hoof-and-mouth epidemic || teacher for a day|| trapping ...kathy savory,copy editing david herbick...

Hoof-and-Mouth Epidemic || Teacher for a Day || Trapping Genes || Do You Hear What I Hear? S E PT E M B E R 2 0 0 1 Hoof-and-Mouth Epidemic || Teacher for a Day || Trapping Genes || Do You Hear What I Hear? S E PT E M B E R 2 0 0 1

Untangling Proteins to Repaır the Brain

F E A T U R E S

18 Clearing Toxic Clumpsfrom the Brain New discoveries link seemingly unrelated, fatal illnesses such as AlzheimerÕs disease and HuntingtonÕs disease to misshapen proteins, providing hope for new treatments. By Maya Pines

14 Quantifying UncertaintyNeil Ferguson used mathematical modeling to help British policymakers stem the fast-spreading hoof-and-mouth epidemic.

18 Making the GradeSome researchers go all out to teach

children about science. Follow their lead

and kids will take notice.

By Kathryn Brown

22 College Student MeetsElectron ManInitial panic turns to insight as students

embrace online learning and, in the process,

become critical thinkers.

By M. Mitchell Waldrop

14

A farmworker disinfects a

truckload of cattle slaughtered

in the 2001 hoof-and-mouth

epidemic at Horralane Farm in

Devon County, some 236 miles

southwest of London.

By Laura Spinney

D E P A R T M E N T S

HHMI TRUSTEESJames 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

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

Irving S. Shapiro, Esq., CHAIRMAN EMERITUS Of Counsel, Skadden, Arps, Slate, Meagher & Flom Former Chairman and Chief Executive Officer, E.I. du Pont de Nemours and Company

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 ProgramsDavid A. Clayton, Ph.D., Vice President for Science DevelopmentStephen M. Cohen, Vice President and Chief Financial OfficerJoan S. Leonard, Esq., Vice President and General CounselGerald M. Rubin, Ph.D., Vice President for Biomedical ResearchNestor V. Santiago, Vice President and Chief Investment Officer

HHMI BULLETIN STAFFCori Vanchieri, EditorDavid Jarmul, Senior EditorJim Keeley, Science EditorJennifer Donovan, Education EditorPatricia Foster, Manager of PublishingKimberly Blanchard, Editorial CoordinatorDean Trackman, Elizabeth Cowley, Copy Editors

Steven Marcus, Peter Tarr, story editingKathy Savory, copy editing

David Herbick Design, Publication Design

Telephone (301) 215 8855 n Fax (301) 215 8863 n www.hhmi.org The Bulletin is published by the HHMI Office of Communications, Robert A. Potter, Director. © 2001 Howard Hughes Medical Institute

Letters to the editor: We invite your comments. Send your letters via e-mail to [email protected] or regular mail to Letters, Office of Communications, Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789. We reserve the right to edit for space and clarity. Please also include your name, address (e-mail or postal) and phone number.

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.

2 NOTA BENE

3 PRESIDENT’S LETTERPutting Patients Back into Biomedical Research

UP FRONT

4 A Crystal-Clear Focus on Ion Channels

6 Memorable Mouse

PERSPECTIVE

7 Giving Credit When Credit Is Due

PERSPECTIVE

26 Repairing the Disconnect Between Research and Teaching

NEWS AND NOTES

28 The Hidden World of Membrane Proteins

30 Neuroscience of Music31 Mini-Courses in Moscow31 New Museum Grants Awarded32 Reason to Stay Another Year

33 A River Runs Through Us

34 If You Can Name That Tone, Thank Your Parents— and Your Music Teacher

35 A Science Connection in Roxbury

35 New Undergraduate Competition

36 HHMI Lab Book

38 HANDS ONMay I Take Your Mouse Order, Please?

40 CLOSE-UP“Home-Grown” Proteins Build Synaptic Strength

42 FROM THE TOOLBOXTrapping the Genes that Wire the Brain

44 HHMI ONLINEHow to ZAP the Signals that Lead to Rheumatoid Arthritis

On the Cover: Electron micrograph of a yeast prion protein, called Sup35. Protein fibrils similar to these can aggregate and tangle in many degen-erative brain diseases, including Alzheimer's and mad cow disease. Image by Tony Kowal and Susan Lindquist

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September 2001 || Volume 14 Number 4

� Six hhmi investigators were elected tothe American Academy of Arts andSciences: Pietro De Camilli, Yale UniversitySchool of Medicine; Brigid L. M. Hogan,Vanderbilt University School of Medicine;Richard L. Huganir, The Johns HopkinsUniversity School of Medicine; Michael A.

Marletta, University of Michigan MedicalSchool; Roel Nusse, Stanford UniversitySchool of Medicine; and Charles S. Zuker,University of California, San Diego, Schoolof Medicine.

� Graeme I. Bell, an hhmi investigator atThe University of Chicago, won the 2000Naomi Berrie Award from ColumbiaUniversity for diabetes research achievement.

� Two hhmi international research schol-ars, B. Brett Finlay, University of BritishColumbia, and Roderick McInnes, theHospital for Sick Children in Toronto, wereelected fellows of the Royal Society ofCanada.

� Sergio Grinstein, an hhmi internationalresearch scholar at the Hospital for SickChildren in Toronto, received the 2001Malcolm Brown Award from the Canadian

Federation of Biological Societies. Theaward is given once every three years forhealth sciences research in Canada.

� Arthur L. Horwich, an hhmi investigatorat Yale University School of Medicine, wonthe 2001 Hans Neurath Award from theHans Neurath Foundation and the ProteinSociety for contributions to protein science.

� Richard P. Lifton, an hhmi investigator atYale University School of Medicine, wonthe 2001 Robert J. and Claire PasarowMedical Research Award for his cardiovas-cular research. He shared the award withPasko Rakic, a Yale University neuropsychi-atrist, and cancer researcher AlexanderVarhavsky of the California Institute ofTechnology.

� Roderick MacKinnon, an hhmi investiga-tor at The Rockefeller University, shared the2001 Gairdner International Award formedical research with Clay Armstrong andBertil Hille (see story, page 4).

� George Mosialos of Greece and Laszlo Nagy

of Hungary, both hhmi internationalresearch scholars, were selected by theEuropean Molecular Biology Organization

N O T A B E N E

to be embo young investigators, scientistsin member countries whose early researchhas been distinguished.

� Thomas A. Steitz, an hhmi investigator atYale University, was named one of threewinners of the 2001 Rosenstiel Award fromBrandeis University for distinguished workin basic medical sciences.

� Joseph S. Takahashi, an hhmi investigatorat Northwestern University, received the2001 W. Alden Spencer Award from theCollege of Physicians and Surgeons ofColumbia University. The award honorsyoung scientists who have made originalcontributions to neurobiology.

� Two hhmi investigators, Marc Tessier-

Lavigne, University of California, SanFrancisco, and Brigid L. M. Hogan, VanderbiltUniversity School of Medicine, were electedfellows of the Royal Society of London.

� Bert Vogelstein, an hhmi investigator atThe Johns Hopkins University School ofMedicine, won the 2001 InternationalChiron Award for Biomedical Research andTraining, given by the Italian NationalAcademy of Medicine.

2 h h m i b u l l e t i n | s e p t e m b e r 2 0 0 1

Holiday Lectures on Science November 29 and 30, 2001

THE MEANING OF SEXGenes and GenderFour one-hour lectures by

Barbara J. Meyer, Ph.D. David C. Page, M.D.HHMI Investigator HHMI InvestigatorUniversity of California, Berkeley Massachusetts Institute of Technology

Simultaneous Webcast

For more information: www.holidaylectures.org

Mention “biomedical research” to people outsidethe scientific world and they may well envisiona physician testing a new drug. They may notrealize that most biomedical researchers studybiological processes rather than specific dis-

eases, and never interact with patients. In recent decades, in fact,many of the most important discoveries in biomedical researchhave resulted from the study of fundamental biological problems,such as how organisms develop, how genes function and how cellscommunicate. These studies, in all likelihood, were conductedusing fruit flies, mice, yeast and other organisms—not humanpatients. That’s the kind of research we’ve emphasized at theHoward Hughes Medical Institute (hhmi), knowing that somefraction of it inevitably contributes to advances in clinical medi-cine that save people’s lives.

For all of the discoveries that scientists around the world havemade about oncogenes, tumor-suppressor genes, the cell cycle andprogrammed cell death, however, fundamentally new treatments forcancer patients have been slow to appear. We know far more aboutthe immune system and retroviruses than we did when aidsappeared 20 years ago, yet that disease remains a growing scourgethat is claiming untold millions of lives, particularly in the develop-ing world. Researchers have identified more than a thousand geneticflaws involved in illnesses ranging from cystic fibrosis to Alzheimer’sdisease, but physicians generally remain unable to fix these flaws.Advances in basic science have been breathtaking, in other words,but translating them into therapies has been difficult.

Ironically, our success in basic science now compels us to lookback to the days when biomedical research almost always meantworking with patients. After all, what is seen in a test tube or a fruitfly, for example, does not necessarily occur in a human being, andonly a small percentage of promising discoveries ends up having adirect impact on medicine. Fortunately, as we deepen our under-standing of how the human body operates at the cellular andmolecular levels, it is becoming possible to carry out new kinds of“patient-oriented research” to learn which insights might pay off.

The experience of hhmi investigators who do work directlywith human patients demonstrates that such a patient-focusedapproach can yield unique and potentially valuable medicalinsights. Recent issues of the Bulletin, for instance, have describedHuda Zoghbi’s research at Baylor on mental retardation, RickLifton’s work at Yale on hypertension and Andy Chan’s work atWashington University on rheumatoid arthritis. Similarly, BertVogelstein at Johns Hopkins has worked closely with patients formany years as he helped uncover the genetic secrets of colon cancer,

as have other hhmi investigators who specialize in heart disease,diabetes and other disorders, combining the latest techniques ofmolecular biology with their special perspectives as physicians.

These “physician-scientists” work closely with patients, which isnot the case with all physicians engaged in research. Indeed, manyM.D. and M.D./Ph.D. researchers pursue the same kinds of researchas Ph.D.s, focusing on basic biological questions; although they mayhave an interest in certain diseases, they do not integrate theirresearch with the medical problems of the patients they treat. Thesescientists have contributed tremendously to biology’s bounty, to besure, but the system should encourage physician-scientists to takefull advantage of their special knowledge and experience.

Wanting to make an impact on this situation, we recentlyannounced an initiative at hhmi to encourage the support ofpatient-based biomedical research. In June, we sent letters to 119medical schools and schools of public health, inviting them to nom-inate physician-scientists to become hhmi investigators. We expectto appoint as many as 10 new investigators—a modest number, butone that builds on the Institute’s existing cadre of patient-orientedinvestigators. Hopefully, other organizations may be stimulated toincrease their investments in this area as well.

At the same time, hhmi is contributing to keeping the pipelineof such scientists flowing through its research training fellowshipsfor medical students and the hhmi-nih Research ScholarsProgram, which enables medical school students to join researchteams for a year or two on the campus of the National Institutes ofHealth. We are also considering additional ways to promote thiskind of research in the future. Having seen our patience in basic sci-ence pay off so handsomely, we believe it’s time to give “patientresearch” a broader meaning.

Thomas R. CechPresident

Howard Hughes Medical Institute

h h m i b u l l e t i n | s e p t e m b e r 2 0 0 1 3

P R E S I D E N T ’ S L E T T E R

Putting Patients Back intoBiomedical Research

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U p Fr o n tA Crystal-Clear Focus on Ion ChannelsRod MacKinnon forges his own path to study potassium gateways.

electrical potential of membranes through-out nature, thereby generating nerve impuls-es and controlling muscle contraction, car-diac rhythm and hormone secretion.”Intimate knowledge of the proteins is expect-ed to lead to the synthesis of pharmaceuticalcompounds that can affect conditions direct-ly or indirectly related to ion flow.

Although MacKinnon toyed with micro-scopes as a youth, his serious interest in sci-ence was bestowed on him by his greatest sci-entific influence—his undergraduate adviserat Brandeis University, Christopher Miller,also an hhmi investigator. Miller, just start-ing his laboratory in the mid-1970s, waslooking at a number of processes involvingion transport, including calcium pumping inthe sarcoplasmic reticulum, a mechanism in

muscle cells that is critical fornervous excitation. MacKin-non joined the effort,becoming Miller’s first stu-dent. Both scientists like topoint out that Miller’s dogGribet was already a labmember, but one can stillsafely say that MacKinnonwas Miller’s first researchassistant who had the handyattribute of opposablethumbs.

MacKinnon went on tomedical school—againstMiller’s advice—and thenpracticed medicine for fouryears. Realizing then that heyearned to return to basicresearch, he made a pilgrim-age to Miller’s lab to talkabout his assumption thatsuch a move would requireadditional training and evena Ph.D. Miller bluntlyinformed his former studentthat the acquisition of a doc-torate was redundant, as theM.D. already fulfilled thatqualification.

MacKinnon thusrejoined the Miller lab, as apostdoctoral fellow investi-gating potassium channels. “Ihad a sense I had a lot ofcatching up to do,” MacKin-non recalls. “And the onlyway to really do that was, Ithought, to knuckle down, and read andstudy and do as much as I could to learn onmy own. I learned a lot from books and Ilearned a lot by just trying things out myself.That made me very confident about learningon my own. And that stuck with me.”

In 1989, MacKinnon started his own lab-oratory at Harvard to study ion channelsusing a technique, called mutagenesis, thatintroduces variations in single amino acids inthe protein sequence. Alterations in the pro-tein’s behavior resulting from a change in alone amino acid reveal those regions of theprotein that are critical for its function. Butthe going is slow, like feeling one’s waythrough a dark room. “It became clear that inorder to understand the chemistry of the

Isaac Newton acknowledged that hisscientific vision was sharper becausehe was “standing on the shoulders ofgiants.” Science historian GeraldHolton, commenting on the accelerat-

ed pace of research, gave Newton’s famousline a modern twist: “We are now uniquelyprivileged to sit side-by-side with the giantson whose shoulders we stand.” Holton’stongue-in-cheek comment certainlydescribes the seating arrangement at the1999 Albert Lasker Basic Medical ResearchAwards ceremony—at least from hhmiinvestigator Roderick MacKinnon’s point ofview. MacKinnon had the privilege of shar-ing the prestigious basic medical researchprize with a personal giant—Clay M. Arm-strong, of the University of PennsylvaniaSchool of Medicine—whose publicationshad an enormous influence on MacKinnon’sdevelopment as a scientist.

MacKinnon, Armstrong and Bertil Hille,of the University of Washington (and amember of the hhmi scientific reviewboard, for neuroscience), were honored for“elucidating the functional and structuralarchitecture of ion channel proteins.” MacK-innon’s particular contribution was the deter-mination of the three-dimensional structureof a potassium ion channel, using x-ray crys-tallography. Simply attempting to examinethe channel via this uncharted route wasdeemed highly questionable by many andfoolhardy by some. Great risk, however, canbring great reward—and his ultimate successwas judged by Armstrong, writing in thejournal Science, to be “a remarkable accom-plishment” and “a dream come true for bio-physicists.”

A great deal was at stake in MacKinnon’squest to understand the as-yet-unseen ionchannel proteins, as the Lasker proclamationattests: “ion channel proteins … govern the

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In this potassium channel, potassium ions (green)

lose a shell of water (red) to pass through a selec-

tivity filter (ball-and-stick).


thing, we would have to see it,” MacKinnonsays, “because ultimately it is a structuralissue. And it was clear that mutagenesis couldnever answer those questions.” He resolved toattempt x-ray analysis of ion channels,which, being membrane proteins, areextremely difficult to crystallize.

Miller advised him to start the projectslowly, on the side, while continuing todirect his bustling lab at Harvard in tried-and-true mutagenesis work. MacKinnonagain considered and then declined his men-tor’s advice. “I felt once again I could teach

myself and talk to people to make sure I wason the right path,” he recalls.

To make the transition to x-ray crystal-lography, MacKinnon accepted an offerfrom The Rockefeller University, and in1996 moved to New York City. There, hiswife and a lone postdoc stood by him as hecranked up his research. “Rockefeller gaveme this big lab,” he recalls, laughing. “AndI was embarrassed to have people visit me.I thought, ‘How am I going to explain thereare only three of us? They’re going to takethe lab away.’”

The quiet, however, was apparentlygood for MacKinnon’s concentration. Inonly two years—during which time hebecame an hhmi investigator and

painstakingly developed his new methodol-ogy—he succeeded in deducing the three-dimensional structure of the potassium ionchannel protein. The structure revealed, forexample, that the channel coaxed potassiumions with a portal that includes an array ofoxygen atoms that surround the ion like acage. The resulting chemical climate is simi-lar to the oxygen-rich, watery environmentthat the ions ordinarily prefer.

The structure revealed why the potassi-um ion channel is selective, encouraging theflow of charged potassium while discourag-ing sodium ions. Both types of ions have thesame charge (+1), and the sodium ion is sig-nificantly smaller, thus a simple sieve wouldaccept both sodium and potassium ions.However, the large size of the oxygencages—perfect fits for potassium ions—pre-vents the smaller sodium ions from everfalling under the electrostatic influence ofenough individual oxygens to be compelledto make the trip through the pore. Nature’sclever structure thus solves multiple prob-lems simultaneously.

Meanwhile, the accolades keep coming:MacKinnon won this year’s Gairdner Foun-dation International Award, which recog-nizes achievement in medical science. Heonce again rubbed shoulders with Arm-strong, who shared the Gairdner, along withHille and Harvard cell biologist MarcKirschner. MacKinnon is now focused ondetermining the structure of another speciesof potassium ion channel, one with a volt-age-sensitive gating system. This channel’sion portal should be quite similar to that ofthe channel already elucidated. But an addi-tional structure that straddles the membraneacts as a voltage meter, reading the voltagedifference between the inside and outside ofthe cell and opening or closing the gate tocontrol the flow of ions. “When we see thatstructure,” MacKinnon says, “I think we’llunderstand how the channel works.”

MacKinnon’s scientific reputation maybe assured, but his research focus couldshift once again. “Right now I’m thrilledwith what I’m working on,” he says. “But Ithink I’ll reach a point where I want tothink about something new. I’m not readyfor it yet, but I’ll probably do it at least oncemore before I’m too old.” Don’t bothertelling him he can’t. —STEVE MIRSKY

MacKinnon is probing the structure of a potassium

channel that controls ion flow by reading the voltage

difference between the inside and outside of the cell.


U p F r o n t

Ask a pro ballplayer about ahome run he hit 30 years agoand he may say, “Runner onfirst, two outs, two strikes,Seaver fastball up and inside, I

pulled it down the line and into the secondrow.” Ask the same man the date of his wed-ding anniversary and the response may comein the form of a wrinkled forehead. Such isthe slippery stuff of memory.

hhmi investigator Eric Kandel wasawarded the Nobel Prize last October for hisdiscoveries concerning the molecular natureof memory. In studies on invertebrates, Kan-del, of New York’s Columbia University,showed that memory storage depends on thecoordinated expression of specific genes thatcode for proteins involved in making newsynaptic connections. (The part of a ballplay-er’s brain in which game situations are storedmust be a synaptic thicket.) There is a flipside, however, as Kandel reported in theMarch 9, 2001, issue of the journal Cell:Working with a transgenic mouse, he and hiscolleagues announced the first direct evidencein a mammal for genes involved in actuallysuppressing memory. (This discovery doesnot serve as an excuse for anniversary amne-sia.)

In a previous mouse study, Kandeldemonstrated that overexpression of theenzyme calcineurin interfered with memo-ry, providing damning circumstantial evi-dence that calcineurin is a memory suppres-sor. “But the really definitive evidence iswhen you remove it and the animal getssmarter,” Kandel says of the strategy used inthe Cell study. Indeed, the animal did getsmarter—in terms of memory of objectsand locations.

Removing calcineurin from the memo-ry-storage mechanism required the creationof a transgenic mouse with a gene for a cal-cineurin inhibitor that was controllable—itcould be switched on and off by administra-tion of the antibiotic doxycycline. This sys-tem allowed the researchers to conclude that

MemorableMouse

their transgenic mouse was normal in allother respects when the inserted gene wasinactive and that no other systems had beenaffected during development.

