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BULLETIN F a l l ’12 V o l .25 • N o . 03

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Out of Africa •

This beauty is Aedes aegypti, a mosquito that can transmit www.hhmi.org vol. dengue and yellow fever , among others. Originally from Africa, it is now found in tropical and subtropical regions around the world. While this mosquito prefers to feast on animals over , it lives in close proximity to blood-hungry relatives that will choose a meal every time. HHMI investigator Leslie Vosshall and her lab group are studying the evolutionary changes behind the insects’ diverse dietary habits. Their research may help reduce mosquito-borne illnesses. Read about Vosshall and the arc of her scientific career in “Avant Garde Scientist,” page 18.

perils of fatty liver vosshall on the scent über cameras 25 / no. Leslie Vosshall 03 30 start to finish at www.hhmi.org/bulletin/fall2012. at finish to start ’s the of from development video his See Campus. Farm Research at Janelia hedeveloped technique microscopy a using over time cells of movement and origin the tracks a in cells fly. color-coded fruit By following a flight-ready become hours within will balloon studded brightly this that believe to It’s hard things. great come beginnings From small embryo, such as the one seen here, Philipp Keller Keller Philipp here, one seen the such as embryo,

Keller lab / Janelia Farm Research Campus

Owen Gatley more importantrole inbiomedicalresearch (one that may become scientists—individuals withmaster’s orPh.D. degrees—could play a without reducing theproductivity oftheresearch enterprise. Staff permanent staff to trainees could have abeneficial effect onthe system The working group believes that even amodest changeintheratio of number ofresearch-oriented jobsinacademia,government andindustry. future scientists are beingproduced eachyear, well inexcess ofthe carried outby trainees. This creates asystem inwhichalarge number of number ofpermanenttechnical staff, withthemajorityof research The typicalacademiclaboratory consists ofaPIandoneorsmall 14-member committee included Leemor Joshua- to thecareerstheyarelikelyfind.HHM modifying trainingprogramstoincludediverseexperiencesrelevant biomedical Ph.D.sintenure-trackfacultypositions,andsuggests director forextramuralresearch,theworkinggroupnotesadecline in by PrincetonUniversityPresident One ofthoseoptions—thestaffscientist—coulduseaboost.Co-chaired of a Junereportbythe trainees shouldbeintroducedtomultiplecareerpaths,according T t o prepareandretainatopnotch,diversescientificworkforce, Observati S h cience,” e trainin HHMI Bulletin,May2011)and NI o H ns B iomedical Workforce Working Group. iomedical WorkforceWorkingGroup. g

p S hirley i p e T S I ally investigatorsonthe ilghman (see“ l ine R T ockey, orr and NI R T H deputy H deputy ichard Lifton. he Future he Future

I A E position categories that reflect the value and stature ofthese researchers. applications that includestaff scientists andurges institutions to create The working group encourages NIHstudy sectionsto bereceptive to grant increasing over thelast few years. successful competition for research funds,acategory that hasbeen “soft money” scientists, whoseemployment dependsupontheir Center andProgram Project grants. They shouldbedifferentiated from apply for theirown grants, butare supported by research project, research program. Intheextramural program, thesescientists donot staff scientists constitute anessential partoftheNIHintramural wide variety oftitlesandemployment conditions. Asanexample, important functionsaspartofinstitutional core facilities, buthave a Today, thesescientists bringstability to many labsandprovide strengthens outside oftheUnited States incoming years). increasingly necessary ifthemarket for biomedicalresearchers nstitutes ofHealth, June14,2012. xcerpted fromBiomedicalWorkforceWorkingGroup Report, WorkingGroupof the A dvisory Committee totheDirector, N ational fall ’12 vol. 25 · no. o3

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Web-Only Content Meet some of the behind-the-scenes specialists who help modern get done.

Turtles and snakes and , oh my! View the critters discovered during a herpetological survey at Janelia Farm.

Read a Q&A with computer scientist Hanchuan Peng on developing sophisticated ways to make sense of biological images.

Watch a fruit fly embryo develop and follow a dragonfly as it captures its prey, thanks to the latest developments in visualization techniques.

Learn about the technology that lets researchers watch a grow, one vibrant cell at a time.

GO GREEN Prefer to receive your Bulletin digitally? Go to hhmi.org/bulletin/subscribe. 24 30

Features Departments cover story PRESIDENT’S LETTER Institute News THE INDISPENSABLES 03 Stabilizing Forces 40 HHMI Awards $50 Million to Colleges 12 The backbone of most labs, these quiet 40 Fifty International Students Get CENTRIFUGE heroes do it all and then some. Support from HHMI 04 Good Stewards 41 Medical Fellows Get a Chance to avant garde scientist 05 Undercover Triathlete Try Research 18 With an outsider’s perspective, 06 Stepping into Sustainability Leslie Vosshall has changed thinking 41 2012 Holiday Lectures on Science— UPFRONT about the meaning of olfaction— Changing Planet: Past, Present, Future 08 Push and Pull for humans and insects. Lab Book 10 ’s Dead End THE FAT YOU CAN’T SEE 42 The Yin and Yang of Plant Defense PERSPECTIVES AND OPINIONS 24 In growing numbers of people, the liver 43 Like a Chinese Finger Trap 34 Connecting Cultures holds a hidden, dangerous store of fat. 44 Wiring the Brain 36 Q&A—What part of your job would Finding the triggers is step one. people find the most surprising? Ask a Scientist the view from here 45 Why do we develop distastes for CHRONICLE 30 Unbounded creativity—and powerful certain foods? Science Education computers—make possible the latest 38 Teaching Genomics, Plainly Nota Bene devices designed to peer into the 46 News of recent awards and other deepest recesses of organs and cells. notable achievements

OBSERVATIONS The Training Pipeline

VISIT THE BULLETIN ONLINE FOR ADDITIONAL CONTENT AND ADDED FEATURES: www.hhmi.org/bulletin COVER IMAGE: CHRIS KING editor’s letter

Where’s My HHMI Bulletin?

