tenacious a foe - howard hughes medical institute · steven marcus, blair burns potter, peter...

The Obedient Stem Cell || Marriages at Work || Cancer Drugs with Precision || Crime Scene Science D EC E M B E R 20 02w

ww

.hhm

i.org

/bul

leti

n The Obedient Stem Cell || Marriages at Work || Cancer Drugs with Precision || Crime Scene Science D EC E M B E R 20 02

HIV has outmaneuvered

every new drug designed to stop it.

HIV has outmaneuvered

every new drug designed to stop it.

ATenaciousF

oeATenacious Foe

F E A T U R E S

12 Is HIV SmarterThan We Are?With each victory against HIV—and

there have been many in the last two

decades—the virus reinvents itself

and evades total defeat.

By Marlene Cimons

18 A MorePerfect Union Scientists who have found partners

in the lab dissect their relationships

and find that good marriages make

better science.

By Dorothy Foltz-Gray

22 HealingConnections Researchers are making progress

with mouse embryonic stem cells—

connecting nerves to muscles and

improving mobility in animals.

By Maya Pines

221812

2 NOTA BENE

4 LETTERS

5 PRESIDENT’S LETTER A Sustainable Future

UP FRONT 6 In Pursuit of the Next Gleevec 8 In Argentina, a Life of Contrasts10 In Synch with the Sun

D E P A R T M E N T S

HHMI TRUSTEES James A. Baker, III, Esq. Senior Partner, Baker & Botts

Alexander G. Bearn, M.D. Executive Officer, American Philosophical Society Adjunct Professor, The Rockefeller University Professor Emeritus of Medicine, Cornell University Medical College

Frank William Gay Former President and Chief Executive Officer, summa Corporation

James H. Gilliam, Jr., Esq. Former Executive Vice President and General Counsel, Beneficial Corporation

Joseph L Goldstein, M.D. Professor and Chairman, Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas

Hanna H. Gray, Ph.D., CHAIRMAN President Emeritus and Harry Pratt Judson Distinguished Service Professor of History, The University of Chicago

Garnett L. Keith Chairman, SeaBridge Investment Advisors, L.L.C. Former Vice Chairman and Chief Investment Officer, The Prudential Insurance Company of America

Jeremy R. Knowles, D.Phil. Dean of the Faculty of Arts and Sciences and Amory Houghton Professor of Chemistry and Biochemistry, Harvard University

William R. Lummis, Esq. Former Chairman of the Board of Directors and Chief Executive Officer, The Howard Hughes Corporation

Anne M. TatlockChairman and Chief Executive OfficerFiduciary Trust Company International

HHMI OFFICERSThomas R. Cech, Ph.D., PresidentPeter J. Bruns, Ph.D., Vice President for Grants and Special Programs

David A. Clayton, Ph.D., Vice President and Chief Scientific Officer

Stephen M. Cohen, Vice President and Chief Financial Officer

Joan S. Leonard, Esq., Vice President and General Counsel

Avice A. Meehan, Vice President for Communications and Public Affairs

Gerald M. Rubin, Ph.D., Vice President and Director of Planning for Janelia Farm

Nestor V. Santiago, Vice President and Chief Investment Officer

HHMI BULLETIN STAFFCori Vanchieri, EditorJim Keeley, Science EditorJennifer Donovan, Education Editor Patricia Foster, Manager of Publishing Kimberly Blanchard, Editorial Coordinator Elizabeth Cowley, Copy Editor

Maya Pines, Contributing Editor

Kalyani Narasimhan, fact checkingSteven Marcus, Blair Burns Potter, Peter Tarr, story editingKathy Savory, copy editing

David Herbick Design, Publication Design

The opinions, beliefs and viewpoints expressed by authors in the HHMI Bulletin do not necessarily reflect the opinions, beliefs and viewpoints or official policies of the Howard Hughes Medical Institute.

December 2002 || Volume 15 Number 4

28 PERSPECTIVETranscending the Status Quo

NEWS AND NOTES30 A Chink in Melanoma’s

Genetic Armor

31 Baseball’s Biochemist

32 Aquariums Teach Ecology and Local History

33 EPA Agrees to Smarter Waste Management

34 Boosting Brain Repair

35 Keeping Up with the Revolution

35 Report Urges Changes in College Biology

36 Young Scientists Learn the Management Ropes

37 INTERVIEWIsraeli Scientist Soldiers On

38 HHMI LAB BOOK

40 HANDS ONInvestigating Murders in Miniature

42 FROM THE TOOLBOXSlipping Past a Cancer Cell’s Defenses

44 INSIDE HHMIHis Brave Father’s Example

45 APPRECIATIONW. Maxwell Cowan

On the Cover: Small HIV particles (blue) on the

surface of a T lymphocyte (orange) are budding

away from the cell membrane. They will enter

the bloodstream and infect more immune system

cells. Photograph by Eye of Science/Photo

Researchers, Inc.

6

Telephone (301) 215 8855 n Fax (301) 215 8863 n www.hhmi.orgThe Bulletin is published by the HHMI Office of Communicationsand Public Affairs.

© 2002 Howard Hughes Medical Institute

■ Five hhmi investigators have been elected to membership in the AmericanAcademy of Arts and Sciences: David J.

Anderson, California Institute of Technology;A. James Hudspeth, The Rockefeller Universi-ty: and Cornelia I. Bargmann, Ronald D. Vale

and Peter Walter, all at University of Califor-nia, San Francisco.

■ David Baker, an hhmi investigator at the University of Washington School ofMedicine, won the 2002 Overton Prize fromthe International Society for ComputationalBiology for applying computational scienceto drug design.

■ Graeme I. Bell, an hhmi investigator atThe University of Chicago, was one of threescientists to receive the 2002 J. Allyn TaylorInternational Prize in Medicine. The awardrecognizes his contributions to diabetesresearch.

■ Morris J. Birnbaum, an hhmi investigator

N O T A B E N E

2 h h m i b u l l e t i n | d e c e m b e r 2 0 0 2

at the University of Pennsylvania School of Medicine, received the 2002 Stanley N.Cohen Biomedical Research Award, givenby the School of Medicine for basic scienceresearch.

■ Patrick O. Brown, an hhmi investigatorat Stanford University School of Medi-cine, received the 2002 Takeda Award inthe life sciences from the Takeda Founda-tion. The award recognizes outstandingachievement in creating and applying newtechnologies. Brown also was one of fivescientists who received a 2002 InnovationAward from Discover magazine. Bothawards recognize him for inventing theDNA microarray.

■ Carlos Bustamante, an hhmi investigatorat the University of California, Berkeley,won the American Physical Society’s 2002Biological Physics Prize for his pioneering

work in single-molecule biophysics.

■ Children’s Discovery Museum of San Jose

received a 2001 National Award for Museum and Library Service, given by theNational Institute of Libraries and Muse-ums, for its hhmi-supported BioSITE program. The award was given to threemuseums and three libraries in the UnitedStates for innovative programs and activepartnerships that demonstrate a commit-ment to diverse communities.

■ Roger J. Davis, an hhmi investigator atthe University of Massachusetts MedicalSchool, was elected to membership in theRoyal Society, the British academy of thenatural and applied sciences.

■ Aaron DiAntonio, Washington UniversitySchool of Medicine, and Phillip D. Zamore,University of Massachusetts School ofMedicine, were among five scientists named2002 W.M. Keck Foundation DistinguishedYoung Scholars in Medical Research. Bothresearchers received support from hhmibiomedical research resources grants to theirinstitutions.

■ Goldstein Becomes HHMI TrusteeJoseph L. Goldstein, a noted scientist who sharedthe 1985 Nobel Prize in Physiology or Medicinefor discoveries related to cholesterol metabolism,has been elected a trustee of hhmi.

Goldstein, chairman of the department ofmolecular genetics at the University of Texas(ut) Southwestern Medical Center at Dallas,has been a member of hhmi’s Medical Adviso-ry Board (mab) since 1985, becoming its chairin 1995. He was also a member of hhmi’s Sci-entific Review Board from 1978 to 1984.

Named to succeed Goldstein as mab chairis Craig B. Thompson, a cancer biologist whoserves as scientific director of the AbramsonFamily Cancer Research Institute at the Univer-sity of Pennsylvania.

Goldstein, 62, received his medical degree in 1966 from utSouthwestern, where he first became interested in genetics andresearch. After periods at the National Institutes of Health andMassachusetts General Hospital—where he met Michael S. Brown,a scientist who became his long-term collaborator—Goldstein

returned to ut Southwestern in 1972 to headits new division of medical genetics.

There, the two scientists began workingtogether to research a human genetic disease—familial hypercholesterolemia. This collaborationled them to unravel the mechanisms of regulatedcholesterol import into human cells, discoveriesthat became the basis of their 1985 Nobel Prize.From his own experience melding laboratory andclinical research, Goldstein has been an advo-cate for increasing support for physician-scien-tists who conduct patient-oriented research.

Thompson, 49, the incoming mab chair,also has a long association with hhmi, both asa scientist and member of the mab. Thompson

was first appointed an hhmi associate investigator in 1987 while atthe University of Michigan. He became director of the Knapp Cen-ter at The University of Chicago and an hhmi investigator in 1993,leaving six years later to assume the directorship of the AbramsonInstitute. Thompson’s lab focuses on the role of genes that regulateprogrammed cell death and their potential use in treating cancer.

CO

UR

TE

SY

OF

UT

SO

UT

HW

ES

TE

RN

■ Three hhmi investigators were amongfive winners nationally of the 2002 City ofMedicine awards. Brian J. Druker, OregonHealth and Science University; Ronald M.

Evans, The Salk Institute; and Stanley J.

Korsmeyer, Dana-Farber Cancer Instituteand Harvard Medical School, were hon-ored by Durham Health Partners ofDurham, North Carolina, for their contri-butions to medicine in the public interest.Druker also received the American CancerSociety’s highest award, the 2002 Medal ofHonor for clinical research.

■ Four hhmi investigators, an Institute vice president and the incoming chair ofthe Medical Advisory Board were among 65 scientists elected to membership in the

National Academies’ Institute of Medicine.Recognized for their contributions to medi-cine were David Eisenberg, University of Cali-fornia, Los Angeles; Stanley J. Korsmeyer,Dana-Farber Cancer Institute; Richard P.

Lifton, Yale University School of Medicine;David L. Valle, The Johns Hopkins UniversitySchool of Medicine; Gerald M. Rubin, vicepresident and director of planning for JaneliaFarm; and Craig B. Thompson, AbramsonFamily Cancer Research Institute.

■ Paula Fraser, an elementary school teacherin Bellevue, Washington, who is active inthe hhmi-supported Science EducationPartnership of the Fred Hutchinson CancerResearch Center, won the 2002 OutstandingPartner in Education Award from the Wash-

ington Association for Biomedical Research.

■ Two hhmi investigators, Thomas M.

Jessell, at the Columbia University Collegeof Physicians and Surgeons, and Anna Marie

Pyle, now at Yale University Medical School, shared the 2002 New York CityMayor’s Award for Excellence in Science and Technology.

■ Eric R. Kandel, an hhmi investigator atColumbia University College of Physiciansand Surgeons, was named an honorary fellow of the Collegium InternationaleNeuro-psychopharmacologicum, an honorary member of the Discipline ofMathematics and Natural Science of theAustrian Academy of Sciences and a Companion of the Royal Society of Canada.He also shared with Arvid Carlsson andPaul Greengard the 2002 Julius AxelrodNeuroscience Award from the NationalAlliance for Research on Schizophreniaand Depression.

■ Richard P. Lifton, an hhmi investigator at Yale University School of Medicine, hasbeen named winner of the 2003 Roy O.Greep Award from the Endocrine Societyfor outstanding contributions to research in endocrinology. Lifton also won the 2002Basic Research Prize from the AmericanHeart Association.

■ William T. Newsome, an hhmi investiga-tor at Stanford University School ofMedicine, received the 2002 DistinguishedScientific Contribution Award from theAmerican Psychological Association.

■ Anthony Pawson, an hhmi internationalresearch scholar at the Samuel LunenfeldResearch Institute in Toronto, Canada, wasone of two recipients of the 2002 Premier’sPlatinum Medal for Research Excellence.

■ Michael F. Summers, an hhmi investigatorat the University of Maryland, BaltimoreCounty, has been named winner of the 2003Emily M. Gray Award from the BiophysicalSociety for the programs he established forminority undergraduate training.

h h m i b u l l e t i n | d e c e m b e r 2 0 0 2 3

■ Horvitz Shares Nobel PrizeH. Robert Horvitz, an hhmi investigator at the Massachusetts Institute of Technology,was awarded with two other scientists the 2002 Nobel Prize in Physiology or Medicinefor discoveries concerning the genetic regulation of organ development and pro-grammed cell death. He shared the prize with Sydney Brenner of the Molecular SciencesInstitute in Berkeley, California, and John E. Sulston of the Sanger Centre in Cambridge,England. The three scientists were honored for their studies of the nematode wormCaenorhabditis elegans toidentify key genes thatregulate organ develop-ment and programmedcell death and for showingthat corresponding genesexist in higher species,including humans.

Horvitz identified thefirst two “death genes,” ced-3 and ced-4, and showedthat these genes are neces-sary for cell death to beexecuted. Later, Horvitzshowed that another gene,ced-9, protects against celldeath by interacting withced-3 and ced-4. He alsoidentified several genesthat direct how the deadcell is eliminated. Finally,he showed that the humangenome contains a ced-3-like gene. In 2002, Horvitzalso received the PeterGruber Foundation’sGenetics Prize.

AS

IA K

EP

KA


Teaching Intelligent DesignI am bothered by the tone of “The Evolu-tionary War” (hhmi Bulletin, September2002)—it felt like scientists of a differentera defending their “flat earth” theory: Notonly must you accept our theory, but youshould forbid consideration of all others.

I understand the scientific objection toliteral creationism—the evidence over-whelmingly disputes it. This is not the casewith the intelligent-design theory. Whileprobably impossible to prove directly, thereis also no proof that contradicts it. Nor isthere conclusive proof of the alternativetheory (in this case, evolution—which iswhy it’s still called a “theory,” after all). Infact, the two theories are not necessarilyeven incompatible.

I agree that evolution should be taughtin our schools, but legitimate alternatives tocurrent theory—whether they be scientific,political, economic or whatever—shouldalso be presented whenever possible. Objec-tively considering alternative hypotheses is acritical part of thinking like a scientist. If asingle theory is presented without the con-text of alternatives, then we are teachingdogma, not science.

I am surprised to see your publicationadvocating for less science education (exclu-

sion of a field) instead of more science edu-cation (inclusion of all reasonable fields).

Randy ScottGainesville, Florida

I find the reactions of people like authorTrisha Gura to be so ironic. From theirpoint of view, those who challenge the sci-entific establishment to give open-mindedconsideration to alternative explanationsare being emotional, unscientific andbiased. But in reality, it is clearly quite theopposite. I’m often impressed with the pas-sions that are generated by this debate—passions that reveal, I believe, a heartfeltcommitment to something much deeperthan scientific facts. William Dembski wasquite right when he wrote that “Naturalismis the intellectual pathology of our age.” I’msorry to see that many hhmi investigatorsare committed so strongly to such anunscientific philosophy. The only scientistcited in the article who seemed to recognizethe true situation was Sean B. Carroll, whodescribed the establishment’s backwardsview when he said, “Evolution is a largebody of scientific fact that is supported by alarge body of theory.”

Tom FletcherCosta Mesa, California

Intelligent design is not just an alternativeto evolution; it is an alternative to science.Suppose for a moment that a scientificallytrained person were to accept that an intel-ligent-design event had occurred in nature.After saying a quick “aha,” this scientistwould immediately begin asking such ques-tions as, How was it done? How could wereproduce this experiment? What were thecritical parameters? Can we have a look atthe failures?

In science, each discovery leads to newquestions: The questions build on pastresults, and they never stop. Intelligentdesign, by contrast, lacks a method for pro-gressively expanding on its findings andleads only to abrupt boundaries, clearly dis-qualifying it as a subject for science educa-tion. This is not to say intelligent designdoesn’t have the power to persuade andstimulate the mind, for right or wrong. If itmust be taught in schools, there’s surely aplace for it in rhetoric or philosophy.

Douglas W. RaymondOrinda, California

Send your letters: Via e-mail to [email protected] or to Let-ters, Office of Communications, Howard Hughes Medical Insti-tute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789.Letters will be edited for space and clarity. Please include yourname, address (e-mail or postal) and phone number.

■ 2002 Lasker AwardRandy W. Schekman, an hhmi investi-gator at the University of California,Berkeley, shared the 2002 Albert LaskerAward for Basic Medical Science withJames E. Rothman of the MemorialSloan-Kettering Cancer Center. Theaward “honors two scientists who dis-covered the universal molecularmachinery that orchestrates the bud-ding and fusion of membrane vesicles,a process that cells use to organizetheir activities,” according to the foun-dation announcement. The cellulartrafficking system they elucidatedunderlies numerous vital processes,including how pancreatic cells releaseinsulin, how nerve cells communicateand how viruses infect.

N O T A B E N E

L E T T E R ST O T H E E D I T O R

■ Matthew K. Waldor, an hhmi investigatorat Tufts University School of Medicine,received the 2002 Squibb Award from theInfectious Diseases Society of America forresearch contributions to knowledge ofinfectious diseases.

■ Paul H. Williams, former hhmi programdirector at the University of Wisconsin–Madison, received a special educationaward in 2002 from the American Societyof Plant Biologists, for his Wisconsin FastPlants and Bottle Biology projects, which,over 15 years, reached an estimated 100million students through 1 million teachersworldwide. HB

AR

BA

RA

RIE

S

t is not unusual that scientists associatedwith hhmi get professional recognition, but announcementsover the past few months are especially noteworthy. H. RobertHorvitz, a 14-year hhmi investigator at the MassachusettsInstitute of Technology, shared the Nobel Prize in Physiology

or Medicine with Sydney Brenner of the Molecular SciencesInstitute in Berkeley, California, and John Sulston of the SangerCentre in Cambridge, England.

In November, President Bush invited Bob Horvitz and the otherAmerican winners for an informal reception at the White House, and Ihad the opportunity to attend as well. Bob and Jimmy Carter, the PeacePrize winner, had an animated conversation about river blindness, adisease endemic to parts of Africa caused by a parasitic worm. Bobknew the biology of the worm, and Carter described the challengeshe’d encountered obtaining and distributing lifesaving medicine.

The work for which Bob won the prize concerns the embryonicdevelopment of the nonpathogenic nematode worm C. elegans.Mutations in the human counterparts to the worm’s cell-death genescontribute to human cancers by preventing the tumor cells from dyinga natural death and allowing the cancer to proliferate. Horvitz’s workrepresents a paradigm for the research endeavors that hhmi sup-ports: innovative, rigorous investigations of simpler biological systemsthat often throw open the door to understanding human disease.

Randy Schekman, an hhmi investigator at the University ofCalifornia, Berkeley, shared this year’s Lasker Award for BasicMedical Research for elucidating the machinery that orchestratesthe budding and fusion of membrane vesicles. The process is essen-tial to organelle formation, nutrient uptake and secretion of hor-mones and neurotransmitters.

hhmi investigator Philip Green, at the University of Washington,accepted the 2002 Gairdner Foundation International Award inToronto in October. His computational tools were essential for thesequencing of the human genome.

Finally, when the Institute of Medicine of the National Academiesannounced its newly elected members, we were pleased to see hhmiVice President Gerald Rubin and hhmi investigators David Eisenberg,Stanley Korsmeyer, Richard Lifton and David Valle on the list. Alsoelected was Craig Thompson, who will assume Joseph Goldstein’s posi-tion as chairman of the Medical Advisory Board on January 1, 2003, sothat Joe can move into his new role as an Institute trustee.

Along with this good news, hhmi faces significant challenges.Our endowment—like those of most nonprofit organizations—hasbeen reduced by fluctuations in the investment markets. Althoughwe have been exercising control over expenditures for biomedical

research, grants and headquarters operations, the Institute hasbegun taking more substantial steps to bring spending in line withour decreased endowment level.

Biomedical research is hhmi’s core mission, and that is reflectedin the way we allocate our resources—for the 2003 fiscal year theinvestigator budget of $442 million represents 71 percent of theInstitute’s total budget. But this level is higher than our currentendowment can sustain over time. Because some budget categorieswill not be decreased—for example, salaries and benefits for investiga-tors, as well as occupancy payments made to host institutions for labo-ratory space—savings must come from investigator-controlled por-tions of the budget. Reductions of up to 10 percent will be required ineach of the next two years in the budgets of individual investigators.

We would like to have avoided this reduction in spending for bio-medical research, but it is prudent for the future of the Institute.Success in managing our spending will permit another nationwidecompetition for new hhmi investigators several years from now. Theresulting reinvigoration of our cadre of biomedical scientists is surelyimportant to the health and vibrancy of our research program.

