome, and the chicken honeybee, the sea urchin and Tetrahymena Hastily made-over apes genome has just received a “high priority” (a freshwater protozoan). Although the chicken genome had smooth rating by the National Human Genome “The chicken fulfilled all our require- sailing in the nhgri panel, the chimpanzee, Research Institute (nhgri) as one of the ments, so giving it high priority was easy,” “our closest living relative,”aroused a great deal next organisms that may be sequenced with recalls Sean R. Eddy, an hhmi investigator at of controversy. Among the arguments: Deci- National Institutes of Health (nih) funding. Washington University in St. Louis, who phering the chimp’s genome sequence will be

hhmi bulletin | september 2002 11 Up Front gained access to the entire ecosystem, he says, addition, bees may be very useful to it changed so speedily that humans may be researchers who study the aging process: very time-consuming and expensive, costing called “hastily made-over apes.”And our loss Queen bees live twenty times longer than about $100 million. (“The good thing about of the ape-like genes, he suggests, may be their workers, despite identical genes. the other genomes is that they’re smaller,”said directly responsible for the human propensity The panel gave high priority to three one scientist.“We can do 5 to 10 of them for to obesity, diabetes, cardiovascular disease, other organisms for specific reasons. Sea the price of only one primate.”) Furthermore, epithelial cancers and neurodegenerative dis- urchins are expected to be of particular value chimps are now so rare and valuable that they ease. Therefore the genes we lost might pro- to scientists who study early embryonic cannot be used for genetic experiments—and vide “a direct biochemical model of how to development, genetic mutations in cancer many scientists believe it would be unethical to remedy…human defects,”according to the and evolution. Tetrahymena could be useful do so because of the chimp’s closeness to Olson white paper, and the chimp might in advancing research on telomeres, the tips humans. The rhesus macaque, which has serve as “a presently unexploited source of of chromosomes that play a major role in proved valuable in many medical experiments, ideas” on how to improve human health. aging and cancer. And the fungi should help offered tough competition; the panel wavered researchers solve problems related to fungal between the two primates. Picking favorites infections, for which very few therapies exist. Yet the chimp won, partly because of a Each of the other four genomes to which the Now that the panel has made its first rousing white paper whose first author is nhgri panel gave high priority has its own selections, scientists in the three major Maynard V. Olson, director of the University set of advantages for researchers. The honey- sequencing centers funded by nih—the of Washington Genome Center in Seattle. bee’s genome sequence, for example, may Washington University Genome Sequencing Paul W. Sternberg, an hhmi investigator at prove to be a gold mine for scientists who Center in St. Louis; the Whitehead the California Institute of Technology, in study the genetic basis of humans’ social traits Institute/mit Center for Genome Research in Cambridge, Massachusetts; and Baylor College of Medicine in Houston—will be Sequencing the chimp genome will give us an free to pick any organism out of the high- priority bin and sequence it. inkling of what it means to be human. Meanwhile, an intricate network of sequencing collaborations has been established Pasadena, who was also on the panel, sup- and ability to learn.“Honeybees live in soci- between private companies, universities and ported the chimp enthusiastically. “In some eties that rival our own in complexity,”says government agencies around the world. The ways, we didn’t need to put a person on the Gene E. Robinson, director of the neuroscience Department of Energy is funding the genome moon and bring him back, either,”Sternberg program at the University of Illinois, Urbana- sequence of Fugu rubripes (the Japanese puffer- says, “but it was a magnificent achievement. Champaign, and lead author of the bee white fish), the frog, the sea squirt, 41 microbes and Sequencing the chimp genome will give us paper. With their famous dances, which tell the poplar tree, which may be used to produce an inkling of what it means to be human.” other bees where the flowers are, bees have liquid fuel. The Institute for Genomic Research According to the Olson white paper, the developed “the only nonprimate symbolic lan- (tigr) is sequencing a variety of bacteria and chimp is genetically so similar to humans guage,”he says. Like humans, bees have an viruses. Baylor College of Medicine and others that only 1.2 percent of its nucleotides intricate system of division of labor, highly are sequencing the rat genome with nih diverge from the human ones. However, organized defense and warfare, complex archi- funds. The Wellcome Trust Sanger Institute because both genomes contain more than tecture and even a well-developed system of recently completed a draft sequence of 2.5 billion base pairs of DNA, this comes to personal sacrifice. The genes that play a role in Anopheles gambiae, the malaria mosquito. about 30 million differences—“a lot of differ- these activities can now be analyzed rapidly Japan’s National Institute of Agrobiological ences between the two, and well worth study- with the help of genetics and new genomic Sciences is sequencing the silk moth. Ger- ing,”says Sternberg. These differences may technologies. many’s Bayer AG chemical conglomerate and shed light on “how the human brain acquired Bees also have much to offer from a Exelixis, of South San Francisco, have just its extraordinary capabilities,”the white medical point of view. Bee hives present announced an incomplete version of the paper points out. They may help explain ideal conditions for bacterial growth because tobacco budworm genome. humans’ long periods of maturation and of their high temperature, humidity, over- Mark Guyer, assistant director for scien- helplessness during infancy relative to apes. crowding (the equivalent of 15 adult tific coordination at the nhgri, has been Some of the major contributions of humans living in a 12- by 18-foot apart- nurturing the selection process but claims to sequencing the primate genome may be med- ment) and the bees’ constant food-sharing. have no favorite animal of his own. “I like ical. A few years ago, Olson developed the the- Given their ability to thrive in these environ- ’em all,”he says diplomatically. He points out ory that in any rapid evolution, it is much ments, bees must have evolved powerful that more white papers arrived in June, more common for a species to lose some of antibiotic peptides, some of which might another set is expected in October and even- its old genes than to acquire brand-new ones. lead to novel therapies. Bee venom is anoth- tually many more genomes will get done. As our species broke out of the rain forest and er promising source of active compounds. In —MAYA PINES

12 hhmi bulletin | september 2002 sequence that are important. One of the best that level of buzz or arguing, but there actu- Genome Insider ways to do that is to find another nematode ally isn’t a lot of serious lobbying. sequence that’s closely related. And a third A conversation with Sean Eddy criterion is “weird biology,”so to speak, where Has the panel seen anything that caused the genome is inherently interesting in its members to laugh? aving helped build the rough own right. An example, which didn’t get Eddy: Sure,but I’d hesitate to name names. For draft of the human genome, approved but probably will be before long, is instance, we’ll see an out-of-left-field white the U.S. genome-sequencing the Oxytricha genome sequence. It’s a cili- paper written on an organism that no one has centers are starting to ate—distantly related to paramecium. The thought hard about—they don’t even know make inroads into the weird thing about Oxytricha is that each the genome size. This is an immediate killer Hgenetics of other animals as well. Deter- Q gene is basically its own little chromo- because there are genomes out there that are mining which animal genomes are most & some. If we had the Oxytricha genome, we big—much bigger than the human genome, worthy of sequencing, though, is the task would have one in which a lot of the gene like the lily genome, which is about 100 giga- of a panel of scientists convened by the A finding had already been done for us, bases (Gb), 30 times the size of the human. National Human Genome There’s no way we would Research Institute (nhgri) of sequence something whose the National Institutes of proposers hadn’t asked the Health (nih). Sean R. Eddy, an basic how-heavy, how-much- hhmi investigator and com- DNA questions. putational biologist who stud- ies the evolution of genomes at You’re a self-professed “cat Washington University in St. person.”How soon should Louis, is on the panel. the cat genome be sequenced? Why is the panel necessary? Eddy: Well, clearly, cats are Why can’t the genome- much more important than sequencing centers decide for dogs [chuckling], so cats themselves? have priority. We haven’t Eddy: If the genome centers had seen a white paper for the to plan which organisms to cat yet, but it’s perfectly jus- sequence next, they’d spend too tifiable. Still, the dog’s much time reading zoology lit- behavioral characteristics erature and not enough time are extremely well-studied; sequencing. nhgri’s idea was if we had a dog genome, the an “open public contract” rate at which people could mechanism: If you think your clone genes involved in dog should be sequenced as a Sean Eddy, shown with Muggins, is waiting to see a white paper on the cat genome. behavioral traits might be service to the community, you accelerated. So even though can submit a 10-page white paper and explain since the ends of the chromosomal DNA I’m a cat person, I’m leaning toward the why. If the panel agrees, the dog genome gets pretty much define the ends of the genes. dog project. I want to see the dog people placed on nhgri’s list of high-priority items. put in a white paper. Then a genome center can look at the list and Is there much lobbying from researchers or say “Ah! The dog! We can do the dog.”The other groups to get something placed on How many genomes can the centers get idea is to use this constant amount of the high-priority list? through? sequencing capacity and fill the pipeline. Eddy: As the genome project expands out- Eddy: If you do everything as rough draft, ward to cover more animals, no one wants to you’d have the ability to do maybe 5 Gb of What are your criteria for selection? be in a backwater that doesn’t have a genome assembled sequence per year at the three Eddy: One criterion is whether the organism yet. You want your genome to be up at the main nhgri centers combined, not count- has long served as a model system for molec- top of the list, or at least part of the club. ing the capacity of other large genome cen- ular-genetics research. Some of these, like Everyone is pushing an agenda, but not par- ters, such as the Wellcome Trust Sanger Drosophila, C. elegans and E. coli,were no- ticularly strongly. You’ll be at a pub or a Institute in England or the Department of brainers, and those genomes got done early. meeting and someone will say, “I think we Energy’s Joint Genome Institute. That means A second criterion involves comparative should do the platypus.”And someone else the nhgri centers can do one or two large genomics. Once I have, say, the C. elegans will say, “Oh no, the platypus is a stupid mammalian genomes a year, plus many sequence, I want to find features in that genome. We should do the koala.”So there’s other smaller genomes. —BRIAN B. REID

hhmi bulletin | september 2002 13 » A small—some say too small—group of physician-scientists believes HumanOn the best science requires patient contact. By Marlene Cimons Terms

ne day in 1994, a man appeared at the Massachusetts General Hospital infectious-diseases clinic and offered himself up for research. A hemophiliac, he had been infected with HIV since 1978, but, remarkably, he had never shown any signs of AIDS.“I feel great,”he told the doctors. “You might want to study me.” Indeed, Bruce D. Walker recalls,“We started studying him like crazy.” The encounter ultimately produced a wealth of results, chief among them the discovery of a unique immune-system response that’s missing in patients who suffer from progressive HIV disease. The findings, published in 1997 in the journal Science,represented “the first Oindication that people could mount a successful cellular immune response against HIV,”says Walker. Just as important was another outcome: The episode was a striking example of how those who labor at the intersection of two worlds— clinical medicine and laboratory research—can achieve critical biomed- ical advances that might not emerge from one or the other arena alone. These physician-scientists—also called patient-oriented researchers or clinical investigators—spend their professional lives crossing the boundaries between the bench and the bedside, convinced that the best science cannot be conducted in the absence of patient contact. “Mice are not humans,”says Walker, one of a dozen physician- scientists recently chosen for appointment as new hhmi investigators (see page 18).“That’s the crux of the issue. All of our work on this

immune response came from a clinical observation that never would DOOHER KATHLEEN

» Interacting with patients has enabled Bruce Walker to ask research questions that probably wouldn’t have come out of lab work alone.

14 hhmi bulletin | september 2002 J.W. STEWART have happened if someone doing basic lab research didn’t have a medical school curriculum established in 1964 that leads to a chance to interact with a patient.” combined M.D., Ph.D. degree—has been “hugely successful in creating a powerful cohort doing great laboratory science,”says DIFFICULT CHOICES Varmus. Similarly, the hhmi-nih Research Scholars Program Yet despite the potential payoff, the number of physician-scientists encourages medical students to become physician-scientists by in the United States is dwindling, according to a 2000 report of the bringing them to the nih campus to spend a year working Federation of American Societies for Experimental Biology. Young alongside nih scientists in the lab. Two-thirds of the physicians scientists and physicians are choosing more traditional career paths. who participated in the late 1980s are actively engaged in research “Only about 11 percent of medical school graduates plan today. careers that are exclusively or significantly devoted to research,”says “Many of us think that this is the most important issue we can David G. Nathan, president emeritus of the Dana-Farber Cancer address, that of encouraging bright young people to enter the field of Institute and a member of hhmi’s medical advisory board.“These physician-scientist,”says David A. Clayton, hhmi’s vice president 1,600 graduates hold the future of medical research in their hands and chief scientific officer.“We are looking at everything we do along because some of them will be trained to translate the fruits of basic those lines, asking whether we can add to what we already do.” research into better care of patients and into prevention of disease. Apart from these training successes, however, physician- We must do everything we can to encourage them.” scientists encounter increasing demands, mostly economic, to Being both a physician and a scientist, by definition, requires spend more time in the clinic than in the lab, which makes it hard expertise in two areas, meaning a hefty time commitment in both for them to compete for funding against Ph.D. researchers who are fields. This places a tremendous burden on many medical students, not encumbered by patient care. And often they receive little if any who often incur large debts while attending school and feel support from their institutions for “protected” lab time, which pressured to pay them off as quickly as possible. Medical school diminishes their ability to conduct basic science. debt, however, is far from the only factor that discourages Observers generally agree that time is a key factor for those who physicians from doing patient-oriented research. opt for the lab over the clinic: Lab experiments can be conducted Harold E. Varmus, who served as director of the National much more quickly than human studies. Recruiting subjects takes Institutes of Health (nih) during the Clinton administration and is time—including approval by institutional review boards and also an hhmi medical advisory board member, says that when informed consent from research candidates—and daunting discussing the plight of physician-scientists it is important to amounts of paperwork. Moreover, trying to care for patients with distinguish between two categories of researchers: those who treat certain diseases, such as cancer, can be unpredictable; they may take patients and perform lab work, and those who primarily conduct focus and energy away from the bench, often at inconvenient times. patient-oriented research—that is, research that intimately and “Research is very competitive, and it’s very difficult,”says Bert specifically involves the patients they see. Varmus, now president of Vogelstein, an hhmi investigator who studies the molecular basis of Memorial Sloan-Kettering Cancer Center in New York City, worries colon cancer at The Johns Hopkins University School of Medicine. more about the latter than the former. “It requires a supreme focus. Any other activities distract.” “The patient-oriented types are a source of concern,”he says. As a result, researchers often are forced to make difficult “Clinical science is difficult, slow and underappreciated, [and] the choices. Vogelstein, trained as both a physician and a scientist, made rising demands on academic health centers for clinical revenue the decision to devote his time to the lab.“My research is centered from patient care cut into research time.”Although significant on patients, but I don’t see them,”he says.“Oncology is one of those people are doing first-rate studies with patients, Varmus asserts, disciplines where it is difficult to combine the two, because patients “their numbers are suboptimal.” [can be] so sick and require constant attention. It’s easier for Initiatives such as nih’s Medical Scientist Training Program—a physician-scientists in other fields, like genetics or endocrinology, because they can see patients on a scheduled basis. “Being a good physician is a full-time job; being a good scientist is a full-time job,”Vogelstein notes.“It’s A Physician-Scientist extremely difficult to do both. It’s like trying to carry out two full-time careers. I didn’t feel I could do justice by Any Other Name to my research or to my patients if I tried to do both, so The term physician-scientist can mean different things to different people and covers I stopped seeing patients. However, the experience of a relatively wide range of researchers. There are those with medical degrees who work being educated in both science and medicine has been exclusively in the lab, never seeing patients. Others may see patients once a week in enormously helpful, and I believe that such joint a clinic or monthly on rounds, but they don’t necessarily study patients as an integral training will prove essential for those interested in dis- part of their research. The final group conducts research—which includes lab work— ease-oriented research in the future.” specific to patients, and their contact with the patients often stimulates the research Yet there are some medical areas where the two questions they ask. The majority of the 12 new HHMI investigators fall into this latter mesh beautifully, says Katherine A. High, who conducts group of clinical investigators, or patient-oriented researchers. More often than not, hematology research at The Children’s Hospital in however, distinctions among the three groups can be blurred and imprecise. Philadelphia, in explaining why she keeps a foot in each world.“If you have a firm grounding in the science, you