Something’s different, all right. You didn’t receive print Bulletin, others have wholly embraced the your August HHMI Bulletin. Not to worry; it just web or iPad editions. Whatever your preference, means that we’re going to a new publication we are committed to continue to bring you stories schedule. Beginning with this issue, the Bulletin of scientifc discovery. will be published three times a year, rather than We hope, too, that you enjoy this issue, partic- quarterly. The issues—called Fall, Winter, and ularly our cover story on “the indispensables”— Spring—will come out in September, January, and those research specialists who are critical to the May, respectively. success of myriad laboratory research programs. Publication of the web and iPad editions of Having spent many years working at the bench, the Bulletin will follow the same schedule, with both in university medical centers and industry, all the vibrant multimedia, interactive elements, I know just how essential these individuals can and extra content you’ve come to expect. During be. Though some shy away from the limelight, we the summer months, when many of you are busy take a moment to shine a light, however briefy, with family and travel, we plan to make regular on the talents and contributions of a few of updates to our website with fresh content. HHMI’s lab heroes—in this print issue and on our We hope the new publication schedule will website. We hope their stories will inspire future suit you, our readers, as we move forward in an generations to follow in their footsteps. increasingly digital age. And we hope that with this change we are lessening the impact on the planet, in at least a small way. While many read- ers tell us they prefer the look and feel of the

HHMI TRUSTEES HHMI OFFICERS James A. Baker, III, Esq. Robert Tjian, Ph.D. / President Senior Partner / Baker Botts LLP Cheryl A. Moore / Executive V.P. & Chief Operating Offcer Ambassador Charlene Barshefsky Craig A. Alexander / V.P. & General Counsel Senior International Partner Sean B. Carroll, Ph.D. / V.P. for Science Education WilmerHale Jack E. Dixon, Ph.D. / V.P. & Chief Scientifc Offcer Joseph L. Goldstein, M.D. Mohamoud Jibrell / V.P. for Information Technology Regental Professor & Chairman / Department of Molecular Nitin Kotak / V.P. & Chief Financial Offcer University of Texas Southwestern Medical Center at Dallas Gerald M. Rubin, Ph.D. / V.P. & Executive Director, Hanna H. Gray, Ph.D. Janelia Farm Research Campus President Emeritus & Harry Pratt Judson Kathy Wyszynski / V.P. for Human Resources Distinguished Service Professor of History The University of Landis Zimmerman / V.P. & Chief Investment Officer Garnett L. Keith HHMI BULLETIN STAFF Chairman / SeaBridge Investment Advisors, LLC Mary Beth Gardiner / Editor Former Vice Chairman & Chief Investment Officer The Prudential Insurance Company of America Cori Vanchieri / Story Editor Jim Keeley / Science Editor Fred R. Lummis Chairman & CEO Nicole Kresge / Assistant Editor Platform Partners LLC Maya Pines / Contributing Editor

Sir Paul Nurse Additional ContrIButors President / The Royal Society Michelle Cissell, Mark Farrell, Lyn Garrity, Dame Alison Richard, Ph.D. Heather McDonald, Anne Sommer Professor / Yale University VSA Partners, NYC / Concept & Design Clayton S. Rose, Ph.D. Finlay Printing / Printing & Binding Professor of Management Practice Kurt L. Schmoke, Esq., Chairman Vice President & General Counsel / Howard University Anne M. Tatlock Director, Retired Chairman & CEO Fiduciary Trust Company International Telephone (301) 215.8855 • Fax (301) 215.8863 • www.hhmi.org ©2012 Howard Hughes Medical Institute

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

2 hhmi bulletin | Fall 2o12 James Kegley forming researchlabhasshifted.Thereare more ofthesebackbone the wholething. sharp elbows. You to manage reallyneed asmallgroupofstalwarts the academic ladder,theycanbecompetitive, withsometimes- the lab. Because graduate students and postdocs are trying toclimb cated moleculargenetics,allthecloning andsequencing. skills inthatarena.AndGinaDaileyisourexpertthecompli - who isinchargeofcellculture—everyonethelabrelieson his valuableasthelab’sfantastically memory. SameforShuangZheng, who shows themhow todoit.She’s beenwithmesince1998andis doc orstudentcomesinandhastopurifyaprotein, she’s theone a biochemist, practiceswhatisbecoming adyingart:whenpost- thelab’sof thelabwhohelpsestablish cultureandatmosphere. A littleolderthanthestudentsandpostdocs,she’s the“motherhen” care ofallthesupplies,equipment, andchemicals, aswellrepairs. running forover12years.Shecoordinates alllabactivitiesandtakes One ismylabmanager,MalloryHaggart.haskeptthe are ahandfulofpeoplewithoutwhomthelabwouldnotfunction. the continuity ofthelab. for toral experiencethemselves.Sotheyareextremelyimportant high level,manywithamaster’s, aPh.D.,andoftenevenpostdoc- scientistsknowledge arevery andexpertisetothem.Andthesestaff long-term peopleinplace,however, thepostdoccantransfer that tion cangetlostifthereisagapbetweenpostdocs.Withfewkey overagain.Thatinforma- head canfeellikeheorshehastostart way—theprogression,ifyouwill. things acertain how wegotwhereareandwhydoingwho understand a coregrouptoserveastheinstitutionalmemoryoflab,people force for innovation and creativity. But at thesametime,youneed ebb and flow of trainees is good—essential even—as it’s a driving moving onafteraboutfourtosixyears.Ononehand,havingthat the of the system. They float in an outat a pretty rapid clip, that holdsthelabtogether. very luckybecausetheyarehardtofind.Andoftentheglue to themas“theindispensables” inthisissueoftheBulletin—youfeel are inpermanentjobs.Whenyoulandareallygoodone—werefer very bestresearchassociates, researchspecialists, andlabmanagers Chances arethey’vebeenafixtureinthelabforwhile.Someof  find a few special individuals who are critical to that lab’s success. Walk intoanyhigh-levelresearchlabtoday andyou ForcesStabilizing Relative to25or30yearsago, thecompositionofahigh-per- forcesof These extremelyskilledspecialists arethestabilizing Then thereareourexpertsinspecific technical areas. CarlaInouye, In myown labattheUniversity ofCalifornia, Berkeley, there If apostdocwhodevelopsnewmethodologyleaves,thelab In researchlabs,graduatestudents and postdocsaretransient. It’s w ill