We have reduced headquarters spending as well, and have institut-ed a moratorium on most new hires. The budget for the grants pro-gram is also being downsized. After this year, for example, the Institutewill discontinue the Research Resources program ($22 million annual-ly) that has helped fund laboratory improvements at medical schools.

Meanwhile, we are proceeding carefully with the Janelia FarmResearch Campus in Loudoun County, Virginia. The project haspassed several significant milestones—including approval for thetax-exempt bonds that will finance construction. We are now in aposition to proceed while evaluating cost-effective approaches toconstruction and program administration. Site work will com-mence by the end of 2003.

By bringing hhmi’s spending to a sustainable level, we ensure theInstitute’s long-term vitality and leadership in biomedical research.This judicious accommodation to reality allows us to preserve the veryattributes that make hhmi unique—our support of pathbreakingresearch, our dedication to enhancing biology education and ourcommitment to creating a new kind of research community.


P R E S I D E N T ’ S L E T T E R

A Sustainable Future

KA

Y C

HE

RN

US

H

Thomas R. CechPresident

Howard Hughes Medical Institute

I

The unexplained bruising, bleed-ing, fatigue and infections ofacute myelogenous leukemiasignal a malignant explosion ofimmature blood stem cells in

the bone marrow. This cellular populationboom rapidly crowds out normal compo-nents of the blood such as red and white cellsand platelets.

Chemotherapy can turn back the cancer,referred to as AML, for a while, but relapse iscommon, and only 2 in 10 patients survive forfive years. Researchers are aiming new treat-ments at the very heart of this cancer—a singlemutation in the DNA of the cancer cell thatdrives the cell’s relentless reproduction in near-ly one-third of AML cases.

A biochemical signal triggered by themutation of the FLT3 gene “is the engine, orthe gas pedal, for the cancer,” says D. GaryGilliland, an hhmi investigator at Brighamand Women’s Hospital and Harvard MedicalSchool. “It renders the cancer cells complete-ly self-sufficient for proliferation.”

The FLT3 mutation is a cancer trigger,but it may also be an Achilles’ heel. It pro-duces a receptor tyrosine kinase on the sur-face of the blood cell that is constantlyactive, serving as a maverick signal foruncontrolled growth. That signal isGilliland’s target, and with the success of themuch-publicized drug Gleevec, which actsagainst another overactive tyrosine kinase ina different form of leukemia, Gilliland andhis colleagues have high hopes of achievingsimilar victory against AML.

Gilliland leads an academic-industrycollaboration that in June 2002 publishedtwo papers showing that a pair of inhibitordrugs blocked the FLT3 signal, dramaticallylengthening survival of laboratory mice withleukemia induced by mutant FLT3.

Drugs such as Gleevec and those tested by

Gilliland’s group are like smart bombs thathome in on signal receptors on the surface ofleukemia cells, shutting down the cancer. Thedrugs block the tyrosine kinase signal at itsreceptor site on the surface of cancer cells, pre-venting it from being relayed to the cell’snucleus, where it would activate the growthprogram. The errant growth signals are foundonly in tumor cells, minimizing toxic sideeffects to normal cells and tissues. Scientistsenvision a time when cancers such as AMLmight be cured using these approaches, or atleast be treated as chronic diseases, held incheck by routine doses of highly specific drugsthat patients can easily tolerate.

The first of this class of drug, Gleevec, isalready on pharmacists’ shelves. It blocksgrowth signals in two types of hard-to-treatcancers—chronic myelogenous leukemia(CML) and gastrointestinal stromal tumor(GIST)—and in both cases has been aston-ishingly effective (see hhmi Bulletin,December 2001).

Most patients who have taken Gleevechave had at least a temporary positiveresponse. It is an oral drug that has few ofthe side effects cancer patients dread, such assevere nausea and hair loss. Initial data indi-cate that it will help patients live longer;however, that question is still under study.

Gilliland’s interest in leukemia beganwith his hematology fellowship at Brighamand Women’s Hospital. Originally trained inmicrobiology (he has a Ph.D. in the field), hewent on to earn his M.D. at the University ofCalifornia, San Francisco. Now an attendingphysician at Brigham and Women’s Hospitaland at the Dana-Farber Cancer Institute,Gilliland collaborated with scientistsinvolved in the development of Gleevec inthe mid-1990s. Impressed with the responseof so many CML patients, he recalls, “Weand others had the idea that maybe we could

use other inhibitors of this type to treatother leukemias.” This conjecture took himto AML and its mutant FLT3 trigger—and toa search for the next Gleevec.

Bringing Drug Companies on Board In 2000, Gilliland took his quest for a tyro-sine kinase inhibitor for FLT3 from the labbench to COR Therapeutics, a pharmaceuti-cal company in South San Francisco. COR,which has since merged with MillenniumPharmaceuticals of Cambridge, Massachu-setts, was developing tyrosine kinase blockersfor heart disease. After screening hundreds ofcompounds using Gilliland’s mutant FLT3cell lines, company scientists discovered apromising one, called CT53518, that was veryeffective at blocking FLT3 signals.

Around the same time, one of Gilliland’scollaborators, James Griffin, a Dana-Farber


In Pursuit of the Next GleevecResearchers are trying new targeted drugs to combat a deadly leukemia.

U p Fr o n t


FLT3 genes. After amonth, the micewere given CT53518by mouth. Com-pared with untreatedcontrol mice—alldead at the end ofthe experiment—theanimals given thedrug were much lessaffected by disease:Ninety percent sur-vived and showedsignificant improve-ment, Kelly says.

A second group,headed by EllenWeisberg, a Harvardinstructor in medi-cine at Dana-Farber,demonstrated simi-lar results withPKC412 in mice. Thedrug killed malig-nant cells while caus-ing no apparent toxi-city in the animals.The two groups werethen paired with col-laborators at Novar-tis and Millenniumto carry develop-ment forward.

Kelly, whojoined Gilliland’s labjust before the FLT3experiments began,developed the mouse

model of AML used to prove the inhibitor’seffectiveness. “Initially, I was skeptical,” shesays. The logistics looked forbidding: Squirt-ing the drug into the throats of so manymice “morning, noon and night” required alarge team of researchers and technicians.“But Gary really got everyone motivated andset off all these collaborations and kept themrolling, and kept everyone excited about it,which isn’t easy to do.” The project was allthe more intense, says Kelly, because theywere racing against other scientific groupsworking on FLT3 inhibitors.

But Will It Work in Humans?When the tyrosine kinase inhibitors interactwith leukemia cells, the cells don’t simply stop

dividing, as one might think. According toGilliland, the cells have already become“addicted” to the nonstop growth signal, andwhen the inhibitor blocks that signal, thetumor cells “crash and die.” In humanpatients, the impact can be dramatic, says Grif-fin. With Gleevec,“it’s really impressive to seepatients’ responses—they can have kilogramsof leukemia cells melt away in a week or two.”

Now the crucial question is whether eitherof the new anti-AML drugs will work as effec-tively in humans as they did in the preliminarymouse tests. In two separate clinical trials, theinhibitors are being given to patients who haverelapsed AML or who are not able to tolerateintensive chemotherapy. In the meantime, atleast three other FLT3 blockers are being orwill soon be tested in humans. One com-pound is from Cephalon of West Chester,Pennsylvania; two others are being developedat sugen of South San Francisco.

Judging by the experience with Gleevec,Gilliland won’t be surprised if the anti-AMLinhibitor drugs—assuming they are effec-tive—will fail in some cases because cancercells figure out a way to get around thegrowth signal blockade. Such resistance hasbeen seen in some of the CML and GISTpatients taking Gleevec, so scientists are pur-suing ways of hitting the target with two ormore drugs at once.

“We expect resistance is going to be anissue with FLT3,” Gilliland says. “But we havea backup plan: multiple agents. If we canbring two compounds with different chemi-cal structures to bear on the same enzyme,we have a good chance of neutralizing theresistance.”

If the drugs do even moderately well intreating this stubborn disease, the story couldhave a poignant coda, albeit a few years downthe road. Watching from the wings is a groupof doctors at Dana-Farber who are eager totry anti-AML drugs in a small number ofchildren who are at great risk of death in thefirst year or two of life. The children have aform of acute lymphoblastic leukemia thatthe Dana-Farber scientists have determined iscaused by mutant FLT3.

“We are working desperately to get theseinto kids,” says Gilliland. But, because thechildren are in their early stages of growthand development, toxicity and efficacy of thedrugs need to be evaluated in adults first.

—RICHARD SALTUS

AS

IA K

EP

KA

physician-researcher who specializes in can-cers of the blood, approached Novartis AG,the maker of Gleevec. This company, too, hada compound that shut off FLT3 signals, calledPKC412. Gilliland geared up his teams tobegin testing the Millennium and Novartisdrugs in laboratory cancer cell lines withmutant FLT3 genes, and then in mice. In theJune 2002 issue of Cancer Cell, two papersfrom Gilliland’s lab described how both com-pounds inhibited the FLT3 tyrosine kinasesignal in laboratory experiments with cellcultures and in mouse models of leukemia.

A group headed by Louise Kelly, aresearch fellow in Gilliland’s lab, created amouse version of AML by giving the micebone marrow transplants of cells with mutant

If resistance becomes an issue with drugs that inhibit FLT3 signals, Gary

Gilliland is ready to hit the damaging enzyme with two or more drugs at once.

Alberto R. Korn-blihtt gazesaround his Uni-versity ofBuenos Aires

classroom and his eyes lingeron the empty desks. Since lastspring, at least a dozen stu-dents have dropped Korn-blihtt’s introductory biologyclass. These kids don’t lackambition, or even good grades.What they lack is bus fare.

For Kornblihtt, an hhmi internation-al research scholar, this is a unique timemarked by both privilege and pain.Argentina, long recognized as Latin Amer-ica’s scientific star—boasting top academiclabs and three Nobel prizes—has collapsedinto a deep economic depression. One outof every two Argentines cannot buy basicfood and clothes. “Whole families, withsmall children, wander along Buenos Airesstreets every evening, collecting paper andcardboard from the rubbish to sell,” Korn-blihtt says.

Yet he heads to work each morning,preparing novel experiments on regulationof messenger RNA in mammalian cells. Hislab is well stocked. He sets aside time towrite journal articles and travels to interna-tional meetings. All of this makes Korn-blihtt—and 15 other Argentines who arehhmi international researchscholars—a distinct minori-ty. “I am one of the luckyones,” he says. Living a life ofcontrasts, these researchersfind themselves in a positionto help others—and raiseawareness about the role ofscience in building a strongereconomy.

Although political insta-bility has racked Argentina for

decades, the financial impacthit hard this year as the coun-try defaulted on internationaldebt, froze bank accounts anddevalued the peso—whichpromptly lost 70 percent of itsvalue. “It used to be that onepeso equaled one dollar,”explains Maria FernandaCeriani, an hhmi interna-tional research scholar at theLeloir Institute of Biochem-istry Research, Campomar

Foundation, in Buenos Aires who is workingto identify the genes behind neurodegenera-tive disorders such as Parkinson’s andAlzheimer’s. “Now it takes almost four pesosto equal one dollar, so the amount of moneyin your hand is one-quarter of what you hadbefore.” In the United States, that would bethe equivalent of spending $6 for a gallon ofgas, $8 for bread and $200 for ordinary ten-nis shoes—without any increase in salary.

The shortfall threatens Argentina’s sto-ried scientific establishment, as supplies runshort, government funds dry up and gradu-ate students scramble for positions abroad.For Argentine scientists, lab supplies—allpurchased from U.S. and European compa-nies—have become prohibitively expensive.“If you don’t have a grant from abroad thatis in dollars or euros, you are basically with-out money to do science,” says Ana Belén

Elgoyhen, an hhmi interna-tional research scholar atconicet, a science fundingagency in Buenos Aires. Aftera six-month freeze onresearch grants, some moneyhas begun to flow again. Butthe grants buy considerablyless than before.

Scientists fear the tumultwill lead to a brain drain. In2002, science enrollment at


U p F r o n t

DO

MIN

IC C

HA

PL

IN/P

INE

CR

EE

K P

ICT

UR

ES

(4

)

AP

WID

E W

OR

LD

the University of Buenos Aires dropped bymore than a third. Graduate students areflocking overseas. “In my generation, peoplewould go abroad for training, with the clearidea of coming back soon after,” says Fernan-do A. Goldbaum, an hhmi internationalresearch scholar at Campomar who is engi-neering proteins to develop new vaccinesagainst brucellosis, a bacterial disease thatafflicts both animals and people in manycountries. “Now, more young people are . . .staying [away] longer or even for life.”

But not all stay abroad. Ceriani returnedto a different Argentina in April after a five-year postdoctoral position at the ScrippsResearch Institute in La Jolla, California.“The contrast is huge, but I don’t regretmoving back,” Ceriani says. She does addthat setting up a new lab would have beenimpossible without hhmi. “When you arestarting from scratch, you need a millionthings—chemical reagents, plasticware,equipment. This is one of the ways hhmifunding has had a major impact on our sci-ence.” hhmi supports 16 scientists inArgentina. Theirfive-year grantsrange from justunder $267,000 to$450,000.

These researchersestimate that fewerthan a third ofArgentine scientistshave funding fromoutside the country.The Wellcome Trust,for instance, awardsgrants to Argentine researchers working with colleagues in the United Kingdom. Sim-ilarly, the National Institutes of Health (nih)offers Fogarty International Research Collab-oration Awards to Argentine researchersworking with U.S. scientists. Other covetedawards come from Italy, Japan and the Euro-pean Union.

Researchers with outside funds are quickto share lab resources. “I am collaboratingwith other scientists, and I offer them thingslike petri dishes and Eppendorf tubesbecause I know they don’t have them, andwe just can’t do collaborative experimentswithout them,” says Goldbaum, who alsoreceived a $32,000 nih grant this year forhis work on vaccines. Kornblihtt remembers

In Argentina, a Life of ContrastsDuring an economic crisis, foreign funding shields some scientists,who contend that science can only help the country.

KORNBLIHTT

ELGOYHEN

CERIANI


One of every two Argentines cannot buy food and clothing. Whole families dig through rubble for objects to sell on street corners and subway stations.

tight times earlier in his career, when he hadto sterilize and reuse plastic petri dishes atleast once or twice. “I’m afraid that somegroups, if they want to keep working, willsoon have to go back to these methods.”

Argentina’s hhmi research scholars seescience as a way forward, and as the country’scrisis deepens, they are sounding the call forstronger investment inresearch. “One could arguethat it’s nonsense to supportscience when you have to feedhungry people,” Kornblihttconcedes. But he contends thatscience and technology will bethe cornerstone of a strongercountry, and he has joinedothers in drafting proposalsfor improved state policies. “Ilink my fight for science with a

fight for independence,” he says. “If we wantto get out of this crisis, we should be moreindependent, both politically and economi-cally—and in that picture, science is key.”Kornblihtt suggests that the governmentincrease the national science budget to at leastone percent of the gross national product andrequire private companies to invest in local

research and development,which, he says, would createnew jobs.

“I think our real impactmay be as an example in themiddle of this disaster,” saysGoldbaum, noting that evennow Argentina has morehhmi research scholarsthan any other Latin Ameri-can country. Within LatinAmerica, hhmi also sup-

ports scientists in Brazil, Chile, Mexico,Uruguay and Venezuela—several of thesecountries are facing economic downturnsas well.

“Our problem is not that we are a poorcountry but that we are a rich country thathas been badly managed,” says Argentina’sGoldbaum. “To see young people doing sci-ence at an international level could have abig impact by showing that this kind ofeffort, in the long term, can bring success.”

Still, everyone feels the emotionaldrain of a country where banks refuse tocash checks and political leaders changelike the shifting sands. “Even if you havean hhmi grant,” says Elgoyhen, “you stillhave to live this disturbing life where youdon’t know what’s going to happen in thefuture. The only way to survive, I guess, isto keep going.” —KATHRYN BROWN

GOLDBAUM


Researchers are discovering thathumans and other creaturespossess a “second-sight” systemthat helps them maintain anaccurate biological clock, or cir-

cadian rhythm. Their findings are leadingsome to suspect that second sight and circadi-an behavior may have evolved in tandem,independently of “primary vision.”

In people totally deprived of cues fromthe outside world—not only light, but allsocial and environmental cues—it takes a bitless than 25 hours for the natural humanclock to complete one full cycle. Many otherspecies also have natural cycles close, but notexactly equal, to the length of a solar day. Yetall creatures are able to stay in synch with the24-hour cycle. This is possible because bio-logical clocks reset themselves daily in aprocess called photoentrainment. This sameprocess helps jet-lagged travelers adjust tonew time zones within a few days.

Light collected by the eyes supplies theinternal clock with information about ambi-ent light, setting the entrainment process inmotion.“The assumption for many years wasthat the standard visual pathway does the job,”says hhmi investigator King-Wai Yau, at TheJohns Hopkins University School of Medicine.

In the visual pathway, light-sensitive pig-ments in the retina’s rods and cones absorbincoming photons, whose energy is convert-ed into electrochemical signals. These signalsare carried from retinal ganglion cells(rgcs) down the optic nerve and into a partof the brain called the lateral geniculatenucleus. Finally, the impulses are dispatchedto the visual cortex for image processing.

“But it’s also well known that a small per-centage of rgcs send impulses to a region ofthe hypothalamus called the suprachiasmaticnucleus (scn),”Yau explains. The scn is thehome of the master circadian pacemaker. Itprovides the equivalent of a timing signal,enabling organs throughout the body to syn-chronize. These signals regulate our body tem-perature, cardiac output and hormonal secre-

tions; they tell us when to rise, when to eat andwhen to go to bed.

Blind mice keep timeIt seemed a matter of common sense that thestandard visual system—the eyes’ rods andcones—supplied information about environ-mental light to calibrate the circadian clock.In laboratory rats whose eyes had beenremoved, the internal biological clock couldnot synchronize with the solar light/darkcycle. This proved that photoentrainment wasimpossible without the eyes. Yet the storychanged in the late 1990s when a group underRussell Foster at the University of Virginiabegan experimenting with mice whose eyeswere genetically engineered to lack function-ing rods and cones. These blind mice wereable to keep their normal circadian rhythm.

“This was big news,” Yau recalls. “It wasboth alarming and interesting. It meantthere must be other cells in the eye that ‘see’environmental light. They respond to light,but they’re not rods and cones. Someonecame up with a cute term to describe thisphenomenon—they called it ‘second sight.’ ”

Yau isn’t entirely happy with the nick-name. Environmental light levels registered bythe second-sight system do not constitute sightin the conventional visual sense, he notes.“Youcan’t use it to recognize your grandmother.”

Rather than produce sharp, photorealisticimages, this second light-sensitive system yieldsinformation about whether it’s daytime, night-time or twilight. Yau and other scientists referto this as “nonvisual photoreception.”

Whatever one calls it, this system’s exis-tence raised new questions about a processscientists thought they understood. If photo-entrainment involved the eyes but was notdependent upon rods and cones, there was animportant mammalian photoreceptor thathad not yet been identified. The likely sus-pects included several forms of the proteinopsin related to pigments in the retina. Oneof these, called melanopsin, was cloned in1998 by Ignacio Provencio at the UniformedServices University of the Health Sciences inBethesda, Maryland.

Melanopsin was found in Xenopus, anAfrican frog with skin that changes coloraccording to the level of ambient light. Whenthe search was extended to other animals, the

molecule was promptly foundin the retinas of both mice andhumans. Early in 2002, Yauand David Berson at BrownUniversity published back-to-back papers in Science, whichindicated melanopsin’s pres-ence in the previously identi-fied subset of retinal ganglioncells that project to the scn.

No one has conclusivelydemonstrated that melanopsinis a photopigment, performingthe same function in the sec-ond-sight system as light-sen-sitive rod and cone pigments

U P F R O N T

In Synch with the SunThe system that keeps us on a 24-hour clock may have evolved alongside behaviors that protected primitive creatures from the sun.

King-Wai Yau mapped the neural circuitry of the light-

sensing system that controls the biological clock.

Michael Rosbash links DNA repair, survival and biological clocks.

CH

RIS

HA

RT

LO

VE

ST

AN

LE

Y R

OW

IN


do in the primary visual system. Berson’sexperiments have, however, shown that reti-nal ganglion cells containing melanopsin areintrinsically light sensitive, and Yau’s work hasyielded a map of the second-sight system’sneural circuitry. “The system projects to allthe right places” in the brain, Yau says. Theseinclude, besides the scn, a part of the brainthat governs contraction of the pupils inresponse to bright light.

The existence of light-sensitivemelanopsin-containing cells does not rule outthe existence of yet another system in the eyeengaged in nonvisual photoreception. How-ever, recent collaborative experiments by Yau’sgroup and Robert Lucas of Imperial College,London, on mice genetically engineered tolack melanopsin, indicate that this possibilityis unlikely, according to Yau. Regardless ofmelanopsin’s status, the work of Yau and col-leagues suggests that photoreception in mam-mals has a range of applications unrelated tothe formation of visual images.