16 hhmi bulletin | september 2002 VID GRAHAM DA

» Katherine High, with hemophilia patient Leonard Selvoski, and warrants support, including more time to do the studies,”says studies the molecular basis of blood coagulation. Varmus. These programs will in turn “encourage others—M.D.s, mainly, but some Ph.D.s too—to enter the field. The many promises can approach clinical problems clearly.”She recalls a patient treated made about moving new discoveries about genes and signaling with the blood thinner coumadin after heart surgery. Bleeding pathways and new chemical methods and the immune system into problems led to several hospital visits and lab tests, none of which clinical practice will be met only if we train adequate numbers of implicated the drug. Finally, High used an assay that showed very low people to do clinical studies and then find opportunities and levels of factor IX, a blood-clotting factor—only when the patient resources for them to do what they are trained to do.” took coumadin. She eventually showed that the patient had a Meanwhile, those who have managed to straddle both worlds mutation in the gene for factor IX that made him extraordinarily speak overwhelmingly of having struck a satisfying balance in their sensitive to the blood thinner. The patient is now kept on low levels of professional lives. They dismiss the hurdles, which they see as being coumadin and the bleeding has stopped. Additional lab experiments more than offset by the rewards of translating their scientific efforts indicated just how the mutation caused sensitivity to the drug. The into human terms. same mutation has since been observed in other patients with “I love what I do,”says hhmi investigator Gerald I. Shulman, sensitivity to coumadin. and in both arenas. He enjoys his time in the lab, he says, but would never abandon patient care. A SATISFYING BALANCE Shulman, a diabetes specialist at Yale University School of Patient-oriented researchers need encouragements, such as hhmi’s Medicine, attributes much of his attitude to the childhood new program to appoint clinical investigators, to “send a signal to experience of watching his physician father interact with his medical schools and other places that clinical research has respect patients.“I followed him on his rounds and loved the

hhmi bulletin | september 2002 17 connections—the wonderful relationships—he had with his The question was: Does this same process happen in humans?” patients,”Shulman recalls. In studying humans, however, “we discovered that a very Repeatedly, physician-scientists emphasize that neither different mechanism was responsible for fat-induced insulin resist- discipline can be pursued in isolation and that lab studies are not ance in skeletal muscle,”he says. “Therefore, there is a whole differ- sufficient to extrapolate to humans—and at times can even be ent set of therapeutic targets to pursue. So if you aren’t studying misleading.“If I study a mouse or a particular cell line, what I find the human, you may be studying something that isn’t applicable. there might not be applicable to the patient,”says Shulman, who is As powerful as animal studies are, without studying patients, you investigating the relationship of insulin resistance to the could be led astray. development of type 2 diabetes. “I think it’s important to be studying the patient with the For example, he cites the work of Sir Philip Randle and his disease,”he adds.“I go back and forth between patient studies in the colleagues at the University of Bristol of nearly four decades ago.“They clinical research center and studies at the bench involving trans- showed—in a classic series of in vitro studies—that insulin resistance genic and knockout mouse models of the disease. What I do in the could be induced in heart cells from rats by incubating them with fatty clinical research center is about 10 times harder than what I do at acids,”Shulman notes.“Randle and colleagues came up with a the bench, but it’s the most important because it involves the actual biochemical explanation that showed the fatty acids caused insulin patient. That’s what matters.” resistance by inhibiting an enzyme involved in glucose metabolism. Moreover, exposure to both disciplines gives physician-

development with clinical research in patients with skeletal malformations, Lee Broadening the hopes to understand the consequences of gene mutations on craniofacial/limb Research Base development. He and colleagues are also investigating gene-nutrient interactions in hmi has selected 12 new investi- TODD R. GOLUB, M.D.,Dana-Farber patients who have disorders in the urea cycle, gators who conduct patient-ori- Cancer Institute, Boston. Golub and which can lead to brain damage and death. ented research. These physician- colleagues are developing diagnostic and scientists have made important prognostic tests for childhood leukemia, EMMANUEL J. MIGNOT, M.D., PH.D., contributions to understanding devising strategies for predicting responses Stanford University School of Medicine, Palo health problems such as cancer, AIDS and to chemotherapy based on gene expression Alto, California. Mignot and colleagues are cardiovascular disease. President Thomas R. patterns and exploring novel treatment studying narcolepsy, a severe sleep disorder HCech says he hopes the group will “find new strategies based on analyses of a patient’s that causes the afflicted to fall into a deep ways to translate basic science discoveries into genome. sleep with little or no warning. He is investi- useful therapies for patients.” gating whether narcolepsy is exacerbated by They will join 324 hhmi investigators KATHERINE A. HIGH, M.D., The Children’s an autoimmune response against specific across the United States, the majority of Hospital of Philadelphia. High studies the cells in the brain. whom focus on basic research directed molecular basis of blood coagulation and toward understanding the genetic, molecular has showed that gene therapy can achieve CHARLES L. SAWYERS, M.D.,Jonsson and cellular bases of human disease. long-term improvement in dogs with hemo- Comprehensive Cancer Center, David Geffen philia. Her team has begun clinical studies in School of Medicine at the University of ROBERT B. DARNELL, M.D., PH.D., The patients with severe hemophilia B. California, Los Angeles. Sawyers collaborated Rockefeller University, New York City. with Brian Druker to design and conduct Darnell studies degenerative brain disorders HELEN H. HOBBS, M.D.,University of the clinical trials of STI-571 for treatment that are provoked by an autoimmune Texas Southwestern Medical Center at Dallas. of chronic myelogenous leukemia and response to certain cancers. Hobbs and colleagues are studying how recently showed how resistance to STI-571 abnormalities in the processing of dietary occurs. He is now working to identify the BRIAN J. DRUKER, M.D., Oregon Health lipids cause human diseases. She is also molecular changes that accompany a form and Science University, Portland. Druker’s principal investigator for the Dallas Heart of brain cancer called glioblastoma as well search for a molecule that would block the Disease Prevention Project, studying 3,000 as prostate cancer. action of a tyrosine kinase that promotes randomly selected individuals and their formation of chronic myelogenous behavioral, environmental, metabolic and ROBERT F. SILICIANO, M.D., PH.D., The leukemia and gastrointestinal stromal genetic risk factors for cardiovascular disease. Johns Hopkins University School of Medicine, tumors led to STI-571, commonly known Baltimore. Siliciano is searching for ways to as Gleevec. Druker played a key role in BRENDAN H.L. LEE, M.D., PH.D., Baylor prevent or treat HIV infection. He and shepherding the drug through clinical College of Medicine, Houston. Linking colleagues have shown that HIV-1 can persist trials in patients. studies on mammalian tissue and organ in a silent form, even in patients on effective

18 hhmi bulletin | september 2002 scientists “a sense of how each world exists,”says Matthew L. all physician-scientists must make a similar decision: to accept the Warman, an hhmi investigator at Case Western Reserve University notion that the practice of medicine cannot be divorced from the School of Medicine in Cleveland.“A lot of clinicians who never science of medicine. “For a physician-scientist, the approach to spend time in a basic science lab don’t appreciate how experiments each patient needs to be similar to the approach to a scientific are performed—what types of samples are needed, what kind of problem,”he says. information needs to accompany the samples,”he adds.“And Robert B. Darnell, at The Rockefeller University, discovered this people who live entirely in a lab do not understand the time and clinic-lab connection early in his career, in 1987, when he was a effort that goes into explaining to a family affected by disease the young neurology resident at Memorial Sloan-Kettering Cancer nature of scientific research.” Center. An outwardly healthy woman in her mid-30s had woken up Warman continues,“I am driven to live in both worlds and dizzy one morning.“Over the course of the next three days, she make connections that would be more difficult for people who live couldn’t read or watch TV; she became completely uncoordinated in only one world to make.” and couldn’t stand up without falling over. She couldn’t feed herself. Finally, she couldn’t take a step.”Her cerebellum, the part of CLINICAL INTEREST AND INSIGHT the brain that coordinates muscle movement, had been destroyed in Brendan H.L. Lee, who studies skeletal development and metabolic a matter of days. Lab tests showed high levels of an antibody to a diseases at Baylor College of Medicine in Houston, says that almost new protein in that part of her brain. This was an immune response to a breast cancer that had gone undetected—a response that had been antiretroviral therapy. They hope to initial encounter. They hope to learn how to successfully suppressing the cancer at understand how it manages to do so, and boost immunity to viruses. Walker is also the expense of her cerebellum. thereby design a means to eradicate the virus. helping several institutions in South Africa In the ensuing years, using blood expand their immunology programs and from patients with similar ailments, EDWIN M. STONE, M.D., PH.D., support training in virology. Darnell’s research team has cloned a University of Iowa Roy J. and Lucille A. series of genes that encode for these pre- Carver College of Medicine, Iowa City. CHRISTOPHER A. WALSH, M.D., PH.D., viously undiscovered neuron-specific Stone’s research interests are in inherited eye Harvard Medical School, Beth Israel proteins.“We are using these rare diseases. He collaborated with hhmi Deaconess Medical Center, Boston. disorders as a Rosetta stone for reading investigator Val C. Sheffield at the University Walsh’s lab is interested in the causes of out new principles of tumor immunity of Iowa to identify the chromosomal mental retardation and epilepsy in and basic neuroscience,”he says.“The location of genes that cause 14 different eye children. He collaborates with clinical power of taking one disease apart and diseases. Stone and colleagues have also geneticists and pediatric neurologists dissecting it is something that is not created the first international center for around the world to improve diagnosis of doable without the clinical interest and molecular diagnosis of eye diseases. childhood brain disorders, and through a insight that comes from seeing patients.” pioneering “Internet Clinic,”he has Charles L. Sawyers, a leukemia BRUCE D. WALKER, M.D.,Harvard described more than a dozen new specialist at the University of California, Medical School, Massachusetts General neurological syndromes whose genetic Los Angeles, Geffen School of Medicine, Hospital, Charlestown. Walker’s group is bases are being investigated. has a similar view. His collaborative work studying patients in the earliest stages of led to the development of Gleevec, a drug HIV infection to determine how the » For more details on the investigators’ work, that has reversed the course of chronic immune system fights the virus during the visit www.hhmi.org/news/052802.html. myelogenous leukemia (see Bulletin, December 2001).“To take the principle of From left (row 1): Katherine A. High, Emmanuel J. Mignot, Brendan H.L. Lee, Charles L. Sawyers; understanding a cancer at the molecular (row 2): Robert B. Darnell, Bruce D. Walker, Helen H. Hobbs, Todd R. Golub; (row 3): Robert F. level, come up with a treatment that Siliciano, Edwin M. Stone, Christopher A. Walsh, Brian J. Druker. exploits that molecular abnormality, test it and find out, amazingly, that it works,”he says,“you can’t imagine how motivated it makes you feel.” Indeed, such an attitude goes to the very heart of the qualities common to those researchers who choose to practice their craft within these two disciplines. “The first is a great curiosity for understanding why something happens,” says Baylor’s Lee.“The second is a great need to use this information to make a UL FETTERS

PA difference in the lives of people.” H

hhmi bulletin | september 2002 19 Engine

20 hhmi bulletin | september 2002 Adam Arkin sees the cell as a mechanical system. He hopes to transform molecular biology into a kind of cellular engineering and in the process, learn how to move cells from sickness to health. By M. Mitchell Waldrop