They haveoursupport,andtheyrespectappreciation. no lesseffectiveasscientists; they’re justadifferent kindofscientist. title orabookshelfofawards—that’s nottheir motivation.Theyare valuable to the progress of research. They are not looking for a fancy scientists have onthesystemasawhole. andbeneficial effectthatstaff attention totheincreasinglyimportant structure (seeObservations,insidebackcover).Thereportdraws biomedical tosupportafuturesustainable researchinfra- should take Draft Report,” whichmakes recommendationsforactionsthatNIH just releasedits“Biomedical Research Workforce Working Group thattheNationalInstitutesofHealth(NIH)has end, itisnotable their servicesbutalsototheresearchenterpriseasawhole.To that notonlytotheindividualsorganizations isimportant whocontribute regarded andvalued. are not appreciated. They know the work they are doing is highly It’s adifferent model.Andthosescientists don’tfeelatallthatthey transgenic animal models orperforming cryo-electronmicroscopy. person istheretoprovideveryhigh-levelservice,suchascreating tist isnot,classicallyspeaking,aprincipal investigator. Instead,that projectteamswhereascienmost organizations.- Janeliahascertain issomewhathigherthanin Campus, theratioofpermanentstaff thesedays.AtHHMI’semployees onstaff JaneliaFarm Research “ The messageisclear:theseprofessionalscientists areremarkably Recognizing theroleofresearchprofessionalsintoday’s laboratory Recognizing the role of research research enterprise awhole. as their services but the to also only the to individuals who contribute organizations important is not professionals today’s in laboratory Ro bert T jian president Fall 2o12

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bulletin 3 4 hhmi safety andlaser safety officer, scurries for itsyellow tailto reappear. as a group peers into the stream waiting der sightingevokes a spotty .Momentslater, asalaman- a pickerel, heguesses, judging by the pant announces he’s found afrog— just eye. “It’s amazingwhat you wriggle ofpinkandgray catches his snake?” someoneasksasanenergetic come quickly. is anobservant group, andthe little to announce themselves, butthis tiles andamphibiansthey seekoutdo and gentlydisplacingstones. The rep- rolling asidelogs,prodding leafpiles, loving recruits—are combing theterrain: Janelia Farm employees and their nature- the call,“Ifound something!” cries ofdiscovery. “Hey, Larry,” comes sounds ofnature are muffled bythe But ononecloudyMay afternoon, the gray tree frogs trillinthetreetops. ers drumpersistently overhead, and rustle fallen leaves, pileated woodpeck in Ashburn,Virginia. White-tailed deer HHMI’s JaneliaFarm Research Campus Spring islively inthewoods surrounding Good Stewards centrifuge Larry Mendoza, JaneliaFarm’s bio- “Hey, Larry, isthisanotherworm A team ofmore than20explorers— f bulletin ip thingsover.” Anotherpartici-

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Fall 2o12 f urry of activity urry ofactivity f nd ifyou f nds

- , andsomeoftheday’s best here hopingto foster theirchildren’s which relocated from the Tamir Gonen’s structural biologylab, to each f of Washington last year. Matthew Iadanza,amemberof reptiles ofany kindinSeattle,” observes the localecology. “We hadvery few Farm andwant to learnmore about sion have come recently to Janelia and fun. is ensuringtheevent iseducational able. Just asimportant,adds Mendoza, the data willbecome even more valu- track population changesover time, explains. Asfuture surveyors beginto health of the local ecosystem, Mendoza that inhabitthislandhelpsreveal the lizards, frogs, salamanders,andturtles pressures, somonitoring thesnakes, ularly sensitive to environmental Farm grounds. herpetological surveys oftheJanelia this crew for thesecond inaseriesof Club, through whichhehasgathered and aco-founder ofJanelia’s Nature the Virginia Herpetological Society unusually vibrant box turtle—come nds—a slenderw Many ofthescientists ontheexcur- Reptiles andamphibiansare partic- f nd. Mendoza ispresident of ater snake, an O U thers are niversity