“Why do we have a brake on memory?”Kandel asks. “There are probably several rea-sons. One is that you probably don’t want toremember everything that you encounter. Alot of things that happen to you are trivial,and getting rid of that information fairlyrapidly is probably a good thing. We don’tknow what the limits of the storage capabili-ties of the brain are, but there probably is,for each major category of learning, a limitas to how much you can put in there.”

The assumption that similar memory-suppression systems exist in human brainsbrings up the issue of filtering: We are nodoubt constantly making judgments as towhat is worthy of inclusion in our collectionof mental memorabilia. “The amazing thingabout the mind is that it’s just filled with prej-udice,” Kandel notes. “The mind is preparedto learn certain things and to remember cer-

tain things, and not others.” Evolution hasprobably ensured that certain memories bestrongly stored—for example, the location ofan abundant food source. Individual memorystrengths, however, like those of our hypo-thetical ballplayer, may be more idiosyncratic.

With an aging population, the detailedunderstanding of the mechanisms of memoryis of obvious interest in pharmaceutical devel-opment. “Clearly, there are two approaches,”Kandel says of any future memory drugs.“You act on positive regulators and makethem stronger, or you work on inhibitory reg-ulators and make them weaker. So calcineurinis a perfectly reasonable candidate.” Theenzyme is not an easy one, though, as Kandelpoints out: Existing calcineurin inhibitorswould also suppress the immune systembecause of the enzyme’s roles in other path-ways in the body. Nevertheless, the search fortechniques to impede memory-suppressiongenes is only in its infancy—and researcherswill quite likely remember to follow in Kan-del’s first footstep. —STEVE MIRSKY

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P E R S P E C T I V E

My colleagues and I were intrigued recently bysomething that happened at several meetings ofbiomedical researchers that we attended—something clearly so common in the culture ofbasic science that the researchers themselves

probably didn’t even notice. At the beginning or end of theirtalks, the scientists showed slides naming every person who con-tributed to their research. They listed not only their faculty col-leagues, but also postdocs, grad students, under-graduates, and technicians and, in some cases, theadministrative and glass-washing staff. Typically,the scientists read each name and carefully delin-eated each person’s achievement—some evenshowed photos of their team members.Throughout their presentations, they noted wherethey had built on the research of others and whichcolleagues had assisted them, often across scientif-ic disciplines.

We were also struck by how seriously the scien-tists viewed their roles as mentors.Not only did they publicly credittheir junior colleagues and staff intheir talks, but many brought post-docs or others to the conferenceand included them in their conver-sations and meals. The junior col-leagues, in turn, routinely andproudly identified themselves inconversation and on their namebadges as being in the laboratory of their mentors. It was obvious,in other words, that everyone was taking responsibility for makingthese mentoring relationships work.

For someone from another discipline—in my own case, reli-gious studies and ethics—this was an impressive set of “culturalperformances” that exemplified important operative values of thescientific community. Now I recognize that scientific research feedsas much on competition and drive as it does on collaboration andcrediting, but the spirit of collegiality I witnessed at these meetingsspurred me to take a fresh look at the norms of my own communityof bioethics. It is not uncommon in the humanities, for example, tohear tales of one scholar using or quoting another’s research with-out attribution. Nor is it unusual for scholars at the same institutionto know nothing about the work of their colleagues, much less tofeel a sense of association with that work. In the hospital, which isthe clinical setting where many bioethicists work, the model of con-versation, reporting and debate is often profoundly hierarchical.This structure emerges from a culture in which one person neces-

Giving Credit When Credit Is DueBy Laurie Zoloth

sarily takes responsibility as the “captain of the ship” and assumesthat much essential support work will be done by people who arenot commonly credited when the outcome of a case is successful.

This situation is ironic because the practice of providing robust,public citation has a long tradition in the world of religious studies.In the Talmud, it is noted that failing to credit your insights, in thename of the one who has taught you, is akin to linguistically “killing

the teacher,” who is thereby “erased” in the textualsense.

Some may argue that, of course, biomedicalresearch differs from the humanities in someimportant ways, because, for example, it is experi-mental or it requires teams—but I think these dif-ferences are not as great as they might seem. In real-ity, much of our work in any university departmentwould also be impossible without a team effort.

My experience attending scientific meetingshas caused me to wonder what might happen if

bioethicists and others in thehumanities adopted practices likethose I observed at the biomedicalresearch meetings. What would itbe like if we fully credited everyonewho helped us think through “our”ideas? What if we routinely recog-nized the teachers who hadbrought us along? How might webegin to implement such norms? I

have begun to discuss these ideas with colleagues and will becurious to see where our discussions lead.

Usually, when scientists interact with bioethicists, the expec-tation is that those of us on the “ethics” side will help the scien-tists think through the moral dimensions of their research. As myrecent experience illustrates, however, the lessons actually flow inboth directions. Personally, I have already learned two ethical les-sons from watching scientists in action and observing their cul-ture. First, all of us should identify with and take responsibilityfor the “shops” we work in, honoring our mentors and mentoringour students. Second, we should remember that honor for ourwork is never a personal matter, but rather a collective effort anda collective triumph, made possible by a team in which each con-tributor, whatever her role or status, is essential.

“We should remember that honorfor our work is never a personalmatter, but rather a collective

effort and a collective triumph.”

Laurie Zoloth, an associate professor of social ethics and director of the Programfor Jewish Studies at San Francisco State University, is among a group of ethicistswho recently participated in scientific meetings at hhmi headquarters in Maryland.

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f ter dec ades of pessimism abo ut the ch a n ces of everfinding ef fective tre a tm ents for Al z h ei m er ’s disease,Hu n ti n g ton’s disease, Lou Geh ri g’s disease and otherprogre s s ive kill ers of the brain su ch as mad cow disease,s c i en tists have produ ced a flood of n ew discoveries thatlink these out w a rdly unrel a ted ailments and su gge s tw ays in wh i ch they might be revers ed or preven ted .

What these diseases have in com m on is a plagueof a bn orm a lly shaped pro teins that sti ck toget h er and de s troy brain cell s .Di f ferent pro teins are at fault in each disease. Th ey affect different part sof the bra i n , and they produ ce diverse sym ptom s . Yet all these pro tei n sa re “m i s fo l ded ,” meaning they have strayed from their proper three -d i m en s i onal shape s ; ei t h er they never re ach ed these shapes as theyem er ged from ti ny pro tein factories inside the cell , or they became cor-ru pted . So, i n s te ad of doing their normal job s , these pro teins form aggre-ga tes of i n s o lu ble gunk, and in this process they deva s t a te the bra i n .Some of t h em — “pri on s” — a re even infecti o u s ; t h ey cause mad cow dis-ease and its human co u n terp a rt ,n ew - va riant Creut z fel d t - Ja kob disease.

The big qu e s ti on now is how to clear up—or preven t — pro tei n

New discoveries link

seemingly unrelated,

fatal illnesses such as

A l z h e i m e r ’s disease and

H u n t i n g t o n ’s disease

to misshapen proteins,

p r oviding hope for

new treatments.

BY MAYA PINES

A

C l e a r i n gTox i c

Clumps f rom the

B ra i n

Protein.Final 10/9/01 8:24 PM Page 8

Prion proteins (red) aggre g a te in a

m o u se neuro b l a stoma cell that is infe cte d

with the prion dise a se called sc rapie.

The cell’s nucleus is shown in blue.



clu m p s . Coming from several different directi on s , re s e a rch ers haveu n covered a va ri ety of po ten tial targets for dru gs . Equ a lly import a n t ,t h ey have learn ed how to try out their new rem edies on ye a s t , f l i e s ,worms or mice .“Th i n gs have re a lly ch a n ged in the past few ye a rs ,” s aysSusan L. L i n d qu i s t ,n ewly el ected director of the Wh i teh e ad In s ti tute forBi om edical Re s e a rch and form er h h m i i nve s ti ga tor at the Un ivers i tyof Ch i c a go, who works mostly with yeast cell s . “The first meeti n gs Ia t ten ded abo ut these diseases were so depre s s i n g … . But now we haves everal different kinds of s tra tegies that look as if t h ey might work ,s oeveryone shares an optimism that just wasn’t there before .”

A myloids in Alzheimer’sSome of the most promising re s e a rch invo lves the dre aded Al z h ei m er ’sd i s e a s e , wh i ch robs so many older people of t h eir abi l i ty to think or torem em ber, and then kills them . Al z h ei m er ’s affects an asto u n d i n glyl a r ge nu m ber of people—10 percent of those over age 62 and ro u gh lyh a l f the pop u l a ti on over age 85.

The brains of Al z h ei m er ’s pati ents are typ i c a lly ri d dl ed with stra n ge ,i n s o lu ble “p l a qu e s ,” wh i ch consist of a myl oid (small pro tein fibers thatform a hard mass). For a long ti m e ,t h ere seem ed no way to get at thea myl oi d — or the disease.

The “defining mom en t ,”according to Sa n gram Si s od i a , a re s e a rch eron Al z h ei m er ’s at the Un ivers i ty of Ch i c a go, came with the discoveryof s pecific mut a ti ons in the d na of certain unu sual families. Not on ly

1 0 h h m i b u l l e t i n | s e p t e m b e r 2 0 0 1

Susan L. L i n d quist can imagine severa lpo s s i ble stra tegies for tre a ting diseasesc a u s ed by misfo l ded pro tei n s : S c i en-tists might find or de s i gn pro teins ord ru gs that would bind to their sti ckysu rf aces and prevent other molec u l e s

f rom get ting tra pped there . Th eym i ght de s i gn pro teins that could insert

t h em s elves bet ween the aggrega tes andh elp break them up. Th ey might alter the

ch a perone balance of the cell to help en su re that the pro tei n sattain their correct shape . Or they could try to increase the activ-i ty of the cell ’s pro te a s om e , a sort of ga rb a ge can in the cytop l a s mthat ch ews up misfo l ded pro teins and gets rid of t h em .

A wi de ra n ge of diseases might be tre a ted with thesea pproach e s , she says . In ad d i ti on to the 20 or so amyl oid disor-ders and at least ei ght CAG - repeat diseases, Pa rk i n s on’s diseaseis a candidate . Th ere are some hel pful tre a tm ents for Pa rk i n s on’stod ay, but they do not get to the root of the disease, wh i ch invo lve sa ggrega tes of the alph a - s y nu cl ein pro tei n . Amyo trophic latera ls cl erosis (ALS, also known as Lou Geh ri g’s disease), too, has beens h own to invo lve pro tein aggrega tes—in this case, the pro tei nsu perox i de dismut a s e .

Th ere is even hope of tre a ting or stopping mad cow disease—bovine spon gi form en ceph a l i ti s , or BSE—before the disease spre ad sto large nu m bers of humans in the form of n ew - va riant Creut z fel d t -Ja kob disease.“I re a lly do bel i eve that most of these neu rodegen er-a tive diseases can be attacked ,” L i n d quist says .“ It may be five or tenye a rs aw ay, but we wi ll be able to make a real differen ce .” — M P

Pro s p e c t sfo r

Tre at m e n t

is Al z h ei m er ’s hered i t a ry in these families, but it also occ u rs very earlyin life : Mem bers may devel op the disease in their forties or fifti e s .

Certain families had errors in the gene that codes for amyl oid prec u r-s or pro tein (APP), a large molecule that is cut up by va rious en z ymes torelease pepti des of a myl oi d - bet a — i n cluding the type that acc u mu l a tes inAl z h ei m er ’s plaqu e s . In other families,t wo different gen e s ,pre sen i l i n - 1 a n dpre sen i l i n - 2, h ad mut a ti ons that also produ ce an increase in amyl oi d - bet a .

With these genes in hand, re s e a rch ers ch a r ged ahead ,c re a ting tra n s-genic mice and other animals in wh i ch the gen e s’ ef fects could be stu d i edra p i dly. One of t h eir first ex peri m ents showed that amyl oid plaques wereprodu ced in the brains of tra n sgenic mice with mut a ted APP gen e s , just likein those of Al z h ei m er ’s pati en t s . This ex peri m ent and others open ed thedoor to the po s s i bi l i ty of finding dru gs that co u n teract the ef fects of t h emut a ted gen e s .Several drug com p a n i e s ,i n cluding Bri s to l - Myers Squ i bb Co.and Am gen , In c . ,a re now racing to devel op com pounds that might pre-vent the en z ymes from snipping the prec u rs or pro tein and thereby stop therelease of a myl oi d - bet a . At the Na ti onal In s ti tute on Agi n g, in Ba l ti m ore ,re s e a rch ers devel oped an ex peri m ental drug call ed ph en s erine that simplydec reases the produ cti on of the prec u rs or pro tei n ,t h ereby lowering the levelof a myl oi d - bet a ; the drug is now in clinical tri a l s .

In 1999, re s e a rch ers at Elan Pharm aceuticals in So uth San Fra n c i s-co announced they had made a vaccine against Al z h ei m er ’s disease—and that it worked in tra n sgenic mice . The vaccine contains bits ofa myl oi d - bet a , prom pting the mice to make anti bodies against this su b-s t a n ce that app a ren t ly prevent Al z h ei m er ’s plaques from forming in thea n i m a l s’bra i n s . Human trials of this vaccine began last year and dem on-s tra ted its safety. Now the com p a ny wi ll test the vacc i n e’s ef f i c ac y.

Bel i eving the vaccine too good to be tru e ,t wo indepen dent te a m sof s c i en ti s t s — one led by Peter St. G eor ge - Hys l op, an h h m i i n tern a-ti onal re s e a rch scholar at the Un ivers i ty of Toron to, and the other byD avid Mor gan of the Un ivers i ty of So uth Flori d a — recen t ly set out toch a ll en ge its ef fectiven e s s . In s te ad ,t h ey en ded up su pp lying evi den ce inits favor. Af ter mice with the equ iva l ent of Al z h ei m er ’s disease receivedthe vacc i n e ,t h eir perform a n ce on mem ory tests cl e a rly improved .

An o t h er group at Tel Aviv Un ivers i ty in Is rael is bet ting on a differ-ent vacc i n e ,A N - 1 7 9 2 , to prevent or treat Al z h ei m er ’s . Th o u gh nothingis yet cert a i n ,s everal re s e a rch ers — i n cluding Lindquist —think that at thec u rrent ra te of s c i en tific progress there is a good ch a n ce of s eeing tre a t-m ents to slow down or prevent Al z h ei m er ’s disease within five to ten ye a rs .

A Clearance MechanismAn o t h er area “ wh ere there’s su d den ly a lot of opti m i s m ,” according toL i n d qu i s t , is Hu n ti n g ton’s disease (HD), a ra re inheri ted disorder thatis best known for having kill ed the folk singer Woodie Gut h ri e . Peop l ewith this disease slowly deteri ora te both men t a lly and phys i c a lly form ore than a dec ade , su f fering uncon tro ll a ble writhing movem en t sa l ong the way. Th o u gh the h u n ti n g ti n gene was iden ti f i ed in 1993, a f tera long search , its normal functi on is sti ll unknown and the mech a n i s mof the disease remains a mys tery. Nevert h el e s s , the gen e’s discovery hasl ed to some intere s ting findings—and new approaches to tre a tm en t .

The key to wh et h er the h u n ti n g ti n gene is normal or defectivetu rn ed out to lie in a kind of gen etic stut ter: a repeti tive sequ en ce of t h ed na tri p l et CAG , wh i ch codes for the amino acid glut a m i n e .S tretch-es of C AG “repe a t s”a ppear in every human bei n g’s h u n ti n g ti n gen e , butin va rying len g t h s . Wh ereas the normal gene has a sequ en ce of bet ween6 and 34 CAG repe a t s , the abn ormal gene contains many more . In fact ,

a ny stretch of d na containing more than 40 of these repeats en su res thatits be a rer wi ll devel op Hu n ti n g ton’s—and the gre a ter the nu m ber ofrepe a t s , the earl i er the disease stri kes and the gre a ter its feroc i ty.Re s e a rch ers also discovered that the abn ormal form of h u n ti n g ti n pro-du ces misfo l ded pro tei n s , wh i ch then sti ck toget h er in toxic clu m p si n s i de the pati en t s’ brain cell s .

People used to bel i eve that on ce Hu n ti n g ton’s disease begi n s , it is irre-vers i ble—that the gunk in the brain cells cannot be dissolved and thatthe brain cells are doom ed to die. But wh en Ai Ya m a m o to and Rene Henof Co lu m bia Un ivers i ty and their co lleagues te s ted this idea last ye a r, t h eyfound otherwi s e . Working wi t hm i ce that had been en gi n eered toc a rry an HD gen e , t h ey devi s ed aw ay to tu rn the gene on or of f a twi ll . Th en they showed that the dis-ease progre s s ed on ly as long as theh u n ti n g ti n gene kept chu rning outm ore of the abn ormal pro tei n .S topping this produ cti on , t h eyreported , “not on ly halts progre s-s i on of the disease, but can revers ea ggrega te form a ti on and progre s-s ive motor decl i n e .”

This was trem en do u s ly goodn ews—not on ly for Hu n ti n g ton’sp a ti ents and their families but forpeople con cern ed with any of t h e

o t h er diseases caused by misfo l ded pro tei n s .“ It proves that mammalsh ave a cl e a ra n ce mechanism that norm a lly rem oves this ju n k ,” s aysArt hur L. Horwi ch , an h h m i i nve s ti ga tor at Yale Un ivers i ty who stu d-ies how pro teins fo l d . He points out that HD and other diseases migh tbe revers i ble if one could find ways to shut of f the produ cti on of t h ea bn ormal pro tei n s . The cells that are de ad could not be revived , ofco u rs e , but those that are sick might be cured .“ It could happen ,”he says ,“ i f one could intervene ra p i dly en o u gh .”

Prodding Proteins into LineOne of the gre a test puzzles in bi o l ogy is prec i s ely how the body ’s bi ll i on sof pro teins fold into their correct three - d i m en s i onal shape s .Wh en aminoacids are first strung toget h er to make new pro tei n s , t h ey flop aro u n di n s i de the cell like coo ked spagh et ti . Th en they ra p i dly con tort into va r-ious parti a lly fo l ded states before adopting their final, active form .

Because scien tists knew that a special class of “ch a peron e”pro tei n sg u i de nascent pro teins tow a rd their proper stru ctu re ,t h ey won dered ifan ex tra su pp ly of ch a perones would help to preven t pro tein misfo l d-i n g. For instance , could it prod em er ging hu n ti n g tin pro teins su f f i-c i en t ly into line to prevent them from becoming toxic to neu rons?

Nancy M. Bon i n i , an h h m i i nve s ti ga tor at the Un ivers i ty of Pen n-s ylva n i a , dec i ded to try this idea out in Dro sop h i l a bec a u s e , as sheex p l a i n ed , “l a te - on s et , progre s s ive diseases su ch as Al z h ei m er ’s orPa rk i n s on’s can take months or ye a rs to devel op in mouse model s , butin fruit flies they take on ly 10 days .” In s te ad of working direct ly wi t hHu n ti n g ton’s , h owever, she foc u s ed on spinocerebellar ataxia type 3( S C A 3 , also known as Mach ado - Jo s eph disease), one of at least ei ght dis-eases caused by too many CAG repe a t s .

Af ter Bonini and her co lleagues inserted the human SCA3 gene intof ruit flies, t h ey found that the flies’ reti n a s , wh i ch contain nerve cell s , ra p-i dly degen era ted . The re s e a rch ers then produ ced a new strain of flies thath ad both the SCA3 gene and a gene for a human ch a perone pro tei n ,H s p 7 0 ,in the hope the ch a perones would come to the cell s’ re s c u e . Th ey did. Th ech a perones su ppre s s ed the disease, and the flies’ eyes rem a i n ed norm a l .

Ot h er re s e a rch ers , su ch as Huda Zogh bi , an h h m i i nve s ti ga tor atBayl or Co ll ege of Medicine in Ho u s ton ,a re working with mice as wellas flies. Zogh bi is working to find molecules that help su ppress the dam-a ge caused by CAG repeats in the fly, t h en use the mouse model toexamine how these molecules produ ce their ef fect s .