“when i was very young,”says adam evolves and how life developed from a control stand that cell until we get some way of order- Arkin, thinking back to the 1970s and his child- perspective.”In short, he says, he wants to know ing this information. We need a theory to hood in New York City,“I used to get up early how everything in the cell fits together. encompass it all. We need the data structures to in the morning and go rooting through the hold it.And we need the knowledge representa- neighbors’trash, looking for mechanical items, THINKING LIKE AN ENGINEER tion that allows us to query it in clever ways and or things like old calculators with those Nixie- Although Arkin is certainly not the only biolo- help us learn how it fits together.” tube displays—stuff with cool electronic wid- gist trying to understand the cell as a system— One way to pursue this goal, he says, is to gets and readouts. I’d bring them back to my as opposed to looking at it gene by gene or pro- use a wide variety of organizing principles. He room, and over time I’d build these massive tein by protein—he is tackling the problem with embraces fields such as electrical engineering things I called ‘machines.’There was always this a broad range of tools and techniques. and communications theory, in which practi- feeling that everything was fitting together in Mathematical modeling,network analysis,com- tioners have long since evolved ways of ana- some fashion. puter simulation, laboratory experiments—he lyzing complex networks. “I still look for that feeling,”says Arkin,a 35- and the 20-plus postdocs and students in his lab- Arkin holds up a printout: “Here is a net- year-old hhmi investigator at the University of oratory are using anything that seems to work. work diagram for sporulation in Bacillus sub- California,Berkeley.The difference is that today, How else, he asks, can you see the under- tilis”—a harmless bacterium that, like its dead- he’s working on “machines” called organisms. lying phenomena? Consider the neutrophil, a ly cousin B. anthracis, the cause of anthrax, will Pointing to a pair of charts that fill up most type of white blood cell that’s critical to the sometimes turn itself into a hardy spore under of one wall in his tiny, crowded office in body’s defense against disease. This organism conditions of stress.How does it make that deci- Berkeley’s Melvin Calvin Laboratory, he says,“I lacks eyes, hands and a brain, yet through sion? “Look at this, this and this,”he says, point- want to know about that!”“That”is a tangle of chemotaxis—the ability to follow subtle chem- ing to clusters of interactions that seem to have lines and nodes that might almost be a circuit ical traces in the environment—a neutrophil can a similar structure. These clusters are examples diagram for the latest Intel microprocessor. In lock on to an invading pathogenic bacterium, of what he and his group have dubbed a regula- fact, each chart depicts a bewilderingly complex track it down as it darts among the surrounding tory “motif.”They all have a promoter to guide universe of everything that’s known about the red blood cells and destroy it with the accuracy the expression of two genes: one is the activator regulatory pathways of bacterial cells. of a heat-seeking missile. “This is an incredible for a process and the other is the inhibitor.If you “I want to know the how and the why,” navigation system,”says Arkin.“But the number think like an electrical engineer about such a sys- declares Arkin. “I want to know how the cell’s of proteins involved in that system is huge—in tem, he says, you can analyze how its overall behavior emerges, how the cell survives and the hundreds,at least.We’re not going to under- behavior will arise from the push and pull of those two genes. “It turns out that this regulatory motif has the ability to be a switch, a pulse generator or an oscillator,” he says, depending on how the push and pull are balanced. Furthermore, he adds, “You get the same pattern of regulation from evolutionarily unrelated proteins. So it’s Photographs by Robert Cardin the structure of the network that’s important, neerıng not the identity of the proteins.” With that insight,you can model these sub- networks as components in an electrical circuit, or perhaps as active nodes in a communications web.“When you put those oscillators and switch- the es back into the network,”Arkin says, “you can determine what its possible dynamics are at a higher level of abstraction.So if I were to perturb the cell by a change in the outside environment, I can begin to analyze how the signal is processed through the network” to trigger sporulation or any other change in behavior. Though the same results could be derived from a full physical model, he adds, this high level of abstraction, if done correctly,could give us a much clearer pic- Cell hhmi bulletin | september 2002 21 ture of how cell behavior arises. biospice to be more than that.”Indeed, he and these components are specialized lines. “But Of course, admits Arkin, this high-level, his allies argued that the system should integrate even in a cartoon there are issues of what you functional approach to cell behavior has plen- every form of molecular data available, from want to include,”says Arkin.“For example, the ty of skeptics, who wonder if electrical engi- DNA sequences to protein structures and central dogma of biology is that DNA gets tran- neering bears anything more than a vague beyond—and then provide a seamless interface scribed into messenger RNA (mRNA), which resemblance to biology. Nonetheless, he says, he for any cell simulation or network analysis a gets translated into a protein. But if you’re not and his students have already used the technique researcher wants to write. going to be talking about the RNA in this exper- to produce some interesting preliminary mod- That’s obviously a huge undertaking, says iment, you don’t want to show it.” els of B. subtilis and several other organisms. In Arkin,which is why “it’s now darpa biospice, Indeed, in this particular view, the complex addition, he and his group are collaborating not just my biospice.” In September 2001,when process of gene expression has been collapsed with many other laboratories on a related the Defense Advanced Research Projects Agency into a simple arrow connecting each gene to the approach to organizing knowledge of the cell: a started funding multiple laboratories to work on appropriate protein. “But the software has to kind of online biology network library and cell- various pieces of the project, Arkin became one know that there is still an RNA in there some- simulation tool known as biospice. of 19 or so principal investigators. Nonetheless, place,”says Arkin. If need be, in fact, the software Arkin doesn’t claim to be the originator of he says, biospice remains “a major core”of his allows the user to drill down and show not just biospice,just one of its earliest and most vocal lab in Berkeley. mRNA, but its binding sites, cleavage sites, ter- proponents—although he does take credit for He calls up a portion of the program on his minators and all the rest. It can go even further the name. That came from an electrical-engi- laptop.“At the heart of biospice is this pathway than that.“For example,”says Arkin, pulling up neering tool called spice, the Simulation diagramming tool, which is our interface with another display, “here’s where someone has Program for Integrated Circuit Evaluation, working biologists.”He shows the “cartooning” drawn two proteins binding to DNA. But what which does pretty much what its name suggests. view, in which a stretch of DNA is a simple does that mean? It could be that this guy binds He says, “when I first started pushing the idea, straight line, the various genes of interest are yel- first, then that guy. It could be the other way there were already a couple of simple programs low ovals embedded in the line, proteins are around. It could be that that guy binds, and he out there for cell simulation. But I meant free-floating blobs and various processes among prevents this guy from binding. And so on. We

the course, students hear guest lecturers—from at least a dozen biological Supercomputers Appeal disciplines—who discuss the creative ways they’ve been integrating com- puters and biology.The undergrads take a shot at it themselves; at the begin- to Biology Undergrads ning of the course, each student chooses a specific gene or protein and uses computers to learn more about it,explains course coordinator Eric Polinko. While the pioneering work of Adam Arkin’s team at the One student studied a protein kinase that is associated with University of California, Berkeley, relies on a remarkably broad range Alzheimer’s disease. He compared versions of the protein in everything of tools and techniques, such versatility may soon become standard oper- from cows to fruit flies, finding that only portions of the protein remained ating procedure in biology labs. identical in them all. These portions should represent the most important Consider the University of Pittsburgh’s undergraduate course on com- parts of the protein, and thus, the most interesting to study, Polinko says. putational biology, which apparently has no trouble luring biology stu- “The computational tools will never replace experimental research, but dents. They’re already computer-savvy, so what might have seemed over- they can point you in the right experimental directions.” ly technical, complex or irrelevant to their predecessors is challenging and “These students get hands-on experience and come out with com- downright exciting to this next generation of researchers. puter skills that will make them highly employable,”Nicholas adds. “The idea that they can apply their interest in computers to biolo- —MARLENE CIMONS gy is very appealing to them,” says Lewis Jacobson, associate professor of biological sciences and project director for the grant from hhmi that supports the course. The goal, he says, is to enhance the undergraduates’ research skills through the use of sophisticated programs and Web sites. A prime attraction is access to the Pittsburgh Supercomputing Center—a joint effort of the University of Pittsburgh and Carnegie Mellon University—that enables the students to work on some of the world’s fastest machines.“Their sheer power is enormous,”Jacobson says. “The kind of stuff that would take your desktop [computer] hundreds of years to do, these computers can do in a second.” The supercomputing center also has a large selection of software and Lewis Jacobson and databases, says Hugh B. Nicholas, Jr., one of its senior scientific specialists. Hugh B. Nicholas, Jr., say “In the neurosciences, we have programs that simulate neurotransmitters computational biology is going back and forth between nerve cells and muscle cells,”he says.“That a hit with undergrads.

is invaluable if you’re trying to study how the brain functions.”Throughout GOLDSMITH SCOTT

22 hhmi bulletin | september 2002 have to allow users to put that point of the paper. So I called kind of information down— them up and started an argu- even if it’s just to say that we don’t ment with Harley. It was a great know how these proteins interact. argument! We had so much fun “So that’s one of the issues that we decided I should migrate we’re really struggling with,”Arkin to do a postdoc in their lab.” says: “How do we represent all “Harley was an amazing that information? And how do we mentor,”says Arkin, “and so was do it so that biologists who don’t Lucy. Harley was working very, know anything about computer very hard to pin down everything models can navigate around this he possibly could about lambda information with ease?” phage. Together we came up with this theory that genes have A SOCIAL EXPERIMENT to be expressed stochastically Along the way, Arkin and his (that is, with lots of statistical team have also been struggling fluctuation in the rate of expres- with an unusually complex social Arkin’s eclectic approach to sion), given the low number of dynamic. Between the program- biology brings together staff molecules that control them.” mers and the various flavors of from almost a dozen fields. That finding was an eye- scientists and engineers, his opener for many biologists, and group spans 10 different disciplines: chemistry, gression,” he explains, “the brain being an it may well have been what got Arkin his next chemical engineering, molecular cell biology, organic kind of machine. I found my way into job at the Lawrence Berkeley Laboratory, mathematics, physics, computer science, elec- a programming job in the neurosurgery located on the hillside just above the trical engineering, bioengineering, mechanical department of a hospital in New York, where University of California campus. He arrived engineering and bioinformatics. His lab has I learned my first laboratory skills. I had told there in January 1998, joined the university’s expanded from fewer than half a dozen mem- them I knew all these computer languages— faculty in July 1999 and became an hhmi bers to more than 20 within the past two years. though I didn’t. I had to learn them, fast!” investigator in October 2000. Perhaps more Everyone is still working through the culture Then, as an undergraduate at Carleton important, however, the finding crystallized clash.“You can imagine that a student coming in College in Minnesota, Arkin switched to phys- his current commitment to systems biology: gets very disconcerted,”says Arkin,“because the ical chemistry—a field that he pursued through “What came of working with lambda phage,” guy next to her is from a different field and looks his early graduate-student years at the he says, “was a renewed understanding that like he knows infinitely more than she does. But Massachusetts Institute of Technology (mit)— everything was connected—that there is order he’s thinking the same thing about her. So they until he found himself working with a biologist and principles to cellular control.” both look at each other and say, ‘My God, I’m on a study of one of the proteins involved in His hope, Arkin says, is that this kind of unqualified for this job,’and there’s that uncom- photosynthesis. That was interesting enough, he systems work will eventually transform molec- fortable period of learning.” says, “but when I began to look at the endoge- ular biology into a kind of cellular engineer- It probably doesn’t help that members’ nous pathways to control this entire process, I ing—a discipline in which practitioners can offices are scattered over all four floors of was just captured.And I started thinking,‘That’s predict, control and design cellular materials as Berkeley’s Calvin building while their new lab how it actually works! And I’m studying only confidently as traditional engineers create, say, space is being constructed. Nonetheless, they one protein?’ ” He wanted to understand it all, a new aircraft. generally give Arkin high marks for his ability he says. In those days—the early 1990s—biol- “Just look at the following Holy Grail to build team spirit. He does it partly through ogists were finally beginning to accumulate problem,”he says.“Given a known genetic pre- his weekly group meetings and discussion sec- enough data to make that fantasy seem possible. disposition of human beings, and the network tions, they say, but mostly through his rapid- “Being a geeky kind of guy,” says Arkin, that controls a cell, predict the best place for a fire personality. “my hypothesis was that there had to be some drug, or a combination of drugs, to move that “Adam just creates an intellectually stim- form of control and computation inside a cell.” cell from sickness to health.You want to be able ulating environment,” says postdoc So in 1992, Ph.D. in hand, he left mit for a to use cellular engineering to cut down the Christopher Rao, who is doing a comparative postdoc with Stanford University chemist time to find drug combinations—or perhaps analysis of how chemotaxis is controlled in John Ross, who was studying how to make even to tailor the drugs to individuals. Escherichia coli and B. subtilis. “It’s not espe- chemical reactions carry out computer-like “There are other practical applications,”he cially well-oiled, but this is exactly the kind of operations. Just as he was finishing up his post- adds,“for example, designing an organism that multidisciplinary research group that every- doc in 1995, he noticed a new paper about will metabolize, say, a dangerous heavy metal body says we need in biology.” lambda phage (a virus that infects E. coli) by like mercury into a compound that we can Arkin’s background is uncommonly eclec- Stanford’s Harley McAdams and Lucy Shapiro. immobilize, extract and put someplace safe.” tic. During his high school years, for example, “It was actually a very, very nice paper,”he says, “It’s an interesting quest, in a knightly sort the one-time trash collector became interest- “but, young upstart that I was, I found lots of of way,”says Arkin,“and I think I want to take ed in the brain. “It seemed like a natural pro- faults with it—most of which were beside the that on.” H

hhmi bulletin | september 2002 23 EFFORTS TO UNDERMINE EVOLUTION EDUCATION—MOST RECENTLY IN THE FORM OF A CONCEPT CALLED “INTELLIGENT DESIGN”—HAVE EVOLVED INTO A 21ST-CENTURY MARKETING CAMPAIGN THAT RELIES ON LEGAL ACUMEN, MANIPULATION OF SCIENTIFIC LITERATURE AND GRASSROOTS TACTICS.