—Jennifer Michalowski a lotofland—aopportunity.” acres here at Janelia,” hesays. “That’s resident entomologist. “We have 689 perhaps atour ofinsectlife ledby a herpetological surveys, bird walks, and upcoming Nature Clubevents—more they disband,hereminds theteam of the manuscript,hetells thegroup. As participants willbeasked to review biannual publication, Catesbeiana. All inclusion in the Herpetological Society’s time, anddiscoverer ofeach this land. lence indicates goodstewardship of habitat, andMendoza says theirpreva- ened inVirginia becauseofloss of box turtles.The speciesmay bethreat- particularly excited by the15eastern declares thesurvey asuccess. Heis ing 11different ,andMendoza team has located 33 animals represent- bring kids!” says. “That’s why you’ve always gotto “I walked right by that turtle,” Mendoza from thegroup’s youngest naturalists. Mendoza hasrecorded thelocation, After three andahalfhours,the

w www.hhmi.org/bulletin/fall2012. found duringtheir outing,seetheaudio slideshow at eb extra: For asamplingofwhatthenaturalists f nd for

Photo of Larry Mendoza by Adam Auel Emma Kelly research onthestructure andfunction races, Ericksonmakes sure that her that science ismy second priority.” I don’twant to give theimpression about my personallife too often inlab; her trek to .“And Idon’ttalk that herlabmates were mysti she laughs,saying it’s understandable workouts. “Idon’tkeep standard hours,” per week and U tioned by thesport’s mainassociation, prizes of$5,000 ormore inevents sanc- which meansshecancompete for earned professional ranking in the sport, for graduate study inplantbiology. to the but hadn’t tried triathlons until she moved Institute ofTechnology petitively asanundergraduate at the if you askher.” “She’ll really onlytell you how itwent “She’s pretty low-key aboutit,” hesays. might have beenasurpriseto others. what shewas upto butcanseehow it investigator KrishnaK.Niyogi, knew daytime hours. no ideahow shewas spendingher mornings andlate nights,butthey had ate student, withlotsofvery early she worked unusualhoursfor agradu- group—most were shocked. They knew where sheearnedgoldinherage from atriathlon competition inBeijing— mates heard that shewas just back When Erika Erickson’s lab Triathlete Undercover SA Triathlon. Shetrains 15to 25hours Along withtraining andtravel to Two andahalfyears later, shehas Erickson ran track andswam com- Her graduate adviser, HHMI-GBMF U niversity ofCalifornia, Berkeley, f ts in her research around f

ed by in labcanmake upfor it.” have abadweek racing, agoodweek training canbalance that out. stability. “IfIhave abad week inlab, my says thedualfocus gives herabitof progresses at areasonable pace. She of involved inphotosynthesis from herusualrunningmates. her competitors were very different 95 degrees andwindy,” shesays. And conditions were incredibly challenging— this summer. represented the that oftheleader, Laura Bennett,who was just 8minutes, 41 seconds behind 10-kilometer run.Hertimeof2:19:03 1,500-meter swim, 40-kilometer bike, focus paidoff. Sheplaced 8thonthe June 2Pan AmericanCupinDallas,her In her “The race went well overall, butthe f rst professional race, the U .S. a t the O lympics O r ifI the Lawrence Berkeley National Labora talents camefrom a2-milerunaround hand experience withErickson’s racing had funandlearnedalot.” intimidated by my competitors. ButI tional responses to arace. Iwas really “bring anentirely different setofemo- ranking system. Those goals, shesays, pride, to winmoney andpointsin the have fun.” They were there for national —Rabiya Tuma don’t thinkanybody was too surprised.” ing. “Shewon the women’s division.I out infront ofallus,” hesays laugh- us went, andErika was just way, way with himorwatch the race. “Several of anyone inthelabwhowould participate just to seeifthey could t ory. Niyogi offered to buylunch for As for herlabmates, theironly “People weren’t at theDallasrace Fall 2o12 f

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bulletin f rst- ­ 5 6 hhmi limited to thefew radishes herbrother dening memories,ontheother hand,are home inGermany. Diana’s childhoodgar- extensivein hismother’s garden at their of thetaste offresh vegetables grown tainable living. Baumann ofhisfamily’s foray into sus- and acoop ofegg-laying chickens. potatoes, jams,andcanned vegetables; chicken; a cellar over three freezers crammed with venison and stocked with bass and cat a large vegetable garden, andapond scattered withfruittrees, berrybushes, two dogsconsume. that heandhiswife, Diana,andtheir gathers almost 80percent ofthefood spare timehehunts,grows, raises, and Research inKansas City, Missouri. Inhis entist at the Stowers Institute for Medical probably be just U row. In fact, if all food production in the local supermarket shuts down tomor- Peter Baumann will not go hungry if the Stepping intoSustainability nited States ground to a halt, he would centrifuge Baumann was lured by thememory “It sortofhappenedgradually,” says The couple lives on5acres ofland Baumann isanHHMIearlycareer sci- bulletin

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Fall 2o12 f ne. f owing with squash, f sh. They have

on thepatio. they planted afew seedsinpots house inthecountryside sixyears ago, England. When thecouple moved to a managed to coax from theground in salads,” hesays. so you canputtheminstir-fries or are very similarto bambooshoots, berries. “The innershootsofthecattails mushrooms, cattails, pawpaws, and current foraging, however, islimited to makes atasty pasta substitute. His as theinnerbarkofabirch tree, which diet withunconventional items, such He’s beenknown to supplementhis weeks-long hikes inEurope andAmerica. gathers, whichhelearned to doduring peppers, greens, squash,andherbs. is home to a variety of beans, tomatoes, pies alittlemore thanhalfanacre and Baumann says. Today, thegarden occu- dog joinedthefamily. “Itreally took off,” the garden gotbiggerandasecond worked, and a year later they expanded: a dogto keep theraccoons away. It a small garden in their yard and adopted got to theharvest before they could. What Baumanndoesn’tgrow he The next year theBaumannsplanted U nfortunately, raccoons