The Workhorse: Ye a stL i n d qu i s t’s favori te model or ga n-i s m , h owever, is S a cch a ro myce scerevi s i a e, or baker ’s ye a s t , wh i chcan be manipulated easily andgrows ra p i dly. Even tu a lly, s h eh ope s ,m odels of HD in yeast wi llprovi de a ro ute for “f i rs t - l evels c reens for ph a rm aco l ogical agen t sthat might reverse some of t h ed a m a ge” f rom CAG - repeat dis-e a s e s . “Obvi o u s ly, s om ething thatworks in yeast might not work inmammalian cell s ,” she says , “butyou can screen thro u gh many,m a ny more com pounds mu ch

h h m i b u l l e t i n | s e p t e m b e r 2 0 0 1 1 1

Susan L. Lindquist has new optimism that work in yeast, flies and worms will

bring important insights into protein misfolding in several fatal diseases.

Two senile plaques from the brain of a person with Alzheimer's dise a se conta i n

d e p os i ts of amy l o i d - b eta protein surrounded by degenerating nerve endings. Th e

black objects are neurofibrillary tangles within degenerating neuro n s.



The ep i demic of m ad cow disease thateru pted in Bri tish herds in 1986 has

s l owed down recen t ly, prob a bly bec a u s ethe co u n try ’s meat indu s try ch a n ged itsm et h ods of rec ycling animal byprod-u cts into cattle feed .

Yet an unknown nu m ber of a pp a r-en t ly healthy people who ate infected meat

in Britain long ago may be incubating a fatalbrain disorder, n ew - va riant Creut z fel d t - Ja kob

disease (vCJD), wh i ch seems to be caused by the same type of i n fecti o u spro tei n s , or pri on s , as mad cow disease. At least 105 people have beeni n fected ,m o s t ly in Bri t a i n , and 98 have alre ady died .

Mad cow disease and vCJD kill so many brain cells that they leaveholes in the vi cti m’s bra i n , making it look like a spon ge — wh i ch is whythese disorders are call ed “s pon gi form” d i s e a s e s . In sheep, the equ iva-l ent disease has been known for abo ut 300 ye a rs as scra p i e , a fatal ill-ness that makes its vi ctims trem ble and wobble fra n ti c a lly, of ten ru b-bing them s elves raw against the fen ces of t h eir pens as they try to stayu pri gh t . Th eir bra i n s , too, a re ri d dl ed with holes.

Was it scrapie that infected Bri tish cows? Maybe . But how co u l di n fectious pri ons overcome the usual barri er bet ween species? Recent stu d-ies by Jonathan S. Wei s s m a n , an h h m i i nve s ti ga tor at the Un ivers i ty ofCa l i forn i a ,San Fra n c i s co (u c s f) ,and gradu a te stu dent Peter Ch i en pro-vi de a po s s i ble answer. Working with two different species of ye a s t ,t h eys h owed that a yeast pri on , Su p 3 5 , can misfold into several “d ra m a ti c a llyd i f feren t” i n fectious shape s ; this property en a bles abn ormal pri ons fromone yeast strain to interact with normal pri on pro teins from other stra i n s ,i n ducing them to adopt similarly abn ormal shape s . In ye a s t ,a bn orm a lpri on pro teins clump toget h er and lose their normal activi ty. In mammals,

clumps of a bn ormal pri on pro teins may damage the bra i n .“Ot h er aggrega ti on diseases are ei t h er sporad i c ,l i ke most cases of

Al z h ei m er ’s , or inheri ted , l i ke Hu n ti n g ton’s ,” s ays Wei s s m a n . “Wh a tm a kes mad cow disease so fri gh tening and unu sual is that it’s infecti o u s .But that also gives you a ch a n ce to el i m i n a te it.”

All mammals, i n cluding hu m a n s ,c a rry the pri on gene Pr P,wh i ch wasd i s covered and named by Stanley Pru s i n er of u c s f in the 1980s. Pru s i n-er and others showed that tra n sgenic mice lacking the pri on gene wereto t a lly resistant to infecti on with scra p i e .“One of the keys tone ex peri m en t sin the pri on hypothesis was to del ete the pri on gene from mice and showthat now they weren’t capable of acqu i ring the disease,”com m ents Art hu rL . Horwi ch , an h h m i i nve s ti ga tor at Yale Un ivers i ty.Wh en these mice weregiven a normal pri on gen e ,t h ey became su s cepti ble to scrapie aga i n .

Several re s e a rch teams have been looking for ways to el i m i n a tePr P- s c rapie aggrega tes or to prevent them from forming in the first place .“We work with molecules that den a tu re PrP pro tei n ,” s ays Fred Co h en ,at u c s f, wh ere he co ll a bora tes with Pru s i n er.“We learn ed that bra n ch edpo lyamines work well in cell cultu re . But they don’t cross the bl ood -brain barri er and don’t get into the bra i n , so they cannot be used on ani-m a l s . However, t h ey could sti ll be qu i te useful as disinfect a n t s .” Th erea re no good disinfectants against abn ormal pri on s , and cases of peop l econ tracting Creut z fel d t - Ja kob disease from su r gical instru m ents orf rom corneal transplants have been reported .

“We also found that some anti bodies actu a lly clear pri ons frommouse cells infected with scra p i e ,” Co h en says .“This argues that pri ondiseases may be tre a t a ble with anti bod i e s .”Most recen t ly,Pru s i n er's te a mex a m i n ed a large nu m ber of com pounds that are known to cross thebl ood - brain barri er and discovered that two older dru gs — ch l orpro-m a z i n e , an anti p s ych o ti c , and qu i n ac ri n e , an anti m a l a rial agen t — pre-vent the form a ti on of PrP scra p i e . Th ey are so en co u ra ged by this find-ing that they su ggest the dru gs are “ i m m ed i a te candidate s” for tre a ti n gCreut z fel d t - Ja kob disease and other pri on diseases, and have beg u nte s ting them in people dying from CJD.

S ti ll , the best approach would be pre-ven ti on , Weissman points out .The new - va ri-ant CJD is “a very aggre s s ive disease,”he says .“Once you have the symptoms of vCJD, itwill be difficult to treat.” Because there’s noblood test for the disease,the American RedCross announced in May that it would stopaccepting bl ood from anyone who has spen tas little as three months in the United King-dom or six months el s ewh ere in Eu rope du r-ing the past two decades.

Weissman would like to know wh a tmakes cows or people susceptible to thesed i s e a s e s . Si n ce some sheep are natu ra llyresistant to scrapie, it might be possible tofind bu lls that are natu ra lly resistant to pri ondiseases and use them to breed more-resist-ant cattle herds.“I f we can learn where madcow disease came from and how it is trans-mitted,” he says,“we may be able to ensurethat the cattle supply is completely free ofm ad cow disease—and to prevent futu reoutbreaks.” — M P

The M a dC ow

C o n n e c t i o n

Jonathan S. Weissman (right) and grad student Peter Chien determined how

prions can jump from species to species.


m ore ra p i dly and mu ch morech e a p ly in yeast than you could inmammalian neu ronal sys tem s .”

Even more import a n t , per-h a p s , re s e a rch on yeast may lead tos ome basic insigh t s . “The prob-l em of why pro teins misfo l d — a n dwhy that is associated with toxic-i ty—is very com p l ex ,” L i n d qu i s ts ays .“ It’s su ch a com p l ex probl emthat I think it’s real ly importantfor lots of people to be working onit, and to be approaching it fromdifferent angles.”

One re a s on for the com p l ex i-ty is that “t h ere seem to be a va ri-ety of d i f ferent ways in wh i ch pro teins can misfo l d ,” she ex p l a i n s .“ Inad d i ti on , t h ere are different kinds of a ggrega te s .” To make matterswors e ,“a ggrega ted pro teins are re a lly misera ble to work wi t h ,” she says .“You can’t crys t a ll i ze som ething that’s an aggrega te , so you can’t use x-ray crys t a ll ogra phy. You can’t use any of the typical tools for the stu dyof pro tein stru ctu re , wh i ch requ i re the pro tein to be ei t h er in soluti onor free . So we’re redu ced to using some fairly pri m i tive too l s , and wh enyou see a big bl ob inside a cell you can’t tell wh et h er it’s the same asa n o t h er bl ob.Yet one bl ob might be toxic and the other not. One migh tprovi de a su rf ace for other pro teins to bind on , while others don’t .

“ It’s not even cl e a r,” she ad d s ,“ wh et h er it’s the aggrega te per se that’stox i c . Could it be some earl i er misfo l ded interm ed i a te? The large aggre-ga tes might be the cell ’s way of s equ e s tering material to pro tect itsel f … .This fundamental probl em has not been solved .”

At least in Hu n ti n g ton’s disease,wh i ch Lindquist has been stu dying inyeast cell s , she bel i eves that the re a lly dangerous state is the small aggrega te s .“ But we don’t know how mu ch that applies to other diseases,”she says .

The Influence of Pr i o n sYeast may in fact provi de the key to understanding not on ly amyl oid dis-eases and CAG - repeat diseases, but also “s pon gi form en ceph a l op a t h i e s”su ch as mad cow disease, wh i ch have been attri buted to pri on s . The veryi dea of pri ons makes many scien tists uneasy because it vi o l a tes the funda-m ental principle that the pre s en ce of nu cl eic ac i d s , su ch as DNA , is essen-tial both to inheri t a n ce and infecti on . Yet pri ons produ ce clumps in thebrain that are infectious event h o u gh no nu cl eic acid seems to bei nvo lved . In ad d i ti on , pri ons canpass their traits ac ross gen era ti on s .

L i n d quist came to pri ons byacc i den t . “We just happen ed to beworking on a pro tein call ed Hsp104,wh i ch is a heat-shock pro tei n — i t’svery important for thermal to l er-a n ce in ye a s t ,”she says .“Ot h er ch a p-

erones just bind to part ly fo l ded pro-teins and keep them from get ti n gi n to tro u bl e , but Hsp104 can actu-a lly take a stru ctu re and ch a n ge it. Itcan take apart newly form ed aggre-ga tes that are caused by heat stre s s .So I prefer to call it a rem odel i n gf actor ra t h er than a ch a peron e .

“Th en we got a call from Yu ryCh ern of f ,” L i n d quist rec a ll s . Nowat Geor gia Tech , Ch ern of f was thena scien tist in Susan Liebm a n’s labat the Un ivers i ty of Ill i n ois wh owas stu dying [PSI], a gen etic tra i tin yeast that seem ed to be dis-obeying Men del ’s laws of i n h eri-

t a n ce .( Su ch traits used to be label ed “n on - Men del i a n ,”but now they arei n d i c a ted by bracket s : [PSI].) “ He had been trying to cl one genes thatcon trol [PSI]’s inheri t a n ce ,” L i n d quist rec a ll s , “and he said the on ecl one that re a lly had a big ef fect was the gene for this pro tein we had beenworking on , H s p 1 0 4 . We had n’t yet publ i s h ed mu ch on its molec u l a rm ech a n i s m s .

“Susan Liebman had been working on [PSI] for a lon g, l ong ti m e .So we co ll a bora ted with her and Yu ry, and we showed that you co u l dc u re yeast cells of this trait just by tra n s i en t ly ch a n ging the level ofH s p 1 0 4 . The normal state was then passed on from one yeast gen era-ti on to the nex t . This was a very strong argument that the trait was inher-i ted thro u gh a pro tein stru ctu re”—in other word s ,t h ro u gh a pri on .

A little later, L i n d quist discovered that Hsp104 also con trols thea ggrega ti on state of the hu n ti n g tin pro tei n , at least in ye a s t . “So nowwe’re using Hsp104 in yeast to ch a n ge the aggrega ti on state of hu n ti n g ti nand to test some models of h ow its tox i c i ty might ari s e ,” she says . Nex t ,she plans to look for “a gents that might interfere with the tox i c i ty,” f i rs tin ye a s t ,t h en in mammals.

L i n d quist bel i eves pri ons arise wh en certain normal pro teins acc i-den t a lly produ ce folding interm ed i a tes that have a sti cky su rf ace .“That su rf ace provi des a tem p l a te for other parti a lly unfo l ded pro tei n s ,wh i ch bind with it and wind up get ting tra pped ,” she ex p l a i n s .“ L i t t l ea ggrega tes of pro tein are then passed on from mother cell to daugh-ter cell thro u gh the cytop l a s m , and wh en the daugh ter cell starts mak-ing her own pro tei n s , these have the same capac i ty to get tra pped on

l a r ger aggrega te s .“ It’s very heri t a bl e . It’s very

reprodu c i bl e ,” L i n d quist says . “ Ifyou cross a cell that has a pri ontrait with a cell that doe s n’t , t h epri on trait is alw ays dom i n a n tbecause it’s got that sti cky su rf ace ,and the other pro teins join up to it.Th en all the cell ’s progeny wi ll havethat trait in them .”

To devel op approri a te te a t-m en t s , i t’s essen tial to unders t a n dthe basic mechanisms of pro tei nm i s fo l d i n g,as well as how misfo l d-ing can perpetu a te itsel f , she says .

A rthur L. Horwich believes that

H u n t i n g to n’s dise a se and similar diso r-

d e rs might be reve rsible, if abnormal

p rotein pro d u ction could be shut down. H

s e p t e m b e r 2 0 0 1 1 3

M u scle cells in a worm's body wall show the effe ct of an excess of CAG re p e a ts ,

as occurs in Huntingto n’s dise a se. A normal C. elegans w h ose DNA contains no

m o re than 19 CAG re p e a ts produces protein that is dist r i b u ted eve n l y

t h roughout the muscle cells (left). With too many CAG re p e a ts, the prote i n

forms uneven clumps (right).


n mid-Ma rch , wh en the Bri tish ep i demic of h oof - a n d - m o uth disease(h m d) appe a red to be spiraling out of con tro l , the govern m en ta ppe a l ed to the co u n try ’s scien tists for hel p. Am ong those wh oa n s wered the call was Neil Fer g u s on at the Im perial Co ll ege Sch ool ofMedicine in Lon don , an h h m i i n tern a ti onal re s e a rch scholar wh odevel ops mathem a tical models of i n fectious diseases.

Fer g u s on’s models are inform ed by the bi o l ogy of d i s e a s e s — f romthe molec u l a r- l evel acti on of p a t h ogens and host immu n i ty to theenvi ron m en t a l ,s ocial and beh avi oral factors that work at the pop u l a-ti on level . His models of h m d l ed him to draw some stark con clu s i on s :

The ex i s ting con trols weren’t working and the long del ays bet ween diagnosis ands l a u gh ter of i n fected animals were fueling the ep i dem i c .A more aggre s s ive erad i c a ti onprogram was needed . This would invo lve the culling of animals on farms su s pected ofi n fecti on within 24 hours , wi t h o ut waiting for con f i rm a ti on from the lab; a ll animalson nei gh boring farms had to be cull ed within 48 hours .

The other three modeling teams that advi s ed the govern m ent came to the samecon clu s i on s . The military was call ed in, and at the peak of the outbre a k , s ome 2000troops were invo lved in the erad i c a ti on nati onwi de , su pported by up to 1000 po l i ce of f i-cers . Almost 2.5 mill i on animals were slaugh tered in 11 wee k s , requ i ring bu rial pitsequ iva l ent to 200 Olym p i c - s i ze swimming poo l s .

Du ring a visit to Cu m bri a , one of the co u n ties hardest hit by the disease (see map,p a ge 16), Fer g u s on parti c i p a ted in one of the army ’s daily opera ti ons meeti n gs . Wh i l el i s tening to the soldiers talk abo ut the logi s tics of the opera ti on , the ra m i f i c a ti ons of h i sre s e a rch became cl e a r.On a sep a ra te occ a s i on , he spo ke to a group of f a rm ers and camef ace - to - f ace with their con cern s .“ Ha l f the farm ers in that room had lost their farm sa l re ady because of h oof - a n d - m o ut h ,” he says . “I esti m a ted that by the end of the ep i-dem i c , up to 70 percent of Cu m brian farms might be affected . That nu m ber shockedt h em , but it is tu rning out to be abo ut ri gh t .”

An o t h er mem ber of the Im perial te a m , Ch ristl Don n elly, found hers el f con f ron tedby a group of a n gry, vocal farm ers in Devon ,a n o t h er badly hit co u n ty in the sout hwe s tp a rt of the co u n try. She de s c ri bed feeling “o ut on a limb.” S ti ll ,m o tiva ted by a de s i re toof fer practical help in a de s pera te situ a ti on ,Fer g u s on and his co lleagues defend their rec-om m en d a ti ons vi goro u s ly.“The h m d ep i demic has significant econ omic con s equ en ce sfor the co u n try, wh i ch I hope my work might help to minimize ,” he says .

As soon as the govern m ent rel e a s ed its data on infected cases to the Im perial team inMa rch , Fer g u s on and his co lleagues spent an inten s ive 10 days feeding cri tical nu m bersi n to their model s . By calculating the likel i h ood that one farm would infect another in a


IQu antifying

Neil Fe rg u son wo r ked to minimize the los ses experienced by U.K. fa r m e rs like the one at right,

who wa l ks past his cows while fires incinera te animals at a nearby farm.

Neil Ferguson used mathematical modeling to help

British policymakers stem the fast-spreading hoof-

and-mouth epidemic. BY LAURA SPINNEY

Hoof&Mouth.Final 10/9/01 2:04 PM Page 14

h h m i b u ll e t i n | s e p t e m b e r 2 0 0 1 1 5

Unc ert a int y


p a rticular length of ti m e , given the sep a ra ti onbet ween farms and the dynamics of the nati on-wi de agri c u l tu ral net work ,t h ey were able to pre-d i ct the futu re co u rse of the ep i demic and to ra n kthe po ten tial ef fects of d i f ferent interven ti on s .

REDUCING R0

S pec i f i c a lly, t h ey measu red the impact of t h o s ei n terven ti ons on R0, the case-reprodu cti onra ti o, or avera ge nu m ber of s econ d a ry casesgen era ted by one pri m a ry case of i n fecti on . Bydef i n i ti on , wh en this figure drops bel ow 1.0 theep i demic can no lon ger sustain itsel f . “Wh a tcon trol measu res do, wh et h er it’s culling or vac-c i n a ti on or a whole ra n ge of o t h er things , is toredu ce that qu a n ti ty,m a ke the disease less infec-ti o u s , give it less ch a n ce to spre ad to otherf a rm s ,” s ays Fer g u s on . He and his team weres i m p ly looking for the qu i ckest and most ef fec-tive way to bring R0 down .

Pu blishing their re sults in the May 11, 2 0 0 1 ,i s sue of S ci en ce, t h ey argued that vacc i n a ti onwould be less ef fective than culling as an em er-gency re s pon s e . Al t h o u gh vacc i n a ti on redu ces the pop u l a ti on of a n i-mals su s cepti ble to the disease, it does not redu ce the infectiousness ofthose animals alre ady con t a m i n a ted , and so, does not redu ce tra n s m i s-s i on . Si m i l a rly, c u lling of i n fected farms alon e , l e aving their seem i n glyh e a l t hy nei gh bors unto u ch ed , would be insu f f i c i en t . By failing to stemn ewly acqu i red though not-yet - a pp a rent infecti on s , su ch re s tri cted cull i n gwould leave R0 at or around the cri tical thre s h o l d , re su l ting in a larger ep i-

demic that tailed of f m ore slowly. “ Ex ten s ivec u lling is sadly the on ly opti on for con tro ll i n gthe current Bri tish ep i dem i c ,”the Im perial te a mcon clu ded .

The policy has been largely su cce s s f u l . Bythe end of May, the nu m ber of i n fected farm swas dropping by half e ach fortn i ght and R0 w a su n der 1.0. Fer g u s on’s advi ce was nevert h eless tomaintain the aggre s s ive cull until the diseasewas com p l etely erad i c a ted . The second seri o u so utbreak in previ o u s ly unaffected York s h i re inm i d - May co u l d , he su gge s t s ,h ave been an indi-rect re sult of the govern m en t’s dec i s i on to rel a xthe po l i c y, a ll owing veteri n a rians more discre-ti on as to wh i ch animals were slaugh tered onf a rms that nei gh bored infected on e s .Even tak-ing that outbreak into acco u n t , the ep i demic hasdecl i n ed in line with the te a m’s pred i cti on s .

OVERSIMPLIFYING REALITY?

S ti ll ,s ome leading h m d ex perts have de s c ri bedthe policy as exce s s ive .Al ex Don a l d s on ,h e ad ofthe In s ti tute for Animal Health labora tory in

P i rbri gh t , Su rrey, and a govern m ent advi s er himsel f , has cri ti c i zed them a t h em a tical models for overs i m p l i f ying re a l i ty. In a stu dy publ i s h ed inthe Veteri n a ry Re co rd on May 19, 2 0 0 1 , he argued that the models wereb a s ed on an avera ge animal, and did not all ow for differen ces in infec-tivi ty, i m mu n i ty and tra n s m i s s i on ro utes among cows ,p i gs and sheep.