BY TRISHA GURA ILLUSTRATION BY BRIAN STAUFFER The

Evolutionarythe ohio board of education had a big problem. Two years ago, a Fordham Foundation study had slapped the state with an “F” for the way it taught evolution in the classroom. In fact, state standards lacked any mention of evolution in the sci- ence lessons for Ohio students, kindergarten through high school. Embarrassed, the state legislature mandated that the board revise the standards by the end of 2002. In the course of adopting new standards, however, the board ran smack into the latest anti-evolution concept: intelligent design. ceWarnt thought science curricula should be limited to evolution alone. The philosophy purports that life is too complex to have evolved “What’s at stake,”says Kenneth R. Miller, professor of biology by chance and therefore must have been the product of a divine at Brown University in Providence, Rhode Island,“is that a major, (in the supernatural sense—perhaps a biblical God or an extra- highly industrialized U.S. state is on the verge of writing intelligent terrestrial force) designer. design into its school curriculum, with the complete absence of any In a push that sparked a fierce row between parents,teachers,leg- scientific support.” islators and board members, proponents of intelligent design were Ohio’s education standards are expected to be finalized by trying to insert the idea into the Ohio science standards as an “alter- December. According to Board of Education member Marlene native to evolution.” Advocates of intelligent design, led by the Jennings, “some sort of compromise” is expected, but details are Discovery Institute, a conservative think tank and activist organiza- unclear. tion in Seattle, insist that their concept is a valid scientific theory and Sound familiar? It should. The Kansas Board of Education that it deserves a place in the K–12 curricula alongside evolution. went through a similar battle four years ago when evolution faced At Cloverleaf Middle School, a public school in Westfield Center, off against creation science, which focuses on biblical origins of Ohio, Kira Nance and her classmates have not been taught about the universe and looks for “evidence”against evolution. In August evolution. The 14-year-old recalls her 8th-grade science teacher talk- 1999, the board voted to drop evolution entirely from its newly ing last fall about adding discussions of evolution to the curriculum. revised standards. Amid the public outcry, one year later, voters “Nobody really cared,”says Nance.“Only a few students had an opin- ousted the two anti-evolutionist board members; a third member ion, and they didn’t voice it clearly.”She says she believes in God and resigned. The new board reinserted evolution into the state sci- doesn’t believe in evolution, but she wouldn’t mind learning about ence standards. it. She’d like to hear about intelligent design as well.“Hearing both In the United Kingdom, meanwhile, scientists have been sides would be a good thing.” enraged over reports that Emmanuel College in Gateshead—a pres- Adults in Ohio appear to agree.According to a public poll com- tigious Christian-run college near Newcastle upon Tyne that has missioned by The Cleveland Plain Dealer and published in June, 59 been praised by Prime Minister Tony Blair—is teaching creation- percent of respondents favored including both evolution and intel- ist ideas as science. At the same time, Japanese education officials ligent design in the state’s academic standards for science; only 8 per- are cutting evolution from the middle school curriculum and mak-

24 hhmi bulletin | september 2002

Evolution Online ing it optional for high school students. The move Meanwhile, adults and children can turn to the Web to learn about Darwinian evolution. is meant to ease pressure on the country’s children, The Museum of Paleontology at the University of California, Berkeley, is develop- according to a report in the April 25, 2002, Nature, ing a Web site that features interactive laboratories. Targeting primary, middle and high but scientists are concerned about the impact on stu- school students, the site, supported by a grant from hhmi,will show how evolution dents’ understanding of biology. affects people’s daily lives. Examples such as the human-microbe “arms race” of antibi- otic resistance form the basis of the lessons. Planting the Seed Evolutionary biologist David R. Lindberg, the museum’s director, calls the Web site’s The hullabaloo about intelligent design, says evo- approach “less esoteric than exploring evolution by discussing why Darwin’s finches all have lutionary biologist David R. Lindberg, director of different beak sizes.”He recalls hearing a public service announcement last fall that remind- the Museum of Paleontology at the University of ed people to get their flu shots because “last year’s shot won’t protect you from this year’s California, Berkeley, “is all really a smokescreen to influenza strain.”Why doesn’t last year’s vaccine work this year? The get back to basic ‘creation science’.” answer is evolution, Lindberg points out. Because viruses and infec- David Lindberg’s This self-styled science sprung from creationism, tious microbes have short life cycles, the rapid development of new museum Web site which became a legal reality when John T.Scopes was strains of flu is really an evolutionary event. teaches about convicted by the state of Tennessee in 1925 of the People don’t commonly think about evolution in the context of one evolution, with no crime of teaching evolution. It wasn’t until 1957 that year, nor is evolution part of their picture of disease and medical treat- apologies. evolution made a classroom comeback, spurred in ment.Yet such examples can bring difficult concepts home for students large part by Sputnik, which generated a competitive and adults alike.“Knowing that some people cannot simply get a penicillin shot to fight an zest in Americans to be scientifically literate.Law solid- infection because the bacterial strain they carry has evolved to resist the drug,”Lindberg says, ified the turnaround in 1968 when, in Epperson v. “gives evolution real meaning.” —BETH SCHACHTER Arkansas,the Supreme Court ruled that states cannot FOR MORE INFORMATION: www.ucmp.berkeley.edu/history/evolution.html ban the teaching of evolution on religious grounds. In response, creationists reframed their doc- trine as creation science. During the 1970s, 22 states proposed that cre- tation of the level of disagreement between scientists,” says Jack W. ation science and evolution be given equal time in classrooms, and two Szostak, hhmi investigator at Massachusetts General Hospital in Boston, states—Arkansas and Louisiana—adopted the idea. Then in 1987, the who studies the principles of Darwinian evolution on populations of U.S. Supreme Court struck anti-evolutionists down again, reaffirming DNA molecules in the laboratory. a federal district court decision that creation science was, in fact, reli- In some communities, these “misinterpretations” have had an gion and therefore couldn’t be taught in schools. impact. In 1996, biology textbooks in Alabama began carrying evolu- While the decision appeared to be a victory for science, Justice tion disclaimers. The practice still continues today. That same year, Antonin Scalia left a loophole. Teachers could still teach “evidence against Governor Fob James used state discretionary funds to send every high evolution,”he wrote. That tiny phrase, part of a larger opinion, became school teacher in Alabama a copy of the anti-evolutionary book Darwin a seed that anti-evolutionists readily planted. They scoured the scien- on Trial,by Phillip E. Johnson, a now-retired criminal-law professor at tific literature and attended scientific meetings, with the purpose of find- the University of California, Berkeley. The author invokes the legal argu- ing and pointing out evolutionary “controversy,”as if the practice of sci- ment of “reasonable doubt”: Because you can’t prove that evolution cre- ence proceeds any other way. ated human beings, he maintains, you must allow for alternatives to it. Scientists do of course disagree on some of the specifics of evolu- “Evolution is not ad hoc theorizing,” counters molecular biolo- tion. For example, they gist Sean B. Carroll. “Evolution is a large body of scientific fact that argue about the exact posi- Jonathan Wells from the Discovery Institute is supported by a large body of theory,” says the hhmi investigator tions that whales and hip- promoted intelligent design at a March Ohio at the University of Wisconsin–Madison. Medical experience with pos occupy on the tree of Board of Education meeting in Columbus. antibiotic resistance, fossil evidence and comparative studies with ani- life and about the exact mals all bolster the case for evolution. sequence of genetic changes that cause tumor The Evolution of Intelligent Design cells to develop resistance The intelligent-design concept stems from the work of English theologian to chemotherapy. Darwin’s William Paley,who in 1802 developed the idea in his book Natural Theology. theory hasn’t explained all He compared particular biological structures, such as the eye, to a watch. these details—at least not Just as this timepiece does not self-assemble, Paley wrote, the intricate yet, say scientists. But the designs of living things implicitly argue for the hand of a “watchmaker.” devil is in the details. In 1989, Percival Davis at the Hillsborough Community College in Meanwhile, anti-evo- Tampa and Dean Kenyon at San Francisco State University resurrected lutionists claim that these the 200-year-old watchmaker argument. In their book Of Pandas and disagreements cast doubt People, they maintain that classic Darwinism—which states that organ- on whether evolution ever isms evolve over long periods of time as a result of random change and PRETE/AP happened at all—“a com- A mutation—cannot explain the structural complexity of life. Therefore,

pletely willful misinterpre- L JAY they conclude, life had to be created by an intelligent designer.

26 hhmi bulletin issue in Ohio. There may be other factors as well, including the way intel- ligent design is being presented.One argument states that evolution is just a theory, intelligent design is also a theory; therefore, the two deserve the same time in classrooms.They “are exploiting Americans’sense of fairness,” says Wisconsin’s Carroll. The anti-evolution approach is being considered on the local level simply because that is where many educational decisions are made in this country, notes Lindberg. Board members are accountable to state legislators as well as to the community members who elect them. This produces incredible disparities between science curricula district-by-dis- trict and even school-by-school. If intelligent design or some other “alternative” to evolution makes it into the state curriculum standards,it will likely dictate the content of text- books,statewide proficiency exams and teacher certification.“Teachers are very much aware that they have to teach to tests,”says molecular biologist Joan L.Slonczewski at Kenyon College in Ohio,who runs an hhmi-fund- ed outreach program for science teachers. They must also satisfy parents. If parents object to the teaching of evolution, for example, and teachers refuse to comply, their jobs are on the line, says Slonczewski. To skirt the problem, many teachers avoid evolution altogether—or wait until the last week of school, when no one has time to voice an objection. This flight (as opposed to fight) approach is having an effect. FRED MERTZ Slonczewski and Carroll, both of whom teach biology, say that some stu- By the mid-1990s, the “scientific” component of intelligent design dents are arriving at college knowing little or nothing about evolution. began to form. In 1996, for example, Michael J. Behe, a biochemist at Lehigh University, in Bethlehem, Pennsylvania, laid out his theory of Treading Lightly “irreducible complexity.”In his book Darwin’s Black Box: The Biochemical Teachers aren’t the only ones grappling with wide-ranging views about Challenge to Evolution,Behe argues that systems like the bacterial fla- evolution. Similar disparity is playing out in zoos, museums and com- gellum—a whip-like appendage that propels the creature through bio- munity programs, partly as a result of teacher actions (or inactions). logical fluids—has several parts that are necessary for its function. In the “I have been here for over eight years and I have not had one teacher absence of any of those parts, the flagellum doesn’t work. If evolution ask us to cover evolution,”says Brad Batdorf, curator of education at the moves stepwise from first conception to today’s version, intermediate Sedgwick County Zoo in Wichita, Kansas. On the other hand, he reports, forms should be able to function. Because they don’t, Behe argues, the some teachers, parents and other visitors have asked not to be taught fully made structure must be designed. anything about evolution. Not surprisingly, the intelligent-design concept has met with criti- That puts Batdorf in a quandary. The zoo is receiving an hhmi grant cisms—the main one being, according to molecular geneticist Bruce T. to develop activities that boost scientific literacy.At the same time, com- Lahn,that “there is no evidence for it.”Lahn,an hhmi investigator at The munity groups also provide funding to the zoo. His strategy is to tread University of Chicago, says that intelligent design, by scientific definition, lightly around the issue. Descriptive signs at the zoo often have subtle ref- cannot be a theory because it cannot be tested,only believed.What’s more, erences to evolution, but Batdorf says he stresses respect for the creatures he notes,no account of intelligent design or its conceptual siblings has ever and their ecological relationships, rather than how they came to be. appeared in any peer-reviewed scientific journal. Slonczewski is also trying to be sensitive.She is structuring her outreach The Discovery Institute’s Stephen C.Meyer says that intelligent design to include evolution not as a separate lecture for teachers but intricately proponents haven’t published articles in peer-reviewed journals because woven into all of biology as an explanation for change—in everything from the scientific community is “biased” against viral mutation to wing development in fruit intelligent design and therefore won’t accept FOR MORE INFORMATION: flies to immunity in human beings. it.“They are excluding publication of a viable UC Museum of Paleontology: Lindberg at the Museum of Paleontology, hypothesis,”Meyer asserts. www.ucmp.berkeley.edu/historyoflife/histoflife.html who last July received a grant from hhmi to Amid the debates, intelligent-design Discovery Institute: www.discovery.org develop an interactive Web site on evolution proponents are making their mark, as evi- National Center for Science Education—an organization (see sidebar), is promoting evolution with no denced by that Cleveland Plain Dealer poll. that defends the teaching of evolution in public schools: apologies.“K–12 science classes should reflect With its convoluted arguments and lack of www.ncseweb.org what scientists call science,”he explains. evidence, how is intelligent design gaining WGBH Boston Evolution project—a PBS miniseries with Carroll agrees:“Love your religion, but such support? online teaching tools: www.pbs.org/wgbh/evolution don’t try to wrap it up and tell me it’s science. “We’re dealing with emotional issues,” For the United States to remain a techno- What do you think? Send us your comments: says board member Joseph D. Roman, who [email protected] logical leader, we have to understand what cochairs the subcommittee that will decide the science is—and teach it.” H

hhmi bulletin | september 2002 27 Cofathlle

Could quirky, new Wanimal modelsi ld help scientists By Kathryn Brown learn how to regenerate human limbs or avert the debilitating effects BAT EMBRYO Differences in when and how identical genes are expressed of a stroke? »»» mean humans have fingers and bats have wings.

28 hhmi bulletin | september 2002 SCOTT WEATHERBEE, NISWANDER LAB ARCTIC SQUIRREL

umans bear little resemblance to Hibernating squirrels have remarkable defenses against brain injury. squirrels and even less to a bacterium that thrives in tins of irradiated horsemeat. But these and other far- flung creatures are offering new insights into the human condition. Although only a Hhandful of organisms—notably fruit flies, nematodes and mice—have dominated comparative biology, scientists are casting a wider net for the biological lessons they say are lurking undiscovered in the wild. hhmi investigator Sandra L. Wolin, at Yale University School of Medicine, and colleagues came across the bacterium Deinococcus radiodurans—the most radiation- resistant organism known—while studying proteins involved in two autoimmune diseases: systemic lupus erythematosus and Sjögren’s syndrome. Researchers have marveled at D. radiodurans since the 1950s, when they dis- covered it flourishing inside tins of meat that had been DREW OF KELLY COURTESY heavily irradiated during food-sterilization experiments. strikingly similar to an RNA-binding protein found in A computer specialist working with Wolin, Anne humans, called Ro. People with lupus often make Marie Quinn, was scanning a microbial genome database antibodies against their own Ro protein, though no one when she realized that D. radiodurans produces a protein knows just how Ro functions. To learn more about Ro’s role, a postdoctoral fellow in One Tough Bug To learn about photosensitivity, HHMI’s Sandra Wolin and postdoc Xinguo Wolin’s lab, Xinguo Chen, created a strain of D. radiodurans Chen study a bacterium that thrives in cans of irradiated horse meat. that lacked the protein. The resulting bacteria were no longer so hardy; they died when exposed to ultraviolet (UV) radiation. “One fascinating thing is that lupus patients with antibodies against Ro often have serious sensitivity to sunlight,”Wolin says. Perhaps, she suggests, a lupus patient’s antibodies interfere with Ro in skin cells, leaving the patient sensitive to sunlight. Her team now hopes to unravel Ro’s precise role. Wolin suspects Ro binds RNAs damaged by UV radiation and targets them for destruction. Hints from Hibernation For some 50 years, a small group of researchers has studied hibernating animals such as the woodchuck and ground squirrel for clues to treating stroke. During a stroke, a person’s blood flow and oxygen in the brain plummet. Much the same occurs as animals begin hibernating, though these sleepers stay safe until spring, when they awaken unscathed.“Hibernation is nature’s solution to enduring in the face of very low oxygen and blood flow,”says John M. Hallenbeck, a senior investigator at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. How do hibernators do it? Over the past decade, researchers have shown that hibernating squirrels basically shift biochemical gears, suppressing metabolism and immune response while boosting antioxidant defenses, among other adjustments.“The key is that all these things happen at once,”Hallenbeck says, and this convergence yields potent results.“These ground squirrels have pretty dramatic protection against brain injury,”notes neurochemist Kelly Drew of the University of Alaska in Fairbanks.