—Nicole Kresge the property won’t faze her at all. as innocuousafew goats wandering chickens, heexpects that something a pro at butchering deer andplucking them,” heexplains. Since Dianaisnow the space andtheidealhabitat for and milkto thefamily’s diet.“We have 50 eggsperweek. table andtherest produce about40to of thechickens enduponthedinner roam around a half-acre enclosure. Some 47 more chicksand16ducks,which in February 2011. This year, they added around andthey mail-ordered 27 chicks time for Dianato agree, butshecame Baumann’s small-scale farm. It took some for chew toys. for thedogs,whoalsogethoofs and stews andgrindinguptherest meat, keeping thegoodcutsfor roasts butcher together. They useallthe f ve deereachfall, whichheandDiana For meat, Baumannkillsabout Baumann isready to addgoat meat Chickens were alate additionto

w scale farmatwww.hhmi.org/bulletin/Fall2012. eb extra: Viewaslideshow ofPeter Baumann’s small-

Emma Kelly upfront

08pu sh and pull What appears chaotic is actually a well-orchestrated process for embryonic head-to-tail elongation.

10 cancer’s dead end There is a way to restore p53’s tumor-suppressing prowess.

web only content

sAME BUT NOT EQUAL A code within the genetic code explains why identical proteins are produced at varying speeds.

NERVE TONIC degeneration—an active process after injury—can be delayed.

Find these stories at www.hhmi.org/bulletin/fall2012.

To work on broad and basic problems that touch on many different fields has been Jonathan Weissman’s goal. He made a recent leap to understand the nuances of production with encourage- ment from two stellar scientists. It’s a gift when one generation of researcher can lean on the one that came before—perhaps through their papers and lab notes or, even better, by chatting over a meal. Go to the online Bulletin to learn about Weissman’s inspirations.

Fall 2o12 | hhmi bulletin 7 upfront

Push and Pull What appears chaotic is actually a well-orchestrated process for embryonic head-to-tail elongation.

Few sights are as captivating as the movements of a developing

embryo. Shapeless tissue remodels itself as cells migrate en masse to form elongated structures that, depending on the species, will become a , a human gut, or the main body of a fly. ¶ Jennifer Zallen’s lab group recently combined Zallen, an HHMI early career scientist at Memorial Sloan-Kettering molecular techniques with Drosophila genet- Cancer Center, studies how embryonic tissues stretch along an ante- ics to characterize one facet of that junctional rior-posterior axis using the fruit fly Drosophila melanogaster as a regulation. In work published February 14, 2012, in Developmental Cell, they identified model system. Shortly after formation of known as rosettes as a fly embryo becomes a biochemical cue that allows cells to disen- the embryo, the mass of fruit fly cells dra- longer and thinner. Computational analysis gage from some neighbors in a rosette so they matically elongates over about a two-hour indicated that most cells repeatedly move can find new ones. They found that a signal- period and establishes a head at one end in and out of multiple 5-8 cell clusters as ing factor, the tyrosine kinase protein Abl, and a tail at the other, a process known as the embryo stretches outward. Each group makes the contact points (known as adherens convergent extension. of cells reorganizes to become longer and junctions) between cells in a rosette more Over the past seven years, Zallen’s lab narrower, suggesting that rosette formation dynamic or fluid—in other words, it allows has used high-resolution, time-lapse imag- could drive morphological change. cells to glide more smoothly against one ing to track embryonic cell migration during Since then, her laboratory has focused another. Fruit fly genetically engi- that two-hour window. She has found that on understanding the multiple signals that neered to lack Abl show poor rosette formation what looks like chaotic pushing and shov- encourage cells to move in and out of tran- and impaired elongation. Surprisingly, the ing between neighboring cells in elongating sient groups. “It is forces generated at the more dynamic junctions in normal embryos tissue is actually a highly cooperative and contacts between cells that cause the cells are also stronger, resisting apparent breaks or orderly process. to rearrange and the tissue to elongate,” tears seen in embryos lacking Abl. Zallen’s group established the ground says Zallen. “These forces place special Equally essential for axis formation are rules of the game in a 2006 Developmental demands on the cell junctions, which must mechanical signals that rope cells into a Cell paper. Tracking single cells in a living be dynamic enough to dismantle individual rosette. In work published in Developmental embryo, they showed that cells consistently contacts but strong enough to prevent the Cell in 2009, Zallen reported that cells join and then exit pinwheel-like structures group from ripping apart under tension.” perceive physical tension exerted by their