Fred Brown of the U. S . Dep a rtm ent of Agri c u l tu re’s Plum Is l a n dAnimal Disease Cen ter in Green port , New York , who was asked by


he same tech n i ques that Nei lFer g u s on has used to model h m din animals are shedding light ons ome of the most com m on ch i l d-h ood infecti on s , as well as kill ers

su ch as h iv / a i d s. The Im perial group isi nvo lved in an intern a ti onal co ll a bora ti on wi t hthe Joint Un i ted Na ti ons Programme onh iv / a i d s (u na i d s) in Gen eva to map thisd i s e a s e , wh i ch pre s ents an en ormous ch a ll en geto model ers .

Th ere are uncert a i n ties abo ut the diseaseprocess itsel f — h ow the vi rus interacts with itshost—and abo ut the beh avi ors that wi ll shapethe ep i dem i c .As Bern a rd Schw a rt l a n der, h e ad ofep i dem i o l ogy at u na i d s, n o te s : Peop l e’s sex u a lprocl ivi ties “a re not stamped on their foreh e ad s .”

Fer g u s on’s group is also working onm e a s l e s ,p a rt ly because the bi o l ogy of the dis-ease is rel a tively well known and det a i l ed his-torical records of its patterns of i n c i den ce are

ava i l a bl e . He is trying to pred i ct futu re inci-den ce trends in the po s t vacc i n a ti on era , as wellas how health scares abo ut vacc i n e s — p a rti c u-l a rly the con troversial com bi n ed measles-mu m p s - ru bella vacc i n e — wi ll affect thosetren d s .

Si m i l a rly, Fer g u s on is analyzing how mass

i m mu n i z a ti on against ch i cken pox and the re su l t-ing redu cti on in natu ral immu n i ty to it is lead-ing to a rise in cases of s h i n gl e s , a cl o s ely rel a ted(and more serious) adult disease that is causedby the same vi ru s . “ Nei t h er exercise would bepo s s i ble wi t h o ut the sort of m ac roa n a lytical too lprovi ded by mathem a tical model s ,” he says .

He also intends to stu dy how diseases evo lveu n der sel ecti on pre s su re s , the two main on e sbeing how a pathogen evo lves thro u gh interac-ti on with the host’s immune sys tem and how itevo lves re s i s t a n ce to dru gs . In ad d i ti on to theobvious clinical implicati ons of this re s e a rch ,i twi ll have broader scien tific con s equ en ce s .

As Fer g u s on ex p l a i n s ,“I am fundamen t a llyi n tere s ted in the pop u l a ti on bi o l ogy of p a t h ogenevo luti on ,because it’s a microcosm for evo luti onas a wh o l e .But since [pathogen evo luti on] hap-pens on a mu ch faster time scale than in otheror ga n i s m s , you can actu a lly ob s erve it and theprocesses shaping it direct ly.” — LS

TModeling Common Human Diseases

M o re than half of the people tre a ted at this clinic

in Ndwe d we, South Africa, are HIV pos i t i ve .

CAS ES PER COU N TY

0

1–10

1 1–10 0

101 and up

U. K. HOOF-A N D - M OUTH OU T B R EA KD i stribution of infections by county


S ci en ce to revi ew the Im perial gro u p’s May 11 paper, s ays that there areso many unknowns in the spre ad of the disease—including ill ega lm ovem ents of l ive s tock and the beh avi or of deer and other wi l dl i fe pop-u l a ti ons—that su ch models could not po s s i bly be acc u ra te .

Fer g u s on says su ch cri ticisms show a lack of u n derstanding of m od-el i n g. In fecti on grows geom etri c a lly in a pop u l a ti on , giving an ep i dem i cthe ch a racteri s tic shape of an ex pon en tial curve . Ba s ed on this pri n c i p l e ,a mathem a tical model divi des a pop u l a ti on into three cl a s s e s : those wh oa re su s cepti bl e , those who are infected and those who have recovered . Itconsists of a set of equ a ti ons that repre s ents the ep i demic process as a feed-b ack loop wh ere the ra te at wh i ch su s cepti ble indivi duals become infect-ed is proporti onal to the nu m ber of those alre ady infected .

At that level , a model is indeed a simplificati on of re a l i ty. The com-p l ex i ties come in with the diverse beh avi ors of d i f ferent diseases—thei m mu n i ty gen era ted by the pathogen , the infectivi ty and ro utes oftra n s m i s s i on wi ll va ry. Wh en any of these para m eters are unknown ,s aysFer g u s on , or wh en the rel evant data are not ava i l a bl e , the skill is to fac-tor them into the equ a ti on s , with altern a tive scen a rios wei gh ted accord-ing to their prob a bi l i ti e s .E ach altern a tive gen era tes a different outcom e ,providing po l i c ym a kers with a worst-case scen a ri o, a best-case sce-n a rio and a spectrum in-bet ween from wh i ch to make their dec i s i on s .As more hard data come in, the equ a ti ons can be ad ju s ted to give a bet-ter fit and more precise proj ecti on s .

In evi t a bly, s ays Roy An ders on ,h e ad of the Im perial group and one ofthe pion eers of i n fectious-disease model i n g,wh en you are dealing with anon going ep i demic the most current data are less precise than you wo u l dl i ke . G iven the urgen c y, h owever, “t h ere is a scien tific com promise to bem ade bet ween detail and som ething that is su f f i c i en t ly robust to give a qu a l-i t a tive guide to po l i c y,”he says .One of the re a s ons for stu dying animal dis-eases su ch as h m d, adds Fer g u s on , is to “of fer the opportu n i ty for mu chm ore com p l ete data to be co ll ected easily and for ex peri m ental and ep i-dem i o l ogical studies to be carri ed out that are not po s s i ble in hu m a n s .”

MERGING MODELS

Wh en it comes to understanding how a disease beh ave s ,m odel ers arecon s t a n t ly delu ged with new inform a ti on from well - e s t a bl i s h ed fiel d ssu ch as immu n o l ogy—the discovery of n ew immu n o l ogical markers ofd i s e a s e , for instance—as well as rel a tively young fields su ch as molec-ular bi o l ogy.At the mom en t ,d i f ferent aspects of disease tend to be mod-el ed sep a ra tely, and the modeling com mu n i ty divi des ro u gh ly intothose who model the spre ad of a disease within an indivi dual and thosewho model it within a pop u l a ti on . The probl em with these parti a lm odel s ,h owever, is that they tend to overl ook interacti ons among them a ny different factors that shape an ep i dem i c .

New - va riant Creut z fel d t - Ja kob Disease (vCJD), the human form ofs o - c a ll ed mad cow disease (see story,p a ge 8), is a good example of the dif-f i c u l ty of m odeling interacti on s . In the August 2000 issue of Na tu re, t h eIm perial team esti m a ted that the pred i cted Bri tish ep i demic would likelya f fect no more than 136,000 peop l e . That was a prel i m i n a ry proj ecti on ,b a s ed on data rel a ting to the 70 or so cases that had been recorded at thatti m e . But all of those early cases came from the 40 percent of the pop u l a-ti on that shares a certain iden ti f i a ble gen etic makeu p, or gen o type . Th erewas a hope at the time that the other 60 percent might be immune to vCJD.

Si n ce then ,m o l ecular bi o l ogical evi den ce co ll ected by John Co ll i n geof Im perial Co ll ege and Un ivers i ty Co ll ege Lon don has indicated that,ra t h er than being immu n e , people with different gen o types might ju s t

i n c u b a te vCJD for lon ger peri od s . The evi den ce comes from Co ll i n ge’ss tudies of k u ru , a similar disease that is sti ll affecting el derly mem bersof the Fore tri be of Papua New Guinea more than 40 ye a rs after thei rpracti ce of e a ting the brains of de ad rel a tives was banned .

His findings ra i s ed fe a rs that the Im perial team had va s t ly under-e s ti m a ted the size of the ep i dem i c . But Fer g u s on points out that theyn ever exclu ded the po s s i bi l i ty that the rest of the pop u l a ti on might besu s cepti bl e . The on ly assu m pti on they made , and one he thinks is ju s-ti f i ed , was that the distri buti on of i n c u b a ti on peri ods is likely to be sim-ilar to that of o t h er pri on diseases. In the case of k u ru , for instance ,t h ei n c u b a ti on peri od va ries from 2 ye a rs to 35 ye a rs , rising to a single pe a kat around 15 ye a rs . By def i n i ti on , the vCJD cases that have alre adycome to light are those with the shortest incubati on peri od s . It may be20 ye a rs before we see the cases with lon ger incubati on s , he says .

The molecular bi o l ogical evi den ce is therefore not at odds with them odel s , Fer g u s on maintains, or the worst-case esti m a te his team gen era t-ed .S ti ll ,one thing he may have to correct for as the ep i demic unfolds is howthose gen etic su s cepti bi l i ties interact with beh avi or. In vCJD, the incuba-ti on peri od is not determ i n ed solely by the underlying gen etics but also bythe amount of i n fected material inge s ted . The more infected meat a per-s on eats, the soon er he or she su cc u m b s .“We don’t have any idea of the dis-tri buti on of do s e s , but it was prob a bly qu i te wi de , and that wi ll mask a lotof the ad d i ti onal va ri a ti on you might get from the gen eti c s ,”s ays Fer g u s on .

Ma rtin Nowak of the In s ti tute for Adva n ced Stu dy in Pri n ceton , NewJers ey, who models the spre ad of vi ruses within an indivi du a l ,bel i eves themain ch a ll en ge facing the field now is to establish a single theoreti c a lf ra m ework that wi ll accom m od a te all the ava i l a ble inform a ti on and its po s-s i ble interacti on s .“ In the en d , one wi ll build models wh ere a vi rus spre ad swithin an infected indivi dual and within a pop u l a ti on ,” he says .

Fer g u s on hopes to start devel oping the met h odo l ogy to build thesecom preh en s ive models over the next five ye a rs to answer basic scien cequ e s ti ons abo ut evo luti on as well as public health (see box ,p a ge 16). Hebel i eves this next gen era ti on of m odels wi ll make po s s i ble more prec i s epred i cti on s , and that modeling wi ll play an incre a s i n gly important ro l ein disease con tro l . Even now, he says ,m ore and more scien tists are re a l-izing that the va lue of m odeling lies in qu a n ti f ying uncert a i n ty, in mak-ing it manage a ble for po l i c ym a kers .

Ask him if t h ere is any disease that can’t be model ed , and he smiles:“Th ere is nothing that can’t be model ed , but there are lots of t h i n gs thatc a n’t be model ed easily.”


H O O F-A N D - M OUTH DIS EASE IN THE U. K.Confirmed daily cases, 20 0 1

So u rce: Re p o rt of the Committee of Inquiry on Fo ot-and-Mouth Dise a se 1968 and MAFF 20 01

H


Rohit Va rma heads a $6 mill i on eye stu dy. He works with leading scien ti s t s . He can

l ectu re of f the top of his head . So shouldn’t te aching a class of k i n der ga rtn ers be a snap for him?

Not at all . Two ye a rs ago,Va rm a ,an oph t h a l m o l ogist at the Un ivers i ty of So ut h ern Ca l i forn i a ,c a rri ed

a skel eton — du bbed Peter — to his son’s kinder ga rten cl a s s . He qu i ck ly launch ed into the basics of bon e s ,

making it all the way down to the rib cage before a gi rl poi n tedly ra i s ed her hand.S h e

w a n ted to know one thing:Wh ere did the skel eton come from? “Th en the dam bro ke ,”

Va rma rec a ll s . Su d den ly, a n o t h er child—and then another — j oi n ed in the ch oru s

of qu e s ti on s . Was this a de ad pers on? What happen ed? How did Va rma get hold of

the body? Va rma shot a look at the te ach er. She smiled—and stood back .

S peaking to a room full of s c i en tists is one thing. Standing before a class of

k i d s — wh et h er kinder ga rtn ers or high - s ch ool sen i ors—is som ething el s e .Wi t h

k i d s , Q-and-A isn’t just an after-talk interva l ,i t’s a way of l i fe .

If you have an hour to share with a cl a s s ,h ow can you make the time co u n t ?

Af ter plen ty of tri a l - a n d - error, s c i en ce edu c a tors and savvy vo lu n teers have som e

h a rd - e a rn ed tips to of fer. “Talking to kids can be a great boost for any scien-

ti s t ,”s ays Nancy Moren o,h e ad of the h h m i- f u n ded Scien ce Edu c a ti on Le ad-

ership Fell ows Program (s el f) at Bayl or Co ll ege of Medicine in Ho u s ton .

“And these are skills you can learn .”

✎Tip 1: K n ow Your Au d i e n c eTo give a great talk, s tu dy up on your stu den t s .You could prob a bly guess

that fo u rth graders aren’t re ady to run gel s — but did you know that even

ei ghth graders have a hard time grasping the com p l ex i ties of d na?

Making t h e

Grade

Rohit Va r m a ’s ske l eton drew a flurry of unex p e cte d

q u e stions in his so n’s kinderg a rten class.


Some re s e a rchers go all out to teach children about science. ✎ BY KAT H RYN BROW N

Teach4Day.Final 10/9/01 9:39 PM Page 18

S c i en tists of ten overe s ti m a te a cl a s s’s gen eral soph i s ti c a ti on .Du ring one recent proj ect , for instance , Moreno and co ll e a g u e sdevel oped lesson plans for el em en t a ry - s ch ool stu den t s . Th eywere parti c u l a rly pleased with a model that used different kindsof popcorn — but ter, ch eese and cara m el — to show that air is amix of ga s e s , with each va ri ety repre s en ting a different ga s . Th ete ach ers who used the model reported that the kids were cer-t a i n ly fascinated , but some took home an unex pected lesson .“ Most of the firs t - grade ch i l d ren con f i den t ly reported that airwas made out of popcorn ,” Moreno says . “You have to learnto be so hu m bl e .”

So before you painstakingly mold ra s pberry Jell-O into areplica of a cell mem bra n e ,m a ke a ph one call . “The te ach erk n ows the stu dents be s t ,” s ays Laura Strei ch ert ,h e ad of t h es pe a ker ’s bu reau at the Wa s h i n g ton As s oc i a ti on for Bi om ed-ical Re s e a rch in Se a t t l e .“ If you make the te ach er your part-n er,your talk has a mu ch bet ter ch a n ce of h i t ting the target .”

Re s e a rch ers can ch eck out the Na ti onal Scien ce Edu-c a ti on Standards to see wh a t’s typ i c a lly taught at each gradel evel . Keep in mind, h owever, that the standards are gen-eral ben ch m a rks—and sch ools va ry wi dely in meeti n gt h em .“ Even if you take third or fo u rth grade as your level and gear yo u rtalk to that, it wi ll not be univers a lly unders t a n d a ble to kids of that age ,”c a uti ons Jon Levi t t , a po s tdoctoral fell ow in the Dep a rtm ent ofIm mu n o l ogy at Bayl or Co ll ege of Medicine and a frequ ent grade -s ch ool vi s i tor. “Th ere’s a big differen ce bet ween sch oo l s , p a rti c u l a rlythose with stu dents from different soc i oecon omic back gro u n d s .”Aga i n ,a te ach er ’s insight is key.

✎Tip 2: Bring Pro p sWh en ever David Sch n ei der, a molecular bi o l ogist at the Wh i teh e adIn s ti tute for Bi om edical Re s e a rch in Ca m bri d ge ,Ma s s achu s et t s , cl i m b sthe steps to a local grade sch oo l , he bri n gs along ex tra vi s i tors : bu gs .“I call them ‘ex treme insect s ,’” S ch n ei der says .“S c a ry on e s , hu ge on e s ,re a lly be a utiful on e s .”S h opping the In tern et ,S ch n ei der buys dri ed bee-tles and but terflies for kids to hold.“ It’s a way of breaking into bug bi o l-ogy,” he says , and it work s .“ I ’ve been amazed by how qu i ck ly yo u n gkids can pick things up. Th ey ’re curious abo ut everyt h i n g.”

Al ive or de ad , real or preten d , props are a great way to re ach kids.Just ask Eric Chu dl er, a neu ro s c i en tist at the Un ivers i ty of Wa s h i n g-ton in Se a t t l e , who has been vo lu n teering mon t h ly at local sch ools fora bo ut five ye a rs . By now, h e’s got props down to, well , a scien ce .Chu dl er bri n gs in six ja rs ,e ach holding the brain of a different ani-m a l ,f rom a cow to a cat. He de s c ri bes the differen ces—in brain sizeand patterns of fo l d s , for instance — bet ween spec i e s , and then askskids to iden tify the brain in each ja r.“Some kids say it’s gro s s ,”Chu dl er

s ays , “but most of t h em think it’s re a lly coo l .”Even simple props can jazz up a talk. What does the brain do? To

t ackle this qu e s ti on , Chu dl er ju ggles plastic brains while he leads thekids thro u gh a guessing game on mu s cle coord i n a ti on , b a l a n ce ands i gh t .What is the brain made of? For this on e ,s tu dents become a gi a n tn eu ron ,l i n ked to each other with rope ,p l a s tic and ping-pong ball s .Wh en Levitt te aches abo ut fri cti on , he asks stu dents to pull a ch i l din a wagon with—and then wi t h o ut — s a n d p a per beneath the wh eel s .

The same approach works with older crowd s . Hi gh - s ch ool kidsdon’t play with wagon s ,but they usu a lly do like ex peri m en ting with thequ i ck - f ree ze properties of l i quid nitrogen ,w a tching flowers cru m bl eor pennies shatter after a dip in the stu f f . “Skip the Power Point pre-s en t a ti on s ,”advises Ma ry Ma r ga ret Wel ch , a bi o l ogy te ach er at MercerIsland Hi gh Sch ool in Wa s h i n g ton .“ Bring som ething to do inste ad .”

✎Tip 3: L i g h ten UpNo matter what gizmos you may bring in your back p ack , vo lu n teerss ay, come to a cl a s s room with the ri ght atti tu de .“ Kids can re a lly sen s ewh et h er or not you are into what you are doi n g, and they wi ll imme-d i a tely pick up on your vi be s ,”s ays Ha rry Orf ,d i rector of Ha rva rd Un i-vers i ty ’s molecular bi o l ogy labs at Ma s s achu s etts Gen eral Ho s p i t a l .“ If

2 0 h h m i b u ll e t i n | s e p t e m b e r 2 0 0 1

G RA D E-SCHOOL KIDS

✏ L i ke nat u re

✏ Id e n t i fy with fa m i l y

✏Worry about fa i r n e s s

✏G et exc i ted easily

✏Need frequent physical activity

M I D D L E-SCHOOL KIDS

✏U n d e r stand et h i c s

✏Challenge rules

✏Think in the abst ra c t

✏Become self-conscious

✏Need positive re i n fo rc e m e n t

H IG H -SCHOOL KIDS

✏ Id e n t i fy with peers

✏Q u e stion authority

✏Can inte r p ret complex science

✏Consider care e r s

✏Need to be inspire d

N a n cy Moreno says re se a rc h e rs can pick

up the skills needed to talk to kids about sc i e n c e .

D i f fe rent Stro kes for Diffe rent Ag e s


yo u’re ten t a tive ,t h ey ’ ll be ten t a tive . If yo u’re having fun, so wi ll they.”Am ong yo u n ger crowd s , in parti c u l a r, en t husiasm is con t a gi o u s .“All

it takes for a young child to get intere s ted in scien ce is some sort of s pe-cial mom en t ,” Va rma says .“ Kids want to be baseb a ll players because wep ay so mu ch atten ti on to them . Th ey don’t see a whole lot of exc i tem en tin scien ce , but there’s a real thri ll in discovering som ething new—and it’seasy to share .”

Even at the middl e - s ch ool level , kids can of ten overcome their inhi-bi ti ons and re a lly en j oy learning abo ut scien ce from a stra n ger.“ Mi d dl e -s ch ool stu dents sti ll tend to have lots of en t hu s i a s m , and they ’re of ten wi ll-ing to accept you just on face va lu e ,”s ays Larry Ann Ot t , a bi o l ogy te ach erat Northglenn Hi gh Sch ool in Denver.“Th eir em o ti ons are close to the su r-f ace .”Hi gh - s ch ool stu den t s ,Ott says , requ i re a different to u ch .“Ol der stu-dents have been thro u gh a lot more , and they tend to be more cynical orsu b du ed ,” s ays Ot t .“ It takes more to captu re their imagi n a ti on .”