Cryptic fliesEvidence of a second light-processing systemin the mammalian eye did not shockresearchers in the lab of hhmi investigatorMichael Rosbash at Brandeis University. Foryears they have been trying to determine, at themolecular level, how the circadian rhythm ofthe fruit fly, Drosophila, is established and howgenetic mutations in clock-related genes affectfly behavior. In 1996, Rosbash and MichaelYoung of The Rockefeller University, working

independently, determined how the fly genesdubbed period and timeless and their proteinproducts form a self-regulating feedback loopthat rises and falls on a 24-hour timetable, con-trolling the fly’s circadian rhythm.

Hints for second sight, it turns out, weremanifest in Rosbash’s fruit fly work. His lab, incollaboration with his Brandeis colleague JeffHall, developed a mutant fly variety called cryb

whose clock remained steady even when thefly was subjected to uninterrupted light. Nor-mally, organisms exposed to constant illumi-nation “go wacko,” Rosbash says, raising thequestion of how the cryb flies managed toremain rhythmic. Their distinguishing featureis a mutation in a gene called dcry that codesfor cryptochrome, a protein believed to beDrosophila’s principal circadian light receptor.“If there were other major photoreceptorsinvolved in entrainment, they would have pro-duced arrhythmia in the cryb flies subjected toconstant light,” Rosbash says.

Yet there must be another system that issensitive to light, because these mutant flies arestill rhythmic and can entrain to different lightcycles. Rosbash and Yau agree that most or allorganisms have some kind of nonvisual light-processing system. And both believe this ‘second’ system probably evolved independent-ly of what we think of as primary vision—although it’s impossible to say which came first.

Evolutionary scenariosIn a paper soon to be published in the Jour-nal of Molecular Evolution, Rosbash and Wal-

ter J. Gehring of the University of Basel sug-gest how second sight may have emerged.They propose that evolution long ago select-ed for creatures that either lived away fromgene-damaging ultraviolet (uv) light fromthe sun or could learn to sense it and flee. Inthe oceans, such a scenario would havefavored creatures that dove to the depths indaylight and surfaced only at night.

Rosbash and Gehring think a light-sensing protein, perhaps a precursor tocryptochromes or the opsins found in themodern retina, set off a warning signal increatures whose DNA was subject to dam-age by uv rays. Cryptochromes are relativesof photolyases, DNA-repair enzymes pres-ent in most contemporary organisms.Cryptochromes and photolyases are struc-turally similar, and both are sensitive toblue light, the only wavelength in the visiblespectrum that penetrates to any substantialdepth in the oceans. For organisms thatmade the sea their home, the ability todetect blue light would have enhanced theirchances of survival.

Rosbash and former postdoc Ravi Alla-da, now at Northwestern University, point toa second possible evolutionary link betweenDNA repair and biological clocks. This linkis casein kinase II, a molecule also involvedin signaling the presence of DNA damage inthe circadian systems of contemporaryplants, animals and Neurosopora fungi.

In their evolutionary scenario, Rosbashand Gehring propose that a second-sightsystem—sensitive to blue light—emergedin complex organisms and functioned asan avoidance mechanism, enabling crea-tures to avoid damage from harmful uvrays. A precursor of sophisticated circadianclockworks? Perhaps. The theory helps sci-entists think about a critical moment inevolutionary history called the Cambrianexplosion, when organisms of considerablecomplexity began to proliferate in theearth’s oceans.

“Life that evolved in the seas had to beable to perceive light,” Rosbash reasons.While it’s widely believed that accuratevision systems emerged in Cambrian times,the Rosbash-Gehring thesis—which theyadmit is speculative—suggests an early stagein this process, and one that also helpsaccount for the origins of biological clocks.

— JOEL N. SHURKIN AND PETER TARR

lateral geniculate nucleus

primary visualcortex

optic nerve

retina

light

optic nerveretina

light

suprachiasmaticnucleus (SCN)

hypothalamus

pinealgland

Two Different Paths For vision (left), pigments in the retina's rods and cones

absorb light and send signals through retinal ganglion cells (RGCs) to the optic nerve and into

the lateral geniculate nucleus. Impulses then reach the visual cortex for image production. For

second sight (right), light is absorbed by rod and cone pigments, but also by a pigment found in a

group of intrinsically photosensitive RGCs. These RGCs convey the light signals to the suprachi-

asmatic nucleus (SCN). The SCN processes information about day length and sends messages to

the pineal gland, which triggers various endocrine responses.

DA

NIE

L F

AZ

ER


JA

ME

S K

ING

-HO

LM

ES

/PH

OT

O R

ES

EA

RC

HE

RS

, IN

C.

Is HIV

SmarterThanWeAre

?

With each large and small

victory against HIV—and

there have been many in the

last two decades—

the virus reinvents itself and

evades total defeat.

By Marlene Cimons


A masked technician uses a

centrifuge to separate virus-

es such as HIV or hepatitis

from blood cells. A high-

speed spin causes the higher

density blood cells (red) to

separate from the virus, seen

as an opaque layer within the

less dense, clear fluid.


hat Robert F. Siliciano saw when he entered his lab five yearsago triggered conflicting emotions. He was elated because theclear substrate in the plates had turned blue, confirming his

hypothesis. But he also felt a deep sadness because it meant badnews for those aids patients who had been enjoying remark-

able clinical benefits from new protease inhibitor drugs.His tests showed that the human immunodeficiency virus (hiv)

was still in their bodies, despite tantalizing hope that the drugs coulderadicate hiv.

“That was a moment that really shook us up,” says Siliciano, anhhmi investigator who conducts aids research at The Johns HopkinsUniversity School of Medicine.“It was the realization that this virus willremain in their bodies forever.”

In the more than 20 years since the earliest aids cases were doc-umented, hiv has proved a formidable foe, thwarting some of thesharpest scientific minds in the world. The National Institutes of Healthhas poured $24.3 billion into hiv research since 1982, including $2.77billion this year alone, with impressive results that have often translat-ed into widespread benefits reaching far beyond the boundaries of aids(see sidebar, page 15).Yet for each hurdle scientists have overcome, hiv,in maddening fashion, seems to devise another to throw in their path.

Each new promising drug, for example, has brought elation with itsefficacy, only to be followed by despair as the virus developed resistanceto it. “We know so much more about hiv than any other virus,” sayshhmi investigator Bruce D. Walker, director of the Harvard MedicalSchool’s Division of aids.“But hiv is a very tough nut to crack. It ulti-mately gets the upper hand.”

Is hiv truly smarter than we are? To be sure,a virus has no innate intel-ligence; it’s just a bit of genetic material surrounded by a protein coat, try-ing to stay alive. “It may look like it’s smart, but it’s doing what it is pro-grammed to do, which is to replicate and adapt,” says Anthony S. Fauci,director of the National Institute of Allergy and Infectious Diseases (niaid).Certainly, other viruses do that too, but hiv, a retrovirus, has the insidi-ous habit of permanently integrating itself into the host’s cells, unlike fluviruses,for example,which wreak their temporary havoc and leave.Becausehiv is a retrovirus, it contains RNA rather than DNA,and uses an enzymeknown as reverse transcriptase to convert its RNA into DNA as it integrates,turning the body’s own cells into little virus factories.

One reason the virus is so difficult to fight, says Robert C. Gallo,director of the Institute of Human Virology at the University ofMaryland in Baltimore (and hiv’s co-discoverer, along with France’sLuc Montagnier), is that “the ability of hiv to replicate itself is tremen-dously greater than that of other retroviruses. And it’s a newer infectionin mankind, so we are less adapted to it.”

“Every time the virus replicates, it is capable of changing,”Fauci says.“And every time the virus mutates, it has the potential of assuming aform that can avoid destruction” by drugs or a vaccine. Also, the virusdoes not exist as one universal strain. There are subtypes, and peoplecan become infected with more than one. New subtypes could present“an even bigger problem for an aids vaccine than the simple mutationproblems people talk about now,”says June E. Osborn, a virologist whochaired the U.S. National Commission on aids and now runs the JosiahMacy Jr. Foundation in New York City. “When I want to worry late atnight, that’s what I worry about.”

Still, a tremendous amount of understanding has accumulated aboutthe behavior of hiv, including the various ways in which the virus infects

immune-system cells.For example,hhmi investigator Dan R.Littman atNew York University School of Medicine and colleagues have focused onhow hiv invades helper T lymphocytes, the cells that are destroyed by hiv.Elimination of helper T cells leaves the body vulnerable to life-threaten-ing infections.Most recently, in a paper published January 2002 in the jour-nal Immunity, the researchers showed that for potent infectivity,hivmustbe taken up by the dendritic cells on mucosal surfaces.“The virus hops ontothe dendritic cell to hitch a ride to the lymphatic tissues, where the T cellsare,and then infects these cells very effectively,”Littman explains.However,at this point,he adds,“I’m not aware of any approaches to exploit the den-dritic cell work to develop therapies or vaccines.”

PROGRESS AMID PROBLEMS

Despite the roller-coaster nature of progress against aids, researcherspoint to great advances in drug development during the past 15 years.The growing arsenal of drugs has transformed an aids diagnosis froman automatic death sentence; patients now expect to manage the dis-ease as a chronic illness.

The first anti-aids drug,AZT, was approved by the Food and DrugAdministration in 1987 with much fanfare. Until then, antiviral drugswere nearly nonexistent, so the rapid development and licensing of AZTwas regarded as a triumph. It prolonged survival and improved quali-ty of life. But AZT, like every aids drug that would follow, proved prob-lematic, bringing nasty side effects and eventual viral resistance. It did,

BIL

L D

EN

ISO

N

W

Robert Siliciano has seen HIV held in check, but the drugs are still too toxic.


however, offer an important lesson—that viruses could be attacked andcontrolled, even if the effect was only temporary.

With that hopeful note, pharmaceutical companies pumped moremoney, time and energy into studying other compounds, while clini-cians tried innovative ways to use them, going beyond single-drug ther-apy to the approach that is practiced today—cocktails of different com-pounds that hit the virus in multiple ways.

Today,16 drugs in four different classes are licensed to treat hiv.Threeof the classes block reverse transcriptase; the fourth, which blocks anotherenzyme,called protease,dramatically changed the landscape of aids treat-ment when it was introduced in 1995.Used in cocktail combinations knownas “highly active antiretroviral therapy”(haart), the protease-inhibitingdrugs proved much more potent than the earlier drugs; the annual num-bers of U.S. deaths plunged 60 percent—from 38,100 in 1996 to 15,300 in2000, according to the Centers for Disease Control and Prevention.

The early impact of the protease inhibitors led some researchers,including David D. Ho, director of the Aaron Diamond aids ResearchCenter in New York City, to suggest for a time that haart might beable to completely eliminate hiv from the body.

Not so. The research of Siliciano and other groups revealed hiddenreservoirs of hiv. Later, Ho’s work showed that low-level viral replica-tion continues, even when patients are on haart. Today Ho says: “Itis clear that eradication is going to be very, very difficult.”Siliciano agrees.“I don’t think it will be possible to hit the resting cells,” he says. “They

are rare, one in a million, and they are not making any RNA or protein.They are indistinguishable from the rest.”

BLOCKING ENTRANCE

Although no one has any illusions at present that some particular drugcombination will be a panacea, researchers remain convinced that newerand better drugs are still the best chance of helping those who are alreadyinfected, so the work on new drugs continues. In July, researchers at theInternational aids Conference in Barcelona heard encouraging newsabout the first new aids drug in six years—T-20, the first member ofa long-anticipated family called fusion inhibitors. Unlike current drugs,which block enzymes needed for replication, fusion inhibitors keep hivfrom entering cells.

The drug, developed by Trimeris of Durham, North Carolina, andto be marketed as Fuzeon by Hoffmann-La Roche, was tested in patientswho no longer responded to other aids drugs. It reduced their blood-borne virus levels by three-quarters, and doubled the percentage ofpatients in whom the virus fell to undetectable levels.

Researchers are also trying to improve existing drugs by changingtheir formulation to encourage compliance; regimens of at least 3 to atmost 20 pills per day have sometimes been difficult to follow. Dependingon the regimen and the patient population, anywhere from 5 to 35 per-cent of patients abandon multidrug therapy.

“With some of these drugs formulated in the same capsule,we can sup-

he early burst of activity in support of AIDS

research occurred against a backdrop of

resentment among advocates for research

on other diseases. Many complained that

AIDS afflicted far fewer people than their

own conditions of interest, yet it received far

more research funding.

In recent years, however, such criticism has been

muted by the growing applications of AIDS research

to other medical areas. Despite the dogged inclination

of HIV to elude scientists’ best efforts, their work has

produced a wealth of knowledge that goes well

beyond the scope of AIDS; in particular, it has pro-

vided models for fighting other chronic viral infections,

historically among the toughest to treat.

As researchers began to better understand how

HIV worked, they discovered that the more hits a virus

took during different stages of replication, the more

effective the result. This led to the development of pro-

tease inhibitors and other drugs that could deliver

one-two punches at different phases in HIV’s cycle.

Scientists are now applying that same approach

to other viral diseases. Both hepatitis C and hepati-

tis B, which together infect an estimated 600 million

persons worldwide, are prime candidates. Like HIV,

hepatitis C makes a protease enzyme that is neces-

sary for viral replication. And hepatitis B makes an

enzyme that is similar to HIV’s reverse transcriptase.

“We are learning in hepatitis C treatment, as we

learned with HIV, that hitting multiple metabolic path-

ways of the virus using multiple drugs is effective,” says

Lawrence Deyton, who directs HIV and hepatitis C

programs for the U.S. Department of Veterans Affairs.

Moreover, “the knowledge gained in understanding

virology and the viral/immune-system interactions—

everything we didn’t know before HIV—will really help

us leapfrog in [hepatitis C research],” Deyton says. “We

are just taking all our cards off the HIV table.”

The same goes for hepatitis B. Patients who

suffer from chronic hepatitis B have a new drug,

adefovir dipivoxil, made by Gilead Sciences of Foster

City, California. The Food and Drug Administration

recently approved the drug to help treat this life-

threatening infection. Adefovir was initially tried in

AIDS patients but was rejected as too toxic for the

kidneys. In lower and safer doses, however, it is

effective against hepatitis B.

The other major hepatitis B drug, lamivudine

(also known as 3TC and epivir), made by the U.K.-

based GlaxoSmithKline, also got its start as an AIDS

treatment. In fact, it is still used against HIV in com-

bination with other drugs.

For hepatitis C, the combination of interferon

and ribavirin—also originally an HIV drug—has pro-

duced a better sustained viral response than single-

drug therapy.

“Before HIV, many drug companies were scared

of researching antiviral drugs,” says Vicki L. Sato, pres-

ident of Vertex Pharmaceuticals in Cambridge, Mass-

achusetts. But lessons learned from HIV “gave us the

confidence to try.” The company has a protease

inhibitor candidate against hepatitis C, called VX-950,

which could go into clinical trials sometime next year.

Researchers also are looking to other areas to

apply AIDS advances. Among those considered the

most promising: blood disorders, autoimmune dis-

eases and cancer. For example, in cervical cancer, non-

Hodgkin’s lymphoma and Kaposi’s sarcoma, both virus-

es and the immune system are believed to play a role.

Similarly, research into HIV vaccines, however

frustrating, may open the door to developing vac-

cines against other infections. “All sorts of novel

strategies are being pursued in HIV vaccine

research,” says David D. Ho, director of the Aaron

Diamond AIDS Research Center in New York City.

“If this ultimately results in a protective vaccine, the

lessons will be most useful for other vaccines, par-

ticularly for malaria and tuberculosis.” —M.C.

T

Lessons Learned–and Shared

reatment is important, and

we should take care of

people who are sick,”

says Barry R. Bloom,

dean of the Harvard

School of Public Health and

HHMI Medical Advisory Board mem-

ber. “But if we don’t prevent trans-

mission, there will be even more peo-

ple sick. The challenge is to get the

most effective balance.” The global

fight against AIDS is not about treat-

ment or prevention, but about both.

Indeed, a report released last

July in Barcelona by UNAIDS (the

Joint United Nations Programme on

HIV/AIDS) recommended a mini-

mum of $10 billion annually, largely

subsidized by the world’s wealthier

nations, to achieve two critical goals:

more affordable drugs and beefed-

up prevention programs. Otherwise, it warned, more

than 68 million people worldwide could die from

AIDS over the next 20 years.

While the rate of new infections and mortali-

ty has been leveling off in the United States and

Europe—thanks to prevention and the availability

of therapy—the same cannot be said of the epi-

demic in developing nations. In sub-Saharan Africa,

for example, 28.5 million people are living with

HIV, but fewer than 30,000 are getting AIDS

drugs. The disease is decimating the adult popula-

tion, having already orphaned an estimated 11 mil-

lion children in the region.

Also, infections are soaring among pregnant

women. In Botswana, for example, HIV prevalence in

this group was 45 percent in 2001.

However, public health experts say that isolated

success stories prove that sustained prevention

efforts—including the willingness to publicly talk

about unprotected sex and other unsafe practices—

and antiviral drug programs can have an impact.

“There are countries that have made marvelous

progress, and in every instance, it relates to the gov-

ernment getting past its prudery,” says June E.

Osborn, a virologist who chaired the U.S. National

Commission on AIDS and now runs the Josiah Macy

Jr. Foundation in New York City. She

cites Thailand, Uganda, Senegal,

Ivory Coast and Brazil as examples of

nations that have been able to turn

the tide.

In Thailand, for example, “where

young men in the military have a long

tradition with sexual commerce, the

yearly new-infection rate among mil-

itary recruits was 20 percent,” Osborn

says. “The government did a turn-

around on preventive messages about

safe sex, and the rate dropped to 3

percent almost instantly.”

In Brazil, the world’s fifth-

largest country, aggressive preven-

tion messages and access to free

drugs have resulted in a drop of HIV-

related hospital admissions by 75

percent since 1997 and a decline in

AIDS deaths of 50 percent, accord-

ing to a 2002 Ford Foundation report.

“Curtailing HIV is in our grasp,” Osborn says. “In

those countries where they realize it’s a matter of life

and death, the simple messages that we have had

from the beginning have worked.”

Bloom agrees. “As primitive as the tools for pre-

vention may be—condoms and exhortation—we

know they are working in places like Senegal, Thai-

land and Uganda,” he says. “HIV never rose in Sene-

gal, and dropped dramatically in Thailand and Ugan-

da. As nontechnical, unsophisticated and unappealing

as it sounds, prevention can work. But it takes a

huge effort.” —M.C.

“T


press viral replication for years with two pills a day,with very few side effects,”says Robert T. Schooley, an aids specialist who heads the infectious dis-eases division of the University of Colorado Health Sciences Center.“If theyare used the way we prescribe them, resistance will be a rare event becausethe virus won’t be replicating fast enough to develop mutations.”

And some patients continue to do well on existing haart. In theseindividuals, Siliciano has seen viral evolution stop. “Those who canmaintain below 50 copies [of viral RNA] per milliliter of plasma havehalted replication and resistance,”he says.“This means, at least in prin-ciple, that it is possible to permanently hold the virus in check.”Still, thedrugs are toxic. But “if we can develop nontoxic drugs, it should be pos-sible for a patient to have a normal life,” he says.

TIMING IS EVERYTHING

One way researchers are trying to make the drug regimens more toler-able and reduce side effects is through carefully timed drug interrup-

tions, which offer a reprieve from drug toxicities, save on drug costs and,in some cases, even train the body’s immune system to kick in and gaincontrol of the virus.

Researchers at niaid have been experimenting with a seven-day-on/seven-day-off cycle in which patients go off treatment but thenreturn to it before the virus starts to bounce back. Fauci and niaid col-league Mark Dybul have followed 10 patients for two years on this rou-tine, and “they are still doing very well,” Fauci says. The researchers aredoing an expanded study of a similar protocol now in the United Statesand, soon to start, in Uganda.

Walker and colleagues at Massachusetts General Hospital have alsotried a novel interruption approach. They’ve been studying 14 patientswho started haart within weeks of learning they were infected. Afterabout 18 months of continuous treatment, they stopped the drugs,returning to treatment only when the virus began to rebound. Overthe course of three years, the researchers found that the time between

Turning the Tide

AL

EX

AN

DE

R J

OE

/AF

PP

HO

TO

Children who lost their parents to AIDS gather at the Tithanizane Orphan Care

Center in Ndirane Township, Malawi. HIV infects 13 percent of Malawi’s population.


stopping treatment and viral rebound hadlengthened. They theorize that early treat-ment helped preserve killer immune-sys-tem cells that recognize hiv and that eachtime the virus returned, those cellsincreased in number.

“It’s our hope that since we are dealingwith a lifelong infection, we can get theimmune system to do a better job. If so, wemight be able to limit treatment and toxici-ties,” Walker says. Despite promising resultsin boosting immunity for patients whoreceive therapy soon after they becomeinfected, this approach does not appear towork in patients who have been infected forlonger periods of time.