AMY ETRA More recently, Drew decided to see just how well hiber-

30 hhmi bulletin | september 2002 nation helps an animal resist brain injury. She and her many other ways, they distinctly differ. As the embryos colleagues inserted microdialysis probes into the brains of develop, for instance, bats grow wings, with cape-like five Arctic ground squirrels, two hibernating and the others webbing between their digits. But mice, like chicks and awake as usual. Several days later, the team compared the humans, lose these “interdigital cells,”and their digits or squirrels’ brains. Those that were hibernating at the time of fingers form with no webbing in between. All four the probe-induced injury fared well, with very little tissue creatures probably share the same limb-development damage. By contrast, the active squirrels showed clear signs genes—they just express those genes during different of injury—significant cell damage and inflammation of the developmental windows, says molecular biologist Lee surrounding brain tissue.“These strikingly different Niswander, an hhmi investigator at the Sloan-Kettering responses do support the idea that hibernation is a good Institute in New York.“How do changes in gene expression model of neuroprotection,”says Drew, whose team give rise to these evolutionarily important differences in published the study in the June 2001 issue of the American animals?” Niswander asks.“If we can understand how these Journal of Pathology. limbs develop in bats, we’ll gain insight into the process in If researchers can identify hibernation’s key the chick, mouse and human.” biochemical steps, Hallenbeck suggests, it may be possible The flatworm is another old model with a new twist. to induce a similar process in stroke patients. Emergency At the University of Utah in Salt Lake City, biologist paramedics, for instance, could deliver drugs that Alejandro Sánchez Alvarado decapitates freshwater minimize brain damage during, or immediately after, a planarians—only to watch those fragments regenerate into stroke. “In a clinical setting, you’d want a patient’s metabolism to drop to some minimal level, while generating molecules that suppress inflammation and fight free A Living radicals,”Hallenbeck says. Scientists still have much to learn about hibernation, Biology and no one knows whether nature’s long winter nap will inspire realistic stroke Lesson therapies. Drew, for one, is optimistic. It’s a velvety green caterpillar. Reviving Old Models It’s a tough brown pupa. It’s a Some of the new creatures being studied large, mottled gray moth. are merely rediscoveries of some of Manduca sexta,or the science’s old models—such as the bat (see tobacco hornworm, is all of page 32)—that fell out of favor when the above, which is one biologists began training their microscopes reason (or three reasons) why on fewer organisms.“If you go back to the the popular biology-lab 1800s or earlier, you’ll find scientific animal has become a pet and

sketches of bat embryos,”remarks Richard OF ARIZONA PROJECT/UNIVERSITY OF THE MANDUCA COURTESY living science lesson in the R. Behringer, a molecular geneticist at the primary grade classrooms of Tucson, Inspires Poetry Eduardo Hernandez plays with M.D. Anderson Cancer Center in Houston. Arizona. The Manduca Project, run by the a tobacco hornworm in its caterpillar phase. “In fact, there’s a heritage of reproductive University of Arizona’s department of biology in diverse organisms, with a wealth biochemistry and molecular biophysics of knowledge to be gained by doing with a grant from hhmi,helps teachers More than 3,500 first, second and third comparative studies.” exploit the 40-day life cycle of the graders so far have raised tobacco About five years ago, Behringer hornworm to capture the attention of first, hornworms from egg to moth. University of decided to combine embryological studies second and third graders. Arizona undergraduates, who work with of mice with research on bats. “We all say Although the young Manduca breeders the teachers and children to study these we’re studying this or that animal to learn don’t realize it, they’re also honing their powers insects, take what they learn back to their more about human biology and disease,” of observation and expanding their knowledge own labs for further exploration. Kim says Behringer. “If that’s true, we should of biological systems, diversity, metamorphosis Keene, for example, did her senior research start questioning the relevance of our and the relationship between structure and project on a digestive enzyme that helps models. At some stages of development, function—all elements of Arizona’s state Manduca sexta move through its many human embryos are very different from science education standards. The project also molts and rapid growth. mouse embryos. So you start thinking, addresses math standards as the children —JENNIFER BOETH DONOVAN why am I studying the mouse? How does measure and graph the growth of their it relate to humans?” hornworms. Some classes have composed FOR MORE INFORMATION Bats may look like flying mice—but in songs and poems about their multilegged pets. www.manducaproject.com

hhmi bulletin | september 2002 31 FLATWORM

fully formed worms. “Flatworms have figured out how to Alejandro Sánchez Alvarado is betting on Schmidtea mediterranea’s access all their developmental processes at any given point regenerative talents to help with limb regeneration in humans. during their lifetimes,”he says. “In this day of genome sequencing and developmental insight, it’s possible that we could learn a great deal about regeneration and stem cell biology from planarians.”For example, if scientists discov- ered the basis of nature’s regenerative talents, people who lost limbs to accidents or illness might ultimately be able to grow replacements. When Sánchez Alvarado began working with flatworms six years ago, many of his colleagues derided his choice as “career suicide.”In developmental biology, after all, Caenorhabditis elegans was the worm to watch. But soon his lab began documenting genes found in planarians and humans, but not in C. elegans or fruit flies.“These may SÁNCHEZ ALVARADO OF ALEJANDRO COURTESY be missing pieces of evolution,”he says,“and it’s definitely a mouse stem cells can reliably turn into different tissues, viable scientific endeavor.” others are uncovering the molecular-mechanics systems of In fact, while some researchers debate whether adult- naturally regenerating animals. These animal architects include hydra polyps, tadpoles, zebrafish, newts and planarians. So far, Sánchez Alvarado’s lab has found about 5,000 Where the Bats Are independent markers of gene expression, called expressed sequence tags (ESTs), in When Lee Niswander goes to work, she gets a her colleagues intervene, the bats mate. the flatworm Schmidtea mediterranea.His squeaky and high-pitched welcome, In fact, mating is what makes the bat group and others are now crafting assays complete with a flutter of wings and a facility so important.“The biggest reason for to profile gene expression during twitching of ears. This unusual greeting is having a colony is the ability to do timed regeneration. The big task will be to from a colony of tropical fruit bats. When matings,”Niswander explains.“We want to pinpoint responsible genes—and their not in her lab at the Sloan-Kettering study bat embryos at precise developmental human homologs, if any, adds Sánchez Institute, Niswander, an hhmi investigator, stages.”That’s possible, she adds, only when Alvarado.“We don’t know whether often works at one of the few bat research she and colleagues can catch a developmental regeneration is the same, molecularly, facilities in the country. Here, about 100 moment in action. (Ever try to lure a across organisms,”he concedes.“But the furry fliers spend their days snoozing and pregnant bat from the sky?) genetics could tell us.” nights exploring. And when Niswander or While at Cornell University’s Medical Even nature’s farthest corners—and College, bat researcher John J. Rasweiler IV, tiniest creatures—may hold hints for Out of the Night Lee Niswander says nocturnal bats now at the State University of New York humans.“Biology often makes progress by are a valuable resource for developmental biology. Downstate Medical Center in Brooklyn, looking at extreme cases,”says hhmi founded the colony with bats collected in President Thomas R. Cech. Because all life Trinidad almost a decade ago. When is related through evolution, he says, Rasweiler left Cornell, the facility’s funding scientists trust that biology’s extremes was in question. But last year, Niswander apply in more mundane settings as well. appealed to hhmi Vice President Gerald M. Cech speaks from experience. In the Rubin for support. For roughly $20,000 per 1980s, his team at the University of year, hhmi has kept the facility open— Colorado, Boulder, discovered self-splicing allowing Niswander, as well as molecular RNA, or ribozymes, in a lowly pond geneticist Richard Behringer of M.D. organism, the ciliated protozoan Anderson Cancer Center in Houston, to con- Tetrahymena thermophila.Since then, duct developmental studies of bats that also scientists have recorded and sequenced promise insights into human biology. 1,800 examples of this type of RNA spread Niswander estimates that housing each bat across much of biological life. costs about 65 cents per day. While Cech advocates making the “We ultimately hope to make this colony most of known animal models and their available to the broader scientific community,” advanced tools, he also sounds the call for Niswander says.“Researchers are growing creative comparisons.“The best insights more aware of our developmental research on often come when you stop to compare SON TANAKA BLANEY SON TANAKA

bats, and this is a valuable resource.” —K. B. JA vastly different species,”he says. H

32 hhmi bulletin | september 2002 PERSPECTIVE Intelligent Design Is a Cop-Out This creationist ploy, if taught as science, could stop discovery in its tracks. By Nipam H. Patel

first became aware of the “intelligent design” movement a who’ve concluded that certain biochemical pathways or cellular few years ago while doing research for an evolution text- structures, for example, are too complex to have evolved—have hit a book. Although we were designing the book for a college wall in their “science” that they deem insurmountable. Is this what undergraduate course, I needed to know what was being we tell our students is proper behavior when coming up against taught at the elementary and high school levels in order to walls, or do we encourage them to have the creativity and tenacity see the impact of various school-board decisions on curricula and to overcome such barriers? Ito assess the likely effect of these curricula on students’ prepared- I think that the majority of researchers enter science because ness for college-level work. As I searched they enjoy exploring the unknown, deci- the Web for information, I was dismayed phering mysteries and feeling the thrill of to come across sites describing this latest solving one section of the puzzle at a time. “evolution,” as it were, of the creationist To succeed, scientists must approach movement. research with determination and resolve, Intelligent design proponents argue that because discoveries rarely come easily. many biological processes and structures are Intelligent design, however, suggests that too complex to have evolved, and thus the once a question becomes too complex, we only way to explain their existence is to sup- should just throw up our hands and pose that they were constructed by an intelli- invoke supernatural intervention as an gent designer. This is not so much a theory explanation, instead of continuing to in its own right as a vehicle to attack the sci- explore deeper. entific study of evolutionary biology, which Scientists cannot claim to have all the creationists like to denigrate as “just a theo- answers, and we realize that currently well ry.”And they are quick to fall back on the accepted theories may be overturned and

tired old claim that scientific debate on the ODD BUCHANAN replaced, but this happens because we con- mechanisms of evolution somehow suggests T tinue to question, explore and test the world that many scientists do not believe that evolution is a fact. around us. And we do so while believing that we will find explanations The intelligent design community has written several books that and that questions—seemingly impossible to answer, or even address, offer its views and “evidence.” In response, the science community today—eventually will be answered if we persevere. It is essential that has directly addressed, and rebutted, those arguments. In Abusing we teach our students that this is the way science is done. Science, Philip Kitcher provides examples of the kinds of evidence to Where would our society be if an intelligent design-like approach support evolution that creationists claim is lacking. Robert Pennock had dominated our thinking in the past? We’d have very little of our in his book, The Tower of Babel,documents the confusions and current knowledge and treatments of diseases. We’d have scant inconsistencies that make up tenets, such as “irreducible complexi- understanding of the pull of gravity, the structure of the solar system, ty,” that are central to the intelligent design arguments. the constituents of matter, the uses of energy, the nature of living In the end, arguments and counterarguments on intelligent things, the science and technology that so improve the quality—and design come down to a clash between faith and science and duration—of our lives. Worse yet, where would we be headed in the attempts to interject religion into science. While open debate is an future if we taught our children this defeatist and backward approach essential component of our society, as is freedom of religion, the to investigating the real world and its place in the universe? most troubling aspect of this movement for me is the notion that While the intelligent design agenda is directed most specifically intelligent design should be taught alongside evolutionary biology at evolutionary biology, we need to realize the effect that teaching in schools as an alternative “scientific” theory. This would send a such an approach would have on all areas of scientific inquiry. It is wrong, even absurd, message about what science and scientific bad enough that students often enter college with a poor back- research is all about. ground in evolution, but if they harbor the more general idea that Intelligent design implies that some “investigators”—those scientific advances—in whatever field—have distinct boundaries Nipam H. Patel, an hhmi investigator at The University of Chicago, studies the evolu- that can only be crossed by resorting to explanations outside the tion of body patterning and neural development at the molecular and genetic levels. realm of science, we will be in serious trouble indeed. H

hhmi bulletin | september 2002 33 NEWS& NOTES RSTEN KJELLSTRAND RSTEN TO Science experiments help students, such as Migel Angel-Lopez (left) and Leonel Chipres (right) learn In from the Fields English in Mario Godoy-Gonzalez’s classroom. t’s Friday afternoon, and Mario Godoy- is water and how much is mineral. Mexico where formal education is limited. Gonzalez’s science classroom at Royal Godoy-Gonzalez is not teaching a sci- “Many of my students bring to this country IHigh School in the rural Washington ence class, per se. His is a unique English as the idea that they will get some education,” farming community of Royal City fills with a Second Language (esl) program that uses says Godoy-Gonzalez. “But most of them the sweet smell of mint, cilantro and hands-on science as a general educational believe their future is just on the field pick- oregano. The aroma comes from the fresh tool. His students learn English—as well as ing apples. I want them to see that they herbs that Godoy-Gonzalez’s students dili- history, geography and math—partly by have other options.” gently mash with mortars and pestles. Even- wielding micropipettes, pouring gels, run- This gutsy experiment began in 1994 tually, the leaves turn to lumps of damp ning polymerase chain reaction machines when the Royal City school district, respond- paste, which will be refrigerated until Mon- and participating in projects that one would ing to a boom in the apple economy and an day. That’s when the class will use a lineup normally expect to find only in advanced influx of migrant workers, hired Godoy- of chemicals to check the plants’ liquid biology classes. Gonzalez, an immigrant from Chile, to run extracts for nutritional compounds: copper Most of Godoy-Gonzalez’s students are the esl program. Godoy-Gonzalez was given hydroxide and sodium citrate to test for children of migrant farm workers who tend the tough task of developing a curriculum sugar, 2,6-dichloroindophenol sodium salt eastern Washington’s apple orchards. The that would keep students in school and give for vitamin C and iodine for starch. They students arrive speaking very little English; them a fighting chance at graduating. He will also determine how much of each plant often they come from small rural villages in turned to science for several reasons. For one