One soluti on , Ott says , is to keep the scien ce rel eva n t . Hi gh - s ch ool stu-dents get swept up into social con f l i ct s , with ch a n ging fri en d s h i p s ,d a t-ing and plans for the futu re .“ If you can bring any of t h i s — gen der dif-feren ce s , s ocial interacti on s — i n to your discussion , it can make a majord i f feren ce in what they rem em ber,” Ott says . Ca tch their atten ti on ,a n dt h eir curi o s i ty wi ll fo ll ow.

✎Tip 4: G et Mov i n gAt meeti n gs ,s c i en tists of ten listen to 50-minute lectu re s . At sch oo l , 50 minutes isan etern i ty. Kids move around a lot. If you want to keep their atten ti on , get mov-i n g, too.“The more you move aro u n d , the more they have to keep watching yo u ,”Levitt says .“Wh a tever you do,don’t stand at a lectern and rave on .”A couple of ye a rsa go, Levitt was five minutes into his first talk to a grade - s ch ool class wh en he re a l-i zed that nothing was sinking in. Kids were el bowing each other, l ooking aro u n d ,p l aying with their sneakers . He qu i ck ly ju m ped up to ch a n ge ge a rs—and he hasn’ts topped moving since .

I fy o u ’ r em ovi n ga ro u n d ,

and thekids get at u r nh a n -d l i n gprop s ,wh a t’st h e

te ach er doing? Tryi n cluding him or her, Moreno advi s e s .

S c i en ce looks easier if a familiar pers on can do it, too.“ If wep ut a te ach er up there in front of the kids, s i de by side with a re s e a rch er, we

s end a message that scien ce is approach a bl e ,” Moreno says . “Th a t’s an import a n tm e s s a ge .”

Wh a t’s more ,S ch n ei der ad d s , the te ach er can keep kids on task. “With the lit-t l er kids, in parti c u l a r, I just don’t have the skills to con trol them ,” he says ru ef u lly.“I wo u l d n’t want to go in co l d ,a l on e . It’s important to have the te ach er close by.”

✎Tip 5: Fo l l ow UpS pending an hour with a class can bring smiles all aro u n d — but fo ll owing up cando even more . Te ach ers may build on your talk, doing lessons afterw a rd to rei n forcewh a tever yo u’ve taugh t . Ch a n ces are , t h ey wi ll also have qu e s ti ons along the way.“ If you re a lly want to make a differen ce ,m a ke a com m i tm en t ,” s ays Keith Vern er,ch i ef of the divi s i on of devel opm ental ped i a trics and learning at Pen n s ylva n i aS t a te Un ivers i ty Co ll ege of Med i c i n e .“ Don’t wait to hear back from the te ach er.In s te ad ,s end an e-mail. Say, ‘ Hey, I en j oyed that. Have any qu e s ti ons come up thatI could answer ? ’ ”

Ma ny te ach ers would wel come the input .“A real partn er is not just abo ut hav-ing som eone come in and give this pre s en t a ti on , but having som eone wh o’s wi ll-ing to be on call ,” s ays Wel ch .“ It’s som eone I can call if t h ere’s a kid who got re a llyexc i ted by som ething or had a qu e s ti on I co u l d n’t answer. Th a t’s the kind of p a rt-n ership we need .”

That sort of p a rtn ership is not very hard to cre a te , adds Ha rvey Lod i s h , a molec-ular bi o l ogist at the Wh i teh e ad In s ti tute . “All re s e a rch insti tutes can do som et h i n g.”Maybe a scien tist can give one talk a year to third graders , or make a special pre s en t a-ti on to high - s ch ool stu den t s . “We can’t ch a n ge the worl d , but we can ch a n ge a littlep i ece of i t .”


C l a s s room and Online Ed u c ation Re so u rc e sSome scientists go back to school themselves befo re stepping fo ot

in a classroom full of children. At the Unive r s i ty of California, San

Francisco, more than 150 scientists have completed six hours of

S c i e n t i st Orientation Wo r kshops, part of an H H M I- s u p p o r te d

school outreach pro g ram there. Seve ral Web sites of fer info r m at i o n

for scientists inte re sted in speaking to schools:

✏U n i ve r s i ty of California, San Francisco, Science and Health

Ed u c ation Pa r t n e r s h i p

www. u c sf.e d u /se p / i n d ex . h t m l

✏Re s o u rces for Involving Scientists in Ed u c ation (R IS E)

www. n a s.e d u /r i se /

✏Sharing Science with Children: A Survival Guide for

S c i e n t i sts and Engineers

www. n o a o .e d u /e d u c a t i o n /tg u i d e s/sc i txt . h t m l

✏H H M I ’s Precollege Science Ed u c ation Pro g ra m

www. h h m i .o rg /g ra n ts/p re c o l l e g e /

David Schneider uses “ext reme inse cts” to spark

c h i l d re n’s curios i ty about bug biology.

H



the most fundamental principles of s c i en ce—that hypotheses have tobe te s ted ,a l tern a tives have to be ru l ed out , obj ecti ons have to be sati s-f i ed and a con clu s i on requ i res evi d en ce.“Ask for su pportive evi den ce ,”s ays Ma rti n ,“and at first they ’re just puzzled .”As the exercises progre s s ,h owever, at least some of the stu dents re a lly do begin to get it.

S tories like Ma rti n’s are being heard more and more of ten . Th a n k sto the pro l i fera ti on of h i gh - powered pers onal com p uters on campusand the rapid growth of the In tern et , co ll eges and univers i ties are ex per-i m en ting with com p uter- b a s ed learning as never before — f requ en t lywith bi o l ogists among the leaders . In deed , m a ny of those bi o l ogi s t sbel i eve that online learning is the best hope for maintaining high - qu a l-i ty, i n d ivi du a l i zed edu c a ti on in the face of u n der gradu a te en ro ll m ents thath ave su r ged dra m a ti c a lly du ring the past dec ade . Some bi o l ogy edu c a-tors would use online sources to help ch a n ge the met h od of l e a rning itsel f ,rega rdless of class size . Th ey find that the g ck and similar sof t w a re pro-grams can be powerful tools for giving stu dents an ex peri en ce as close aspo s s i ble to real scien tific re s e a rch — what curri c u lum reform ers call“ i n qu i ry - b a s ed ”l e a rn i n g.S tu dents are en co u ra ged to ask their own qu e s-ti on s ,s tru ggle tow a rd the answers and, in ef fect , te ach them s elve s .

RA ISING SKILLS AND EX P ECTAT IONS

Cert a i n ly that was the intent of the kit’s co - c re a tor, bi o l ogist John R.Ju n g ck of Bel oit Co ll ege in Wi s con s i n , who wro te the program in 1985

C O L L EGE STUDENT M E ETS

E L ECT RO NM A N

Initial panic turns to insight as students embrace online learning.B Y M . M I T C H E L L WA L D RO P

His students tend to freak out at first ,s ays Pre s l ey Ma rti n , de s c ri bing the introdu ctory bi o l-ogy co u rse he te aches at Hamline Un ivers i ty in St.Pa u l , Mi n n e s o t a .Wh en they walk into the co u rs e’s lab-ora tory secti on for the first ti m e , the stu dents findt h em s elves face - to - s c reen with the Gen etics Con-s tru cti on Kit (g ck)—a com p uter simu l a ti on of

Men delian inheri t a n ce that wi ll com pel them to do some real scien ce .To begin an ex peri m en t , the g ck gen era tes a “f i eld co ll ecti on” of ,s ay,

f ruit flies, e ach with a com bi n a ti on of tra i t s — wh i te eyes or red eye s , ben twi n gs or stu bby wi n gs or stra i ght wi n gs and so on .The program also pro-vi des the tools for performing gen etic cro s s e s ,p lus a spre ad s h eet to ana-ly ze the outcomes stati s ti c a lly. It does n ot explain the hidden gen etic mech-anisms that produ ced those outcom e s . Nor does it of fer a trad i ti onal labm a nual that tells the stu dent how to find out . In s te ad , the stu dent is ex pect-ed to dec i de what traits to look at, what crosses to try, what hypotheses tocon s i der and, perhaps most import a n t ,wh en to be sati s f i ed that a hypo t h-esis is correct , just as a scien tist faced with a real field co ll ecti on must do.

“Th ey ’re re a lly uncom fort a bl e ,”s ays Ma rti n , who is ch a i rman of t h eHamline bi o l ogy dep a rtm en t .“Th ey ’re used to probl ems wh ere they ’reex pected to get the ‘ri ght answer,’ so it’s hard for them to deal with thef act that the program isn’t going to tell them wh en they get the ri gh ta n s wer.” In s te ad it con f ronts them with the task of l e a rning firs t h a n d

LearnOnline.Final 10/9/01 9:42 PM Page 22


Michigan Sta te’s Jo h n

Merrill uses online

animations and comic-

book chara cte rs to dra w

st u d e n ts into first-ye a r

b i o l o g y. A hamburg e r

with fries makes se n se

out of proteins and fa ts.

A superhero dubbed

E l e ct ron Man “prote cts ”

cellular re s p i ration.


with bi o l ogist John N. Ca ll ey, t h en atthe Un ivers i ty of Ari zon a . In a 1988a rti cl e , Ju n g ck and Nils S. Peters onof Wa s h i n g ton State Un ivers i tyex p l a i n ed that the te aching and thes of t w a re work toget h er to rei n forcethe “3 Ps” of re s e a rch : probl em - po s-i n g, probl em - s o lving and peer per-su a s i on—the peers in this case bei n gthe other stu den t s .

That 3-Ps approach has, in tu rn ,been the guiding principle of t h eBi o QUEST con s ortiu m , wh i chJu n g ck and a group of l i ke - m i n deds of t w a re aut h ors fo u n ded in 1986.The con s ortiu m , wh i ch is loc a ted atBel oit Co ll ege and funded part ly wi t hh h m i gra n t s , maintains a libra ry ofs ome 70 too l s ,s i mu l a ti on s , d a t a b a s-es and other re s o u rces devel oped foru n der gradu a te bi o l ogy. E ach re s o u rceis peer- revi ewed , ava i l a ble on cd -rom and en h a n ced by data re ad i lyretri eved from the In tern et . Am on gthe of feri n gs are the ori ginal Gen et-ics Con s tru cti on Ki t , Sequ en ce It! (a simu l a ted pro tei n - s equ en c i n glab) and bi rd d— Be a gle Inve s ti ga ti on Retu rns with Darwinian Data(a tool for ex p l oring evo luti on thro u gh a database of t a xon omy, s on grecord i n gs , d na s equ en ces and measu rem ents on some 650 spec i m en sof G a l á p a gos finch e s ) .

Ju n g ck is espec i a lly taken with how su ch too l s , com p l em en tedby e-mail, d i s c u s s i on groups and chat room s , h ave ra i s ed the skill sand ex pect a ti ons of s tu dents to a whole new level . “You see themen ga ged in co ll a bora tive probl em - s o lvi n g, l ooking at mu l ti p l e

hypo t h e s e s ,s h a ring data. A te ach er in one of our work s h ops told merecen t ly that their worst proj ect this year is bet ter than their be s tproj ect three ye a rs ago. An o t h er said, ‘ we never knew our stu den t swere that cre a tive .’ ”

He admits that this kind of s c i en ce te aching is never going to beas easy as the trad i ti onal approach , In tern et or no In tern et . “ Forte ach ers , i t’s more inten s e ,” he says . “With oodles of proj ects goi n gon all the ti m e , and with stu dents accessing all these com p l ex too l s ,you have to be wi lling to let the stu dents te ach you things . And that’s


How well can phys i o l ogy stu dents unders t a n da ny of the human body ’s three - d i m en s i on a l ,dynamic sys tems wh en they are con f i n ed tol e a rning abo ut them from lectu re s , tex tboo k sand flat, s t a tic pictu res? At Stanford Un ivers i-ty, s tu dents can take an active and more re a l-i s tic ad d i ti onal step : Th ey can log on to theh h m i Vi rtual Labora tories and stu dy ren a lphys i o l ogy by manipulating the diameters ofc a rtoon arteri o l e s — m i nute bra n ches of a rter-ies in the kidney — to see the ch a n ges in filtra-ti on ra te s . Th en they can simu l a te uri n a lysis onf ive “p a ti en t s”and see how a daunting mathe-m a tical con cept call ed the co u n terc u rrent mu l-

ti p l i er actu a lly affects the con cen tra ti on of s od i-u m , ch l ori de and po t a s s ium as liquid move st h ro u gh the tu bules of the kidney.

The renal physiology lab, supported byan h h m i gra n t , is the first of f ive vi rtual labs

being de s i gn ed at Stanford to give largeintroductory physiology classes hands-on,lab-like experiences without going to a lab.Other virtual labs will focus on human gas-troi n te s ti n a l ,c a rd i ova s c u l a r, re s p i ra tory andneurobiological systems.

“This is more than a digital tex tboo k ,”s ays Ca m i llan Hu a n g, vi rtual labs proj ectm a n a ger. “ It is fun, and it helps stu den t su n derstand difficult con cepts and rel a te wh a tt h ey are learning to their everyd ay live s .” In aprel i m i n a ry com p a ri s on of s tu dent ach i eve-m en t ,s tu dents who used the vi rtual lab scoredh i gh er than those who on ly atten ded lectu re sand re ad the tex t , Huang report s .

—JENNIFER BOETH DONOVA N

»Mo re info rm a tion and dem o n s tra tion labs can be

found online at: su m m i t . s t a n ford . edu / h h m i /

“ H a n d s- O n” Re n a lP hys i o l o g y

St u d e n ts can dilate or const r i ct arterioles of the

k i d n ey and see the impact on glomerular filtra t i o n .

John Jungck of Be l o i t

College designed the

G e n etics Const r u ction Kit

and other compute r- b a se d

learning modules to help col-

lege st u d e n ts learn to

become effe ct i ve pro b l e m

so l ve rs. A n other pro g ra m ,

called BI R D D, shown below,

d e scribes the impact of

G a l � p a g os finches on

Charles Darwin's re se a rch.



a hu ge ch a n ge in the social con tract of the cl a s s room .”Me a nwh i l e , Ju n g ck says , “for the stu dents this is a lot more work

than just passively sitting in front of an instru ctor, taking note s . But evens o, f rom all of our stu d i e s , the stu dents who go thro u gh this proce s sretain more . Th ey stay in the co u rses lon ger. Th ey more of ten go on andt a ke ad d i ti onal scien ce co u rs e s . Th ey are bet ter at app lying what they ’vel e a rn ed to social and legal issu e s . And they seem to have a convers a n t ,s peaking knowl ed ge of s c i en ce for a long time after they finish.”

F I RST-Y EAR BIO LO GY ONLINE

None of the sof t w a re in the Bi o QUEST libra ry was spec i f i c a llyde s i gn ed to help te ach ers cope with overc rowded cl a s s e s , but that isdef i n i tely an issue at Mi ch i gan State Un ivers i ty, wh ere an interd i s c i-p l i n a ry team of bi o l ogists and edu c a ti on specialists is attem pting top ut the sch oo l ’s en ti re firs t - year bi o l ogy curri c u lum on l i n e . Af ter all ,n o tes microbi o l ogist John Merri ll , one of the leaders in that ef fort ,“unless the state su d den ly throws a hu ge amount of m on ey at us sothat we can have everybody in small cl a s s e s , I sti ll have to te ach thesehu ge co u rses with 400 stu den t s .”

The proj ect ,c a ll ed “ F i rst Year Online,”began in 1998 as part of a five -ye a r, $1.6 mill i on grant from h h m i, s ays proj ect director Estelle Mc Groa r-ty,and it soon proved to be an even more daunting task than the team hadi m a gi n ed .“ It took us most of a year after we were funded just to figure outh ow to approach online bi o l ogy,”she says .“ E a rly on ,for ex a m p l e ,we madethe dec i s i on that we would not provi de a com p l ete vi rtual co u rs e . Bi o l o-gi s t s ,m ore so than the phys i c i s t s , feel that there has to be a face - to - f acecom pon ent in te ach i n g.”

Ma terials are pre s en ted using l o l, the Lectu re Online platform thath ad just been devel oped at Mi ch i gan State by physics re s e a rch assoc i-a te Gerd Kortem eyer. L i ke com m ercial co u rs e - m a n a gem ent sof t w a re ,l o l of fers tools for keeping track of ad m i n i s tra tive details su ch asen ro ll m ent and grade s ,a n d , most import a n t ly, it all ows instru ctors toc u s tom i ze the online con tent to suit their particular need s .

H OW TO HELP STU D E N TS LEA R N

“Th ere is a pret ty strong body of evi den ce that stu dents don’t learnmu ch by just being tol d a bo ut scien ce , as in being lectu red to, or ju s tre ading abo ut it,” s ays team mem ber Joyce Pa rker of the divi s i on of s c i-en ce and mathem a tics edu c a ti on .“Th ey first have to be en ga ged in som es ort of probl em , so that they can see a purpo s e : ‘ Here’s som et h i n gi n tri g u i n g, l et’s try to understand it.’ ”

The online modules are de s i gn ed to start by piquing the stu den t s’i n tere s t — s om etimes pret ty shamel e s s ly. P h o to s y n t h e s i s , for ex a m p l e ,i spre s en ted as an animated play in ei ght act s , with the water molec u l ea n t h ropom orph i zed as a tra gic hero who sac ri f i ces himsel f for the goodof the cell . Cellular re s p i ra ti on and the el ectron tra n s port chain are pre-s en ted in com i c - book styl e , com p l ete with a caped cru s ader:“The Storyof E l ectron Ma n .”

“We use what work s ,” l a u ghs Merri ll , who parti c u l a rly en j oys thel a r ge bi om o l ecules modu l e .“We start each su btopic with a pictu re of an i ce juicy hambu r ger with a side of Fren ch fri e s , and then we havea rrows poi n ting to, s ay, pro tein in the meat.”

Once you’ve got the students’ attention,then what? “The studenthas to wrestle with the materi a l ,”s ays plant eco l ogist Diane Ebert - May,d i rector of Mi ch i gan State’s Lyman Bri ggs Sch ool—a re s i den tial com-munity for students in the natural sciences—and a frequent consult-

La ptops Link Chemistry Students and Te ac h e r s

U. S . Pre s i dent James A .G a rf i eld on ce said that the ideal co ll egeconsists of a profe s s or on one end of a log and a stu dent on theo t h er en d . A net work of 16 iBook laptop com p uters is put ti n gch em i s try stu dents and fac u l ty at Den i s on Un ivers i ty in Gra nvi ll e ,O h i o, on “the same log” in a way that Garf i eld could not havei m a gi n ed in 1881.

Wi reless and mobi l e , the laptops move easily from cl a s s-rooms to labora tories thro u gh o ut the ch em i s try dep a rtm en t’st wo bu i l d i n gs . Bi och em i s try stu dents use the net worked com-p uters to do re a l - time data analys i s , record assay data, tra n s formand plot data points and test the devi a ti on of co ll ected data fromex pected va lu e s . Th ey also can access and manipulate a pro tei ns tru ctu re database du ring cl a s s , with the profe s s or on hand toh elp them over hu rdl e s . S tu dents in gen eral ch em i s try learn touse a spre ad s h eet for data proce s s i n g, s t a ti s tical analys i s , gra ph-ing and linear regre s s i on . A spectro s copy database and sof t w a refor analyzing nu clear magn etic re s on a n ce spectra bring com p l excon cepts to life at every or ganic ch em i s try lab ben ch .

Su pported by an h h m i gra n t , the ch em i s try dep a rtm en t’sl a ptop net work has inspired Den i s on’s bi o l ogy dep a rtm ent toc re a te a wi reless laptop com p uter net work of its own ,s ch edu l edfor use du ring the 2001–2002 ac ademic ye a r. —J B D

ant to the First Year Online project. “You can tell them, tell them andtell them again—and if t h ey have a different mental model ,t h ey won’tget it. Most incoming freshmen think that only animals respire; theyh ave tro u ble with the con cept that plants do too. Th ey think thatplants get their food from the soi l , and for get that there’s this stu f fc a ll edcarbon dioxide in the air. In fact,the whole notion of the carbon cycleand its con n ecti on to gl obal warming is a hard con cept . So in thehhmi project we try to give them modules on concepts that we knoware hard to understand.”