IN PURSUIT OF A VACCINE

Most aids researchers acknowledge thatadvances in drug therapy have moved at amuch faster pace than vaccine research.Nevertheless, no one is giving up the chase.More than two dozen candidate vaccines haveundergone early (phase I and phase II) stud-ies in humans for safety and efficacy,and somehave progressed to large, phase III studies.

Farthest along of all experimental aidsvaccines is aidsvax, a product developedby VaxGen of Brisbane, California, andmanufactured by Genentech. It was the firstto enter phase III trials—enrolling nearly8,000 volunteers in the United States,Canada, the Netherlands and Thailand—and early data are expected in 2003.

aidsvax is based on the traditionalapproach of trying to prevent the virus fromestablishing an infection by generating anti-bodies that will immediately bind to the virusand neutralize it. aidsvax uses hiv’s sur-face protein, gp120. Experts generally remainpessimistic, however, believing that a truly effective vaccine against hivneeds to both prevent infection and provide what is known as cell-medi-ated immunity, which is the ability of immune-system cells to kill thosecells that are already infected.

Merck & Co. is testing two versions of its candidate vaccine inhumans: The first inserts an hiv gene called gag into a plasmid DNAvector, and the second inserts gag into a modified adenovirus. The com-pany is conducting studies in uninfected individuals, as well as hiv-pos-itive patients undergoing haart therapy.

Also, the U.S.and Thai governments announced at the Barcelona con-ference that they are planning the largest vaccine trial yet, testing two prod-ucts on more than 16,000 subjects in Thailand. The test will first inocu-late subjects with a vaccine designed to stimulate cell-mediatedimmunity. Developed by the French company Aventis Pasteur, it is a live-virus vaccine that uses the canarypox virus engineered with the genes ofseveral hiv proteins. This will be followed by the administration of

aidsvax. This is a process known as “prime boost,” in which patientsare “primed”with one vaccine, then after a period of time, they are givena “boost” of either the same vaccine or a different one.

Though the researchers behind such efforts are hopeful, they can’tbe too confident. hiv-vaccine research efforts, however creative, haveall failed to produce broadly useful results. The same characteristicsthat enable this crafty virus to confound treatment—first and fore-most, its ability to mutate—also make it highly adept at eluding animmune-system attack. A universally protective candidate has proveddifficult to achieve.

Public health experts insist that while the research continues, the sin-gle most effective way to thwart hiv is to return to the basics. And thatmeans prevention through behavior modification (see sidebar, page 16).

niaid’s Fauci agrees. “The best way to stop hiv, quite simply, isto not allow it to spread from person to person,” he says.“Interrupt thechain of transmission. That’s the way you outsmart this virus.”

Structures Revealed

In 1998, Wayne A. Hendrickson, an

HHMI investigator at Columbia University,

and colleagues solved the three-

dimensional structure of the HIV-1 protein,

gp120, that makes first contact with

human cells. When this surface protein

(red) encounters a lymphocyte that bears

the protein CD4 on its surface (yellow),

the gp120 docks with the lymphocyte. The

virus also must bind to a chemokine recep-

tor, discovered by Dan R. Littman and oth-

ers, in order to begin infection.

Two groups of HHMI investigators in 1997 inde-

pendently revealed the structure of a protein

fragment, called gp41, from the surface of HIV that

penetrates a cell’s membrane, allowing the virus to

gain access to the cell’s reproductive machinery.

Peter S. Kim, who was an HHMI investigator at the

Whitehead Institute for Biomedical Research,

headed the first group. He is now at Merck. The late

Don C. Wiley and Stephen C. Harrison, both at

Children’s Hospital in Boston and Harvard

University, were members of the second group.

H

▲▲

KIM

LA

BO

RA

TO

RY

, W

HIT

EH

EA

D I

NS

TIT

UT

E F

OR

BIO

ME

DIC

AL

RE

SE

AR

CH

PE

TE

R K

WO

NG

AN

D E

RIK

MA

RT

INE

Z-H

AC

KE

RT

/CO

LU

MB

IA U

NIV

ER

SIT

Y

� Yuh Nung Jan

and Lily Jan saw an

obvious opportunity

in working together.


But for scientists who share both marriage and laboratory—who livetogether, raise children together and work together—the language of loveis often indistinguishable from the language of science. As one such sci-entist puts it,“My wife and I are so intimate professionally that we can dis-cuss science in shorthand.It’s wonderful.”Another is more cryptic:“Scienceis the only bit of our marriage that has always worked 100 percent.”

The success of such couples isn’t just luck. In fact, scientists who man-age to share both pillows and pipettes generally have certain traits incommon: mutual respect for each other’s work; separate, careful-ly carved-out research niches; moreor less equal status and a feelingof shared success. They also have uncommonlygood marriages. Mostthink their spouse thesmartest person theyknow and the personwhose opinion mattersmost. Their mutualdelight in the wonders ofthe lab deepens their rela-tionship: Stalking elusivescience with someone you loveis serious fun.

Take Lily Y. Jan and Yuh NungJan, one of several collaborating coupleswithin hhmi. The Jans, both hhmi inves-tigators at the University of California, SanFrancisco, have shared a marriage since 1971 and a labsince 1979. Both study the nervous system of flies, searchingfor themes common to other organisms, and most of the time theysimply alternate authorship prominence on their publications. Theirtheory is that when two people work together, the whole of their workis greater than the sum of the two separate parts.“Inevitably you fight, and then you figure out how toavoid fighting,” says Lily. “But if you truly care abouta question, you want to find the right way. So youargue until you figure out how to make it work.”

But harmony—not argument—seems to dom-inate the Jans’ life. They met as physics students at theNational Taiwan University in Taipei and married asgraduate students in biology at the California Instituteof Technology in Pasadena. Their first mentor, the latemolecular biologist Max Delbrück, who won the 1969Nobel Prize in Medicine, kept their work separate, urgingthem to tackle problems independently. Still, the pair lovedtalking science together, the way some people like arguing pol-itics or philosophy. As Lily puts it,“We’re both curious about thequestions the other is addressing. It’s just simple curiosity.”

In 1974, when the Jans had to choose partners in a neurobiolo-gy course, they chose each other, taking advantage of what seemed tothem an obvious opportunity. In essence, they began sharing fruit fliesthe way other couples share china and silver. Nothing seemed more nat-ural, says Yuh Nung.“In our case, working together works out very well.

She is very patient, and I’m a little the opposite. She is capable of focus-ing on one area and learning everything about it. I tend to come out withwild and crazy ideas, and occasionally there is a good one. So with ourcombination, we can turn some good ideas into useful work.”

As he speaks, Yuh Nung sits at his computer in a small office filledwith piles of papers—papers written by postdoctoral fellows and grad-

uate students, journal articles, graduate applica-tions—and a painting of fruit flies done by his

daughter, Emily, when she was in high school.(Down the hall, Lily’s office looks much the

same.) Lily looks at him, nodding occa-sionally. She waits for a few seconds untilshe is certain he has finished speakingand then tackles the same question.YuhNung and Lily are calm, respectful andcomplementary to each other. It is easyto imagine them working together.

It’s also easy to see that the Jans are notjoined at the hip.They have done what most

successful collaborators do: They have eachdeveloped their own area of expertise. Yuh

Nung focuses on the development of the nervoussystem, Lily on its function. “Then we each have

some independence in the lab and in the commu-nity,”explains Lily.The arrangement is practical as well:

Yuh Nung goes to meetings related to development andLily to those about function, a division that proved espe-

cially valuable when their daughter,now 25,was small. It wasduring those years that teamwork mattered most.“We basically

worked on raising our daughter and collaborating on projects,”says Lily,recalling that each evening Yuh Nung would walk her home

so she could relieve her mother, who watched Emily (Max, their 17-year-old son was not yet born.).“Then he would go back and stay with theprep until 2 a.m. We had to work shifts on the same experiments.”

Even as the two talk about the tough times, when both kids andpetri dishes needed tending, they seem unsur-

prised, almost unaware that they haveaccomplished what many spouses wouldfind impossible. “It’s the only life we’vehad,” says Yuh Nung, shrugging.

The Jans’ collaboration was madeeasier by their simultaneous entry into

science. Neither was more advanced thanthe other. Not all couples share that advan-

tage, however. When hhmi investigator andcancer biologist Charles J. Sherr met Martine F.

Roussel, he was running a laboratory at the NationalInstitutes of Health (nih) in Bethesda, Maryland. Roussel,

six years his junior, was a Ph.D. student in cancer biology at VillejuifHospital in Paris and later at the Pasteur Institute in Lille, France. Thetwo maintained a long-distance relationship until 1980, when Rousselwent to nih as a Fogarty Scholar.

At first, Roussel and Sherr merged households but not beakers. “Irefused to work with him for three years,”says Roussel.“My concern was

AMore

PerfectUnion

By Dorothy Foltz-Gray

Scientists who have found

partners in the lab dissect their

relationships andfind that goodmarriages

make better science.

To most of us, “May I use your centrifuge?” hardly sounds like pillow talk.

FR

ED

ME

RT

Z


that I wouldn’t get credit for what I did. Buteven though we were in two labs, we spent somuch time thinking about science together. Itwas so clear that we were working togetherintellectually. So Chuck said,‘Do experimentswith me. At least we will get something out ofit.’ And as soon as we started working togeth-er, our projects were successful.”

Working together was one thing; buildingcareers was another. What Roussel and Sherrunderstood about each other—that they wereintellectual equals—wasn’t as easy for out-siders to grasp, since one scientist was juniorto the other and a woman to boot. In 1983,St. Jude Children’s Research Hospital inMemphis, Tennessee, recruited Sherr to headits new department in tumor cell biology andadded his new wife as a junior faculty mem-ber. “There weren’t many women scientiststhen,” says Sherr. “Every time she did something, they would say it wasmy work. There was an underlying prejudice because she was a woman.”

Roussel agrees that her path was a rocky one.“I was an appendage.I was there because they wanted Chuck. I didn’t like it, but there was notmuch I could do.”Sherr was also his wife’s department chair, which madedecisions about promotions and raises tricky at best. “I was the worstpaid,” says Roussel,“and Chuck didn’t want to promote me because hedidn’t want people to think he was favoring me.” He’s still her depart-ment chair, but now she reports to someone else.

As Sherr puts it,“I was her greatest supporter and her greatest obsta-cle. That ambiguity was always there. We’ve just handled it better thanmost people.”

Roussel faced other obstacles as well. She spoke little English whenthe pair met, and writing, whether in English or in French, was neverher strong suit. While presentations about oncogenes were difficult inFrench, they were terrifying in English. As Roussel struggled to masterthese professional skills, she found that she would soon need to mastera new skill, mothering. In 1985, she and Sherr had a son, Jonathan, andRoussel took three weeks of maternity leave—with unexpected results.Other scientists in the lab had taken over Roussel’s experiments in herabsence, so she was forced to develop projects independent of Sherr’s.Soon she began to get her own funding, which, in turn, led to promo-tion and independent recognition.

Today, both Sherr and Roussel are full members (the equivalent of

� Martine Roussel has worked

hard to step out of husband

ST

EV

E J

ON

ES

Science Schooling Marriage“You have to be rational in our profession, to see

the other side of things. That carries over. I consid-

er it a stroke of luck to have met a scientist.”

— Johann Deisenhofer, married to Kirsten Fischer

Lindahl, both HHMI investigators at the University

of Texas Southwestern Medical Center

Competition“We don’t nickel and dime who did what.”

— Philippa Marrack, married to John W. Kappler,

both HHMI investigators, National Jewish Medical

and Research Center, Denver

“People ask, ‘How do you feel when she wins so

many awards?’ I say, ‘I feel great.’” — Thomas A.

Steitz, married to Joan A. Steitz, both HHMI

investigators, Yale University

Collaboration“If you collaborate with another scientist, on

occasion, things can happen that poison the

relationship. But Helen and I have a large basket of

trust a priori that facilitates collaboration.”

— David Piwnica-Worms, director of the

Molecular Imaging Center, Washington University,

St. Louis, married to Helen M. Piwnica-Worms,

HHMI investigator, Washington University

Communication“Every so often John and I have a fight, but the

science trundles along.” — Philippa Marrack

“The good news is that couples who work together

are constantly communicating so issues can be

worked out immediately. The bad news is that

there’s opportunity for friction at almost any time.”

—Jonathan G. Seidman, HHMI investigator,

Harvard Medical School, married to Christine E.

Seidman, HHMI investigator, Brigham and

Women’s Hospital and Harvard Medical School

Shared Identities“People who don’t know you have trouble

separating you. They say, ‘Who’s the brains

there?’”— John W. Kappler

“Someone always wants to know who did it.

But science is not a solo act.”

— Christine E. Seidman

Boundaries “Our life is a seamless interface as we go back and

forth from office to home. It all blends together as

one big adventure.” — David Piwnica-Worms

Attraction“I don’t think it was the biochemistry that drew

me to her.”— Thomas A. Steitz

Marriage Under a MicroscopeFor a scientist married to another scientist, each sphere—work and home—inevitably affects, and

sometimes instructs, the other. Below, some HHMI investigators and their spouses offer their observations:


full professors) at St. Jude’s. Struggle is a verb they use in the past tense,although Roussel notes there is occasionally friction about who getscredit for what.“We have tough discussions. In science, you have to dis-cuss every fact, and the facts have to be right, and so you apply this toyour relationship as well. You learn how to speak up, to say what youthink, even if it’s not pleasant. But two strong people cannot be at thetop simultaneously all the time. You have to give in at some point.”

Sherr tells a revealing story. Roussel, a gardener, wanted a com-puterized watering system for their yard in East Memphis. Sherr balkedat the expense, the inevitable complications. But Roussel persisted. Everyday, says Sherr, she’d mention how nice a watering system would be.Finally, Sherr agreed to review some information, and Roussel calledfor quotes. Sherr grilled the contractors and settled on a system justhigh-tech enough to interest him. Suddenly he was a kid with a new toy,and she had a blossoming garden.With gardens or shared careers,“eachperson has to get something,” says Roussel.

Not all married scientists choose to cultivate their garden togeth-er, or at least not the same patch. hhmi investigators Eric Wieschausand Trudi Schüpbach, both molecular biologists at Princeton University,have drawn firmer lines between their careers than either the Jans orSherr and Roussel. Wieschaus and Schüpbach met in Zurich in 1975,as Schüpbach was completing graduate work and Wieschaus a post-doctoral fellowship. Initially, they published a few papers together, butwhen they arrived at Princeton in 1981, he as an assistant professor andshe as a nontenured research biologist, they set out on different researchpaths.Wieschaus studied embryo development in flies, and Schüpbachstudied oogenesis, or what happens in mother flies as eggs form.

“The lines were pretty clear between our research programs earlyon,” says Wieschaus. “We had to keep them distinct initially, in partbecause she didn’t have a professorship. It would not have been goodfor her to be seen as just another member of my group.”

By the mid-1980s, Schüpbach had funding for her own laboratory,and, as their professional identities became more distinct, they beganto tiptoe back together. Now Wieschaus’ lab is on the same floor asSchüpbach’s; they hold joint lab meetings, and postdoctoral stu-dents float between the labs to exchangeideas and information. “We confer oneach other’s projects,”says Schüpbach.“That’s one of the pleasures of beingin the same field. You can share littledaily triumphs—like when some-thing works or when someone findssomething out.And you can share yourdepression when the experiments didn’twork—for the fifth time.”

When people have their own successes, theycan gracefully share huge triumphs too, as Schüpbachdid when Wieschaus won the 1995 Nobel Prize inPhysiology or Medicine.“I knew how important the work was,so it was really gratifying to see it honored in that way,”says Schüpbach.“A lot of people working with flies were very happy. It validated the workwe’re doing.And I’ve never felt that I was toiling away, with no one notic-ing what I do. But I can imagine that if one were working very hard andno one was saying anything, it would be harder.”

Both Schüpbach and Wieschaus are quick to acknowledge theirambitions. Knowing what it takes to cross a scientific border helps them

to accept each other’s long hours in the lab and to share household tasks.Most days, Wieschaus rides home from the lab on his bicycle, thinkingabout what he’ll cook for dinner, while Schüpbach helps their 17-year-

old daughter, Laura, with homework.Wieschaus likes to cook,mostly because he knows the work will result in success—

a prediction less certain in a lab.When their three daughters (Ingrid, 27; Eleanor, 20

and Laura) were young, however, dreamy bike rideswere a luxury.“There was a lot of pressure on our timetrying to bring up the children, do the housework,”says

Schüpbach. “It was really important that both partnersequally respected each other’s work so that each one

would take on these other responsibilities. I never felt thatEric saw his work as more important than mine. When our

children were sick, for instance, we would check with eachother about who was doing what and who could take off work.

In science, in the middle of an experiment, you have to be thereor lose a lot of work.”

Being there, being supportive, being forthright—these themessurface again and again as couples dissect their collaborations. Thepoint is, good marriages make better science. The 19th-centurySpanish scientist Santiago Ramón y Cajal put it slightly differently. Theperfect spouse for a scientist can be “the helium that propels him sky-ward,” he wrote in his 1897 book Advice for a Young Investigator. “Andif fame should smile, its brilliance will surround the two foreheads witha single halo.” H

� Eric Wieschaus

does the cooking while

wife Trudi Schüpbach

oversees homework.

DA

VID

GR

AH

AM

“In science,you have to discuss

every fact, and the facts have to be right,

and so you applythis to your

relationship as well.”

M U S C L E C O N T R O L

A cross section of an

embryonic chick’s spinal cord

shows the nerve pathways taken

by a chick’s own motor neurons (red)

and by motor neurons derived from

mouse embryonic stem cells (green).

The transplanted mouse cells

performed as well as the

chick’s own cells.


JE

SS

EL

L L

AB

Stem cells—the precious and finicky immature cells that can grow intospecialized cells or renew themselves—are finally being harnessed. After yearsof research into how organisms develop from a fertilized egg into an adult andhow the earliest cells differentiate, a few teams of scientists are finding ways tomake stem cells do their bidding, at least in mice and other animals.

One team of scientists has coaxed mouse embryonic stem (ES) cells to grow intomotor neurons—the specialized nerve cells that control the movement of muscles. Whenthe team inserted these newly made motor neurons into a chick embryo’s spinal cord, theyfound that the neurons grew long extensions called axons and made contact with musclecells just as well as the embryo’s own motor neurons did. This extraordinary finding byhhmi investigator Thomas M. Jessell at Columbia University’s College of Physicians andSurgeons and his colleagues was given early publication online by Cell on July 17, 2002,and was published in the August 9 issue. It raised hopes that several incurable musclediseases, including amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’sdisease), as well as spinal cord injuries, might eventually be treated with such cells.

Along similar lines, Ron McKay and his team at the National Institute of NeurologicalDisorders and Stroke in Bethesda, Maryland, have successfully directed mouse ES cells tobecome neurons that release dopamine, the chemical lacking in Parkinson’s disease. Thescientists also showed that these neurons restore some aspects of mobility in a rat modelof Parkinson’s, a possible harbinger of more effective therapies for this common disease.

All stem cells are immature, unspecialized cells with great potential, but some aremore limited than others. ES cells—those derived from very early embryos—can becomeany type of cell in an organism and can renew themselves indefinitely. But adult stem cellshave already started on a particular pathway of differentiation. They can still generate avariety of cell types, but the choices are restricted.

hhmi investigators Allan C. Spradling, Sean J. Morrison and Mark T. Keating (seesidebar, page 26) and others are examining how adult stem cells might be made to treatdiseases. The therapeutic potential of adult stem cells is particularly important because ofcurrent U.S. restrictions on research involving human ES cells.

THE RIGHT SIGNALS For his systematic, decade-long study of how the nervous systemfunctions—“specifically, how different cell types in the vertebrate nervous system actuallybecome different”— Jessell relied initially on stem cells from embryonic neural tissue. Atfirst, he could not even tell these neural progenitor cells apart.“At the very early stages ofdevelopment, it’s impossible to recognize a motor neuron or a sensory neuron by its appear-ance,” he explains. But each class of neurons turns on a different set of genes. These genes areactivated by different sets of transcription factors, proteins whose signals turn on specific

A handful of researchers are making progress with mouseembryonic stem cells—connecting nerves to muscles andimproving mobility in animals. BY MAYA PINES

HealingConnections

genes in a cell’s nucleus. Because these factors could be recognized byspecific antibodies that were available to him, Jessell soon learned toidentify various types of neurons at their earliest stages.

While studying the early developmental signals that normallyproduce motor neurons, Jessell decided to find out whether “naïve EScells” could be converted into motor neurons by means of the samesignals. With great satisfaction, he now reports that the answer isyes—at least in mice. Hynek Wichterle, a Czech postdoctoral fellow inJessell’s lab, recently proved it in an experiment that “demonstratesone can learn from embryonic development and apply it directly toES cells. Just by exposing the mouse ES cells to developmentallyrelevant signals, we drove them to differentiate all the way to motorneurons.”