34 hhmi bulletin | september 2002 thing, these students were culturally close to tioning of this region. nature. For another, passing mainstream sci- Lost on the Tip Mathematical models of memory from ence was one of the toughest obstacles on the 1970s suggested that, based on its their road to graduation. There was only one of the Tongue anatomy and wiring, the CA3 region of the problem—Godoy-Gonzalez himself knew hippocampus was a likely center for asso- very little about science. emory loss is a common com- ciative memory, says Tonegawa. Pattern So he sought help wherever it was avail- plaint among the elderly. In the completion was hypothesized to be a key able. During his first year, he enrolled in the Mearly stages of Alzheimer’s disease, function of such associative memory cen- Summer Institute in Life Science, an hhmi- conjuring up a memory becomes an impos- ters, he says. But, until now, researchers sponsored program at the University of sible chore. In both cases, according to have not had a tool to test this hypothesis Washington in Seattle, which introduced hhmi investigator Susumu Tonegawa, the in live animals. Tonegawa and his col- him to hands-on science instruction. Since memories are sitting dormant in the brain; leagues developed a method called “spatial then, he has participated in other enhance- the challenge is retrieving them. targeting” that enables them to knock out a ment programs, including the hhmi-sup- “As all of us age, we experience some gene in a specific area of the brain. For this ported Science Education Partnership at memory impairment in which we have study, they knocked out the gene for the Seattle’s Fred Hutchinson Cancer Research more trouble remembering, say, the name NMDA receptors in the CA3 region. The Center, where secondary school teachers of a person we definitely know,”says Tone- neurons in the CA3 region are wired partner with faculty scientists for hands-on gawa, who directs the Picower Center for together in a characteristic way—each science workshops and research experiences. Learning and Memory at the Massachusetts sends axons that synapse onto themselves He even spent two summers assisting scien- Institute of Technology (mit). “We feel like or other cells of the same kind, forming a tists who use DNA microarrays to study the the name is just on the tip of the tongue, “recurrent network.”When the NMDA genetics of plant-seed dormancy. but it won’t quite come.” receptors are knocked out, the efficiency of Like apple growers diverting water to Tonegawa led a team of researchers, the nerve-signal transmission throughout their orchards, Godoy-Gonzalez has chan- including then hhmi postdoctoral fellow this network is drastically compromised, neled this knowledge straight to his class- Kazu Nakazawa, in identifying a gene according to Tonegawa. room with activities that bring lessons to involved in the type of memory-retrieval The researchers engineered the mutant life. When he taught about the stars and process called pattern completion—the mice so that the gene for the NMDA recep- planets, members of the Yakima Astronomy Club accompanied his students and their “Memories are sitting dormant in the brain; families on a late-night stargazing session, bringing telescopes that were powerful the challenge is retrieving them.” —Susumu Tonegawa enough to pick up vivid detail in the Moon’s craters. After learning about volcanoes, ability to recall complete memories from Godoy-Gonzalez gave his students shovels, partial cues. Their hope is that this work, and they began digging in a nearby roadside. published May 30, 2002, in Science Express, Several inches down, they were amazed to the online version of Science, and in the find a layer of ash from the 1980 eruption of July 12, 2002, issue of Science,may ulti- Mt. St. Helens. mately lead to new or better targets for In the past two years, 16 of Godoy-Gon- drugs that help counter some of the zalez’s students have gone on to community deficits of Alzheimer’s disease and relieve college. One is studying agriculture at those frustrating “senior moments” that Washington State University. Another is en begin to emerge in middle age. Tonegawa’s route to becoming a doctor. “Had we not coauthors included colleagues at mit and had Mario and the program he has devel- scientists at Baylor College of Medicine in oped, these kids would have been lost,”says Houston and Hokkaido University School the school’s principal, Jack Hill. “They of Medicine in Japan. would have dropped out.” For these studies, the researchers gener- In 2000, Godoy-Gonzalez was named ated and analyzed mice with a genetically the state’s migrant teacher of the year. His altered hippocampus, a brain structure model is both simple and practical, says involved in learning and memory. They

Sylvia Reyna, program supervisor at Wash- showed that the CA3 region of the hip- LAB OF TONEGAWA COURTESY ington’s Migrant Education Program. “He pocampus is responsible for the retrieval of Swimming in water filled with pellets that obscure really is making some pathways for others complete memories from partial cues—and the exit platform, the mice must rely on outside to follow.” —GARRY HAMILTON that age or disease might impair the func- cues and memory to find a way out of the pool.

hhmi bulletin | september 2002 35 NEWS& NOTES

tor ceased functioning after the animals had molecular variations matured—eliminating the possibility that that occur within knocking out the gene would affect devel- and between organ- opment of the CA3 region. They were able isms in order to to show that the CA3 region functioned examine the effects of normally except for the NMDA receptor. evolutionary forces To test the effect of disabling the poses a huge mathe- NMDA receptor, the scientists studied how matical challenge. As both normal and mutant mice behaved in lead author of an the Morris water maze, which consists of a April 4 paper in pool filled with murky water that has a Nature,Bustamante small platform hidden just beneath the used advanced statis- surface. A black curtain surrounds the tical tools to study

dimly lit pool, and on the curtain in each TROTT GRAHAM this question in the of four directions the scientists placed Carlos D. Bustamante uses statistics to sort out questions about evolution. fruit fly (Drosophila) visual cues consisting of distinctive spot- and the mustard lighted patterns. weed (Arabidopsis). He and his colleagues In their experiments, they found that Biology by deployed their statistical firepower, including normal and mutant mice placed in the pool a tool developed originally in statistical were equally capable of learning and Numbers physics known as the Markov-chain Monte remembering where the hidden platform Carlo method. was located. The researchers saw stark dif- he mapping and sequencing of tens “The novelty about the statistical ferences, however, when they removed three of thousands of genes from humans, approach used by Bustamante is that it allows of the four visual cues and tested the ani- Tfruit flies, yeast and several other the information from multiple different genes mals’ ability to recall the platform’s location. organisms has created a data windfall for to be combined in a statistically rigorous “Normal animals had no problem remem- research into the long-standing question of way,”says Rasmus Nielsen, a population bering where the platform should be, based how the living world came to be so diverse. geneticist at Cornell University who was sec- on only one cue,”says Tonegawa. “But the The interpretation of this trove of informa- ond author on the Nature paper.“This allows mutant animals showed a severe impair- tion requires a new breed of scientist. us to learn much more from large data sets,” ment in recalling the memory based on par- Enter Carlos D. Bustamante, 27, who has such as those involved in the Drosophila and tial cues. It was a very specific deficit.” assembled a formidable collection of skills Arabidopsis research, says Nielsen. In addition to the behavioral testing of for attacking questions about evolution. A The study revealed that both genetic the knockout mice, researchers in collabo- recent Ph.D. from Harvard University, where drift and natural selection have been ration with coauthor Matthew A. Wilson of he had an hhmi predoctoral fellowship, involved in the evolution of genes in the two mit studied the neurophysiological basis of Bustamante has firm grounding in classical species but that the process is not the same the CA3 deficit. They used microelectrodes biology, population genetics and molecular in both because Drosophila and Arabidopsis to measure the electrical activity of specific biology and is well versed in computational have different mating systems. In Arabidop- cells in the CA1, another region of the hip- and statistical methods of analysis. sis,negative selection (selection against new pocampus (which affects its output and Darwin of course focused on natural variants) is dominant, presumably because overall performance), as the animals selection—the preservation of traits that of high levels of self-fertilization. In con- explored an open arena surrounded by four enable organisms to adapt to specific envi- trast, in Drosophila,which does not self-fer- visual cues. They found that when three of ronments—as the chief force propelling evo- tilize, positive selection (selection for new the four visual cues were removed, the lution. Even he, however, noted that natural favorable variants) dominates. knockout mice showed impaired ability to selection wasn’t the only evolutionary force. Daniel L. Hartl of Harvard, a population reactivate the hippocampal cells that had In more recent times, scientists have argued geneticist who oversaw Bustamante’s Ph.D. become active when the animals were first that small, random changes in the frequency work, hailed the Nature paper as “gorgeous. It acquiring memory of that location. of genes in populations—known as genetic opens the door to a genome-wide analysis of “The combination of behavioral and drift—can increase certain genes’ prevalence protein evolution in virtually any organism.” neurophysiological studies of these knock- even when they don’t confer a selective While he was still in high school, after out mice constitutes a very rigorous demon- advantage. The question of how much of the immigrating to the United States from his stration of the importance of the CA3 genetic differences between species is due to native Caracas, Venezuela, Bustamante was NMDA receptors in associative memory natural selection and how much to random drawn to the work of evolutionary biologist recall,”says Tonegawa. processes is still hotly debated. Stephen Jay Gould and geneticist Richard C. —DENNIS MEREDITH Sorting out the enormous number of Lewontin, who were both at Harvard. After

36 hhmi bulletin | september 2002 transferring to Harvard for his sophomore ing his method to human evolutionary year of college, Bustamante got himself posts issues. By identifying genes that have been Students Love as an undergraduate researcher in Lewon- especially important in human evolution, it tin’s lab and as a teaching assistant for may be possible to find genes that play a role the Details Lewontin and Gould, who died in May 2002. in susceptibility to disease. Such genes could Bustamante now looks back on both assign- become targets for new drugs that would n unscientific-looking instrument ments as “incredibly formative experiences.” interact with these genes or their proteins. that resembles a small blow-dryer For his part, Lewontin calls Bustamante one Following a fellowship year at Oxford Aon a long cord is revealing life’s tiny of the best students he has ever had and a University with one of the world’s top details to school children. Students only scientist who appears headed for great suc- groups studying theoretical population have to touch the fat end of the device to a cess and leadership in his field. genetics, Bustamante will join Nielsen in butterfly wing or to an embryonic fish, and In his graduate work at Harvard, Busta- Cornell’s new department of biological sta- instantly a finely focused image of a lacy mante developed statistical methods for tistics and computational biology as an wing scale or a developing organ flashes using genetic data from any type of popula- assistant professor. tion to test evolutionary hypotheses. He “The biologist of the future may not immersed himself in graduate-level statis- have a ‘wet lab’ at all,”says Nielsen. “The tics courses, ending up with a master’s generation of data is so cheap right now, degree in statistics as well as a Ph.D. in biol- what’s needed is someone like Bustamante ogy. This training has set him apart; Lewon- who can sit down and make sense of it.” tin comments that parts of the Nature paper “I don’t think there’s been a more excit- are so arcane that “the number of people ing time” to be in the fields of evolution and who can read it critically must be counted genetics, says Bustamante. “Historically, pop- on the fingers of one hand.” ulation genetics has been theory-rich and Bustamante’s interests are not only in data-poor.”Not so today. “We have tons and the realm of theory. He is working on apply- tons and tons of data.’’ —RICHARD SALTUS Undergraduate Grants Foster Teaching, Interdisciplinary Courses

How can research universities encourage gradu- bachelor’s degree in science and a master’s ate students and postdoctoral fellows to develop degree in teaching.

their teaching skills? A $2.2 million grant will enable the Univer- PHILIP GOULD sity of Colorado at Boulder to develop the Colin and Daniel Gould (the photographer’s sons) What can universities do to bring disciplines Genomics Teaching Place, a combination labora- give the magnifying machine a try. such as genomics and computational biology tory and teaching facility where undergraduates into the undergraduate curriculum, and how can and K–12 students and teachers can study onto a television screen for all to see. they best expose undergraduates to the interdis- genomics, bioinformatics and computational Kelly Riley, a 7th-grade life sciences ciplinary nature of modern biology? biology. Montana State University will use its teacher in East Baton Rouge, Louisiana, How can institutions of higher learning encour- $1.9 million grant to develop a six-week sum- loves the device, known as the “Scope-on-a- age more minorities to pursue careers in science? mer-research program for high school students Rope” video microscope (soar). “It is the and teachers from Montana’s seven Indian best laboratory instrument I have ever had, To support innovative answers to these questions, reservations. A $2 million grant to the Universi- and I apply it in every single unit I teach,” HHMI has awarded $80 million in four-year ty of Maryland, Baltimore County, will help the she says. “Kids break down the door in their grants to 44 universities. Washington University university develop an undergraduate academic eagerness to use it.” in St. Louis, for example, will receive $2.2 million and community-support program—targeting Her sentiments are echoed in K–12 over four years to establish a science-education minorities underrepresented in the sciences— school systems in a dozen other states fellows program. After completing traditional modeled after the university’s successful Meyer- across the country, as more teachers learn summer-research fellowships, students who are hoff Scholarship Program supporting minority about the miniature, self-lighted video interested in science education can spend another achievement in science. camera with interchangeable magnifying summer in science classrooms developing educa- —JENNIFER BOETH DONOVAN lenses. The versatile, lightweight device— tional materials. These fellows will pursue a novel, »For a list of new grant recipients: called the VL-7EX by its manufacturer, five-year combined-degree program leading to a www.hhmi.org/news/070902.html Scalar Corporation of Tokyo, Japan—can

hhmi bulletin | september 2002 37 NEWS& NOTES

be used by even the youngest students. Placed in physical contact with an object, the lens automatically focuses to produce magnified, real-time images that are trans- mitted through fiber optics to a television set. With its two lenses yielding magnifica- tions of 30X and 200X, the “scope” can be handheld or used as a compound or dis- secting microscope. With the touch of a button, images can be freeze-framed and printed, and moving video images can be recorded with an ordinary vcr. The concept of Scope-on-a-Rope was born at Louisiana State University’s (LSU’s) Socolofsky Microscopy Center, where an early $12,000 model designed for industrial inspections—searching for defects in electronic boards, for example— was first tested in 1992. Harold Silverman, dean of LSU’s College of Basic Sciences, saw its potential as a science teaching tool. Several models, less expensive and better suited to K–12 classrooms, were developed in partnership with the manufacturer, cul- minating in the latest $2,000 version.