Ul ti m a tely, the proj ect’s goal is to produ ce 20 to 30 su ch modu l e scovering the con tent found in most introdu ctory bi o l ogy tex tboo k s . Indevel oping the modules inten ded for the first sem e s ter of i n trodu cto-ry bi o l ogy (“Cells and Mo l ec u l e s” ) , Merri ll says , the group has beenl e a rning a lot of l e s s on s . “One is that devel oping online edu c a ti on a lm a terials is a hu ge undert a k i n g. In the way that we’ve done it, i t’s a lotl i ke wri ting a tex tbook—and I don’t think we were prep a red to wri te atex tboo k .P lus it requ i res all the same skills as devel oping a com p l ex Webp a ge . It’s qu i te a ch a ll en ge for a fac u l ty mem ber to learn the gra ph i c a lde s i gn tools you need for that.”

A second lesson ,s ays Merri ll , is that online te aching is re a lly an artform .“The best pieces we’ve produ ced have an indivi dual voi ce and sen-s i bi l i ty.”Th ere’s no formula for that, he says ,“except to recogn i ze it wh enit happen s .”

» For more info rm a tion on BioQU E S T, visit: bi oqu e s t . or g /

» For more info rm a tion on MSU’s Fi rst Year Online Proje ct , vi s i t :

l ectu re . l i te .m su . edu / ~ bi o / f yo l /

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ane just started her freshman year at a top-ranked state university. John is a freshman at anIvy League school. Both were outstanding high-school students interested in pursuing careers inscience and medicine, so they chose those insti-tutions precisely because of their reputations for

research excellence.John and Jane may be in for a shock. They could

find themselves in packed lecture halls, listening toinstructors who would rather be almost anywhereelse. Their labs and seminars may be taught by grad-uate students who often are doing it not for the love of teaching,but to pay for their Ph.D.s. Meanwhile, the research leaders withwhom John and Jane hoped to study may be tucked away in theirlabs, supervising their research teams, writing grants and avoidingundergraduates whenever possible.

Unfortunately, we have evolved a built-in disconnect betweenresearch and teaching at many of our biggest and best universities.While undergraduates go toresearch institutions to get anoutstanding baccalaureateeducation, the faculty at thosesame universities seek (andneed) to do cutting-edgeresearch that often dependson peer-reviewed funding. Tomove important research for-ward, faculty attention isdiverted from local teachingneeds to a sometimes over-whelming concern about theattitudes of review panels inWashington. Although facultyvalue and for the most partenjoy teaching, it is researchthat tends to yield the rewardsof tenure, rank and pay—inother words, professionalrespect—while teaching usu-ally winds up low on thetotem pole.

Yet good research andteaching can coexist, and actu-ally reinforce and invigorate

Repairing the Disconnect Between Research and TeachingBy Peter J. Bruns

each other in provocative ways. Science educationmust involve more than facts and concepts; studentsneed to learn how we do research and be exposedenough to the excitement of discovery to beinspired to learn more about science. In a worldincreasingly dominated by science and technology,even those who will not become science majorsneed to learn enough about the content and processof science to be informed decision-makers andrational, critical thinkers throughout their lives.

Research scientists and their institutions some-times say that teaching takes valuable time and attention away fromresearch, but this is a short-sighted view. Teaching adds value toresearch by providing the fresh insights that flow from creativeinteraction among undergraduates, graduate students, postdoctoralfellows and senior scientists. It also provides apprenticeship experi-ences in science education for graduate students and postdoctoralfellows—the scientist-educators of the future.

In my years at Cornell, Iwatched with joy as undergrad-uates became fully integratedin my research group and thoseof many of my colleagues.They clearly brought freshideas and wonderfully chal-lenging, if naïve, questions tolab meetings and daily interac-tions. Still, individual researchprojects by the top few stu-dents at research universities,although desirable, are notenough. The synergy ofresearch and teaching needs toextend beyond the few and bepart of the standard fabric ofscience education in researchuniversities.

In that spirit, hhmi haslaunched a new initiative tohelp bridge the gap betweenlab and classroom. TheInstitute has committed $20million to support 20 “hhmiProfessors” for four years at

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A Novel Initiative: The HHMI Professors Program

WHAT’S NEW? These awards will be the first undergraduate bio-logical sciences education grants ever made by hhmi to individuals.

PURPOSE To overcome the traditional “research vs. teaching”dichotomy by encouraging successful research scientists to devotetime and creativity to undergraduate teaching.

INSTITUTIONAL BASE Eighty-four research and doctoral uni-versities have been invited to nominate up to two professors, whowill submit proposals for innovative undergraduate teaching pro-grams that build on the strengths of their research and teaching.

NOMINEE QUALIFICATIONS Individuals appointed as hhmiprofessors will be recognized biomedical research leaders whoalso have demonstrated teaching ability and would like to domore in undergraduate education while continuing their research.A panel of scientists and educators will review the nominees’research, teaching performance and proposals.

HOW MANY AND HOW MUCH? Twenty hhmi professors willbe chosen; each will receive a four-year award totaling $1 million.

WHEN? The awards will be announced in September 2002.

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research universities across the nation. The program’s goal is simple:to encourage faculty members who are very creative scientists toapply some of that creativity to undergraduate education.

The hhmi Professors program is designed to legitimize andreward great teaching, encouraging science departments at researchinstitutions to place a higher value on undergraduate teaching. Bysupporting the development of innovative, crossdisciplinary andmultiyear lab courses, the Institute hopes to enhance the alliancebetween research and education and to generate new undergraduatecurriculum materials that can serve the entire science community.

At hhmi, a gap has tended to separate investigators who con-duct research in universities and medical centers from their peerswho receive support through the Institute’s science education grantsprograms. I hope that by participating in both research and science-education meetings at the Institute, the hhmi professors will cre-ate synergy between those groups, a goal to which the Institute’sleadership is committed.

Nominations for hhmi professors have been invited from 84institutions and will be selected by an expert panel of scientists andeducators. Nominees will each have a proven track record inresearch, as well as some teaching experience. They will also havetwo other assets of special importance: innovative ideas on how tochange the fundamental ways in which science is presented to

undergraduates, and an ardent desire to try out these ideas.In the tradition of hhmi’s appointment of investigators, the

awards to hhmi Professors will support promising individualsrather than projects; the awardees will be given the freedom to tryinnovative ideas, which includes the liberty to change direction. Wehope to empower imaginative people to direct their skills and ener-gies to undergraduate science teaching, and then share the results.

The baseline for this experiment is not zero. I certainly have col-leagues all over the nation who have worked hard to bring innova-tive science education to undergraduates. But no individual or cam-pus in isolation can change the center of gravity on this issue. TheNational Science Foundation has just begun a distinguished teachingscholars program and the Carnegie Foundation for the Advance-ment of Teaching is supporting initiatives such as Portland StateUniversity’s Center for Academic Excellence. We hope that puttingthe hhmi imprimatur on scientist-educator programs will furtherstimulate a cascade effect, motivating more science departments andtheir institutions to seek out and reward good undergraduate teach-ing. In any case, it will help form the beginnings of a cadre of scien-tist-educators that can be instrumental in improving the quality ofundergraduate science education for generations to come.

Peter Bruns is hhmi’s vice president for grants and special programs.


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An entire class of proteins has longresisted the best efforts of scientiststo fathom its mysteries. These mol-

ecules—known as membrane proteinsbecause they reside within the fatty mem-branes that encase the body’s cells (and cer-tain internal parts of cells)—are involved ina vast range of vital functions. They regu-late the flow of nutrients into cells, let wasteproducts out and relay messages that sup-port life or trigger cell death. By chaperon-ing microbes into cells or by failing to func-tion properly, membrane proteins can alsoplay a role in making us sick. They are basicto the improved understanding and treat-ment of depression, Alzheimer’s disease,cystic fibrosis, blindness, childhood diar-rhea and a host of infectious diseases.

Despite their obvious importance,fewer than 30 of the estimated 20,000membrane proteins that exist have beendescribed structurally—atom by atom.They are notoriously difficult to purify andcrystallize.

The University of Texas MedicalBranch at Galveston (utmb) has importeda possible solution from Europe, along withits codeveloper, Ehud Landau. He’s deviseda way to quickly remove the proteins fromtheir stable lipid-layered environment,purify them and insert them into a newmaterial that imitates their native milieu.The proteins remain stable enough to crys-tallize, which is a prerequisite for solvingtheir structures by using x-ray crystallogra-phy. Landau and colleagues first used thisconcept, the lipidic cubic phase, to crystal-lize a membrane protein found in bacteriacalled bacteriorhodopsin in 1997.

“It is terrific to see Ehud following upon his stunning success in bacteri-orhodopsin crystallization with tests onother membrane proteins,” says hhmiinvestigator Wayne Hendrickson, a struc-tural biologist at Columbia University.“Even if the applicability of lipidic cubic

Ehud Landau (left) and Javier Navarro have set out

to solve the structures of membrane proteins by

recreating the molecules’ native environs.

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The Hidden World of Membrane Proteinsphase proves to be limited, I expect thatwhat he learns about how membrane pro-teins interact with lipids will be highlyinstructive.”

In August, Landau and colleagues pub-lished the molecular architecture of a sec-ond bacterial membrane protein, called sen-sory rhodopsin II. Discerning its structure isimportant, says coauthor Javier Navarro,because “this bacterial protein is structurallyand functionally related to a family ofG protein-coupled receptors,” which, henotes, are the targets of some “60 percent ofall drugs currently in use.” Knowing thestructure of sensory rhodopsin II brings theresearchers closer to understanding the G protein-coupled receptors, some of whichmediate sight, smell, neurotransmission andthe body’s recognition of the humanimmunodeficiency virus.

Even with the excitement of determin-ing this new structure, Navarro admits thatthe road is slow going. “We’re working tocrystallize 15 membrane proteins rightnow,” he says, including some G-proteincoupled receptors and a protein involved incystic fibrosis. “If we get one a year, thatwould be fantastic.”

Landau and Navarro are codirectors ofutmb’s Membrane Protein Laboratory—one of three core facilities of a comprehen-sive new program built with support froman hhmi grant designed to help medicalschools build facilities, hire faculty and cre-ate centers of excellence. The other corelabs are devoted to the genetics of mem-brane proteins and the development ofsmall molecules designed to activate orinhibit the function of these proteins.

With a thick beard and horn-rimmedglasses, Landau exudes an intense scientificwork ethic. The Israeli researcher spent yearsas a physical chemist studying the nuancesof how lipids—the main components of cel-lular membranes—behave under differentconditions. Landau and Navarro became

fast friends and colleagues in 1998 whenNavarro, a clean-cut and high-spirited nativeof Peru, took a year-long sabbatical at thelab Landau was running at the University ofBasel in Switzerland.

Landau and his collaborator, JurgRosenbusch, a pioneer in membrane-pro-tein research, had recently developed anovel concept to stabilize membrane pro-teins in three-dimensional bilayers—theuse of the “lipidic cubic phase.” Navarro,who, like Rosenbusch, knew the evasive


behavior of membrane proteins, was eagerto learn the new technique.

The lipidic cubic phase stood outbecause it promised to speed the pace ofresearch in a field in which progress hadbeen terribly slow, mainly for two technicalreasons. First, unlike other proteins, thoseresiding within fatty layers of cellular mem-brane don’t dissolve in water. Whenresearchers try to purify them—separatethe proteins from their membranes—thewater-loathing, fat-loving layers of themembrane uncoil, gelling into a uselessmass like the white of a hard-boiled egg. Toovercome this problem, researchers tradi-tionally have turned to detergents, whichremove fats the way soap removes dirt—byforming protective belts around the pro-tein. But detergents also can damage pro-teins, and milder substitutes that accom-plish the same task have been hard to find.

A second difficulty, related to the first,is that membrane proteins are difficult tocrystallize—a necessary step for getting

detailed, three-dimensional images of themolecules. For decades researchers havebeen growing nonmembrane proteins intowell-ordered networks, or crystals, that canthen be bombarded with x-rays. The result-ing diffraction patterns are analyzed to pro-duce pictures of the molecules’ architec-ture. It’s tough to crystallize membraneproteins, however, because this process, likepurification, relies on detergents. Unfortu-nately, “what works for one doesn’t [neces-sarily] work for the other,” says Navarro.Researchers, he says, often have to screenmany detergents and settle in the end forless than optimal results.

“You have to do an enormous amountof work,” agrees Richard Henderson, astructural biologist at the Medical ResearchCouncil in Cambridge, England. A pioneerin membrane-protein research, Hendersontoiled for 17 years before publishing, in1975, the very first structure of bacteri-orhodopsin, which is found in the salt-lov-ing bacterium Halobacterium salinarum.

Bacteriorhodopsin turns light into cellularenergy, making it nature’s simplest photo-synthetic machine.

Henderson’s structure was ground-breaking—but crude by present-day stan-dards because it showed only the protein’sgeneral folding pattern. Scientists prefer theultimate insight: an atom-by-atom pictureof the molecule. No one succeeded untilLandau and Rosenbusch, together withFrench crystallographer Eva Pebay-Pey-roula, published their structure of bacteri-orhodopsin in Science magazine 22 yearslater, in 1997.

Landau and Rosenbusch had devised away to achieve their goal. They reasoned thatthe membranes’ own three-dimensional net-work of lipid bilayers would stabilize mem-brane proteins in a way that artificial deter-gent solutions never could. In essence, theteam asked, why not try to replicate mem-brane proteins’ natural oil-and-water home?

“Lipids and water are in principleimmiscible—they don’t mix,” says Landau,“but we can manipulate them into a newmaterial—the lipidic cubic phase—thatallows us to work with membrane pro-teins.” By rapidly dissociating these proteinsfrom their native lipid containment, purify-ing them and then very rapidly incorporat-ing restructured versions of them into thenew bilayered material, says Landau, “theyare much more stable because they are in anative-like environment.” This techniqueoffers a great practical advantage, addsNavarro, because the onerous process ofscreening detergents has been eliminated.

Since Landau’s arrival at utmb, scien-tists from around the world have come toGalveston to learn the new method, andothers are sending protein samples to thelab for characterization. “Our methodopens up possibilities to work with unsta-ble membrane proteins that researchershaven’t been able to crystallize in the past,”explains Landau.

“Structural biology of membrane pro-teins is one of the most important frontiersin biology today,” he says. “It’s about timethese proteins got their due.”

— STEVEN J. MARCUS & ALANA MIKKELSEN

Segments of this article were adapted with permissionfrom the UTMB Quarterly, Winter 2001.


notes, the master musicians are morefamiliar with the music and can anticipatethe key changes. Still, “being able to detectthis expertise with EEG is truly exciting,”says the electrophysiologist.

Both science students and music majorssay they benefited from the course. JessicaHoge, a pianist who majored in music andneuroscience, used the data generated bythe concert-experiment for her senior thesisand submitted a scientific paper for publi-cation. She says the whole experience hasinfluenced her music as well. “When I playnow, I’m definitely aware of the mechanismworking in the listeners’ brains.”

Chien adds that musicians have longsuspected the effects of music on the brain,but “now we have proof.” For nonmusi-cians, the hands-on activity was critical tothe learning of the science, Cross says.Music brings familiarity and relevance tothe classroom. “It makes our job easier.”

A number of factors inspired Cross,Dale and Chien to create the course. The

college encourages cross-disciplinary col-laborations, students were showing interestin learning about music and the brain andthe local Alexander String Quartet—havingparticipated in an annual artists-in-resi-dence program on the campus for 10years—was a handy resource.

In next spring’s course, using vocalmusic as stimuli, new telemetry equipmentwill allow the researchers to leave the heavycomputers in the lab. A new imaging sys-tem will enable them to map more regionsof the brain.

In addition to the music course, othercross-disciplinary courses will include“Neuroscience of the Visual Arts,”“Neuro-science of Dance,”“History of Neuro-science” and a philosophy course called“Mind and Brain.” Dale says he is lookingforward to these new collaborations. “Thefaculty gets so excited about these models,”he says, “and, when you get the facultyexcited, that excitement is absorbed by thestudents.” —CAMILLE MOJICA REY

N E W S & N O T E S

It’s a cool spring evening at AlleghenyCollege in Meadville, Pennsylvania.The Alexander String Quartet—profes-

sional chamber musicians who perform atthe college every year—is tuning up on thestage of Ford Memorial Chapel. As the audi-ence files in, a few students scurry aroundthe balcony attaching electrodes to theirclassmates’ heads and connecting the wiresto large computers hauled across campus forthe occasion. For tonight, the old stonechurch is converted into a living laboratory.

This combination concert-experimentwas part of an interdisciplinary course,“Neuroscience of Music,” offered for thefirst time during the spring 2001 semesterby faculty neuroscientist Jeff Cross and hiscolleagues—electrophysiologist AlexanderDale and concert pianist Alec Chien. “It isthe participant model of science,” Dalesays. “The subject participates in theresearch.” The pilot course was so success-ful that the scientists will soon team upwith visual artists and dancers to providenew and unique learning experiences forthe students, while further investigatingthe workings of the human brain. “Neuro-science has the wonderful advantage ofbeing applicable to every human endeav-or,” Dale explains.

Supported by a grant from hhmi, themusic course involved a series of concertsin which electroencephalograms (EEGs)recorded alpha and beta brain waves of stu-dents as they listened to the music. Later, inthe laboratory, the students measured thebrain activity of the quartet members asthey listened to the piece of music they hadperformed earlier. Comparisons showedthat alpha-wave patterns—characteristic ofrelaxed wakefulness—were similar in bothsets of listeners.

As expected, Cross says, beta-wave pat-terns—those indicating intense mentalactivity—appeared in both groups in thebrain’s right frontal area in response tochanges in key. However, the beta wavesappeared an average of four measures earli-er in the quartet members. Of course, Dale

Neuroscienceof Music

Alexander Dale, Jeff Cross and Alec Chien (left to right) blended their scientific and musical expertise

to teach students about research.

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Twenty-nine museums, aquariums, zoos and nature centers have won new hhmigrants totaling $12 million. A number of the programs focus on environmentalstewardship in inner city, rural and other areas where there are high concentrations

of disadvantaged children and families. The Fairchild Tropical Garden in Miami, for exam-ple, will receive a $290,000 grant to reach the local, largely Cuban, community. The pro-gram, called Green Treasures, involves schoolchildren, teachers, families and older peoplewho emigrated from Cuba in hands-on study of the scientific, economic and culturalimportance of plants. The objectives of the grants are to strengthen the science literacy ofteachers, children and their families; to provide resources for improved science teaching; toengage families and communities in science education; to develop an interest in science-education and research careers; and to foster collaboration between informal science edu-cation centers and other community institutions.

A list of the new grantees follows. Profiles of some of the programs can be found onthe hhmi Web site at: www.hhmi.org/news/071001.html.

� Arizona Science Center, Phoenix, Ariz.

� Bronx Zoo, New York, N.Y.

� Cable Natural History Museum, Cable, Wis.

� Chicago Academy of Sciences Peggy Note-baert Nature Museum, Chicago, Ill.

� Chicago Botanic Garden, Glencoe, Ill.

� Children’s Discovery Museum, San Jose, Calif.

� The Children’s Museum, Boston, Mass.

� Dakota Science Center, Grand Forks, N.D.

� EcoTarium, Worcester, Mass.

� Fairchild Tropical Garden, Miami, Fla.

� Garden in the Woods of the New England Wildflower Society, Framingham, Mass.

� The Gulf Coast Exploreum, Mobile, Ala.

� The Imaginarium, Anchorage, Alaska

� Irvine Natural Science Center, Stevenson, Md.

Mini-Courses in Moscow

A mini-course on immunology andtumor immunology is routine—except when it involves two Ameri-

can scientists traveling to Moscow to lead theevent.“It may be a seditious thing to say, butwe actually don’t have serious education inimmunology, and particularly in tumorimmunology, in Russia,” says course organiz-er Sergei Nedospasov, an hhmi internationalresearch scholar at the Engelhardt Institute ofMolecular Biology of the Russian Academy ofSciences.“The need for such lectures is vital.”