Wichterle notes that he had “a huge chunk of luck”: He managedto produce all these changes by using only two signals. One is retinoicacid, a product of vitamin A that binds to receptors in the nucleus.The other is Sonic hedgehog, the product of a gene that was firstidentified in developing fruit flies and that Jessell found expressed inthe mouse spinal cord, where it plays a critical role in thedifferentiation of motor neurons.

“There are three main steps that an ES cell needs to take in orderto become a motor neuron,” says Jessell. “The first is the ‘decision’ to

become a generic neural progenitor cell. The second is the decision tobecome a spinal cord progenitor cell. The third is the decision tobecome a particular progenitor cell that gives rise to a motor neuron.”The retinoids “are good at converting neural progenitor cells intospinal progenitor cells, and then hedgehog is good at convertingspinal progenitor cells into the kind of cells that are precursors of themotor neurons,” Jessell says. “Where we got lucky is with the first step.For some reason, ES cells tend to become nerve cells almost bydefault, as first suggested by hhmi investigator Douglas Melton (atHarvard University).”

The third step was not so simple, however, because differentconcentrations, or grades, of sonic hedgehog have different effects.“Hedgehog’s graded actions normally produce at least five differentclasses of neurons,” Jessell points out. “Typically, only 25–30 percentof the cells that emerge from exposure to sonic hedgehog are motorneurons. I think it’s going to be essentially impossible, in the contextof neural stem cells, ever to find situations where 100 percent of thegenerated cells are of one particular neuronal subtype.”

To get around this problem, he explains, “we used a genetic trick.Wichterle, together with postdoctoral fellow Ivo Lieberam, markedthe motor neurons with green fluorescent protein. Then by puttingall the cells through a fluorescence-activated cell sorter, we could

separate the fluorescent ones from the others and getessentially 100 percent purity.”

RATIONAL DESIGN Ultimately, Jessell is seekingprecision, control. He points to several clinical trials in whichpeople with Parkinson’s disease were treated with humancells that produce dopamine, “not of ES cell origin but offetal brain origin.” A few patients benefited from theseattempts, but some actually got worse. “That may be becausethe cells introduced into those patients were a heterogeneousmixture,” Jessell says. “It’s not surprising that the clinicaloutcome is variable if you cannot control the precise numberor proportion of dopamine-producing cells that you areputting in.”

Such control would be even more important in dealingwith other diseases, he believes. “In Parkinson’s, at least youknow that you really need dopamine-producing neurons,” hesays. “But in other diseases, it is not clear which cell type isneeded to reconstruct a circuit or prevent neuraldegeneration. In the context of ALS, for instance, do youwant to put in motor neurons or would you be better offwith spinal interneurons or glial cells, which normallysurround the motor neurons and may actually support thesurvival of the remaining ones?” Or, for that matter, shouldall classes of spinal cord cells be used?

Having a way to purify the appropriate cells “puts you ina position now where you can ask such questions,” Jessellsays. He is also pleased that “we have manipulated mouse EScells simply by exposing them to different environmental sig-nals—we have not changed the genetic makeup of the ES cellitself,” he says. While some other scientists introduce genesdirectly into the ES cell, “we have just added factors that weknow are involved in the normal developmental process andlet the ES cell do the rest.” As a result, Jessell has gained a tool

D I R EC T I V E S IG N A LS Thomas Jessell can turn mouse ES cells into motor neurons.

MA

RC

BR

YA

N-B

RO

WN


that might eventually be used with humanES cells as well.

“If we wanted to apply this strategy now toa human ES cell, we could simply take the same

factors,” Jessell says. “It turns out that the two factors we use—Sonichedgehog and retinoic acid—cross species barriers. Furthermore,one of our collaborators, Jeff Porter at Curis, in Cambridge,

Massachusetts, has identified a small molecule that acti-vates the hedgehog pathway, so we can now direct EScells to become motor neurons simply with small,synthetic chemicals. You don’t even need mysteryfactors anymore.”

Eager to test whether the neurons they grew frommouse ES cells were functional motor neurons, Wichterledecided to put them into live chick embryos. Why chicks?“Because their embryos grow in eggs rather than wombs,”Jessell explains. This makes it much easier to gain accessto the neural tube and “introduce the ES cell-derivedmotor neurons into the spinal cord at exactly the sametime that the host motor neurons are being generated.” Ina sense, Jessell says, “we are giving the ES cell-derivedmotor neuron an even chance.”

The scientists found that “even in this completely dif-ferent host species, the ES cell-derived motor neurons

settle in the right place in the spinal cord, extend axons out and formdifferentiated synapses with target muscle” over the same time courseas the chick’s own motor neurons. In fact, Jessell says, “it was a deadheat.” The fluorescent green markers continued to function, so hecould follow the path of the ES cell-derived motor neurons.

His team has already started to explore whether human ES cellswill behave in the same way. “We are collaborating with a group of

Douglas A. Melton, an hhmi investi-gator at Harvard University, isexploring what gives stem cells theirspecial abilities—what accounts for

their “stemness.” And he has found hundredsof genes likely to play a role.

Together with his colleague Richard C.Mulligan and other Harvard associates, Meltoncompared the activity of the three best-knowntypes of stem cells—embryonic, neural andhematopoietic (blood-forming)—with theactivity of other types of mouse cells. Theresearchers discovered that 216 genes wereturned on at least three times more frequentlyin the stem cells than in other cells.“These 216genes are likely to reveal core stem cellproperties, or ‘stemness,’ that underlie self-renewal and the ability to generate differentiat-ed progeny,” they reported in the September12, 2002, issue of Science Express.

When the scientists tried to find outwhere these 216 genes were located, theywere surprised to learn that only 60 of themhad been mapped to any chromosome. Anastounding fraction of these latter genes—12out of 60—sat on mouse chromosome 17,which also contains genes known to be

involved in embryo development and insperm development. The 12, of course, willnow be studied with special interest.

Another surprise was that the stem cellsexpressed unusually large numbers of“expressed sequence tags,” which mark genesof unknown function. “For young scientists,this finding is especially exciting because itshows that … no one has a clue to what thegene products do,” says Melton. “It’s easily adecade’s worth of work just to define thefunctions of the genes that we have definedas characteristically active in these stem cells.”

Although all stem cells expressed the 216genes, they did so in varyingproportions.“The threetypes of stem cells were notidentical” in their activity,Melton points out. The activ-ity of hematopoietic stemcells was more similar to thatof other cells in the bonemarrow than to the activityof any other samples, he says.By contrast,“embryonic stemcells and neural stem cells aremuch more similar to each

other than they are to their differentiatedcounterparts … This fits with a ‘default’ modelwe proposed, which is that the default fate ofembryonic stem cells is to become neurons.”

The team’s studies are likely to aid thesearch for new types of stem cells, Meltonbelieves. “For example, nobody has yet beenable to identify adult pancreatic stem cells—acentral effort in our laboratory,” he says. “Butnow we know that if we’re going to isolatesuch cells, we should look for those thatexpress many of these ‘stemness’ genes.”

Melton is motivated by more thanscientific curiosity. Hoping to find a cure for

his 10-year-old son, Sam,and millions of others withtype 1 (juvenile) diabetes, helaunched a major driveabout a decade ago to turnhuman embryonic stem cellsinto the special kind ofpancreatic cells, called betacells, that supply the insulindiabetics lack. This effort hasbeen slow going, he reports,but it did lead him to hisstemness discoveries. —M.P.

EASY TRACKING

After implantation into

the spinal cord of a chick

embryo, motor neurons that

were derived from mouse

ES cells can be recognized

by their green

fluorescence.

Discovering the Genes for “Stemness”

MELTON

JE

SS

EL

L L

AB

KA

TH

LE

EN

DO

OH

ER


For the past six years, Mark T. Keatinghas been trying to figure out whyhumans and other mammals wholose a limb or an organ can’t do what

salamanders, worms and fish do in suchcases: grow a new one. In mammals, cells thattry to repair an injury just form a layer ofuseless scar tissue over it. But in newts, thecells that swarm over a fresh wound rapidlyturn into a layer of stem cells that effect acomplete repair.

Keating, an hhmi investigator atChildren’s Hospital in Boston, now believesthis is the standard way that many animalsregrow lost or damaged body parts. First,the wounds stimulate some mature cells torevert to their infancy as primitive stemcells, or “dedifferentiate”; then these cells arereprogrammed to form new tissue ororgans. Certain genes are turned onto start both operations.According to Keating,“humans probably still havethe genes that enable otheranimals to regenerate tissue,but these genes weresilenced, turned off” duringevolution. Therefore, theymight be turned on again,given the right stimulus.

Keating and his colleagues identi-fied their first such gene, msx-1, severalyears ago while doing research onhuman heart disease at the Universityof Utah. They discovered that msx-1

turns on in newts whenever these animals needa replacement part. Mice have a similar msx-1gene, and the scientists found a way to turn onthis gene at will in mouse muscle cells.

Next, Keating, who had moved toChildren’s and Harvard Medical School bythen, used a different stimulus—an extract ofregenerating limb tissue collected from newtsafter their forelimbs had been amputated.This extract worked wonders on mouse mus-cle cells, making about 18 percent of themdedifferentiate and reenter the cell cycle—notvery much less than the 25 percent of newtmuscle cells that did the same. In their reporton this work, Christopher J. McGann andShannon J. Odelberg (both at the Universityof Utah) and Keating wrote that these studies“indicate that mammalian cells have retained

the intracellular signaling pathwaysrequired for dedifferentiation”

and that the primaryobstacle to regeneration

in mammals may bethe lack of signals to

start the process.More recently, Keating and his associates

compared how zebrafish and mammals reactto heart injury. They found that zebrafishregenerate heart muscle with little scarring.However, other vertebrates respond byproducing large connective-tissue scars. Theresearchers then proposed that “scarring andregeneration compete” and that the vigor ofeach process is critical. In normal zebrafishwith heart injury, for instance, a fibrin clotformed, but cardiac muscle fibers “invariablypenetrated the clot and constructed a bridgeof new muscle around the wound.” Bycontrast, zebrafish with a mutation thatimpairs cell division produced fewer musclecells and ended up with big scars. Theresearchers now believe that stimulatingheart muscle cells to proliferate, in responseto the proper genetic signals, “will reduce scarformation and facilitate cardiac regenerationin mammals as well.” Keating adds, however,that “it’ll be a while before anything of thissort is tried in humans.” —M.P.

scientists in Israel [led by Nissim Benvenisty of the HebrewUniversity in Jerusalem] who have experience in turning human EScells into neurons,” Jessell says. The goal, he says, is “to find outwhether you can efficiently convert human ES cells into humanmotor neurons.”

If so, “one could really start to evaluate whether this would be asensible way of approaching ALS, spinal muscular atrophy or spinalcord injuries,” Jessell says. But he warns that there are big hurdlesahead. “The motor system relies heavily on the precision ofconnections and circuits. Simply having generated a motor neuron isnot sufficient. I think the challenge will be to reconstruct appropriatecircuits,” he declares. Partly for this reason, Jessell is now studying thenext steps in the differentiation of motor neurons.

To help develop new therapies, Jessell has also started tocollaborate with neurologists who are doing research on ALS as wellas other spinal cord disorders and injuries. “There are many groups

interested in cell-based treatments of diseases like ALS,” he says,“but one of the difficulties in comparing results is that most peoplehave been using different cells in different systems. If we cangenerate motor neurons under fairly standardized conditions, wecan provide them to anyone who is interested, and it will be easierto compare their results.”

Jessell is working particularly closely with Robert Brown, directorof the Neuromuscular Disorders Unit at Massachusetts GeneralHospital. “Bob Brown is a world expert on ALS,” Jessell says, “and hehas mouse models of ALS. It will be interesting to test whetherintroducing motor neurons derived from mouse ES cells in thesemodels actually does any good.”

The two research teams are also investigating the basic cause ofALS. A gene whose mutation is known to result in ALS in humans isthe gene for an enzyme called superoxide dismutase 1, or SOD1.Brown uses a mouse model of ALS engineered with the same

Will Humans Generate Replacement Parts?

F O L L O W T H E N E W T

When a newt's limb is

amputated, mature cells near

the injury dedifferentiate and

become stem cells. After forming

a mound and multiplying, the

cells redifferentiate to rebuild the

limb—all in about 40 days.

Mid LateAmputation Early Early differentiation differentiationand wound bud differentiation

healing

Complete regeneration

SOURCE: DEPARTMENT OF ZOOLOGY, UNIVERSITY OF GUELPH, ONTARIO, CANADA


H

mutation, with resultant motorneuron degeneration. Yet “nobodyknows why motor neurons areselectively vulnerable to death inALS,” Jessell points out. He hopes todiscover the answer by comparingmotor neurons that are derivedfrom normal ES cells to motor neu-rons derived from ES cells bearingthe SOD1 mutation.“Then we canask what has changed, biochemical-ly, that might be a predictor of thelater degeneration of the motorneurons,” he says.

Scientists who work with stemcells are finding it difficult tochoose among the many differentresearch paths now opening up—and finding it particularlychallenging to work with humanES cells. Although all mouse EScell lines “behave in a ratheruniform way, that may not be true in human EScells,” Jessell says. Yet researchers may have a hardtime finding out. Most of them rely on federalfunds, which can be used to study only a limitednumber of human ES cell lines. And as Jessell pointsout, “human ES cell lines are so poorly characterized,compared to many of their mouse counterparts, that nobody actual-ly knows how much they vary and whether the full range of develop-mental potentials is going to be offered in those lines that now havefederal approval.”

WHAT ABOUT ADULT STEM CELLS? The researchers who havechosen to work with adult stem cells face other problems. In manytissues, adult stem cells are relatively unexplored and still full ofsurprises. They become most active when tissues wear out or aredamaged, yet they are often hard to find. Besides the nervous system,researchers are looking at blood, skin, nails, hair, saliva and spermcells—where the need for replacement is particularly obvious.

Allan C. Spradling, an hhmi investigator at the CarnegieInstitution of Washington in Baltimore, Maryland, has focused onwhat he calls niches, special microenvironments in various organssuch as the skin, gut and gonads. Each niche houses one or moreadult stem cells and regulates their activity. His team has identifiedthree types of regulatory cells that form such niches and keep thestem cells from differentiating prematurely.

The strongest evidence for such regulation in mammaliantissue probably comes from studies of spermatogenesis, Spradlingsays. Thousands of stem cell niches have been found lining thewalls of the seminiferous tubules in which sperm develop.Spradling has focused on the niches that surround germline stemcells in fruit flies and on the signals they send to the stem cells.Such signals appear to have a powerful influence on the behavior ofadjacent stem cells, he says. By comparison, the stem cells “maythemselves be relatively unspecialized.” Therefore, the environment

of stem cells will have to be controlled with careif one hopes to use them in some form of

therapy.More data on the complexity of using adult stem

cells comes from Sean J. Morrison, an hhmi investigatorat the University of Michigan, who found that the properties

of some adult stem cells were quite different from those of embryonicor fetal stem cells. Morrison managed to isolate “neural crest” stemcells from the gut tissue of adult rats, even though such stem cells(which give rise to various tissues, including the peripheral nervoussystem) were supposed to exist only in the embryo and fetus. Then heeither cultured them or transplanted them into chick embryos tostudy their activity. It turned out that these adult stem cells could dosome of the same things as embryonic and fetal stem cells but not oth-ers; for example, they could not differentiate into cells that make twoimportant neurotransmitters, serotonin and noradrenaline.

Morrison also found that neural crest stem cells he had isolatedfrom the gut of rat fetuses differed from those that came from the sci-atic nerve. After transplanting cells from both sources into thedeveloping nerves of chick embryos, Morrison discovered that stemcells from the gut produced mainly neurons, whereas those from thesciatic nerve made only glial cells, a type of supporting cell. This find-ing, he says, “suggests that it’s really important to match the origin ofthe stem cell to the therapeutic job that you’re trying to do.”

“There is a great debate in the field of regenerative medicine as towhether one should start with ES cells or with adult stem cells,” Jessellsays. “Many groups are trying to get adult neural progenitors todifferentiate into particular cell types. Our study shows very clearlythat a mouse ES cell can become a motor neuron in a very predictableway, but so far, no one has shown that an adult neural progenitor cellcan become a motor neuron.”

“I think the potential of adult progenitor cells is exciting,” Jesselladds, “but in my view, the evidence that they perform as well as theirembryonic counterparts is not strong at the moment.”

R I G H T C E L L

F O R T H E J O B

Sean Morrison's team cultured

these smooth muscle cells from

neural crest stem cells of an adult rat.

They found the activity of the stem

cells differed depending on their

origin, pointing to the importance

of matching the cell to the

therapeutic goal.

MO

RR

ISO

N L

AB

It is considered unacceptable for any adult American to beunable to read or to be ignorant of important political andeconomic issues. But the same cannot be said of scientific lit-eracy. In our society, even well-educated and productive citi-zens and policymakers often lack a basic understanding of

science. Tens of millions of Americans do not grasp even funda-mental scientific concepts—such as the difference between virusesand bacteria or between a protein and DNA—and too little is being done about it.

I believe the scientific community has aresponsibility—and an excellent opportuni-ty—to help improve K–12 science education,which is clearly in need of reform. Our respon-sibility lies not only in preparing high schoolgraduates to enter scientific careers but, morebroadly, in educating them to become scientif-ically literate citizens.

It is on the shoulders of primary and sec-ondary schools to teach rudimentary scientificconcepts, and rightfully so. Why should weexpect our colleges to explain to enteringfreshmen the phases of the moon, basic prop-erties of matter or fundamental concepts ofhuman physiology? These topics are well with-in the developmental capacity of young stu-dents and are best taught during early stages ofcognitive development, instilling a solid conceptual basis for under-standing the physical and biological world.

Unfortunately, the K–12 system as presently constituted is notalways able to handle the challenge. Despite past setbacks, however,I strongly believe that public schools are more than capable of pro-viding their students with an excellent grounding in science, and Isuggest that collaborations between professional educators and sci-entists are an excellent way to begin helping them to succeed.

Many capable educators, and now the law itself, support theestablishment of direct and meaningful partnerships. Most stateshave implemented science standards, and the recently enacted NoChild Left Behind Act of 2001 stipulates that by 2007 every stateinclude in its accountability reporting the results of student testsassessing proficiency in science. Just as important, specific language

in title II of the act encourages the establishment of partnershipsbetween universities and public schools to improve math and sci-ence education, and provides funding to do so.

Within this new environment, two broad strategies promise sci-entists opportunities for exerting the greatest influence: (1) playinga role in integrating the “science experience” into teacher prepara-tion, professional development and interactions with K–12 students

and (2) establishing working partnershipswith public school teachers and administra-tors in science curriculum development.

the science experience Thinking scientifically can be likened to driv-ing a car. If we had to think about each indi-vidual step, it would be difficult to get any-where. Instead, through practice, we intuitive-ly and fluidly proceed through the steps ofdriving. This “behind the wheel” experience isessential. Rules for driving are described inmanuals and tested by official written exams,but no state waives the road test. Similarly,scientific facts are found in books, learnedfrom lectures and tested by multiple-choiceexams, but the ability to think scientificallycomes only through practice. The mission ofscience education ultimately should be to

instill, through actual experience, a working familiarity with theprocesses of scientific thinking and problem solving. Once thatfamiliarity is achieved, the understanding of scientific facts andconcepts becomes almost instinctive.

Because most educators, including many science educators, havenot themselves practiced science, it is difficult for them to teach theirstudents or other teachers to think scientifically. Reaching teachers inthis manner necessitates the direct involvement of scientists in theplanning and delivery of teacher “in-service” training programs.

Scientists can begin by contacting the superintendent of theirlocal school district to get involved. If established programs do notexist in the district to facilitate partnerships (which is likely to bethe case), then such a program must be initiated. Models of success-ful programs can be obtained through Internet searches. Look forcontact information and communicate directly with the scientistsinvolved in these programs.


P E R S P E C T I V E

Transcending the Status QuoScientists and school educators need to join forces to raise student proficiency in science.

By Keith Verner

Keith Verner is chief of developmental pediatrics and learning at The PennsylvaniaState University College of Medicine, Hershey, Pennsylvania.

KE

NN

ET

H S

MIT

H/P

SU

Partnership programs can be as simple as summer employmentor sabbatical arrangements that involve individual teachers directlyin research laboratory projects. More ambitious and comprehensiveplanning can establish workshops and institutes involving largenumbers of teachers. The work should focus on scientific contentand concepts as well as hands-on experimentation—componentsoften unavailable to teachers in their classrooms and in other pro-fessional development programs.