8 hhmi bulletin | Fall 2o12 Brendan Monroe cellular gatherings. namely, tobringcellstogetherintomulti- one purposethatmechanical forcesserve, needle. Thisexperimenthelped explain cently labeledmyosinwasrecruited tothe then using live imaging to watch as fluores- Drosophila embryowithaglassneedleand wasbyliterallytugging onaimentally together toformarosette. contract likeadrawstring, pullingcells that extendacrossmultiple cellsand motor protein myosintojoin longcables mote rosettecohesionbypromptingthe neighbors. These mechanical signalspro- One way her group showed this exper- that leadstoelongation.” needed toseeifthesecellsmove inaway picture. Liveimagingofvertebrate cellsis behavior that is difficult to assess in a static cells. “Butrosetteformationis a dynamic tem) exhibitspinwheel-likeswirlsof that givesrisetothecentral nervous sys- brate neuraltube(theembryonic structure animals,” shesays,notingthattheverte- something thatlookslikerosettesinother “Right now, people have seen snapshots of in embryos remains unknown. like push andpullcellsinasimpleorganism Whether thesamemechanisms that drive convergent extension Drosophila driveconvergentextension biology.” big unsolvedquestion indevelopmental a three-dimensional animal. Thisisthe how cellsgettotherightplacebuild she says.“Butweknow much lessabout about factorsthatdetermine cellidentity,” the past20years,peoplehavelearnedalot populations ofcellsactcollectively. “Over long-term goal:tofigureouthow large tubular organs,Zallenhas an ambitious evolvedadifferent waytoform Even ifsheandothersdiscover that

w Drosophila atwww.hhmi.org/bulletin/Fall2012. eb extra: W

– eliselamar Seeavideoofrosetteformationin Fall 2o12

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9 upfront

Cancer’s Dead End There is a way to restore p53’s tumor-suppressing prowess.

At first glance, the tumor suppressor gene p53 would seem like an ideal weapon against cancer. It puts the brakes on cancer progression and is impaired in about half of human tumors. ¶ The Functional Genomics Facility at the University of Colorado at Boulder began In models of cancer, HHMI investigators Tyler Jacks and Scott operations in May 2010 with Espinosa at Lowe restored p53 activity in tumors and the tumors regressed. its helm. “We could finally do our dream experiment,” Espinosa says. However, p53 activation kills some cancer allows us to interrogate the function of In a series of investigations published cells, but not others, and no one knows every gene in the human as it online June 3, 2012, in Nature Chemical why. HHMI early career scientist Joaquín relates to p53,” Espinosa says. “With func- Biology, Espinosa’s group identified genes Espinosa has set his sights on finding an tional genomics, we can ask—which genes that, when inhibited, allow p53 to kill answer, and with it, a strategy for making influence the cancer cell types that wouldn’t otherwise p53-based therapies effective. It’s a goal he’s mediated by p53?” respond. They accomplished this using an pursued with relentless passion. To do functional genomics requires experimental drug called Nutlin-3, which “He’s an extremely creative thinker,” expensive equipment and huge libraries of activates the p53 protein, yet fails to induce says former HHMI President Thomas Cech, costly reagents, and only a few such facili- cell death in most tumors. Using functional who is an HHMI investigator and colleague ties exist in the world. Espinosa wanted one genomics, Espinosa’s team screened thou- of Espinosa’s at the University of Colorado at the University of Colorado at Boulder. of genes and identified a few hundred at Boulder. Where a traditional approach He had a vision for a functional genomics whose inhibition made Nutlin-3 effective at might focus entirely on the p53 gene itself, facility in Colorado that would not only killing cancer cells. To their delight, they Espinosa has adopted a broader and far advance his own research, but also put his discovered that compounds to inhibit the more ambitious target—he aims to inven- colleagues at the forefront of biomedical protein products of two of these genes, ATM tory all the genes and pathways that govern research. “Joaquín enjoys doing things for and MET, were already available. how cells react to p53 activation. the benefit of the scientific community,” When they combined the ATM or Espinosa’s approach grew from his real- Cech says. “He’s more than a team player, MET inhibitors with Nutlin-3, the treat- ization that if you want to harness p53’s he’s an instigator of teamwork.” ment destroyed cancer cells that didn’t tumor-squelching effects, you also need to Espinosa’s first proposals to fund his respond to any of the drugs individually. “If block the myriad pathways that tumors use functional genomics experiments were you treat cancer cells with one of the drugs, to circumvent p53’s killing orders. Espinosa rejected by the National Institutes of nothing happens, but if you treat them with sought to identify all of the p53-disarming Health and private foundations. But he both drugs, the drugs kill them,” Espinosa pathways and the genes that control them persisted, eventually securing support from says. The drug combination delivered a with a technique called functional genom- HHMI, the BioFrontiers Institute, and the one-two punch—Nutlin-3 turned on p53,

ics. “This is a very new technology which University of Colorado Cancer Center. then the ATM or MET inhibitor blocked VSA Partners

10 h h m i b u l l e t i n | Fall 2o12 the proteins that would allow the can- By hitting multiple genetic targets, Clinical trials are costly and time-con- cer cell to thrive despite p53 activation. Espinosa hopes to drive cancer cells into a suming, and Espinosa hopes his studies “With one genetic screen, we identified a dead end. “You can block resistance genes can help drug researchers predict and combination of drugs that will kill tumors before they ever have a chance,” he says. anticipate how their p53-related treatments that otherwise resist them,” Espinosa says. With this strategy, new treatments can be will work in the clinic, long before they’ve His team is collaborating with clinical designed to overcome a tumor’s natural spent millions on trials. “These are very investigators to test these drug combi- work arounds. “The future is not in iso- basic experiments we can do in the lab to nations in animal models and human lated drugs, but rather in combinations of get ahead of problems we’ll see in clinic.” tumors grown in mice. drugs,” Espinosa says. W –Christie Aschwanden

Fall 2o12 | hhmi bulletin 11 the backbone of most labs, these quiet heroes do it all and then some. written by ILLUSTRATED by madeline drexler CHRIS KING

roblem solvers, shelf stockers, bench scientists, record keepers, machine fixers, weekend warriors, den mothers, old hands, fresh eyes, mentors, managers. Every research lab has behind-the-scenes specialists without whom modern science could not get done.