Philip Greenberg of the University ofWashington and Robert Schreiber of theWashington University School of Medicineled the four-day course in May at MoscowUniversity’s Center for Molecular Medicine.They are among more than 15 researchers,including several hhmi investigators, whocomprise a “visiting faculty” that has beguntraveling to Russia to discuss the latestachievements in immunology in general andtumor immunology in particular. Nedospasovlaunched the three-year educational programlast September with support from the NewYork-based Cancer Research Institute and theLudwig Institute for Cancer Research.

Nedospasov wants his colleagues, espe-cially younger scientists, to have more contactwith leaders in immunology research. On acompetitive basis, he helps select groups of 10to 15 trainees from Russia and other coun-

tries of the former SovietUnion to participate in“journal clubs” with thelecturers and attend thelarger lectures.

Program organizerssay they hope that if theprogram proves success-ful over its three years,colleagues will begin toparticipate in greaternumbers, leading tomore such efforts inMoscow and elsewhere.The program’s Web siteis lmi.webzone.ru.—ANDREI ALLAKHVERDOV

Local students Genevieve Rinker (left) and Rebecca Hopson help Anchorage-based Imaginarium bring

the excitement of science to Alaska's children.

New Museum Grants Awarded

� The Maritime Aquarium, Norfolk, Conn.

� Missouri Botanical Garden, St. Louis, Mo.

� Museum of Science, Boston, Mass.

� National Aquarium in Baltimore, Md.

� New Jersey State Aquarium, Camden, N.J.

� Rock Creek Nature Center, Washington, D.C.

� The Science Museum of Minnesota, St. Paul,Minn.

� The Seattle Aquarium, Seattle, Wash.

� Sedgewick County Zoo, Wichita, Kan.

� Staten Island Children’s Museum, Staten Island, N.Y.

� UC Berkeley Museum of Paleontology, Berkeley, Calif.

� University of California Botanical Garden, Berkeley, Calif.

� University of Wisconsin–Madison Arboretum

� Zoo New England, Boston, Mass.Nedospasov

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Reason to Stay Another Year

tain hematopoietic stem cells, could notalone help the irradiated mice to recover.However, she could save them by trans-planting bone marrow.

Both fetal liver and bone marrow con-tain stem cells that should be capable ofrestoring bone marrow. Why couldn’t thefetal liver cells alone manage it? Katsumotobegan focusing on the potential role ofaccessory cells, which aren’t stem cells butsomehow support the engraftment process.Accessory cells are prevalent in bone mar-row, but exist at much lower concentra-tions in fetal liver.

When Katsumoto mixed fetal liver cellswith accessory cells derived from bonemarrow and injected them into irradiatedmice lacking GM-CSF, the bone marrowregenerated and the mice were rescued.“These accessory cells aren’t the immatureprecursor cells that reconstitutehematopoiesis,” Katsumoto says. “Still,these cells were somehow facilitatingengraftment.”

However, enough accessory cells had tobe present to compensate for the injury tothe stroma that occurs in response to irra-diation. Will adding GM-CSF protect andnurture sufficient numbers of accessorycells to improve engraftment? Katsumotohopes to find out.

“What we can start thinking aboutdoing,” Katsumoto says, “is using GM-CSFto improve engraftment. This might beespecially important when umbilical-cordblood or other sources of stem cells thatcontain few accessory cells are used.”

Her project mentor, Kevin Shannon,noted that his lab, which mainly focuses onleukemia, would not normally have pur-sued this line of research. With Katsumotopreparing to complete her last year of med-ical school, however, he says the lab will doso, at least for the short term.

When she graduates from ucsf, Kat-sumoto is sure she will pursue internalmedicine, although she admits she is alsofascinated by hematology/oncology. “I real-ly just love the practice of medicine,” shesays. “It’s so wide open—there are so manyopportunities.” —LISA CHIU

Medical student Tamiko Katsumoto explored

blood-cell development during HHMI fellowship.

ma—the spongy mix of fat, fibroblasts,macrophages and other components thatsupport blood-cell development.

“I realized around February of that firstyear that we had a really striking result,”Katsumoto says. “If I wanted to carry theproject through, I needed another year.”Katsumoto, who was doing her researchunder an hhmi medical student researchfellowship, decided to apply for a secondyear of support. She was among the veryfew who received it.

She was working with mice lacking thegene for granulocyte macrophage-colonystimulating factor (GM-CSF)—a substancethat stimulates the growth of certain bloodcells. After irradiating the mice lackingGM-CSF to destroy their bone marrow, shediscovered that fetal liver cells, which con-

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To travel the path of discovery, onehad better be open to extending theadventure a little while longer.

That’s exactly what medical studentTamiko Katsumoto found herself doingwhen her project dropped tantalizingresults in her lap.

Originally scheduled to spend oneyear in the lab of Kevin Shannon at theUniversity of California, San Francisco(ucsf), Katsumoto ended up addinganother year to her stay in order toexplore fundamental mechanisms ofhematopoietic stem-cell engraftment—themeans by which immature blood-formingcells take up residence in the fetal liver andthen move on to the bone marrow. In theprocess, she uncovered a previouslyunknown role for the bone marrow’s stro-


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The Texas town of McAllen sharesmore than a border with its Mexican neighbor, Reynosa, in

the state of Tamaulipas. The RioGrande/Rio Bravo Watershed is theregion’s primary water source, and it isone of North America’s most endan-gered river systems. In May, the McAllenInternational Museum brought amobile, hands-on exhibit—Our Water-shed—to the Universidad Autonoma deTamaulipas. It is part of a bilingual envi-ronmental education project called “A River Runs Through Us,” supportedin part by a science education grantfrom hhmi. Children from six Reynosaarea high schools were trained by muse-um staff to serve as guides to the 4,200 elementary school students from 30schools who visited the exhibit.

Above: Sixth graders from Colegio Reforma, a Reynosa elementary school, use a model ofthe Rio Grande/Rio Bravo Water-shed to see how dams change theflow of a river.

Lower Left: Carlos Alberto PérezAbrego, left, and Rámon DavidPérez Hernandez, students atCETIS 71, a Reynosa high school,operate small hand pumps tocause “rain” to fall from clouds ina model of the water cycle.

Lower Right: A visiting studentplays the role of "watermaster,"whose task is to distribute fairly—among cities, industry, agriculture and wildlife—thewater that McAllen and Reynosa share.

A River RunsThrough Us


N E W S & N O T E S

Jane Gitsch i er, h h m i i nve s ti ga tor atthe Un ivers i ty of Ca l i forn i a , Sa nFra n c i s co (u c s f) ,s tudies the gen eti c

basis of ch i l d h ood disorders . One of h er lat-est ex p l ora ti on s ,i n s p i red by her training asa classical singer, is the gen etics of perfectp i tch—less a disorder than a ra re mu s i c a lgi f t . With co lleagues at u c s f, i n clu d i n gNel s on Frei m er, n ow at the Un ivers i ty ofCa l i forn i a , Los An gel e s ,G i t s ch i er has fo u n dthat this abi l i ty to name a note ,i m m ed i a telyand ef fort l e s s ly, wh en it is sounded tends torun in families. The re s e a rch ers don’t yetk n ow wh i ch gene or genes are re s pon s i bl e ,but they ’ve begun the linkage studies to findo ut . Th ey do know, h owever, that the tra i trequ i res early musical training to bl oom .

How ra re is perfect pitch , rea ll y ?Jane Gitschier: I gave a talk on perfect pitchat h h m i last ye a r. The staff h ad the Stei n-w ay tu n ed for the occ a s i on . I gave the audi-en ce of a bo ut 100 people our opera ting def i-n i ti on of perfect pitch : If I played a ton ewi t h o ut an ex ternal referen ce , a pers on wi t hperfect pitch could iden tify that ton e . Th en Ip l ayed four notes on the piano. Just one per-s on , a po s tdoc , qu i ck ly ra i s ed his hand andcorrect ly named the four note s . The audi-en ce app l a u ded . It’s very clear that this is ana bi l i ty the avera ge pers on does not have .

Do people with perfect pitch know theyh ave it?JG : Ye s , and they give the same answers to

t h ree basic qu e s ti on s . How long does it takeyou to tell what a tone is? Th ey re s pon d ,“ Im m ed i a tely.” How long have you knownyou have perfect pitch? “ My whole life .”How acc u ra te are you? “I never miss.”

Is this a case of n a t u re needs nu rt u re ?JG : Ex act ly. You need to have some kind oftraining to devel op perfect pitch . It make ss en s e . You cl e a rly need to be ex po s ed to thedef i n i ti on of a note—this is a D-flat, this isan A- s h a rp. If you don’t get that mu s i c a li n p ut by a certain age ,a round age six, yo u’ lllose the ch a n ce to have perfect pitch even ifyou have the ri ght all el e .

Can a pers on devel op perfect pitch wi t h-o ut the gen etic pred i s po s i ti on? JG : People claim you can, but I’m du bi o u sa bo ut it. You can devel op very good rel a tivep i tch — get to know what an A feels like ona vi o l i n , for ex a m p l e . You might seem toh ave perfect pitch . But you may not have iton other instru m en t s .

How wi ll this re s ea rch ben efit people inmu s i c ?

JG : (La u gh i n g) I don’t thinkt h ere i s a ny app l i c a ti on forpeople in mu s i c . I think there’sa lot of a pp l i c a ti on for sci-en ce—in the stu dy of bra i ndevel opm ent and neu ron a lp l a s ti c i ty, and in edu c a ti on a li s sues as well . For ex a m p l e ,i tcould help us dec i de wh et h erto ex pose our ch i l d ren to cer-tain things ,l i ke new language s .I tri ed to give my daugh terpiano lessons by the time shewas six ye a rs old. It bec a m eobvious to me that she doe snot have perfect pitch , so I did-n’t push it. On the other hand,s h e’s doing a be a utiful jobl e a rning Ch i n e s e .

—CORI VA N C H I E R I

If You Can Name Th at To n e ,Thank Your Pa re n t s —and Your Music Te a c h e rA conve rsation with Jane Gitsc h i e r

Jane Gitschier ex p l o res the genetics of perfe ct pitch. She and daughter Annie Ste i n b e rg enjoy playing music to g et h e r.

Think yo u’ ve got that magical

a b i l i ty to name that tune in one

n ote? Te st your inborn skill with

G i t s c h i e r ’s pitch te st online at :

www. h h m i .o rg / b u l l et i n .

NewNotes.Final 10/9/01 8:19 PM Page 34


Located in the heart of Roxbury, alargely minority, inner-city neighbor-hood of Boston, the James P. Timilty

Middle School shines in science education.In the rigorous statewide achievement testsfor the eighth grade, Timilty’s studentsoutscored most of Boston’s schools in sci-ence and technology and in a combinedmeasure of achievement in four broad sub-ject areas. The school has been singled outwith several national and statewide awardsfor its overall high student performance.

Timilty’s success, administrators say,reflects several factors, including its skilledand dedicated staff; its adoption of ProjectPromise—a program featuring an extendedschool day, team teaching, shared decisionmaking and smaller classes; its inspired stu-dents and a little help from its friends.Since 1989, a partnership with nearbyMassachusetts General Hospital (mgh) hasenabled the school to tap the hospital’sresources. Each year, some 250 hospitalemployees spend time as mentors, occa-

sional classroom lecturers and hosts toyoung visitors. Since 1994, the mgh/Tim-ilty Partnership has been strengthened withthe Science Connection program, fundedby an hhmi grant.

The objective, says the partnership’sadministrative director Carlyene Prince, is

NEW UNDERGRADUATE COMPETITIONHHMI has invited 200 research and doctoral universities to apply for a new round of under-graduate biological sciences education grants. An estimated 50 to 60 four-year grants rang-ing from $1.2 million to $2.2 million will be awarded in 2002.

In addition to the existing objectives, such as preparing students for careers in biomedicineand providing engaging science curricula for nonscientists, new program objectives include:

� Enable graduate students and postdoctoral fellows to supplement their research trainingwith teaching and mentoring experiences that prepare them for roles as scientist-educators.

� Develop models for overcoming the traditional dichotomy between research and teaching.

� Foster a team approach to research among faculty, undergraduates, fellows and graduatestudents.

� Explore the interactions of biology and other disciplines, including mathematics and com-puter science.

� Share university educational resources with other institutions, including colleges and sec-ondary and elementary schools.

� Provide increasingly challenging science experiences to undergraduates during their four-year college stay. —JENNIFER BOETH DONOVAN

to “demystify” science for the students. Sci-ence Connection’s longest-running activityin this spirit—its “cornerstone,” saysPrince—is the Science Fair Mentoring Pro-gram. Each mgh volunteer is paired with aTimilty student for the six months leadingup to the school’s annual science fair. Stu-dents are chosen not so much for theirgrades as for their motivation, says Timiltyscience teacher Robert Cho, the program’sformer manager. They are “kids who reallywanted to be in the program.”

In 2001, Timilty sent more studentprojects to the citywide science fair thanany of Boston’s 26 other middle schools,and many won awards. The Science Con-nection program has additional compo-nents. “Science in the Classroom” featuresteaching stints by mgh employees rangingfrom one-time visits to continuing rela-tionships with a class. Twice a year, the stu-dents’ family members join in for “ScienceFamily Activity Night.”“We expose theseyoung men and women, who often live in avery small circle, to science,” says mentorGuillermo Banchiere, director of environ-mental services at mgh. “By showing themlots of things they probably didn’t knowexisted, we expand the universe for them.”

—STEVEN J. MARCUS

A Science Connection inRoxbury

Eighth grader Javier Martinez-Gonzalez demonstrates his award-winning research project with a fel-

low student. He compared the lung capacity of boys and girls through a calibrated arrangement of

buckets and a tube immersed in water.

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I N B R I E F

Fault the ion channel Genetic mutations

that yield flaws in a specific ion channel have

been tied to a rare disorder characterized by

muscle paralysis, irregular heartbeat and

growth problems. The finding offers a new per-

spective on how faulty ion channels—pore-like

proteins that poke through cell membranes and

control the flow of potassium, sodium and other

ions into and out of the cells—can cause disease

in humans. Researcher: Louis J. Ptácek.

www.hhmi.org/news/ptacek3.html

Motor neurons need vitamins Spinal

muscular atrophy (SMA), the most common

genetic cause of infant mortality, may be exac-

erbated by insufficient amounts of folic acid and

vitamin B12 in the diet. The HHMI investigators

who made this discovery plan to collaborate

with clinical scientists to explore whether vita-

min therapy might offer some relief from the

muscle weakness and wasting experienced by

SMA patients. Researcher: Gideon Dreyfuss.

www.hhmi.org/news/dreyfuss2.html

Genes and benign tumors Researchers

have determined the normal role of two genes

that are mutated in the inherited disorder

tuberous sclerosis complex. Ordinarily, these

genes, Tsc1 and Tsc2, help regulate cell growth

and organ size; their protein products are likely

part of the insulin-signaling pathway. These

genes may offer a novel target for treatment of

type 2 diabetes, as well as tuberous sclerosis

complex, which causes widespread benign

tumors in the brain, skin, lungs and kidneys.

Researcher: Tian Xu.

www.hhmi.org/news/xu2.html

Tracking forward motion Researchers

have distinguished some of the cues that the

human visual system uses to estimate the

speed of an approaching object. As the object

gets closer, the visual system extracts informa-

tion about its motion by estimating the rate of

change in its size.

Researcher: Eero P. Simoncelli.

www.hhmi.org/news/simoncelli.html

Room forImprovement in Statin Drugs

Researchers have provided the firstmolecular look at how a popularfamily of cholesterol-lowering drugs

does its work. They’ve captured images ofthe widely prescribed statin drugs, includ-ing Lipitor and Zocor, in the process ofblocking cholesterol synthesis—and theysee room for improvement.

Statins block the enzyme HMG-CoAreductase (HMGR) from grabbing hold ofa molecule called HMG-CoA to begin cho-lesterol production. As a result, the cell suf-fers a shortage of cholesterol and compen-sates by importing ready-made cholesterolfrom the bloodstream. This, in turn, lowerscholesterol levels in the blood.

The scientists used x-ray crystallographyto produce images of six different statinsbinding with HMGR. Although thestatins have different shapes, theyall imitate part of the HMG-CoAmolecule, and trick HMGR intograbbing hold of the statin. Thiscoupling twists the enzyme slightlyout of shape, preventing it fromforming its active site—the busi-ness end of the enzyme that bindswith HMG-CoA. hhmi investiga-tor Johann Deisenhofer at the Uni-versity of Texas Southwestern Med-ical Center in Dallas and Eva S.

Istvan, now an hhmi postdoctoral

fellow at Washington University in St. Louis,published their findings in the May 11, 2001,issue of Science.

“This finding is important because itshows that the statins work by attachingthemselves to an inactive form ofHMGR,” says Deisenhofer. “That suggeststhat you can’t assume that a drug willhave its effect by attacking the active formof an enzyme. You may have to design adrug that attacks the inactive form of theenzyme and prevents the enzyme frombecoming active.”

The researchers also noticed that exist-ing statins fail to block an additional regionof HMGR, suggesting that the drugs mightbe improved to more tightly bind to theenzyme and further reduce its activity.Deisenhofer emphasizes, however, thattight binding to the enzyme may not be thewhole story. Statins appear also to interactwith other proteins, as evidenced by theireffects on blood-vessel growth, bone for-mation and the immune system.www.hhmi.org/news/deisenhofer.html

—MARC KUSINITZ

A representation of part of the surface

of HMG-CoA reductase (yellow and

green) shows how one statin drug, sim-

vastatin (purple), binds to the enzyme.

The drug blocks the enzyme from

becoming active and instigating

cholesterol synthesis.

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Brain wiring turnabout A potent chemical

signal known to guide the wiring of neurons in

the developing nervous system also steers

migrating muscle fibers to their proper connec-

tions. The signal initially repels muscle cells, and

later becomes a powerful attractant. The dis-

covery of the signal’s dual role, and its drastic

turnabout, shows how tissues may use the

same signals for different purposes during

development. Researcher: Corey S. Goodman.

www.hhmi.org/news/goodman2.html

Where cell death begins Two proteins

inside the cell, BAK and BAX, are essential to

setting off programmed cell death (apoptosis).

They act by disrupting mitochondria, the cell’s

energy-producing machinery, causing leakage of

the protein cytochrome c and triggering cell

death. Inhibiting BAK and BAX activity may

ease nerve-damaging disorders that involve

excessive apoptosis, whereas promoting the

proteins’ activity might slow the runaway cell

growth of cancer. Researcher: Stanley J.

Korsmeyer.

www.hhmi.org/news/korsmeyer.html

How the brain’s clock ticks By creating

mice with a mix of cells that produce either

normal or abnormal circadian rhythms,

researchers are learning how neurons synchro-

nize their behavior to control the body’s 24-hour

internal clock. Researcher: Joseph S. Takahashi.

www.hhmi.org/news/takahashi3.html

Virus wraps up ribosome Researchers have

discovered how hepatitis C virus (HCV) forces

infected cells to shut down their own protein syn-

thesis and make the virus’ proteins instead. Addi-

tional studies might reveal ways to block this

HCV takeover strategy, thereby improving treat-

ments for HCV infection. Researchers: Jennifer

A. Doudna and Joachim Frank.

www.hhmi.org/news/doudna.html

Fly genes for taste and smell By identify-

ing a large family of fruit fly genes involved in

taste and smell, scientists have taken a signifi-

cant step toward deciphering the molecular

logic of odor and taste perception. This work

could lead to improved methods for protecting

humans and crop plants from insects.

Researcher: Richard Axel.

www.hhmi.org/news/axel2.html

Researchers have discovered a sensingmolecule on the surface of naturalkiller (NK) cells that enables them to

battle viral infections. The finding is animportant step in understanding innateimmunity—how the body rapidly launchesits first strike against invading pathogensbefore other components of the immunesystem can take action.