To this end, a group of us in Pennsylvania has worked to estab-lish the Governor’s Institute for Life Science Educators. It is anintensive in-residence program at the Penn State College ofMedicine attended each summer by one hundred K–12 teachers.They spend their mornings in activity-based, content-rich grouplessons that begin on Monday with the dissection of a humancadaver and become more “molecular” as the week progresses, inte-grating biochemistry and biophysics. Afternoon and evening ses-sions are devoted to grade level-specific content and lesson plans, aswell as effective teaching strategies. Teachers genuinely value thisexperience, and the testing of participants’ content knowledgebefore and after the program has established its success. The key, wefind, is that if teachers clearly see how their students will benefit,they will become committed to the process.

There are other opportunities. What better time to foster scien-tific thinking than during a future teacher’s university training,when he or she resides on the same campus as practicing scientists,postdocs and science graduate students? For the scientist whoseinstitution includes a college of education, the first step is to contactthe administrative office and initiate collaboration between the col-leges. In addition, scientists should instill in their own students theimportance of excellent K–12 science education and discuss careerchoices that may lead them into the classroom.

Scientists also can bring the experience of science directly tostudents by providing summer or after-school projects or employ-ment for talented high school science students. Such early opportu-nities have pointed both medical and graduate students I knowtoward science careers. Direct interaction with students in K–12classrooms is also important, provided these occasions transcendfamiliar “show-and-tell” and “career day” formats and become inte-gral to the science curriculum. Meaningful collaborations must bebased on national and state science standards and have clearlydefined and measurable outcomes, such as performance on stan-dardized state science tests.

theory and practiceTo design hands-on instruction that is properly integrated with thecurriculum requires an interweaving of scientists’ deep contentexpertise with educators’ real-life classroom practice. This was thevision that guided us over the past decade in utilizing teams of sci-entists and public school educators at the College of Medicine tocreate the LabLion elementary school science program (lablion.org).

LabLion is designed to address national and state science stan-dards and provide an overall framework for understanding broadscientific concepts. This comprehensive K–6 program includes theestablishment of a fully equipped lab in the elementary school, acompletely “hands-on” curriculum, teacher professional develop-ment and creation of community outreach programs. All directlylink scientists to the curriculum. LabLion reaches more than25,000 elementary school students across Pennsylvania, and wehave recently made plans for its dissemination elsewhere in thecountry, where it will be known as LabLearner. We need suchblends of theory and classroom activity within every subdisciplineand every level of science education.

Failing to educate our public school students in science has far-reaching consequences, not the least of which includes risking ourability to maintain a competitive edge in an ever-increasingly tech-nology-based economy.

We do not have to stop being scientists in order to play a signifi-cant role in K–12 education. At the same time, the basic educationcommunity deserves much more than part-time partnerships andpromises. We scientists cannot back away once the novelty or com-munity spirit wears off.

The time is right. If we genuinely commit to educating our youngstudents, we stand to make a major and lasting contribution to thefuture of science education—and, inevitably, to the future of scienceitself. If we do not, I believe we lose the right to criticize our system ofearly science education; we will have to live with the knowledge thatwe failed to seize an opportunity for meaningful change.


H

JO

HN

BIO

ND

O/P

SU

LabLion students at Harrisburg’s Marshall Elementary School study anatomy.


N E W S & N O T E S

Aseries of recent discoveries mayexplain why malignant melanoma ismuch deadlier and harder to treat

than many other cancers. The findings,published in the journal Cell by a team thatincludes several hhmi fellows and investi-gators, have important implications for thedevelopment of new drugs that might bringmelanoma under control.

Melanoma occurs when melanocytes,which are normally stable, begin to divide.Melanocytes provide fair-skinned people withdefense against sun damage. When exposed toultraviolet (UV) rays, melanocytes manufac-ture melanin, giving the skin a tanned appear-ance. Repeated or prolonged UV exposure,however, can damage the genetic material ofmelanocytes, causing them to divide uncon-trollably and give rise to malignant melanoma.

Melanocytes that have become malig-nant are notoriously difficult to kill. Statis-tics from the American Cancer Society bearthis out: While melanomas account for only4 percent of the 1 million new skin cancercases diagnosed in the United States annual-ly, they account for 80 percent of all skincancer deaths.

What makes melanoma so tough? Thekey, reasoned hhmi predoctoral fellow GaëlG. McGill at Dana-Farber Cancer Instituteand a team of investigators, lies in whatmakes melanocytes special in the first place.Over eons of evolutionary time, melanocytesdeveloped the ability to withstand andrespond to assaults such as exposure to UVradiation that would cause other types ofcells to undergo genetically programmed celldeath, or apoptosis. “Triggers that kill othercells don’t kill melanocytes,” McGill explains.“These are cells that must have evolved a

A team including Gaël McGill (left) and David Fisher (right) has found a master switch for melanoma.

particular resistance to apoptosis.”The aim of many cancer therapies is to

induce apoptosis in malignant cells; itstands to reason, therefore, that cells withspecial resistance to apoptosis will notrespond to these types of treatments.According to David E. Fisher, a formerhhmi postdoc who is now an associateprofessor at Harvard Medical School andDana-Farber Cancer Institute, “while a con-nection between pigmentation and survivalis probably beneficial for normal pigmentcell function, the flip side is that it may con-fer super survival properties and impedesuccessful therapy” once a pigment cellbecomes malignant.

Fisher, McGill and a team in Fisher’s labhave devoted themselves to discovering theprecise genetic processes within melanocytesthat confer their resistance to cell death. Theteam, which includes hhmi predoc

Gabriela Motyckova and postdoc MartinHorstmann, the Cell paper’s co-lead author,has also performed experiments suggestingnovel ways of rendering malignant versionsof the cells susceptible to apoptosis.

The researchers discovered that stimula-tion of a transcription factor called MITFupregulates the expression of the Bcl-2 gene.In a large body of earlier work, team mem-ber Stanley J. Korsmeyer, an hhmi investi-gator then at Washington University in St.Louis and now at Harvard and Dana-Far-ber, and other scientists had demonstratedthat Bcl-2 is a potent cell-death suppressor.Fisher and others had also characterized thebiochemical and functional properties ofMITF, determining that it is a “master regu-lator” of the process by which melanocytesdevelop. When either MITF or Bcl-2 aremutated or missing, black mice turn graydue to the death of melanocytes.

A Chink inMelanoma’sGenetic Armor

JA

SO

N G

RO

W

The third author on The EMBO Jour-nal paper reporting this effort was M.D.-Ph.D. student Abhijit A. Patel. “Joan andAbhi were great,” McCarthy says. “Abhimade me feel at home and took the time toexplain how experiments worked. Theydidn’t treat me as a jock or a dim under-graduate—they treated me as a fellowresearcher.” Then again, McCarthy earnedsuch treatment. “Never before in 31 yearsof teaching at Yale have I had an under-

graduate work in the lab for as


In collaboration with Todd R. Golub, anhhmi investigator at the Whitehead/Massa-chusetts Institute of Technology Center forGenome Research and Dana-Farber, the teamhas used DNA microarrays to demonstratethat in human tumors, the expression of thecell-death suppressor Bcl-2 is tightly linked toMITF. These experiments reveal that the linkis present in both normal melanocytes and inmalignant melanoma cells. Specifically, whenMITF is present, the researchers haveobserved a rise in the amount of BCL-2 pro-tein and suppression of apoptosis.

The results reported in the Cell paper alsodescribe attempts by McGill and his collabo-rators to inhibit the activity of MITF in nor-mal and malignant cells. Blocking MITF byinfecting the cells with genetically engineeredadenoviruses, they succeeded in killing bothhealthy and cancerous melanocytes. At thesame time, they demonstrated that theprocess works in reverse; cells in which theBcl-2 gene was naturally overexpressed wereable to survive the researchers’ attempts toinduce apoptosis by blocking MITF.

Now that a link has been establishedbetween MITF and Bcl-2, some researchersbelieve that a new chapter in melanomaresearch—and skin biology in general—hasbeen opened. The team’s findings “really fillan important gap of knowledge,” saysMeenhard Herlyn, a researcher at The Wis-tar Institute in Philadelphia who studies themechanisms behind the transformation ofmelanocytes into melanoma.

Earlier research showing that Bcl-2 is asuppressor of cell death has already inspireddrug developers to conduct clinical trialswith agents that seek to shut down the genein cancer cells. McGill points out, however,that because Bcl-2 is expressed in every cellof the body, drugs that inhibit it could giverise to unwanted side effects. MITF, howev-er, is present only in melanocytes and a verylimited number of other cell types.

Researchers in the Fisher lab are workingto find agents that block MITF or interferewith its interaction with Bcl-2 expression.These would have potential as targeted thera-pies for malignant melanoma. The task, saysFisher, is to “understand where within thepathway [between MITF and Bcl-2] theremight be drugable targets.”

—CAMILLE MOJICA REY

On June 4, 2002, Matthew McCarthy, anew graduate of Yale University whohad majored in molecular biophysics

and biochemistry, was drafted by baseball’sAnaheim Angels for its farm-team system,step one for players with major-leaguepromise. A month later, while the leftypitcher was perfecting his curve ball inProvo, Utah, his first scientific paper waspublished in The EMBO (European Molec-ular Biology Organization) Journal.

Baseball was McCarthy’s ticket toscience. In 1998, the Orlando highschool pitching star visited NewHaven and was sold on Yale aftermeeting baseball coach John Stuper,who had pitched the St. Louis Car-dinals to victory in game six of the1982 World Series, enabling themto play and win game sevenagainst the Milwaukee Brewers.

McCarthy eventually took abiochemistry course taught byhhmi investigator Joan A.Steitz. I didn’t have a passion forscience, or biochemistry, until Itook Joan’s course,” McCarthyrecalls. “It was the best courseI took at Yale. She’s top-notchas a professor and aresearcher. And she was thennice enough to give me achance in her lab.” WhenMcCarthy asked if he couldperform original researchin the summer of 2001, he applied for and received an hhmi summerundergraduate research fellowship. He start-ed working in the Steitz lab immediatelyafter the baseball season.

McCarthy studied gene expression as afunction of two different entities that spliceout portions of RNA so that it can get trans-lated into the correct proteins—the U2-dependent spliceosome and the U12-dependent spliceosome. He helped showthat the U12 is much less efficient than themore common U2. The guess is that U2probably gets sent up to bat when feedbackloops in the cell determine that less proteinshould be produced.

Matthew McCarthy’s baseball card lists his

earned run average, strikeouts and other stats,

but no mention of his published scientific paper.

Baseball’s Biochemist

short a period as six months and trulydeserve coauthorship,” says Steitz.

While such praise is heartfelt, Steitzadmits to having a soft spot for ballplayers.She and her husband, fellow Yale facultymember and hhmi investigator ThomasA. Steitz, are the parents of another recentYale molecular biophysics and biochem-istry graduate and pitcher, Jon, a top draft


N E W S & N O T E S

Christina Langbecker’s 3rd-grade socialstudies class at the Side by Side Com-munity School of South Norwalk,

Connecticut, is preparing for a field trip tothe nearby shore. But first, they have to findtheir way.

With compass and city map, the stu-dents chart their course to the local beach,where each is responsible for finding an ani-mal—a blue crab or an oyster, for exam-ple—in its natural environment. Some stu-dents search the sandy shore while othersinvestigate a rock jetty or a salt marsh—thethree major habitats of the Long IslandSound. They are trying to understand whysome animals prefer one kind of home andothers favor entirely different conditions.

Why study marine science in a socialstudies class? Because, as the students dis-cover, the ecology of Long Island Sound and

its various types of marine life and habitatare intricately linked with the history of thepeople who live and work there. Oyster har-vesting, for example, is a centuries-old wayof life along the Connecticut coast.

“This is like the Berlitz Method of learn-ing science: total immersion,” says Marie Ian-nazzi, interim director of the Side by Sideschool. After Langbecker’s 3rd-graders finishtheir marine-animal scavenger hunt, forexample, they discuss the relationshipsbetween the plants and animals of the soundand their habitats, they compare animals inthe aquarium and those in their natural envi-ronments, they investigate the kinds of indus-tries along the shore and how they mightaffect marine life and they design and carryout experiments. The students also paintmurals of the sound’s plants and animals.

At the end of their projects, each 3rd-

pick by Milwaukee in 2001 and currentlyin the Brewers’ minor-league system. CraigBreslow, yet another student in the sameprogram, also became a Brewers’ farm-hand. (Apparently, understanding the bio-chemistry of anabolic steroids actuallybeats taking them.)

Most people probably don’t think ofYale as a brimming source of baseball talent,but 17 players have signed professional con-tracts since Stuper took over the team in1993. Going back further, major leaguersfrom Yale include pitcher Ron Darling, amember of the 1986 World Series-winningNew York Mets, and original 1962 Metsplayer Ken MacKenzie, who returned to Yaleto coach baseball in 1969.

Although fans may assume that profes-sional ballplayers are all millionaires travel-ing to games in private jets, the minorleagues are called the “bus” leagues for a rea-son. “We traveled 17 hours to play a team inCanada and 14 hours to get to Billings[Montana],” McCarthy says. “We have 12-hour days—running, lifting weights, playingthe games. It’s definitely not as glamorous asyou’d think. We stay in lots of crummymotels. But we are playing baseball for a liv-ing, and that’s great.”

While McCarthy is on the road, theAngels organization is focused on refininghis talent. “They’re making mechanicaladjustments in my delivery, so my velocity isdown a bit and at times it’s hard to hit spots,especially when facing good competitionlike Prince Fielder.” Fielder’s dad is formermajor-league slugger Cecil Fielder, a geneticlegacy McCarthy and his biochemistry bud-dies can no doubt appreciate more thanmost other minor leaguers.

Despite McCarthy’s athletic promise, “Ipredict that Matt will leave his mark in thefield of medicine,” Joan Steitz wrote in a ref-erence letter for McCarthy. The 22-year-old’s experiment with baseball, however,will make medicine wait. He’s put off apply-ing to medical schools. First, he hopes tomove up the Angels’ minor-league ladder in2003 and play for the Cedar Rapids Kernels.

Dwight Gooden was called “Doc”when he pitched for the Mets. Perhapspitcher Matthew McCarthy will take themound one day having truly earned thenickname. —STEVE MIRSKY

Aquariums Teach Ecology and Local History

Rick Sigmund, an educator at Norwalk, Connecticut’s Maritime Aquarium, helps 3rd graders from the

Side by Side Community School explore local marine life at nearby Calf Pasture Park.


grader produces a written report and pres-ents his or her findings to an audience ofpeers and parents. “The students exhibit afirm grasp of marine science and its impli-cations,” says Iannazzi.

These Side by Side student activities arepart of a new program, called Project alta(All Living Things Adapt), designed by sci-ence educators at the school and at the Mar-itime Aquarium in Norwalk, with supportfrom hhmi. Project alta weaves science—and the scientific method—into the school’ssocial studies curricula from kindergartenthrough 8th grade. The goal is to show stu-dents how science pervades their lives.

Across the country, other aquariumshave helped develop similar projects withhhmi support. The National Aquarium inBaltimore, Maryland, and 10 of the city’spublic schools created “AquaPartners” for4th- and 5th-grade students and teachers tostudy the Chesapeake Bay and its marine life.The New Jersey State Aquarium aims toboost minority participation in the scienceworkforce by providing summer sciencecamps, an after-school ecology club and ahigh school “junior staff” program to localstudents. Sound Science, a program devel-

oped by the Seattle Aquarium withSeattle Public Schools, uses themarine life and habitats of thePuget Sound to teach science toschool children.

Each aquarium program pro-vides teachers with course materi-als and exposure to the mostrecent discoveries, often throughhands-on participation inresearch. Teachers also participatein workshops, laboratory studiesand field excursions.

The programs, most of whichbegan in 2001, are in the processof being independently evaluatedby experts in learning. But, JackSchneider, director of education atthe Maritime Aquarium in Nor-walk, knows the programs work.He sees the excitement of learning,he says, by “the enthusiasm of thestudents, the pride and compe-tence of the teachers and the lookson the parents’ faces.”

—TRENT STOCKTON

EPA Agrees toSmarter WasteManagement

The U.S. Environmental ProtectionAgency (epa) has endorsed two keyrecommendations of an hhmi-led

initiative to make the handling of hazardouswaste from university laboratories less bur-densome and more effective. The changesshould enable universities to reduce their vol-ume of hazardous waste, increase recyclingand more efficiently handle waste removal.

In an August 2002 memorandum to itsregional offices, the epa stated that central-ized university health and safety offices canassume the responsibility of handling haz-ardous wastes in accordance with epa regu-lations. This approach would supplantholding individual laboratories responsi-ble—the standard in some regions of thecountry. The epa also stated that universi-ties can treat some waste on-site to cutdown on volume and toxicity.

These changes address problems stem-ming from enforcement of hazardous-wastestandards, in place since 1981, that weredesigned to regulate chemical manufactur-ing plants that create large quantities ofwaste. These same rules also applied to uni-versity research laboratories, which tend togenerate small quantities of waste, thoughfrom an ever-shifting panoply of chemicals.

Inconsistent interpreta-tion of epa rules fromregion to region promptedhhmi’s Office of LaboratorySafety in 1999 to assemble ateam of environmentalhealth and safety directorsand regional and nationalepa representatives to try toeffect change (see hhmiBulletin, December 2001).The group formulated “bestpractices” for handling haz-ardous waste and put itsideas into action at 10 partic-ipating universities.

In October 2001, thegroup issued a report urging

the epa to adopt the performance-basedstandards developed by the team and to“promote conformity and consistencyamong epa regional offices and state envi-ronmental-protection agencies” in applyinghazardous-waste regulations.

The August 2002 epa memo, while aseemingly small step, will make a huge dif-ference in the day-to-day operations ofuniversity research laboratories, says W.Emmett Barkley, director of hhmi’s Officeof Laboratory Safety. With overall disposalshifted to trained university waste-manage-ment officers who handle the waste streamfor the entire institution, each lab nolonger needs to do its own labeling andclassification of hazardous waste, nor navi-gate the sea of paperwork necessary forepa compliance. It also means labs havemore flexibility to adopt effective pro-grams, such as trading in unused chemicalsrather than sending them to hazardous-waste facilities.

“The memorandum validates whatsome universities are already doing,” saysBarkley. “We expect that many of theremainder of the large research universitieswill now adopt the performance-basedapproach outlined in our report.” The epais considering additional actions to addressother recommendations made in thegroup’s report, Barkley added.

“The epa has enunciated an approachto regulating hazardous wastes in the uni-versity laboratory that recognizes theunique culture of an academic research

organization,” says RobertR. Rich, immediate pastpresident of the Federationof American Societies forExperimental Biology,which had joined withhhmi in urging changes inwaste handling. “This col-laboration has proved thatacademia and governmentcan successfully and cre-atively partner to increaseefficiency, environmentalhealth and safety.”

—KARYN HEDE

» The HHMI report is available

online at www.hhmi.org/

research/labsafe/

BEST PRACTICE PROJECT PARTICIPANTS

Duke University Medical Center

Harvard University

Stanford University

The Rockefeller University

University of Colorado, Boulder

University of Pennsylvania

University of Texas SouthwesternMedical Center

University of Washington

University of Wisconsin–Madison

Washington University School of Medicine

CO

UR

TE

SY

OF

MA

RIT

IME

AQ

UA

RIU

M


N E W S & N O T E S

TO

M K

EL

LE

R

BoostingBrain Repair

After former President Gerald R. Fordsuffered a stroke at the 2000 Republi-can National Convention in Philadel-

phia, neurologist S. Thomas Carmichaelappeared on cnn as an expert in stroketreatment. His interviewer asked if the emer-gency room staff were at fault for not recog-nizing Ford’s symptoms on his first visit. ButCarmichael, at the time an hhmi postdoc atthe University of California, Los Angeles(ucla), pointed out that early symptoms ofstroke are difficult to recognize, and, worseyet, when a stroke is suspected, treatmentoptions are often limited.

Now an assistant professor at ucla,Carmichael and his colleagues are trying tofill the treatment void with a newapproach—tracking brain waves that coaxgrowth of new electrical connections in thebrain. Their most recent findings, reportedin the July 15, 2002, issue of the Journal ofNeuroscience, suggest a similarity betweensignals sent out in response to stroke andsignals known to stimulate the building ofneuronal circuits in developing brains.

Carmichael is not trying to find drugsthat protect the brain against damage.“We’ve seen 37 failed clinical trials of neuro-protective agents,” Carmichael says. “Thefield is ripe for a new agent that works in adifferent way.” He is instead attempting toexploit the brain’s ability to repair itself afterthe damage has occurred.

“All stroke patients recover to somedegree,” Carmichael says. Ford, for example,recovered almost completely from the bal-ance and speech problems that promptedhis visit to the emergency room. Most often,however, patients do not fully recover.“They may go from 80 percent disabled to30 percent within six months to a year,” hesays. The remaining disabilities—ofteninvolving slurred speech or various degreesof paralysis—overshadow the recovery.