Their bland bureaucratic titles—research HHMI’s Janelia Farm Research Campus, in Ashburn, Virginia. technician, resource manager—belie their vital “The people at the top get way too much credit. And the tech- contributions. These women and men are not wannabe nicians and managers don’t get enough. Academia very much principal investigators (PIs) or discouraged academics. rewards individual achievement—less so, team achievement.” Some have specialized expertise; others are jacks-of-all-trades. Adds Rubin, “Labs are full of students and postdocs who come They are ambitious, not for fame, but for personal excellence and go every three to four years. It’s important to have somebody and the chance to make a lasting contribution, however unher- with a sense of continuity and context.” alded, to science. Here are the stories of five indispensable lab team members, “There are very few laboratories that do not have at least one among many acknowledged by grateful HHMI investigators. technician who often plays the role of lab manager, making sure the trains run on time, the supplies are ordered, the equipment gets repaired. It would be very hard to run a lab without such a my phone is person,” says Shirley Tilghman, a molecular and presi- never off. dent of . It’s a career option that needs serious consideration, according to Tilghman, who cochaired the National Institutes of Health Biomedical Research Workforce Working Group. The group’s ROB edwards Research Technician III June report calls for professionalizing the crucial research-affili- The Pulse of the Lab ated roles of lab specialists and paying them accordingly. “Make them a professional category that academic medical centers and research institutes and universities recognize as valuable—in fact, invaluable—parts of the biomedical workforce.” Seventeen years ago, Rob Edwards noticed an ad for a radio A little recognition wouldn’t hurt, either. “As in most areas, frequency engineer in the HIV-focused laboratory of HHMI credit flows up the hierarchy,” explains Gerry Rubin, director of investigator Michael Summers. On paper, Edwards may have

14 hhmi bulletin | Fall 2o12 i’m with jeremy for the long haul.

phil smallwood Research Technician III seemed an odd fit for the lab: no academic experience, just lots of maestro at the bench work for defense contractors. “I don’t want to say this, but my old job depended on war—and sometimes, on destroying people’s lives,” he says. Today, after nearly two decades working alongside Summers, Edwards’ career has been recast. “What we do here “Embryonic stem cells have to be tended and fed every day. They saves people’s lives. It has a purpose.” don’t know about weekends or holidays,” says Phil Smallwood, At the University of Maryland, Baltimore County, Summers a research technician for 18 years in the laboratory of Jeremy and his team are studying the architecture of HIV to understand Nathans, an HHMI investigator at the how it and other retroviruses assemble, and how the viruses pack- School of Medicine who studies the mammalian visual system. age their genetic material to infect other cells. This scientific “When I’m actively working with the cell cultures, I’m here pursuit hinges on nuclear magnetic resonance (NMR) spec- seven days a week. I have been here Christmas Day, New Year’s troscopy—which is where Edwards enters the picture. He is Eve, New Year’s Day,” says Smallwood. “This is why Jeremy trusts responsible for two 600-megahertz NMR machines and a mam- me: he knows that it will get done and it will get done correctly. moth 800-megahertz instrument with a cryogenic probe. “There These cells are going to be turned into a mouse. I won’t cut cor- are so many things that can go wrong,” he says. “The magnet, the ners, because Jeremy is basing his reputation on the conclusions probe, the platform, the software, the console, the amplifiers.” that he will draw from these mice.” But NMR machines are just part of Edwards’ job. He designs “Extraordinary experimentalists” is how Nathans describes the electrical and mechanical components of laboratory upgrades Smallwood and research specialist Yanshu Wang, another essen- and ensures the continuous operation of centrifuges, water purifica- tial lab team member (see Web Extra, Lab Heroes). “They have tion systems, electrical generators, and other critical research tools. the same relationship to doing experiments that Itzhak Perlman “I keep everything up and running, because you never know when has to playing the violin.” a grad student or a postdoc will have that sample—the protein For Smallwood, who has created 40–50 mouse lines in Nathan’s they’ve been working on for a year,” Edwards says. “When they’re lab—transgenics, knock-ins, knockouts—the musical analogy is ready to roll, there can’t be any obstacles on the instrument side.” apt: away from work, he is an accomplished flutist. “You always Edwards also mentors young scientists in Summers’ lab— have to practice—you can’t rest on your laurels. It’s the same including a large number of minority grad students and postdocs, in science. You always have to keep learning new techniques, who may not have received ample encouragement in the past. “He advancing with technology, or you’ll get left behind.” has served as a positive force for about 50 high-achieving minor- Smallwood also draws on another analogy to explain the craft ity students who have worked in my laboratory,” says Summers, of science: cooking. “The first time you make a cake, you follow “often privately enforcing his own interventions to challenge the the recipe. It’s the same with an experiment: you can’t change a students and support them during times of academic struggles.” variable right away. But after doing it for many years, you get a feel As Edwards explains, “I’m a minority also; I know you can get for how the cell behaves, for what works and what doesn’t. Take down on yourself. So I always say, ‘I believe in you.’ That’s what something as simple as pipetting an back and forth, such Mike said to me when I first started here: ‘You can do it, I hired as in trypsinization, a process to chemically separate cells. I was you for a reason, just be confident.’ Now that I have that confi- originally taught that you add the trypsin once and place the colo- dence, when I see someone without it, I try to instill it.” nies in the incubator. But the colonies don’t completely break up. Edwards brings this sense of purpose to every facet of his I found that if you pipette the trypsin back and forth a few times job. “My phone is never off. My vacation time is maxed,” he says and then put the colonies in the incubator, it’s like night and day. with a laugh. It’s a little trick that goes a long way.”