Grants from hhmi helped support devel- WILLIAM K. GEIGER opment of the video microscope and the Robert Kao studies the anticancer properties of a by-product of his mother’s homemade soy milk. related curriculum and helped establish teacher workshops and a scope-lending program in Louisiana to promote use of From Soybean Finding, the instrument in classrooms. Silverman, Cindy Henk of the Socolofsky Microscopy Center and others have introduced the A Career in Science Sprouts scope to other regions of the country through scientific meetings and teacher hat, Robert M. Kao wondered at Kao got the opportunity to test his outreach efforts. age 13, was in the yellowish liquid premise through an hhmi-supported pro- More than 54,000 students in Louisiana Wthat his mother threw away after gram that each year enables up to 20 public alone have used the scope over the past soaking soybeans in water to make soy milk? high school juniors and seniors from decade. “We want to create interest in sci- That simple question led Kao to work in a Montgomery County, Maryland, to per- ence for everyone,” Silverman says. “Kids laboratory at the National Cancer Institute form supervised research at the National tell me that using the scope is the most (nci) before he graduated from high school, Institutes of Health (nih). “The students amazing experience they have had.” Typi- and to a research finding with potential appli- who succeed in the program are the ones cally, the first thing they do with it is self- cations in cancer prevention and treatment. who always want to know ‘why’—and who explore, turning and twisting the scope to The yellowish liquid, called soybean keep working to find an answer,” says Lesli look at their own fingerprints, hair, sweat leachate, contains a mixture of water-solu- Adler, one of Kao’s science teachers at glands, clothing or jewelry. High school ble compounds. Kao remembered reading Thomas S. Wootton High School in students are no less captivated, often show- in a gardening handbook that it might ben- Rockville, Maryland, and leader of a two- ing more interest in their regular micro- efit plant growth. Over the next several week laboratory course that prepares stu- scopes after they’ve seen the possibilities years, he carried out a series of school dents for their year of nih research. introduced by the soar.According to Sil- experiments that led to a contrary finding: Most teens in the program assist nih verman, “the quality, crispness and ease of Soybean leachate actually retarded the scientists with ongoing institute research generating an instant image are the combi- growth of corn plants. “I began thinking to projects. But Kao persuaded cancer nation that makes this instrument work in myself, if it inhibits plant growth, maybe it researcher Michael J. Birrer to allow him to the classroom.” —RENEE TWOMBLY would inhibit cancer cells,”he recalls. pursue his own soybean-leachate investiga-

38 hhmi bulletin | september 2002 tion in Birrer’s nci lab. against 60 different cancer cell lines. nci put its patent application on hold, and Many researchers have sought to isolate “It didn’t show what they considered a Kao was back in the Birrer lab, working to cancer-preventing agents from soybeans; robust activity,”Birrer reports. Kao took the confirm his original findings and to isolate, epidemiological studies indicate that a diet news calmly. “Well, that’s a bummer,”he identify and test some of the compounds in rich in soy-based foods correlates with said to Birrer on hearing the disappointing the leachate. lower rates of some cancers in Asian coun- result, “but where do we go from here, and Although he plans a career in science, tries. Yet Kao was surprised to find that no what are your suggestions?” Kao later Kao hasn’t yet decided whether to pursue an studies had been done on soybean leachate’s explained that he was “prepared for any- M.D., Ph.D. or both. By any reckoning, he’s composition or its effects on cell growth. thing,”knowing that the lab in Frederick off to a flying start. “It is conceivable that Working with Virna D. Leaner in the would use different testing methods than he has identified an overlooked source of Birrer lab, Kao tested soybean leachate and those he had used. potentially active anticancer molecules,”Bir- several proteins extracted from it on two Birrer, meanwhile, doesn’t regard the rer says. “But whether or not the soybean ovarian cancer cell lines—one slow grow- Frederick lab results as final. “It may be that leachate works out to be a cure for cancer, ing, one fast growing—as well as on normal there are multiple factors in there that need Bob is going to be a very good cancer ovarian cells and a line of breast cancer to be used in concert,”he says. Last summer, researcher.” —PATRICK YOUNG cells. The leachate had minimal effect on the breast cancer cells and the normal ovarian cells. But, stunningly, it stopped growth in both ovarian cancer cell lines. HHMI Professors Promise The findings proved so novel that nci filed a provisional patent application on to Break the Mold them. This gave the institute one year to do additional research and file a formal appli- hmi has named 20 university scientists as the Institute’s first hhmi professors. cation—a rare if not unprecedented result Each will receive $1 million over four years to put his or her creativity, which is from a high school student’s nih research. Husually focused on research, to work in undergraduate classrooms. For example, The work also won Kao recognition in the one professor plans to create a “community of scholars,”enlisting undergraduates as 2001 Intel science awards. early as their freshman year to partner in research teams with more advanced under- Kao’s work has been backed by the graduates, graduate students, postdoctoral fellows and faculty. Another will target non- strong support of his family. He is the son science majors with a lecture and laboratory course on genetic engineering that address- of Taiwanese parents who have encouraged es legal and social issues as well as the underlying molecular biology. his scientific endeavors. His father, Tzu- “We wish to empower scientists at research universities to become more involved Cheg “David” Kao, is a biostatistician on in science education and the faculty of the Uniformed Services Uni- come up with really Manuel Ares, Jr. University of California, Santa Cruz versity of the Health Sciences, the mili- innovative ideas that Utpal Banerjee University of California, Los Angeles tary’s medical school in Bethesda, Mary- break the mold and take Sarah Elgin Washington University in St. Louis land. His mother, Pheng-Fan, is a a fresh look,” explains Ellen Fanning Vanderbilt University homemaker who took responsibility for Institute President Hilary Godwin Northwestern University making sure her son got to the laboratory Thomas R. Cech. “hhmi Bob Goldberg University of California, Los Angeles on time. While doing his research at , seeks to develop a cadre nci Jo Handelsman University of Wisconsin–Madison Kao lost an uncle to a malignant brain of scientist-educators Graham Hatfull University of Pittsburgh tumor, reinforcing the young scientist’s who will become leaders Ronald Hoy Cornell University commitment to his study. “He taught me in undergraduate teach- Elizabeth Jones Carnegie Mellon University the human side of cancer,” Kao says. ing as well as research. Darcy Kelley Columbia University In the fall of 2001, Kao entered Boston The hhmi professors University of Washington College in Chestnut Hill, Massachusetts, and their teaching strate- Mary Lidstrom which he chose because it is close to a big gies will serve as models Richard Losick Harvard University city but is not an urban campus. While Kao for fundamental change Yi Lu University of Illinois, Urbana-Champaign focused on his studies as one of 50 fresh- both on their own cam- David Lynn Emory University men in the university’s Emerging Leader puses and elsewhere, Rebecca University of Texas at Austin Richards-Kortum Program, Birrer, his nih mentor, was fol- helping to support and Yale University lowing up on his intriguing experiment. encourage research uni- Alanna Schepartz Birrer sent a sample of the most active versities in their efforts Tim Stearns Stanford University soybean-leachate extract to nci’s labs in to enhance undergradu- Graham Walker Massachusetts Institute of Technology Frederick, Maryland, where it was tested ate education.” Isiah Warner Louisiana State University and A&M College

hhmi bulletin | september 2002 39 HHMI LAB BOOK RESEARCH NEWS FROM HHMI SCIENTISTS

IN BRIEF colleagues reported their findings in the March Viral Cousins 2002 issue of the journal Molecular Cell. Preventing colon cancer Vitamin D These findings and others suggest that all may protect against colon cancer by help- hree broad classes of viruses exhibit three classes of viruses originated with a com- ing to detoxify cancer-causing chemicals unexpected parallels in the way they mon ancestor. “One reason we are excited produced when high-fat foods are digest- Treproduce. Although each type of virus about these results,”says Ahlquist, “is that they ed. A drug resembling vitamin D might copies its genes differently after commandeer- suggest that common strategies might be help prevent the disease by activating a ing the genetic machinery of the host it developed against multiple types of viruses.” pathway that detoxifies a bile acid called infects, researchers have found that the viruses » www.hhmi.org/news/ahlquist.html lithocholic acid. The researchers warn all use similar structures to do so. This finding against boosting intake of vitamin D itself, suggests that major groups of viruses may which can lead to dangerous levels of cal- have similar evolutionary origins. If so, identi- cium in the blood. fying such a connection may be the first step to devising new treatments for a wide range of Researchers: David J. Mangelsdorf and viral diseases. Ronald M. Evans hhmi investigator Paul Ahlquist and col- www.hhmi.org/news/mangelsdorf2.html leagues at the University of Wisconsin–Madi- son engineered yeast to support the replication Astrocytes in the spotlight of brome mosaic virus—a well-characterized, Researchers have evidence that astro- positive-strand RNA virus—to better under- cytes—brain cells once thought to be bit stand its behavior and replication. Positive- players in building the supportive scaf- strand viruses are the largest class of viruses; Poliovirus folding of neurons—may actually play a they include the viruses that cause hepatitis C, leading role in triggering the maturation polio and the common cold. and growth of adult neural stem cells. As the researchers were building a pic- Growth factors produced by astrocytes may be key to regenerating brain or Shared Origins According to Paul Ahlquist, his spinal tissue that has been damaged by group's findings and those of other scientists suggest trauma or disease. that three classes of viruses evolved from a common Researcher: Charles F. Stevens ancestor. In the long term, common properties of www.hhmi.org/news/stevens2.html poliovirus, HIV and rotavirus, for example, may allow new antiviral strategies developed for one of these Shot rods Researchers have learned viruses to be generalized to the others. how a molecular change in a protein causes a form of retinitis pigmentosa, an ture of the positive-strand replication HIV inherited disease that causes progressive process, they realized that many of its char- loss of vision and ultimately blindness. acteristics were similar to those of both dou- Their studies may offer a broad explana- ble-stranded RNA viruses (such as rotavirus, tion of how the rod photoreceptor cells in which kills about 1 million children annually the eye slowly die. in developing countries) and retroviruses (a Researcher: William N. Zagotta group that includes HIV). They found, www.hhmi.org/news/zagotta.html among other discoveries, that two important positive-strand virus proteins, 1a and 2a Jammed off-switch When the HLTF polymerase, directly parallel the functions of gene goes awry, the result may be colon two retrovirus proteins, Gag and Pol. cancer. Researchers have observed that “We found detailed similarities involving turning off the gene creates an abnormal multiple protein and RNA functions in central ALLINI JAMES/BSIP/PHOTOTAKE (ROTAVIRUS), DENNIS KUNKEL/PHOTOTAKE (HIV), PR. M. AYMARD/ISM/PHOTOTAKE (POLIOVIRUS) PR. M. AYMARD/ISM/PHOTOTAKE (HIV), KUNKEL/PHOTOTAKE DENNIS (ROTAVIRUS), ALLINI JAMES/BSIP/PHOTOTAKE “off-switch,” permitting cells to grow out steps of replication,”says Ahlquist. He and his Rotavirus CAV

40 hhmi bulletin | september 2002 Off Track In IN BRIEF normal Drosophila of control and become cancerous. Identi- embryos, blood cells fying the DNA change, which may play a (red) migrate role in roughly 40 percent of colon can- throughout the cer cases, may improve understanding of entire body (top how colon cancer begins and spreads. image). Without a Researcher: Sanford D. Markowitz functional VEGF www.hhmi.org/news/markowitz.html receptor, blood cells don’t reach their destination in the RNA police Researchers have identi- posterior of the fied a mechanism that they say seeks out embryo. Instead, and destroys abnormal messenger RNA they form clumps so that errors in the genetic code are not in the head region passed on to proteins. This normal polic- (bottom). ing mechanism, called nonstop decay, could potentially be blocked to improve