Carmichael hopes that finding the brainsignals that stimulate repair after a strokewill lead to drugs that can boost recovery tonear-normal levels of function. He began

tracking down the brain’s repair-promotingsignals after seeing evidence established byother researchers that such signals exist:Nerve cells in the brain can produce newsprouts that grow into long offshoots calledaxons to rewire important brain circuitsthat are disrupted when the blood supply iscut off during a stroke-like injury.

To find out how stroke damage sparksthe growth of these sprouts, Carmichaeland colleagues monitored electrical activityin the brains of rats immediately afterchoking off critical brain arteries by zap-ping them with a thermal probe. “We weresurprised at how interesting these signalsturned out to be,” Carmichael says. Ratherthan picking up an indiscernible jumble ofelectrical activity, electrodes placedthroughout the rat brains recorded distinctpatterns that indicated the brains were get-ting a tune-up. Bursts of discharges werefirst detected surrounding the stroke-dam-aged area within a day of injury. Two tothree days later, a chorus of neurons in adistant part of the brain answered backwith a slower, rhythmic electrical refrain. Ifthe distinct pattern was present, the neu-

rons grew sprouts. Without it, no sproutsappeared.

“Relatively speaking, the [sprouting]neurons were miles away,” Carmichael says.Prompted by the distress signals, axonsestablished long-distance projections to theprecise site where connections had been lost.

Carmichael and colleagues encoun-tered another surprise: The signaling patterns found in stroke-damaged brainsmirrored patterns detected in developingbrains during periods of rapid growth.The work on the original wiring of thebrain was done independently by hhmiinvestigator Lawrence C. Katz, at DukeUniversity, and hhmi Medical AdvisoryBoard member Carla J. Shatz, at HarvardMedical School. Their results, Carmichaelsays, indicate that the signals found by hisgroup may be part of a general braingrowth-promoting system.

He plans to continue tracking these sig-nals to pinpoint the sites of repair-relatedelectrical activity, with hopes of finding achemical signal that could lead to drugsdesigned to boost axon growth after stroke.

—JILL WAALEN

S. Thomas Carmichael has coaxed neurons in rats to grow new axons after stroke-like injury.

the mechanic can list the parts and deter-mine how they function as a system.

Genomics and chemical genetics are“popping the hood” for biology, providing acomprehensive, yet finite, parts list andinstruction set that eliminates the unpre-dictability of studying life systems, Landersays. GenBank is already indispensable forworking biologists and will become impor-tant for students, too. Although studentscannot sequence a genome or knock out agene to study its effects, they can accessGenBank to conduct “virtual” experiments.

For example, they could study evolutionby downloading and comparing genes for celldivision, reproduction and sensory receptorsfrom human, mouse, fly and bacteriumgenomes, Lander says. They might find thatgenes for cell division have changed little over

millions of years, while thosefor reproduction changedvery differently from speciesto species as these organismsevolved. For smell-receptorgenes, they would find a pro-liferation in mice, while manyof the human versions havebecome nonfunctional. Thiswould indicate that mice relyon smell more than humansdo and that unneeded genesdeteriorate.

ChemBank, though still aprototype, will provide similarpower by cross-referencingproteins, small molecules andexperimental observations,says Schreiber. Students could,for example, demonstratehow a drug interacts with cel-lular signals in a way thatcauses unwanted side effects.

Schreiber describes thesedatabases as “hypothesis-generating engines” that aregreat equalizers. High schoolstudents can have the sameaccess as scientists. “The onlylimit,” Lander says, “is yourimagination in thinking upquestions” and in the com-puter’s ability to recognizepatterns in the data.

To realize such creativity,


Report Urges Changes in College Biology Undergraduate biology education is not keeping pace with the rapidly changing arena of biologicalresearch, concludes a new report from the National Research Council of the National Academies.BIO2010: Transforming Undergraduate Education for Future Research Biologists is the culmination ofan 18-month examination of how best to prepare the next generation of life-sciences researchers.The study was sponsored by hhmi and the National Institutes of Health (nih).

“Biology has changed,” says Joan A. Steitz, an hhmi investigator at Yale University and a mem-ber of the committee that wrote the report. “The frontiers are now on the interface with morequantitative sciences, such as structure determination and bioinformatics. Therefore, biology stu-dents need stronger backgrounds in mathematics, engineering, physics and computational sciencein order to succeed in future research.”

The committee, which was asked by hhmi and nih to make recommendations on undergrad-uate biology-curriculum reform, proposed that biology majors should receive much broader expo-sure to the methods of the physical sciences and mathematics. At the same time, the committee rec-ognized that students should receive a broad liberal education as well.

After studying several approaches, the group recommended the incorporation of physical andinformation-science content into existing biology courses. In addition, they suggested that labora-tory courses become as interdisciplinary as possible and provide exposure to real-world laboratoriesthat routinely use techniques from both the biological and physical sciences.

In effect, the committee urged college and university faculty to retool their courses to include thenew integrative biology. And to give some assurance and inspiration, the report highlights case studiesof innovative teaching methods that have been successful both at large universities and small colleges;the report also lists links to Internet-based resources.

The just-implemented hhmi Professors program essentially affirms the report’s conclusions andputs some of its recommendations into action. In announcing the new program’s first 20 appointees,Institute President Thomas R. Cech noted that “we wish to empower scientists at research universitiesto become more involved in science education and come up with innovative ideas that break the moldand take a fresh look.” —KARYN HEDE

» The full text of the BIO2010 report is available at www.nap.edu/catalog/10497.html. Print copies may be

obtained by calling (888) 624-8373 or (202) 334-3313.

Stuart L. Schreiber hopes his ground-breaking research in chemical genet-ics, which identifies the chemicals

that modulate cellular processes, will oneday be so obvious that high school studentswill shrug, “Of course, how could it be anyother way?” Eric S. Lander, a leader ingenomics, the identification of the genesthat program those processes, agrees. “Thegoal of this extraordinary scientific revolu-tion,” he says, “is to be taken for granted asquickly as possible.”

Schreiber, an hhmi investigator at Har-vard University, and Lander, director of theWhitehead Institute/mit Center forGenome Research, collaborated on the 2002

hhmi Holiday Lectures on December 5and 6, called “Scanning Life’s Matrix: Genes,Proteins and Small Molecules.” They point-ed to the power of Internet databanks ofgenetic sequences, such as GenBank, and ofchemical interactions, called ChemBank, astools for research and medicine.

Lander uses a car analogy. Studying tra-ditional biology, he says, is like being a carmechanic who cannot look under the hood.The mechanic can listen to the engine orexamine pieces that fall off to hypothesizehow it works. Still, he has no way to knowhow many parts there are or what they do.Then somebody pops the hood. At first, theengine looks complicated, but eventually

Keeping Up with the Revolution


N E W S & N O T E S

student and scientist alike must cultivatean interdisciplinary mind-set, saysSchreiber. “Life science is tackling complexproblems that can only be solved throughmultidisciplinary approaches.” Heacknowledges, however, that this is easiersaid than done. Teachers should focus onunderlying connecting principles thatmany fields have in common. To make thatjob easier, he encourages using familiar,simple and precise language, devoid of thejargon that isolates scientists from otherfields of research. In addition, Schreiberurges teachers and students to “go to gen-

eral science lectures, watch “nova,” readScientific American” to become familiarwith work in many different fields.

To make true progress, however, multi-disciplinary approaches must be integratedwith information sciences, he says. “Ourexperiments generate staggering sheets ofdata that would run around the planet. Wecannot easily make sense of that informa-tion unaided, but with the help of comput-ers, amazing patterns emerge.”

Thus it’s no surprise, Schreiber andLander note, that teachers need sophisti-cated tools for translating new discover-

ies into usable classroom exercises.Today, it takes a courageous teacher withadvanced computer skills to incorporatethese databases into classroom learning.One day, however, they predict that thenecessary tools will become ubiquitous.No one will be able to conceive how peo-ple ever learned biology in the dark agesbefore genomics and chemical genetics,just as most scientists cannot imaginehow anyone studied chemistry before theperiodic table. —CATHRYN M. DELUDE

» For more information, see www.hhmi.org/

lectures/2002

Johannes Walter facedunfamiliar challenges ashe started up a molecular

biology lab at Harvard MedicalSchool in 1999. At the Universi-ty of California, San Diego, hehad excelled as a postdoc, pub-lishing papers on DNA replica-tion in prestigious journals suchas Science and Molecular Cell.But running a laboratory asprincipal investigator (PI), hesoon realized, required morethan scientific smarts.

For one thing, assembling atop team of postdocs wasn’tgoing to be easy. “You’re a new PI, nobodyknows who you are and you’re competingwith the best in your field,” says Walter. Hequickly learned the recruitment game—sending inquiries by e-mail to colleagues inthe field, flying in candidates from nearand far, even hosting some of them at hishome in Boston—and the effort paid off.His Harvard lab now hosts a researchgroup of eight, including postdocs, gradu-ate students and a research assistant.

During years of graduate work andpostdoctoral fellowships, young scientistsfocus on their research, with hopes thatstrong papers will help them garner first-rate faculty positions. When these sameresearchers land jobs as assistant profes-

sors, however, the tasks of coordinatingstaff, budgets and grants often pose a harshreality—they weren’t trained for this.

“Our energies are so focused on gettingthe job—then what?” asks E. LynnZechiedrich, a PI in molecular virology andmicrobiology at Baylor College of Medicine.Answering that often-overlooked questionwas the goal of the first annual Course inScientific Management held at hhmi head-quarters in Chevy Chase, Maryland, in July.Sponsored by the Burroughs WellcomeFund and the Institute, the course includedsessions on collaborations, writing NationalInstitutes of Health (nih) grant proposalsand time management and mentoring skills.Postdocs and new faculty—127 in all—

Young Scientists Learn the Management Ropes

attended from the United States and abroad.Karen M. Ottemann, a microbiologist in

her third year as an assistant professor at theUniversity of California, Santa Cruz, says thestep from postdoc to PI requires not only a

shift in thinking but a wholereconstruction of one’s day: “Youtransition to being a PI, and youhave all these new responsibili-ties. You have to mentor morestudents and less-seniorresearchers, you have to attendfaculty meetings, write yourgrants—and balance it all.”

Some find managing theirmoney to be the big challenge.That might explain why atten-dees packed the session onapplying for the coveted nihRO1 grant—the gold standardin multiyear, federal grants.“The

most surprising thing was cost,” says Bernar-do L. Sabatini, a second-year PI at HarvardMedical School, where he runs a five-personneurobiology lab.“I thought I was okay withthree or four private foundation grants. ButI’m running through money like you would-n’t believe.” Average startup costs for newlabs in the life sciences can run from$100,000 to $1 million, excluding salaries,according to the Burroughs Wellcome Fund.

Many saw the four-day course as anespecially welcome opportunity to speakwith others who were going through thesame process, and those who had survivedit. “It’s reassuring,” says Yashi Ahmed, a newPI at Dartmouth College, “that many peoplehere have the same fears.” —ELI KINTISCH

Postdocs and new PIs attended a course to learn how to run a lab.

PA

UL

FE

TT

ER

S


Shulamit Michaeli, an hhmi inter-national research scholar at Bar-Ilan University near Tel Aviv, stud-ies messenger RNA productionand protein sorting in a family of

parasites called tryapanosomatids—thecauses of sleeping sickness, Chagas dis-ease and leishmaniasis. The latter isendemic in the Middle East, where it isspread by the bite of sand flies. The dis-ease affects the spleen, liver and bonemarrow and can be fatal.

In a country where suicide bombingsand military skirmishes have become a wayof life, Michaeli knows only too well themeaning of “under the gun.”

Isn’t it difficult doing science in your war-torn country?Michaeli: We live under pressure, but I likemy work so much that it helps me cope. Iconcentrate on the science and try not tothink about the bombings. The university iswell guarded, so the safest place to be is inthe lab. Still, the war is everywhere. The sol-diers are on the tanks, but this is everyone’swar. The kid who goes to school, any of mystudents, anyone who goes to a shoppingmall or gets on a bus is a soldier. This is notgoing to break our spirit. We see it as ourmission to continue life as normally as wecan. I can contribute by continuing myactive research and academic activities.

How does the situation affect the graduate students and postdoctoral fellowsin your lab?Michaeli: All 13 of my students are in thereserve forces, and 5 of them have beencalled to active duty since April [2002]. Onehas been called up twice. Sometimes theyphone from the tanks to check on theirresearch; one of them called recently to makesure his parasites were fine. We try to contin-ue their work while they are away—our labis a family, and we all pull together to get thejob done—but I don’t allow anyone to take

ty of California, Berkeley] and at ucsf[the University of California, San Francisco].I am sure I could get a good job in the Unit-ed States or Europe. But I went to the U.S.to train so that I could go back to Israel asa professor of microbiology. It was mylife’s goal. I was born in Israel, and I’mproud to be Israeli. We are only a smallcountry, but we are asking important ques-tions that are central to science. I amproud of my country’s achievements, andI believe we must cherish and fight forwhat we have. My parents are here. Myheritage is here. I want my children to growup proud to be Israelis too. I do not thinkabout leaving. Also, not one of my stu-dents plans to leave Israel. Even my twograduate students and a postdoc fromChina haven’t left. In fact, one of themrecently brought his wife and child to joinhim here.

—JENNIFER BOETH DONOVAN

over another’s work or to takecredit for it. Beyond the proj-ect and the papers, it is thestudents themselves I am con-cerned about. When one ofthem was doing military serv-

ice, a bomb exploded andinjured him; bits of shrap-nel are still coming out allover his body. One piecehit very near his eye, andhe was lucky not to lose hiseyesight. In the lab right

next to mine, a graduate stu-dent lost her husband on theirfirst anniversary.

Aren’t you afraid for yourpersonal family?Michaeli: Of course. One ofthe bombings was in Herzliya,the town where my parentslive, in the shopping centerwhere they buy fish for theweekend. Right away I called,but at first the phone lines were all occu-pied, and I got really nervous before Ifound out that they were safe at home. Ihave three wonderful children, Ram, 7,Shai, 9, and Bar, 11, and I am always won-dering, where are the kids? When schoolvacation starts, my husband [Moshe Gold-berg, a chemist who works for the IsraeliMinistry of Defense] and I become evenmore nervous, because the kids want to goout everywhere. I’m not just concernedabout their physical well-being; I am con-cerned about their emotional well-being,growing up under constant fear.

When I go to other countries and hearpeople talking about their plans for summervacations, I realize how different we are. I amthinking about whether my family and mystudents are going to be alive next summer.

Have you ever considered leaving Israel?Michaeli: I trained at Berkeley [the Universi-

QA&

Shulamit Michaeli’s students call from the tanks to check experiments.

Israeli Scientist Soldiers OnA conversation with Shulamit Michaeli

KE

NT

KA

LL

BE

RG

I N T E R V I E W


Relief for Rett syndrome Scientists

have designed a mouse model of Rett

syndrome, the leading cause of mental

retardation in girls. Using the model,

they plan to probe how the MECP2

gene, which is mutated in the disorder,

affects brain function.

Researcher: Huda Y. Zoghbi

www.hhmi.org/news/zoghbi5.html

When Gleevec fails The drug Gleevec

doesn’t work in some patients who have

chronic myelogenous leukemia (CML),

it turns out, because specific mutations

in a rogue gene render the drug ineffec-

tive. Screening for the mutations will

help determine the best therapy for each

patient. The discovery may also lead to

better anti-CML drugs.

Researchers: Charles L. Sawyers and

John Kuriyan

www.hhmi.org/news/gleevec.html

When a vaccine fails A subtle abnor-

mality in the immune system may pre-

vent certain people from responding well

to a vaccine for Lyme disease. The dis-

covery of this abnormality, which other-

wise appears to exert no ill effect, under-

scores the importance of exploring the

immune system’s protective pathways

for fending off microorganisms. The stud-

ies also suggest several ways to improve

the Lyme disease vaccine.

Researchers: Richard A. Flavell, Erol

Fikrig and Ruslan Medzhitov

www.hhmi.org/news/flavell2.html

Structural problem Subtle defects

in the processing of a single protein that

provides structural integrity to muscle

cells can lead to muscular dystrophy. This

finding will help improve diagnosis and

genetic counseling and should eventually

help doctors tailor their interventions.

Researcher: Kevin P. Campbell

www.hhmi.org/news/campbell4.html

I N B R I E F

DR

EW

BE

RR

Y/T

HE

WA

LTE

R A

ND

ELI

ZA

HA

LL I

NS

TIT

UT

E

H H M I L A B B O O KR E S E A R C H N E W S F R O M H H M I S C I E N T I S T S

New Take on a Malaria Vaccine

New therapies formalaria are in demandbecause the malaria

parasite, Plasmodium falci-parum—which affects some5–10 percent of the world’spopulation—is rapidlybecoming resistant to stan-dard drugs. Most vaccinesunder study have been madeto target parasite proteinsand have not proved effective.

hhmi internationalresearch scholar LouisSchofield has taken a differ-ent approach, with promis-ing results. He and his teamat the Walter and Eliza HallInstitute of Medical Researchin Melbourne, Australia, hadpreviously shown that themain toxin produced by theparasite—a sugar called gly-cosylphosphatidylinositol(GPI)—caused a stronginflammation response incells in culture and in mice.This meant that the immunesystem was aggressivelycombating the molecule. Sothe researchers, togetherwith Peter H. Seeberger at the MassachusettsInstitute of Technology, identified the specificpart of GPI that made it act as a toxin andcause such a reaction, and they fashioned apure version of this part of the GPI molecule.

To see if this GPI extract might work in avaccine, Schofield and his colleagues injectedmice with it (in combination with large carriermolecules that trigger recognition by theimmune system) in an attempt to immunizethe animals against malaria. They thenexposed the mice to the malaria parasites andfound in initial tests that the potential anti-GPI vaccine indeed provoked a strong anti-body response, protecting the mice in part

against some of the severe complications ofmalaria, including pulmonary edema.

“The study provided the first proof of thetoxin’s role in malaria,” Schofield says. “Itestablished the toxin as a cause.” Results of theresearch appeared in the August 15, 2002,issue of Nature.

Next steps: “We want to develop the vac-cine further and develop a program to simpli-fy the synthesis, making it easier and cheaper,”Schofield says. Over the next few years, he andhis colleagues plan to create a variety of anti-GPI vaccines and test them in other animalmodels of malaria.

» www.hhmi.org/news/schofield.html

Target the Toxin Infected mosquitos inject malaria parasites

into an animal’s bloodstream. The parasites invade red blood cells and

multiply within. Diseased red blood cells burst open, releasing parasites

and toxins. Schofield and colleagues are using part of the toxin to stim-

ulate immunity against malaria.


Weed for cancer? A chemical isolated

from a weed that grows in mountain

meadows of the western United States

kills the cells of an aggressive childhood

brain cancer in mice. The compound,

cyclopamine, blocks a signaling pathway

that appears to be important for the sur-

vival of medulloblastoma.

Researcher: Philip A. Beachy

www.hhmi.org/news/beachy2.html

Cancer cell wrecking ballResearchers have identified a compound

that selectively kills tumor cells by

destroying their mitochondria, or meta-

bolic power plants. The compound,

named F16, seems to be active at rela-

tively low concentrations, which the sci-

entists suggest will be important in

reducing any toxicity.

Researchers: Philip Leder and

Valeria R. Fantin

www.hhmi.org/news/leder.html

Trading places By determining how a

form of lymphoma can develop in mice

when large pieces of chromosomes

exchange locations, researchers have

gained a fresh perspective on how can-

cers arise from an increased “dosage” of

specific genes or regions of the genome.

The discoveries should lead to a better

understanding of how deficiencies in

DNA repair and in the cellular DNA dam-

age-detection system can cause tumors.

Researchers: Frederick W. Alt, Cheng-

ming Zhu and Kevin D. Mills

www.hhmi.org/news/alt3.html

Stocking up on stem cellsResearchers have discovered a protein in

the roundworm Caenorhabditis elegans

that maintains a reservoir of germline

stem cells—the cells that are the source

of sperm and eggs. The protein, FBF, is

necessary for germline stem cells to

develop into both sperm and egg; with-

out FBF, the stem cells mature into only

sperm. The finding helps bring together a

growing body of evidence on how stem

cells are regulated at the molecular level.

Researcher: Judith Kimble

www.hhmi.org/news/kimble2.html

I N B R I E F

Building a Bigger Brain

Researchers have found a protein switchthat increases the growth rate of thecerebral cortex in specially engineered

young mice.“We saw [embryonic] mice with enor-

mous brains,” says Anjen Chenn, an assistantprofessor of pathology at the NorthwesternUniversity Institute for Neuroscience. Thecerebral cortex of these transgenic mice grewdramatically, expanding horizontally in areabut not in thickness. These changes producedthe characteristic ridges and grooves thatanatomically distinguish human brains fromthose of lower animals.

The switch that’s responsible, called ß-catenin, appears to be “telling the precursorcells to keep dividing, rather than stoppingand making a mature differentiated neuron,”says Chenn. He and hhmi investigatorChristopher A. Walsh, at Beth Israel DeaconessMedical Center and Harvard Medical School,reported their findings in the July 19, 2002,issue of the journal Science.