NK cells are lymphocytes best knownfor their ability to kill developing tumorcells. They have also been thought to count-er infections in the earliest phases of thebody’s immune response, but how thesecells could attack their targets had neverbeen demonstrated, according to hhmiinvestigator Wayne M. Yokoyama and col-leagues at Washington University School ofMedicine in St. Louis and coauthor Anthony

A. Scalzo at the University of Western Aus-tralia. Their findings were published in theMay 4, 2001, issue of Science.

By exploring the region on mousechromosome 6 known to contain clustersof genes for receptors found on NK cells,they found a receptor called Ly-49H thataccounts for the ability of some mice toresist otherwise lethal infection withmurine cytomegalovirus (a herpesvirusthat infects mice). The researchers then

First-LineVirus Fighters

Yokoyama and colleagues propose that natural

killer (NK) cells express a receptor, Ly-49H, that

enables them to recognize a ligand (purple trian-

gle) on the surface of cells infected with murine

cytomegalovirus. This leads to activation of the

NK cell to release granules (orange balls) that

disrupt the infected cell's plasma membrane and

cause the cell to die.

studied the immune response of the BXD-8strain of mouse, which lacks only the Ly-49H receptor on NK cell surfaces. Withoutthis receptor, the mice were susceptible tomurine cytomegalovirus. In addition, whenLy-49H was inactivated in mice that pos-sessed the receptor, the mice died, unable tocontrol the virus. These studies providedkey evidence that the Ly-49H receptorsparks the NK cells’ attack against the virus.

“These findings strongly suggest thatNK cells have a specific role in immunitythat was not previously known,” saysYokoyama. “NK cells apparently use Ly-49Hto recognize something on the membranesof cells infected with murine cytomegalo-virus and initiate an immune response thatdestroys those cells. This further impliesthat NK cells may use this receptor or oth-ers to recognize and attack other infec-tions.” Basic understanding of NK cell acti-vation could lead to better treatments,especially for people with aids and otherswith weakened immune systems who arehighly susceptible to viral infections.www.hhmi.org/news/yokoyama.html

—MARC KUSINITZ

H A N D S O N


May I Take YourMouse Order, Please?It’s not quite as routine as

ordering a magazine or abouquet of flowers, but the

process of buying specializedmice for experiments in genet-ics and related fields hasbecome commonplace. TheJackson Laboratory, which runsthe world’s largest mouserepository, supplies approxi-mately 2 million mice each yearto universities, medical schoolsand research laboratories.

The not-for-profit institu-tion in Bar Harbor, Maine, also has its ownresearch program, whose investigations rangefrom diabetes to sleep disorders, and it offersa variety of training programs for visiting sci-entists. It remains best known, however, asthe place that researchers call to get mice bredwith a vast array of genetic variations—morethan 2,500 strains. Already the most widelystudied research model for human diseasesand disorders, the mouse has become evenmore essential since scientists developedtechniques to “knock out” or otherwise mod-ify specific mouse genes, most of which haveclose human counterparts.

Researchers interested in genes connectedwith cancer, for instance, can find hundreds ofmouse strains that might be useful. Stocknumber 002265 is a mouse that lacks the Bcl2gene involved in leukemia and other cancers, acharacteristic that makes it useful in the studyof cancer itself or in learning about underlyingbiological processes such as programmed celldeath. Other mouse strains related to cancerare so numerous that the lab’s 535-page cata-log lists them under “Oncogenes,” “GrowthFactors” and similar categories. The catalogalso offers mouse models for numerous otherdisorders. Scientists at the Jackson Lab, likeSimon John, an hhmi investigator who stud-ies the genetics of glaucoma, and at numerous

other institutions supplied thestrains to the laboratory forbreeding and distribution tothe scientific community.

The lab distributes mousedna as well as live mice, and itis assessing the feasibility of shipping frozen mouseembryos or sperm thatresearchers could use to buildtheir own mouse colonies. Allmaterials undergo rigorousquality-control testing toensure health and genetic

purity. The lab also maintains a comprehen-sive database about mouse genetics, which isavailable through its Web site, www.jax.org.hhmi has provided more than $5 million tohelp the Jackson Laboratory meet the grow-ing demand by researchers for geneticallyaltered mice.

� Scientists from around theworld can order mice by phone, faxor mail, or online at jaxmice.jax.org.

They can use credit cards andother forms of payment butencounter some interesting

restrictions. Some mutant mice,for instance, must travel with

hardier mice, called shippingcompanions, to survive the stressof shipment. Scientists also needto provide advance notice if they

want pregnant females, which dobest if shipped between the 11th

and 15th days of pregnancy.

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� Inventory control is a challengefor the lab, which provides coloniesto match demand whenever possi-

ble but sometimes must restrictquantities of certain strains. Many

factors affect the availability of astrain, especially when it is firstreleased for distribution. These

include how well the strain breeds,the size and viability of typical

litters and whether one gender ispreferred as a research model. For

example, both of these mousestrains are useful in cancer

research. Scientists can order onlyas many as 10 of each sex per

month of the first strain, but theycan order 25 or more per month of

each sex of the second strain.

� Some mice, like the first onedescribed here, have genetic muta-tions that occurred spontaneouslyin nature. Others, like the secondentry, have mutations thatresearchers created deliberately.

� The older the mouse, the more itcosts. This mouse costs $157.70 at

three to five weeks of age and$162.65 at eight weeks. A

breeding pair costs $195.20. Theprices for other strains vary. Thereare also shipping fees—$9.00 percontainer—and charges for items

such as export documents.


C L O S E - U P

“Home-Grown” ProteinsBuild Synaptic Strength

Many neuroscientists believe thatsynaptic strength—the ease withwhich a signal traverses the

synapse, which is the gap between twoneurons—plays a central role in learningand memory. When a music student firstreads “C major 7 chord” on a score, forexample, it takes considerable effort tostrike the correct keys on the piano. Afterreading and playing the chord 500 times,however, the neural pathway thattranslates a visual image into a musicalconcept and then into a fingering patternbecomes established, enabling the fingersto strike the keys faster and more accurate-ly. At the molecular level, the “wearing in”of this neural pathway translates into thebuilding-up of synaptic strength and amore powerful signal.

The cell biology of this process hasposed a paradox, however. To build synapticstrength, new proteins are neededimmediately at the dendrites, the synapse-forming branches emerging from the bodyof the neuron. These proteins must be trans-ported from elsewhere because, according toconventional wisdom, they are made in ribo-somes inside the cell body, not in thedendrites. If so, how are the proteinstransported to the correct synapse quicklyenough to account for learning?

Erin M. Schuman, an hhmiinvestigator at the California Institute ofTechnology, has investigated this apparentanomaly and now offers another view.“Since we know that all synapses areindividual, protein would have to beshipped to each, and that would be a trafficnightmare,” she says. Instead, Schuman con-cludes that dendrites use a “home-grown-protein” approach that is considerablyswifter and surer than the problematic“manufacture-and-ship” tactic. Using atechnique that she invented, she has shownthat dendrites make the proteins themselves,

when and where they’re needed, rather thanimport the proteins from the cell body.

Proving this hypothesis required consid-erable experimental dexterity. Schuman’sstudies used green fluorescent protein (GFP),derived from jellyfish, to signal that proteinsynthesis was occurring. Her team built a“reporter” molecule containing the GFPmessenger RNA (mRNA), which carries theDNA’s instructions for synthesizing proteinsin the ribosomes. The team flanked the GFPwith two key elements: one that causes thereporter mRNA to travel from the cell body(where it is made) to the dendrite, andanother that responds to the neuron’s signalto “make protein” by regulating the synthesisof GFP on the mRNA template.

To start the protein synthesis, Schumanused a growth factor called BDNF. After afew minutes, reporter protein levels in manyparts of the dendrites did rise, as shown bythe increased brightness of GFP under alight microscope.

To prove that the proteins were beingsynthesized in the dendrites, Schuman andher graduate students Bryan Smith andGirish Aakalu tried several hundred times tokeep dendrites alive after being severed fromthe cell body. The neurons came from the rathippocampus—a part of the brain that isessential for learning and memory. Roughlya dozen dendrites survived, and each showedprotein synthesis after stimulation withBDNF, indicating that the synthesis musthave occurred in the dendrite rather than thecell body.

The data were intriguing. For one thing,throughout the experiment, protein synthesisoccurred at the same spots within thedendrite, suggesting that locally synthesizedproteins might be delivered to only a fewsynapses. These experiments, Schuman stress-es, show the simplicity of a process that’sessential to learning and memory. “Our datashow that protein is made right in the

dendrite. This means that an activatedsynapse need not send a signal to the cellbody to make new protein and ship it back.There is a local control mechanism. Theevents at the synapse are in very close proxim-ity to the protein-synthesis machinery.”

In practical terms, Schuman notes thatthe protein involved in fragile X syndrome, agenetic abnormality that causes mentalretardation, is an RNA-binding proteinfound in dendrites. “Understanding dendrit-ic protein synthesis may help us understand,somewhere down the line, what goes wrongwith fragile X syndrome,” Schuman says. Ifthat hope is not realized, there is still abroader benefit: Every step towardunderstanding the transmission of nerve sig-nals across synapses produces a clearerpicture of learning and memory.

— DAVID TENENBAUM

These images show protein synthesis occur-

ring at the dendrite, where proteins are

ultimately needed to build synaptic strength.

They reveal an efficient system for learning and

memory. Instead of proteins being produced in

the neuron cell body and shipped to the far-

flung dendrites, they are synthesized locally,

right where they do their work.

Protein synthesis

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AProtein synthesis along dendrites, seen at

high magnification. Upper: part of a den-

drite before stimulation with BDNF. Lower:

same dendrite after stimulation. The location

of synthesis does not change, but it intensifies

after stimulation, as shown by the transition

from blue to red and the appearance of blue in

the dendritic spines.

MDendrites before (left) and 120 minutes

after (right) BDNF treatment. Arrow

shows where the dendrite was severed from

the cell body.

BOn a single, severed dendrite, protein

synthesis lasts hours after the BDNF

stimulus. The five colored trails indicate pro-

tein synthesis at 30-minute intervals after

stimulation. Distance from the cell body (bot-

tom scale) shows synthesis taking place in the

same locations—possibly at synapses.

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

Trapping the Genesthat Wire the BrainIn a molecular choreography of great

precision and timing, young neuronsare alternately attracted and repelled by

different molecules as they wend their waytoward targets in the brain and spinal cord.Disruption of this delicate process and theconsequent misrouting of neurons can havecatastrophic consequences—schizophreniaand autism, for example.

Despite the daunting nature of the task,researchers are making remarkable progressin understanding how trillions of neuralcircuits are formed in the mammalian brain,especially how different types of moleculesalter the trajectory of axons. Located at thetip of neurons, axons contain all of the“hardware” needed to pilot growing neuronsthrough the nervous system. Axons arestippled with receptors that enable them tosense and respond to molecular guidancecues. If a receptor binds to an attractant mol-ecule, for example, the axon is pulled towarda target. Alternately, if the receptor binds to arepellent molecule, the axon is pushed away.

Understanding how neurons are pushedand pulled toward their final destinations istime-consuming work. In addition to beingtedious, the assays and experiments used todiscover axon guidance factors in mammalsare costly.

In an effort to speed things up andreduce expenses, a team of researchers hasdeveloped a faster screening method to iden-tify genes that guide neural wiring in themammalian brain. hhmi investigator MarcTessier-Lavigne at the University ofCalifornia, San Francisco, William C. Skarnesat the University of California, Berkeley, andtheir colleagues unveiled their new techniqueand discussed some of its early applicationsin an article published in the March 8, 2001,issue of the journal Nature.

“Until now, we’ve gone about trying toidentify brain-wiring mechanisms oneguidance event at a time, one molecule at a

time,” says Tessier-Lavigne. It took him andhis colleagues more than four years, forexample, to identify the netrins, a small fam-ily of axon-guidance molecules. With theteam’s new “gene-trapping” technique,however, researchers can cast a much widernet to study many genes simultaneously andthen determine the effects of mutations inthose genes.

The improved gene-trapping techniquedescribed in Nature was built on two genera-tions of gene-trap technology. In the originalmethod developed in the 1980s, genes inmouse embryonic stem cells were mutatedby randomly inserting a genetic marker with

two components: the first, a gene thatproduces a blue color in cells carrying it; andthe second, a drug-resistance gene. Thus, theembryonic stem cells with insertions ingenes (rather than insertions in the non-genecomponents of the cell’s dna) could beisolated by applying a drug to weed out thosecells that did not take up the drug-resistancegene. The desired cells could also bedistinguished by their blue color.

In 1995, Skarnes refined the gene-traptechnology by including a gene segment thatwould activate the blue marker only if thedna had fused itself into a gene for a secret-ed protein or membrane protein, such as areceptor. This refinement, called a secretorytrap, enabled the researchers to narrow thelist of trapped genes to those coding forsignals or receptors involved in axonguidance.

“The secretory trap is a nice bonus,” saysTessier-Lavigne, “because we can focus on

exactly the kinds of moleculeswe’re interested in—mainlyreceptors and ligands (themolecules that bind to receptors).These genes represent a small frac-tion of the genome, and this trapconcentrates on just that fraction.”

Even with Skarnes’s improve-ments, the gene trap neededadditional modifications before itwas ready to fish out axon-guidance molecules. “In early stud-ies, we found that mice with‘trapped’ neuronal genes didn’tshow proper axon staining becausethe blue marker got trapped in theneuron’s cell body,” Tessier-Lavigne says. This poor stainingmade it more difficult to explorethe effects that specific gene muta-tions had on brain wiring.

In the work published inNature, Tessier-Lavigne and hiscolleagues fixed the stainingproblem by inserting an additionalmarker, plap (placental alkalinephosphatase), in the gene-trap sys-tem. If plap is present, axons arestained purple. “This modifiedgene-trap strategy enabled us to

Marc Tessier-Lavigne says the improved gene-trapping tech-

nique enables researchers to zero in on genes that direct grow-

ing neurons toward their destinations in the brain.

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mutate a gene for a guidance-moleculereceptor, and by including the plap marker,we were able to see the purple-stained,altered neuronal wiring and rapidly assesswhat had gone wrong with the wiringprocess,” says Tessier-Lavigne.

Using the modified technique, theresearchers produced 46 lines of mice withdefined defects in axon-guidance molecules.“With these mice, we have proven that wecan trap genes that are specifically expressedin the nervous system,” he says. “We can alsosee discrete patterns of axonal labeling, andwe can uncover mutant phenotypes.”

Studies on two of the genes—Sema6Aand EphA4, known to be involved in neuraldevelopment—demonstrated that thetrapping method could also identify axon-guidance mutants. “With EphA4, we showedthat we could reconstruct a known mutantand use it to learn additional informationabout where the gene is expressed and howthe mutation alters brain wiring,” saysTessier-Lavigne. “And with Sema6A, weshowed that we could use the technique todiscover a new mutant that affects only asmall subset of axons in an otherwise normalnervous system.”

These results suggest that the new gene-trapping method may enable rapid progressin understanding how neurons wire thebrain. “Neurons that project their axons to aparticular area follow a code oftranscription-factor activation thatpresumably activates genes for surface recep-tors that, in turn, dictate what the axondoes,” says Tessier-Lavigne. “We’re hopingthat gene trapping can help identify anunderlying receptor code by focusing veryspecifically on receptors involved in axonguidance and finding their expressionpatterns as well as their mutant phenotypes.”

To make these advances widely availableto researchers studying the normal wiringpattern of the brain, Tessier-Lavigne and hiscolleagues are putting their gene-trap dataon the Web at www.genetrap.org. The mutantmouse lines produced by this techniqueshould also be of use to fellow researchers.“These mouse lines have very specificpopulations of axons that are labeledpurple,” Tessier-Lavigne says. “In some casesit’s the first time that a marker has beenidentified for those axons, and those markersprovide a valuable resource.”

Above: In the brain of a neonatal mouse, gene-trapping without PLAP staining (top) shows a blue color at

the position of cells in the cortex, but doesn’t show their axons. With the refined technique using PLAP

staining (bottom), the axons show clearly in purple. Below: Well-labeled axons cross at the midline of the

mouse brainstem, then project down the spinal cord to control motor activity. When both copies of the

EphA4 gene are disrupted, the axons are misrouted, resulting in clumsy rear leg movements.

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HHMI ONLINE

How to ZAP theSignals that Lead toRheumatoid Arthritis

For decades, physicians tended to treat rheumatoid arthritis conserv-atively, progressing carefully to the most powerful therapies. Duringthe past several years, however, several new drugs have emerged that

permit physicians to treat patients quickly and aggressively to help avoidcrippling illness. They are using these new drugs, singly and in combina-tion, to greatly ease the pain, swelling and stiffness that once seemedinescapable in a disease that affects more than 2 million Americans.

Andrew C. Chan, a rheumatologist who recently completed eightyears as an hhmi investigator at Washington University School ofMedicine in St. Louis, has treated many arthritis patients and thinks

these advances are only the beginning. Chan and other researchershave determined in remarkable detail how a complex cascade ofmolecular events enables the immune system to recognize and attackforeign invaders. In rheumatoid arthritis and other autoimmune dis-eases, such as multiple sclerosis and lupus, the immune system mistak-enly launches an attack against the body it is supposed to protect. Bylearning precisely how the process works, with one molecular eventtriggering the next, Chan hopes to find ways of shutting it down inthese autoimmune disorders.

These illustrations—part of a new animation at hhmi’s BioInterac-tive.org—show some of what Chan and others have discovered aboutthis signaling cascade, which starts with a T cell recognizing what seemsto be a foreign antigen and ends with the T cell replicating in huge num-bers. At each step along the way, there’s a flurry of activity. In the begin-ning, for example, enzymes in the T cell’s cytoplasm move to dockingsites near the cell’s membrane, where they start interacting in a precisepattern. Chan and his colleagues have shown that one enzyme, ZAP-70,plays an especially important role in this process. Blocking the action ofZAP-70 with new drugs, they hope, may prevent the proliferation of Tcells that causes the joint inflammation and other debilitating effects ofrheumatoid arthritis.

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Rheumatoid arthritis features a diverse cast of molecular actors. Thedrama begins when an “antigen-presenting cell,” shown as APC at the top of this stylized drawing, comes in contact with the immune

system T cell, shown in purple. APC displays a distinctive antigen, shown as agreen dot, which triggers a cascade of signals within the T cell.

A The antigen binds to the surface of the T-cell receptor, shown in pink.

B Activated Lck kinase, shown as a glowing red ball, modifies the ITAM subunit of the T-cell receptor. It does so by adding a phosphate group throughphosphorylation, a key process that occurs throughout the signaling cascade.

C The enzyme ZAP-70 docks onto the region of ITAM that has beenphosphorylated, shown in white.

D Lck kinase phosphorylates ZAP-70, shown by a small white circle.

E Now activated, as shown by the glowing red, ZAP-70 phosphorylates LAT,the white circle within the orange bar.

F The phosphorylated LAT has its turn, providing a docking site for activatedPLCγ, the glowing red oval.

G PLCγ interacts with PIP2, the yellow oval within the T-cell membrane.

H PLCγ catalyzes PIP2 to produce IP3, the green circles that begin entering thecytoplasm, shifting the action to other parts of the T cell. Many steps remain.

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The green circles, or IP3, shown in the last drawing of theprevious sequence have now made their way to the T cell’sendoplasmic reticulum, which they signal to begin releasing calci-

um. Along with calmodulin and calcineurin, the calcium triggers a transcrip-tion factor, NF-AT, to enter the cell’s nucleus. NF-AT and other transcriptionfactors induce a gene within the nucleus to produce the protein IL-2, whichthen leaves the T cell.

Multiple copies of the IL-2 protein, shown as blue ovals, bind toreceptors on the T cell’s surface, causing the cell to start replicat-ing.

With the IL-2 proteins binding to its surface, the T cell beginsreproducing in large numbers. The process is usually beneficial,enabling the immune system to build up its forces to fight dead-

ly invaders. In the case of rheumatoid arthritis, however, the proliferatingT cells harm the body itself—which is why Chan and others seek to blockthe signaling process.

A new animation at hhmi’s BioInteractive.org shows in detail thenormal T-cell signaling cascade that is activated inappropriately inautoimmune diseases such as rheumatoid arthritis. The Web sitealso features “virtual laboratories,” click-and-learn demonstrations,scientific lectures and other online learning tools.

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

These images by Erin Schuman and colleagues show proteins being synthesized at dendrites separated from the cell body (at black squares). They indicate that neurons can produce proteins right where they’re needed for learning and memory, instead of ferrying them from the cell body to distant dendrites. The lower image shows increased protein production after addition of a growth factor. Story on page 40.

NONPROFIT ORG.US POSTAGE

P A I DSUBURBAN MD

PERMIT NO. 6561

Protein synthesis

Highest

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