COURTESY OF KRASNOW LAB OF KRASNOW COURTESY treatments for genetic diseases such as cystic fibrosis. When the researchers inactivated the gene Researchers: Harry C. Dietz and for the VEGF receptor, they found that blood Roy Parker Guiding Blood cells never reached the posterior region of the www.hhmi.org/news/dietzparker.html body; they couldn’t find their way to their nor- Cells with VEGF mal destination. “These results support a sce- nario in which chemical migration signals are Ratting out HIV The rat may soon be esearchers may have figured out how placed at many positions along the migration a useful animal model for HIV. Scientists blood cells reach their final destinations pathway,”says Krasnow. “It’s a bit like attract- have created a transgenic rat carrying in developing embryos. They’ve discov- ing a duck by leaving a trail of bread crumbs.” the genes for human components R required for HIV to enter cells. Certain ered that vascular endothelial growth factor, or He and colleagues at Stanford and the South VEGF, a protein better known for guiding the San Francisco–based biotechnology company rat cells expressing this HIV receptor growth of new blood vessels, including those Exelixis reported their findings March 22, complex were highly susceptible to infec- that nourish cancerous tumors, also helps to 2002, in the journal Cell. tion by HIV. The model, they hope, will direct blood cells along specifically marked The work suggests that blood vessels may someday enable them to test potential routes. In fact, evolutionarily speaking, this have evolved from blood cells, according to drugs and vaccines against the virus and may have been VEGF’s original calling. Krasnow. Other researchers have shown that better understand its behavior. The movement of blood cells has been the VEGF pathway plays a critical role in Researcher: Oliver T. Keppler, former well documented in adult mammals, but the hemangioblasts, a type of early stem cell that HHMI postdoctoral fellow, Goldsmith Lab, cells’ migration during development is not gives rise both to blood cells and the endothe- University of California, San Francisco understood. To learn more about the molecu- lial cells that become blood vessels. It had not J Exp Med (2002) 195:719–36. lar processes underlying cell migration, hhmi been clear why these two major cell types are investigator Mark A. Krasnow at Stanford Uni- linked developmentally, but Krasnow believes Snake eyes A protein similar to a neu- versity and his team turned to Drosophila his results provide an explanation. rotoxin found in snake venom affects the melanogaster, the common fruit fly. Because “If during evolution of vertebrates a sub- same receptors in the brain as does nico- VEGF is vital to blood-vessel formation in set of blood cells acquired the ability to form tine. The protein, lynx1, dubbed a “proto- adult mammals, the researchers thought it tubes through which other blood cells can might have an analogous role in the fly. move, then endothelial cells are really just a toxin,” may be a new tool for probing Instead, they saw that the VEGF pathway is highly specialized type of blood cell, all of how nicotine and other drugs activate directed at developing blood cells. VEGF pro- which arise from a common stem cell and the brain’s pleasure centers. Beyond its teins line many of the routes that blood cells some of which continue to express VEGF obvious application in addiction research, travel, and the proteins’ function there is to receptors and use VEGF signaling for later lynx1 may also aid in the study of certain activate the VEGF receptor on the blood cells, steps in their development or function.” human genetic diseases caused by simi- telling them when and where to migrate. » www.hhmi.org/news/krasnow.html lar, but defective, proteins. Researcher: Nathaniel Heintz HHMI Lab Book written by Steven I. Benowitz www.hhmi.org/news/heintz2.html

hhmi bulletin | september 2002 41 HANDS ON 1 Animal Magnetism —and other creative ways to show kids, and teachers, the practical side of science

hat makes physics and engineer- Cleveland Clinic, for example, ing essential to medical science? Zborowski uses magnets to sep- WIn Cleveland, a group of inner- arate embryonic stem cells from city teens and secondary school science their diffuse surroundings. teachers know the answer. In fact, they Concepts such as force at a know a number of answers. distance, vector mechanics and In a program of school-year and sum- calculus come to life for the stu- mer workshops developed by biomedical dents and teachers in the hands engineering faculty at the Cleveland Clinic of Zborowski’s colleague William and supported by a grant from hhmi,stu- A. Smith. He shows them his dents from John Hay High School and sci- work in progress: a magnetic ence teachers from all over Cleveland are screw that would make an artifi- learning that heart-valve and joint replace- cial heart longer-lasting because ments—operations that have become it would pump with no friction almost commonplace—could not be saving and no wear. Force is transmitted lives and restoring mobility without the magnetically rather than by the contributions of physics and engineering. thread contact of a traditional Magnets, too, are proving useful in a variety nut-and-screw arrangement.

of clinical and research settings, although Smith hopes his magnetic screws ANIEL LEVIN (4) D it’s admittedly “a challenge to present mag- will last three times longer than nets and magnetism in an attractive and today’s screws. Only additional research will amputees move their prosthetic legs and stimulating way,” says Maciej Zborowski, a tell. “We are 5 years away from clinical trials feet more normally. Cleveland Clinic researcher. He rises to the in humans and 10 years from this being a Next, Davis displays some failed joint occasion, however, in a teachers seminar on product on the shelf,” he says. replacements—real human knees and hips physics in medicine by showing that indeed, “Too often in schools and even in col- encased in cubes of epoxy. Examining them, as he puts it, “everything is magnetic.” leges, there is a failure to make any connec- teachers and students learn the anatomy of One of Zborowski’s favorite teaching tion between what’s learned in the class- the joints and the kinds of materials that do tools is a levitating frog that’s featured on room and solving real-world problems,” and don’t work in replacements. Finally, all the Web site of the Nijmegen High-Field Smith adds. “We must show teachers practi- adjourn to the operating theater to watch a Magnet Laboratory in Amsterdam. Teachers cal applications of scientific principles. We live joint-replacement operation. and their students agree that one movie of a must help young people understand how Janeth Eby, a curriculum specialist at live frog floating upward—inside a magnet- what they are learning is directly involved in the Cleveland Clinic, has helped Davis and ic-field system that exploits the ordinarily the development of better technologies.” his colleagues turn their hands-on study of weak though inherent “molecular magnet- Brian Davis, another Cleveland Clinic failed joint replacements into a Web-based ism” of all living things—is worth much researcher, heads the hhmi-supported lesson for high school students. She also more than the proverbial thousand words. community science education programs helped develop a second unit, on heart Students and teachers tend to be famil- there. A biomedical engineer, he has a flair valves; a third—on the spine—is coming. iar with ferromagnetism; they’ve seen small for the dramatic that quickly captures teens’ The heart-valve unit, which uses a lasagna magnets attract iron filings or nails. But they and teachers’ attention. “How do you make noodle as a model, teaches another valuable learn from Zborowski that there are other a dead foot walk?” he asks, proceeding to lesson: A model need not resemble the kinds of magnetism, as the frog graphically describe his research using a robotic device object or system it’s modeling. “In science,” demonstrates; that magnetism of metal dif- that attaches to the tibia or shinbone of a Eby points out, “it is more important for a fers from magnetism in biological organ- human cadaver and moves the eight leg ten- model to work the same way than it is for isms; and that magnets can separate liquids dons that are required for walking. them to look alike.” as well as solids. In his research at the Eventually, he hopes, the robot will help —JENNIFER BOETH DONOVAN

42 hhmi bulletin | september 2002 2

1 Science teacher Janeth Eby, at left, shows John Hay High School students Arielle Bell, Josephine Williams and Edy Hasrouni how to use cooked lasagna noodles to model the action of the heart valve opening and closing. A plastic bottle squirts water through the “valve,” to model the pumping action of a ventricle. Students see the effects of calcification on heart valve function when parts of the noodles are left uncooked, hardened like a calcium deposit: The lasagna tears after just one or two pumps of water from the bottle.

2 About to enter 12th grade at John Hay High School in Cleveland, Leonard Curry is already skilled in tissue dis- section. Here he prepares a sample of myocardial tissue for subsequent materials testing. Known stresses are applied to a material such as a heart valve, and the sub- sequent stretching or compression is measured. Curry is working on studies to determine the relative contribu- tions of proteins such as elastin and collagen to the over- all stiffness or flexibility of a heart valve.

3 Cleveland Clinic researcher William A. Smith is design- ing blood pumps using magnetic screws to reduce friction and wear. High school student Kemetta McBride watches him test an artificial heart in a fluid-filled chamber that mimics the blood pressures found in living patients. 4 Project director Brian Davis uses real, failed joint replacements encased in epoxy to show students how biology, physics, mathematics and medicine work together in designing artificial joints and understanding why they fail.

FOR MORE INFORMATION The frog that learned to fly: www-hfml.sci.kun.nl/froglev.html A study of failed replacement joints: www.lerner.ccf.org/education/k12/biomaterials/

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hhmi bulletin | september 2002 43 INSIDE HHMI International Scholars Down Under

hmi international research scholars from 29 countries converged in June Hon Cairns, Queensland—the tropical north of Australia—for a unique set of face- to-face scientific exchanges. Russian, South African and Mexican researchers compared notes on tuberculosis research while Argentine and Swiss scientists conferred on pathogen-survival McFadden, Magdalena Plebanski and Louis Russian international scholar Alexander Konstan- mechanisms. Scientists from Canada, Schofield. Coppel, a professor at Monash tinov makes friends with a mother kangaroo at a Hungary and the Czech Republic discussed University (Victoria), chaired the local rainforest wildlife sanctuary in Queensland. their respective studies of signaling organizing committee. pathways. An Israeli who investigates The international scholars also gave native creatures, and they spent an afternoon trypanosomes learned about the work of a formal presentations on their latest work. exploring the Great Barrier Reef. Venezuelan and a German directly from Marcelo Rubinstein of Argentina, for To help maintain research efforts those scientists, who study similar parasites. example, described a novel mouse model for around the world—in many countries, Hosting the meeting were hhmi’s 11 testing the role of dopamine D4 receptors in under difficult economic circumstances— Australian research scholars: Deidre Carter, attention deficit and hyperactivity disorder. hhmi supports the research of Ross Coppel, Alan Cowman, Brendan Crabb, Australian Louis Schofield discussed his ani- competitively selected biomedical scientists Simon Foote, William Heath, Gunasegaran mal-model studies of a synthetic antitoxin in their home countries in the Baltics, Karupiah, Malcolm McConville, Geoffrey vaccine that protects against the most severe Eastern and Central Europe, the former effects of malaria. Soviet Union, Canada and selected Hungarian scholar László Nagy (left) and Marie While they were in Queensland, the countries of Latin America. The program Lipoldová from the Czech Republic (right), present research scholars also managed to see some also supports scientists throughout the their research. Australian organizing committee chair of the locale’s exotic environment. They world who are studying infectious diseases Ross Coppel (center) chats with Indian scholar Chetan visited a rainforest habitat where they met and parasitology. Chitnis and his wife, Amika Mehndiratta. kangaroos, crocodiles, pythons and other —JENNIFER BOETH DONOVAN DOMINIC CHAPLIN, PINE CREEK PICTURES CHAPLIN, PINE DOMINIC

44 hhmi bulletin | september 2002 INSIDE HHMI On Stage and Off, This Lawyer Performs

hen Joan S. Leonard was a full- This was an area time mother of two small chil- ripe for public con- Wdren in the 1970s, she organized frontation. Academic informal concerts at her home. A violinist scientists had assumed and a cellist joined Leonard at the piano to they could use whatever entertain friends with renditions of Mozart technologies they needed and Schubert piano trios. Issues of scientific in the laboratory with- discovery and intellectual property were not out worries of infringing on her radar screen. patents. After all, their Today, Leonard is vice president and work was for the public general counsel of the Howard Hughes good. When companies UL FETTERS

Medical Institute, responsible for all of started becoming more PA hhmi’s legal affairs. She still enjoys being on aggressive about what Joan Leonard searches for common ground on intellectual property issues. stage—most recently accompanying James R. scientists could do with Gavin III as he crooned Sinatra favorites their patented tools, the researchers balked. General Counsel José Trías, who had worked during his farewell to Institute staff. She con- Ultimately, DuPont responded to nih with her at the Washington, D.C., law firm of tends that hhmi itself should move more concerns and developed a license for aca- Paul, Weiss, Rifkind, Wharton and Garrison. squarely into the spotlight. demic and nonprofit users with few restric- Two years later, she became general “We make enormous contributions tions. “A workable approach to difficult intel- counsel under horrific circumstances: Trías through our research, and we can play a larg- lectual property issues has to acknowledge and his wife Julie Gilbert were murdered er public role—in fact, I think we should,” the realities of the marketplace as well as the during a robbery of their home. hhmi staff she says. “As more and more public policy research laboratory,” Leonard says. “In the were devastated, but Leonard soon had to issues involve sophisticated scientific con- nih advisory group, I saw the valid, deeply decide whether to assume Trías’ role as gen- cepts that appear daunting to the person on held and often antagonistic perspectives of eral counsel. “José had mentored us to be the street, the Institute has the ability to be a scientists, academic institutions, biotech good lawyers,” she said. “We had assembled a trusted source of advice as to what the sci- companies and pharmaceutical concerns.” group on the strength of José’s vision for this ence is and what it means.” Leonard’s participation in these debates office, and I felt a responsibility to pursue it.” Leonard has already helped hhmi stand grew out of the role her office plays in imple- Leonard says she’s proud that Trías’ out in public discussions about intellectual menting hhmi’s strict rules on investigator vision endures today. Each of her staff of six property—an increasingly hot issue as more relationships with industry. For example, lawyers is a generalist first, handling all the corporate money flows into basic research investigators are limited to 36 days of con- legal issues—from personnel to intellectual and the lines blur between academic and sulting per year and must obtain Institute property—facing hhmi scientists. Each commercial laboratories. In 1997–1998, she approval to consult. Institute lawyers careful- lawyer also cultivates two or three specific served on an advisory committee to the ly review every agreement and approve only subject areas, such as investment or immi- National Institutes of Health (nih) that if all terms are acceptable. In 2001, Leonard’s gration issues. “José wanted an office in examined limitations on access to research staff successfully negotiated more than 740 which people had a real sense of what this tools and demands made by companies for materials-transfer agreements, 12 collabora- institution does,” Leonard adds. “The “reach through” rights. The most publicized tions with industry and another 200 or so lawyers come here because they’re interested example among many was DuPont and its consulting arrangements; they also reviewed in the mission, and they feel most effective popular technique for developing genetically more than 74 licenses of technologies devel- in that mission if they’re engaged in a range engineered mice, called cre-lox. The compa- oped by hhmi scientists. of work that includes contact with investi- ny began requiring users to give it rights to When Leonard attended law school after gators and their laboratories.” whatever discoveries were made using the 15 years at home, she was intent on becom- Leonard considers herself very lucky to technology. “Many scientists felt that it was ing a tax attorney. Well on her way to build- be where she is today. “Raising two children the equivalent of Microsoft claiming rights ing that career, a different door opened. She was the best job I’ve ever had,” she says. to a book you wrote because you used Word joined hhmi in 1992 as a general practice, “This is a real close second.” to compose it,” Leonard says. in-house lawyer when she was hired by then —CORI VANCHIERI

hhmi bulletin | september 2002 45 »»»» IN THE NEXT ISSUE

» Has HIV outsmarted us? Twenty years after scientists deter- mined the cause of AIDS, a cure still evades us. What is it about this virus?

» Married to the work Meet HHMI investigators whose partners at home are their best collaborators in the lab.

» When economies collapse Researchers in Argentina and other Latin American countries are strug- gling to keep their laboratories afloat as their nations’ economies sink.

Let the Sun Shine How have humans, mice, plants and insects evolved to

make the best use of light? TAXI

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