Scientists have known for quite some timethat during human evolution, the size of thecerebral cortex—the “gray matter” regionthat’s responsible for higher intellectual abili-

ties—expanded much more than the rest ofthe brain. During an hhmi postdoctoral fel-lowship in Walsh’s lab, Chenn set out withWalsh to learn how and why.

The cerebral cortex varies a great deal inshape and size among animals. It is small,smooth and flat in rodents, for example, and alarge, wrinkled sheet made up of repeatingcolumns of cells in humans and other pri-mates. “The human expansion has occurredlargely in the surface area, making it 1,000-foldlarger than in the mouse,” says Walsh. “Wewanted to find out what factors controlled theexpansion of neurons and other brain cellsand how that might be regulated.”

They had some clues. ß-catenin was onecandidate for regulating the proliferation ofprecursor brain cells because it is known tocontrol cell growth and has been implicated insome brain tumors. To see whether it regulat-ed brain growth, the scientists created trans-genic mice that overexpressed ß-catenin in theneural precursor cells.

The team plans to study ß-catenin’s rolein a variety of other species with different-size cortexes. But they harbor no illusionsthat it calls all the shots. “We are certain,”says Chenn, “that the increase in brain sizeover evolution is going to be more compli-cated than just due to changes in one geneand one protein.”

» www.hhmi.org/news/walsh.html

HHMI Lab Book written by Steven I. Benowitz

WIT

H P

ERM

ISSI

ON

FR

OM

SCI

ENC

E, 2

97:3

65-6

9, F

IGS.

3A

&B

, 20

02

CO

PYR

IGH

T A

AA

S

Mindful Mouse The brain of the normal mouse embryo (left) is small, smooth and flat. In mice

specially engineered to overexpress ß-catenin, the cerebral cortex or "gray matter" of the brain is

enlarged, with ridges more characteristic of human and primate brains.


H A N D S O N

Forty high school students gathered at the University ofMaryland’s College Park campus this summer to play withdolls—all in the name of serious science. During a weeklong

course on forensic science, they heard experts explain the fine pointsof DNA fingerprinting, microscopic analysis, crime-scene and evi-dence preservation and ink chromatography. But the capstone was asession with a special set of dollhouses that simulate crime scenes.

By featuring forensic science, the hhmi-funded summer scienceprogram, called Jump Start, captures the interest of students enthralledwith popular television programs such as CSI and Crossing Jordan, saysKaci Thompson, director of undergraduate research and internshipprograms at the university’s college of life sciences. It also happens toincorporate aspects of several scientific disciplines—including anthro-pology, biology, chemistry, criminology and psychology.

After spending four days studying the techniques of the forensicscientist, students peer inside meticulously crafted dollhouse crimescenes depicting victims, locations and lines of evidence. Theydebate possible scenarios. “I don’t think he was whacked,” says onestudent. “He’s not in an awkward position at all.” Another adds, “Ithink if he was dragged, his arms would be stretched back.” Later,they assess their powers of deduction when instructors reveal whateach scene actually represents.

Thomas P. Mauriello, a professor of forensic sciences in the uni-versity’s department of criminology and criminal justice, conceivedof the dollhouses 10 years ago after seeing a similar set at the Stateof Maryland’s medical examiner’s office, where they are used fortraining. Mauriello designed and furnished the dollhouses, with thehelp of graphic artists, to use as a teaching tool in his undergradu-ate class, Introduction to Criminalistics. He says the structures helphim integrate the techniques of forensic science into a cohesive andrealistic process.

The Jump Start students, juniors and seniors hailing from thegreater Washington, D.C., area, are selected on the basis of grades,teacher recommendations and essays. According to Thompson,the program doesn’t necessarily aim to encourage students topursue the field of forensic science. Rather, it tries to showstudents how knowledge of a broad range of scientific meth-ods can be used to solve real-world problems.

Katherine Beling, a senior at Baltimore’s CatholicHigh School, liked the approach. “This gave us a chanceto use our own imaginations rather than just look at DNAsamples under a microscope.” Now in its fourth year, theprogram also includes two additional one-week highschool courses, one focused on biotechnology and the otheron animal behavior and physiology. —EUGENE RUSSO

Investigating Murders in MiniatureDollhouse crime scenes teach students how science can solve real-life problems.

1. Chinyere Okol, TimothySimons, Prabu Selvam, JuneStreets, Taniesha Hunter andBenjamin Miller (from left toright) discuss a dollhouse crimescene. Based on evidence pre-sented (blood stains, footprintsand possible murder weapons, forexample), they exchange ideasabout the nature of the crime,the time at which it was commit-ted, the cause of death andwhether or not the scene actuallydepicts a crime at all.

MO

LLY

RO

BE

RT

S (

5)

1


2. Evidence, including footprints, abroken table lamp, blood stains andmarks from the burglar’s crowbar,help students piece together how thisliving room burglary took place. Theposition of the door and the lamp andthe two different blood stains suggestthat the perpetrator stood behind thedoor, struck and killed the homeown-er with the table lamp, cutting him-self in the process, and then fled.

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

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

34

2

F R O M T H E T O O L B O X

Slipping Past a CancerCell’s DefensesProtein transduction carries therapeutic possibilities.

In at least one respect, mammalian cellsare like homeowners in a high-crimeurban neighborhood: They are extreme-

ly careful about who they let through thefront door. Unlike houses, of course, cellshave many thousands of “doors”—channelsand receptors—dotting their exterior, andamong the more obvious criteria for passagethrough any of these is size. Large, complexmolecules such as proteins usually don’t havea chance. They’re much too bulky tonegotiate tiny channels or to slip through thepores of the cell’s membrane.

Like the alert urban homeowner, the cellhas good reason for being vigilant. In nature,observes Steven F. Dowdy, an hhmi investiga-tor who studies cancer at the University ofCalifornia, San Diego,“large” typically meansviruses and other pathogens—precisely thesort of visitors that the body’simmune system works hard to repel.Formidable cellular membranes are aprotective measure evolved bymulticelled organisms for the expresspurpose of keeping big, nasty thingsout whenever possible.

Not every large molecule is apredator, however; some, if theycould be brought inside diseasedcells, might have therapeutic effects.That’s the premise driving the workof Dowdy and his colleagues: Theyhave devised a method they hopewill enable them to smuggle somevery large molecules intomammalian cells—specifically, can-cer cells. Their technique is calledprotein transduction, the art ofconvincing a resistant cellmembrane to accept somethingmuch larger than its liking.

Specifically, Dowdy seeks topiggyback large proteins onto

smaller protein fragments, called peptides,and then slip the entire package through atarget cell’s membrane. Once across this bar-rier, the shipped protein is always at leastpartially akimbo. But the cell’s internalmachinery refolds the protein into itscorrect, therapeutic shape. In such a case, thecell’s aversion to big things is overcome by aningenious molecular sleight of hand, bad forthe diseased cell but potentially good for thewell-being of the larger organism. Onceinside a cancer cell, for instance, a refoldedtherapeutic protein might precipitate thedemise of the cancer cell, while other, healthycells in the area would be unaffected.

Elaborating on the metaphor of the well-guarded house, Dowdy says imagine that youwant to tell the residents (or, perhaps morefittingly, the appliances) to do something.

But the only way information can enter thehouse is through the mail slot, a tiny area rel-ative to the size of the house. A singleenvelope that can fit through the slotcontains a limited amount of information,Dowdy says. “Some [information] can bevery specific—go to the corner, buy somemilk.” But in general, the level of instructionsis tightly constricted. This is analogous to theinformation load carried by the small-molecule drugs that are currently available.

“What we’ve done with protein transduc-tion is we’ve taken your computer, slipped itthrough the same mail slot, reassembled it onthe inside with all the information on thehard drive intact,” he says. Once a protein issmuggled past the membrane, basic cellbiology takes over. Within the cell wall aremolecules called heat shock proteins, orHSPs. These elite repairmen cruise around insearch of damaged proteins to refold andrestore into good working order. Fortunately,says Dowdy, HSPs are indiscriminate: Theydon’t care how a misfolded protein falls ontheir doorstep, only that it’s there. If they canfix it without expending too much energy,they will do so; otherwise, they pack it off to

DA

VID

KIL

PE

R

Protein transduction in a mouse model

of human metastatic ovarian cancer. Fifteen min-

utes after injection of a peptide labeled with

green fluorescence, most cells in the abdominal

cavity, where ovarian cancer cells have invaded,

have taken up the peptide.

1

Steven Dowdy says that, in theory, transduction can be used

to treat headaches, colds and genetic disorders.



CO

UR

TE

SY

OF

DO

WD

Y L

AB

2 3the proteosome, a cellular demolition factory.

“The really amazing part is that whenyou introduce the proteins, they take on theproperties of what’s inside the cell,” Dowdysays. Most proteins that attempt to enter a cellget chewed up into their constituent aminoacids, he says. They become cellular food. Inprotein transduction,“the proteins stayintact. They can be taken to the nucleus, theycan assemble with other proteins in the cell,they can be cleaved by enzymes. While wedon’t know that they do everything, theycertainly do a lot of things.”

Preliminary studies in mice and rabbits,including Dowdy’s work, show that proteintransduction works. He’s shown that peptidescan pass through the membrane of ovariantumor cells in lab mice. As a result, the p53tumor suppressor gene is switched on, and themalignant cells halt their activity and destroythemselves in a process known as apoptosis. Sofar Dowdy and colleagues have succeeded inextending the lives of such animals two- tothreefold, as compared with a control group ofsimilarly sick mice. Yet they haven’t been ableto push much further.“It’s moving in the rightdirection, but it has clearly taken more effortthan I had naively expected,” Dowdy says.

Dowdy first started serious work on trans-duction in 1997 and published his first paperon the mechanics of the method in 1999. Hisinitial experiments in animals were so promis-ing, he says, that he became overly optimisticabout how quickly he could bring the technol-

ogy to people.“Can we deliver largemacromolecules into a cell? Yes. Enough tomake a difference in animals? Yes.” But inhumans? “We don’t know yet,” he admits.

Dowdy has long been fascinated by theminuscule. He landed in graduate school atthe University of California, Irvine, afterchoosing biology over particle physics.Ironically, it was as an undergraduate on adate at California’s Yosemite National Park—a place where scale tends toward theenormous end of nature’s spectrum—that hecaught the transduction bug. “We ended upspending practically an entire hike discussingthe problem of introducing large moleculesinto cells and trying to devise mechanisms tobreak down that barrier.” The exchange musthave been stimulating—Dowdy’scompanion, a budding computer scientistnamed Lisa Howard, married him.

Dowdy’s group is focused on transducinganticancer agents, such as enzymes andproteins, to kill tumors but not normal cells.He points out, however, “In theory, you coulduse this approach for headaches, the commoncold and potentially for genetic disorders,too,” by adjusting the therapeutic proteindelivered into target cells.

One company that has had some earlysuccess in protein transduction is CellGate.The Sunnyvale, California, biotech firmrecently completed a phase I safety study in 15people with an experimental therapy for psori-asis, a skin condition affecting about 7 millionAmericans. CellGate isn’t using a largemolecule in this trial, but rather a small one(the immune-suppressing drug cyclosporine)hitched to a “passkey” molecule. But theprinciple is the same, says Edward F.Schnipper, the company’s president and chiefexecutive officer.

CellGate also has its sights set on moredeadly diseases, including a variety ofcancers. The firm has partnered with severallarger companies, including Johnson &Johnson, to commercialize the technology.Dowdy says he’s encouraged by CellGate’spreliminary results—which only test safety,not effectiveness, and don’t involve large pro-teins. He’s hoping to move his work intohuman studies, but experience has taughthim to remain cautious. “Humans are goingto be much more complex and moredifficult” than lab animals, he predicts, andin his view, “It’s better to be conservative.”

—ADAM MARCUS

Transduction can change the biology of human fibroblast cells in culture. Two types of the same

protein—known to alter membrane architecture—were transduced into the cell membranes. In

panel 2, the protein contained an inactivating mutation and the cell surface remained smooth.

In panel 3, using a version containing an activating mutation, spikes appeared within 10 minutes

in more than 95 percent of the cells.

Joseph D. Collins, hhmi’s new direc-tor of information technology, grewup in segregated Mississippi. He says

he was attracted to hhmi because its mis-sion suits his aspiration—born early fromhis father’s example—to make a difference.

Collins’ father, Reverend J.D. Collins,was a civil rights activist and one of the firstblacks to register to vote in Leflore County.He formed the Progressive Negro VotersLeague in the 1940s to help other blackspass the mandatory written test that wasbarring them from the voting booths.

At the height of the civil rights move-ment in 1966, Collins recalls, his fatherbrought seven guests home with him after afreedom meeting at his church. In those days,most hotels in the Deep South were unavail-able to black people, so visiting activists oftenstayed in local homes. That evening, theguests included Martin Luther King, Jr., andfellow civil rights leaders Ralph Abernathyand C.T. Vivian. “It was a very interestingnight,” says Collins, who was 17 years old atthe time.

He remembers his father and King quot-

ing the New Testament as they debated theappropriateness of carrying weapons. King, ofcourse, was against the use of force; mean-while, J.D. told Joe to sleep that night with hisrifle beside his bed. “My father, although aminister, was not a pacifist,” he says. Whitesupremacists had burned crosses in theCollins’ front yard and shot out the windowof his father’s shoe repair shop, and the rev-erend meant to protect his family.

That night, Collins’ mother, Katie, col-lected the autographs of the civil rightsleaders in her old, spiral-bound addressbook. King wrote “Thank you for all of yourwonderful hospitality,” and Abernathyadded “Your contribution to freedom hasmeant so much to all of us.” She gave thebook to her son a few years ago.

Inspired by his father’s determination,Collins applied to top-ranking colleges andchose the University of California, Berkeley.He stepped into a cultural whirlwind: MarioSavio advocating free speech; Haight-Ashbury’s free-love movement; and Huey P.Newton, Bobby Seale and the Black Panthersholding meetings on the steps of Sproul Hall.

I N S I D E H H M I

His Brave Father’s Example

The distractions were too much, Collins says.He eventually transferred to HowardUniversity in Washington, D.C., where heearned a bachelor’s degree in electrical engi-neering and a master’s degree in computerscience. “Attending Howard allowed me topursue my studies in an oustanding academicenvironment that also enabled me to emulatethe social, political and moral examples setforth by my parents,” he says.

Although he laughs at the notion,Collins’ career path was a straight shot intoleadership within the technology field. Afterjobs at ibm and Exxon, he returned to hisalma mater, taking on more and moreresponsibility. Before coming to hhmi, hewas associate vice president for informationsystems and services at Howard University,responsible for all central information tech-nology (it) support, a $13 million annualbudget and a staff of 100.

“I wanted to go back to Howard afterearning experience in the field and offerwhat I could to the institution that gave methe opportunities,” he says. “Now I’m work-ing for an institution whose mission in bio-medical research is also making a difference,but on a much larger and different scalethan Howard University. The potential toprovide world-class technology support forour investigators and other staff, who areinvolved in world-class biomedical researchand science education, is exciting for me.”

His main goal for the Institute’s itdepartment is to tightly integrate everyapplication (such as human resources,grants, purchasing and investments) so thatusers “can access what they need wheneverthey need it, all via the Web.”

Collins’ family situation has come a longway since his youth in Mississippi—to thepoint, he says, that his two children regardtales of the civil rights movement as ancienthistory. “When my daughters were growingup, I didn’t talk about the past a lot. I shield-ed them from it.” But before his father died in1995, he interviewed his parents on tapeabout their lives. “I plan to give a copy to mykids and grandson. I gave one to my sisterand she was blown away.” He hopes to pre-serve his mother’s old address book withthose notable autographs as well, to give hischildren a tangible and priceless remem-brance of their heritage. —CORI VANCHIERI


WIL

LIA

M K

. G

EIG

ER

Joseph Collins’ group provides information technology support from headquarters and two field offices.

W. Maxwell Cowan, hhmi’s vice president and chief sci-entific officer from 1987 to 2000, died in June at age 70.Cowan, an accomplished neuroscientist, structured theInstitute’s scientific program and took a personal interest inidentifying scientists around the country whose work meritedhhmi support. Cowan had a lasting impact on many.

Eric R. Kandel, hhmi investigator, Columbia University, andNobel Laureate

I had already heard a great deal about Max Cowan by the timewe met in 1974, and I knew he had a prodigious knowledge ofbrain anatomy. In our initial discussion, I was taken by his com-ment that anatomy had no interest for him except as it enlight-ened the study of function. With time, I cameto realize that this principle guided much ofhis thinking. I saw this again the next year atCold Spring Harbor, when he was explainingthe topographic surface anatomy of thehuman brain to a beginning class. Max heldin his hand a brain rigidly fixed in formalde-hyde, yet he made this fixed brain come alivein a functional way that was simply extraordi-nary. I later saw a similar demonstration at aCongressional hearing: Max was carrying aporcelain jug under his arm containing a fixedhuman brain. At the door of the Senate, Maxwas asked by the guard what he was carryingunder his arm. He answered without crackinga smile, “A human brain. Whenever I testifybefore Congress I always carry a spare.”

As neuroscience matured, Max emerged as a major force inthe effort to combine anatomy and function, a synthesis that led tothe coherent discipline we now enjoy. He was among the first toappreciate the importance of studying development, not only as akey for understanding mature brain function but also as a bridgeto the rest of biology, especially molecular biology. His studies ofneuron cell death and nerve process retraction are still classics.

Max was a natural leader. He was recognized as such and wasconstantly sought out for important leadership positions. His lead-ership role reached new heights at the Hughes. He loved thehhmi and his various roles in it. Until his last few days Maxremained productive. He could not have asked for a more success-ful and rewarding career as a scientist and as a leader of science.

Marc Tessier-Lavigne, hhmi investigator, Stanford University As a starting assistant professor, I only knew Max by repu-

tation, and that reputation was profoundly intimidating. In my

first encounter with him after joining hhmi, I could barelycontain my nerves, yet within minutes, I started to feel at ease.The calm cadences of his voice, his South African lilt and thewarmth of his praise were avuncular and disarming. I wasastonished at how much he knew of me and my work. Butbeyond his legendary analytical ability, what struck me mostwas his genuine concern for me and my career. Over time, Iincreasingly turned to him when I needed advice or a soundingboard. Max Cowan truly cared and thereby helped shape mycareer in profound ways.

Carla J. Shatz, member, hhmi Medical Advisory Board and former hhmi investigator

Max Cowan was one of my scientificfathers—a real “fairy godfather.” In 1976,he served as external examiner for myPh.D. thesis. Over the years, I know thathe worked on my behalf behind thescenes and that I owe a good deal of theprofessional recognition that has comemy way to his support. Without Max,many of us would not have had theopportunity to become hhmi investiga-tors. He worked hard to establish compet-itive standards, opening the door, forinstance, to the appointment of manywomen—myself among them. I treasurehis role in my life.

Thomas C. Südhof, hhmi investigator, University of TexasSouthwestern Medical Center at Dallas

Max’s biggest strength may have been his ability to see thebig picture, in and out of science. Max taught me to see beyondan individual scientific result or a particular historical moment,a short-lived scientific triumph or humiliation, toward the larg-er goal of building knowledge and understanding.

Corey S. Goodman, president and CEO, Renovis, Inc., and former hhmi investigator

I first met Max in the summer of 1977 at a conference inBoulder. I had just finished graduate school, a shy student inawe of “Dr. Cowan,” but found the courage to ask him to lookat a manuscript. He listened, congratulated me, gave greatadvice and a lot of encouragement—something that wouldcontinue for decades. Max was a mentor, and as I got older, healso became a good friend. Neuroscience lost a great champion,scholar and leader with Max’s death.

A P P R E C I A T I O N

W. Maxwell Cowan

PA

UL

FE

TT

ER

S


H

ww

w.h

hmi.o

rg/b

ulle

tin

Howard Hughes Medical Institute4000 Jones Bridge RoadChevy Chase, Maryland 20815-6789301.215.8855 www.hhmi.org

NONPROFIT ORG.US POSTAGEP A I DSUBURBAN MDPERMIT NO. 6561

»»»» IN THE

NEXT ISSUE» Let Sleeping Dogs LieDogs and mice help two teams of scien-tists discover the cause of narcolepsy, galvanizing the field of sleep research.

»Tartar Control for the JointsOne in three Americans has some form of arthritis. That calls for new thinking about a crippling disease.

» Leptin’s Last WordThe hormone leptin may not be the obese person’s key to melting fat, but it’s become a prized tool for studying metabolism.

This Doberman has a genetic defect that leads to the sleep

disorder narcolepsy. After extreme excitement or

surprise, the dog abruptly loses muscle tone and falls

into a state of paralysis, which eventually passes. M

IGN

OT

LA

B

tenacious a foe - howard hughes medical institute · steven marcus, blair burns potter, peter...

Documents