Fall 2o12 | hhmi bulletin 15 The co-inventor of 10 —beneficiary of Nathan’s uncom- ended up with only three cross-progeny. Only one of those had mon largesse in sharing professional recognition—Smallwood the genotype that I was looking for.” doesn’t feel like an unsung hero. Yet while he appreciates the rec- Such perseverance and attention to detail is essential in her ognition, he doesn’t crave it. “The students, they come in, find role. It’s also about mutual support, she says, a concept that seems a project, get published, go on for a postdoc, look for a job. I’m to have been bred into the C. elegans world by Janelia Farm senior content to be in the background. Jeremy arrives in the morning fellow Sydney Brenner, a molecular biologist who shared the 2002 and there I am at my bench. I’m a constant. I’m with Jeremy for in Physiology or Medicine. “When Brenner started this the long haul.” science in the 1970s, he said that the worm community should work together in a spirit of cooperation. He felt that science would we do a lot advance much faster that way,” she says. “I like that philosophy.” of quality control. it’s those little steps i worry about. peggy kroll-conner Research Technician III a star in the worm world todd laverty shared resource manager working on the fly

Among the many niche communities in the giant enterprise of science, worm experts are a special cadre. Caenorhabditis ele- gans—the slender and sinuous nematode—may be a model “A lot of things go on behind the scenes to make science hap- organism, but it also requires model experimental techniques. pen,” says Todd Laverty, who for 29 years has supported the And in the small guild of C. elegans specialists, Peggy Kroll- work of Gerry Rubin, director of HHMI’s Janelia Farm Research Conner is a star. Campus. For 23 of those years, Laverty managed Rubin’s lab at Judith Kimble, an HHMI investigator at the University of the University of California, Berkeley. For the last six, he has over- Wisconsin–Madison who studies the fundamental controls of ani- seen the Drosophila and Media Prep shared resources at Janelia. mal development, has for 16 years relied on Kroll-Conner’s finesse. His specialty is feeding, sheltering, moving, breeding, and oth- “Peggy is the heart and soul of all our genetics,” says Kimble. “She erwise nurturing fruit flies, as well as preparing meals for other has become the person who generates some of the most finicky laboratory animals. “It was obvious, right from the beginning, that strains in the lab. In the worm community, she is known as being I had found my niche.” exceptionally fastidious—her strains always have the correct geno- At Janelia, Laverty manages some 18,000 fly stocks—that type and, just as important, are not contaminated.” is, 36,000 vials of flies, 50 to 100 flies per vial, each a unique According to Kroll-Conner, the key to ensuring that frozen genetic line. He shepherds the stocks through a 28-day lifecycle: worm stocks are free of mold and bacteria is good sterile tech- egg, three larval stages, pupa, and hatched fly. Each morning, nique. She vigilantly labels items to prevent strain mix-ups. Once peering through a at flies dozing on a pad suffused the worms are frozen, she thaws a portion to make sure the ani- with , he selects virgin females for genetic crosses. mals are viable and the stock pristine. She returns test thaws to the Each week, he starts new generations in fresh vials, using a duck scientists who created the worms, so they can validate the strains. feather to gently transfer the prospective parents from one plastic She also revalidates her own strains. “In other words,” says Kroll- abode to the next. And each month, he manages the production Conner, “we do a lot of quality control.” of 130,000 vials of fly chow: a mixture of cornmeal, molasses, Alongside the ever-present threat of contamination is the agar, and yeast—and gets four-star reviews from lab managers for challenge of fashioning strains with multiple mutations. “Mother quality and consistency. Nature doesn’t give up her secrets easily,” says Kroll-Conner. “I “I can remember telling people, when I started out, ‘What try to figure out a way to balance the mutations in a user-friendly I’m going to be doing 20 or 30 years from now, I don’t know. way, to minimize the work needed to maintain the worms.” But I’m happy now doing what I’m doing,’” Laverty says. After Certain mutations are more challenging than others, she says. he’d worked for Gerry four or five years, he remembers riding In one experiment, she had to set up a mating with a strain of in an elevator with a gray-haired co-worker. “I teased him: ‘Who worms whose reproductive systems quickly developed tumors. “I gets gray hair working in a lab?’ Funny thing: now I’m that gray- set up numerous mating plates with large numbers of worms and haired guy!”

16 hhmi bulletin | Fall 2o12 “Labs are full of students Laverty is the only person Gerry Rubin brought from his and postdocs who come Berkeley lab to Janelia. “There was no one better than Todd to and go every three to four set up a facility to support all the Drosophila labs here. He is years. It’s important to have very calm, and he’s very good at managing people and building somebody with a sense a team,” says Rubin. “In my Berkeley lab, at times he had to deal of continuity and context.” with as many as 15 postdoctoral fellows, all with different needs and demands. He does a remarkable job of keeping everybody happy.” In a high-pressure laboratory setting, Rubin adds, “That’s gerry rubin a very unusual ability.” Laverty describes himself as “a pleaser by nature. I get satisfac- tion out of starting a task and following through. PIs get the big ideas: ‘This is really cool, let’s figure this out. I’m not going to declined. He persisted, and the result has been a professional worry about the little steps right now.’ It’s those little steps that I match made in heaven. worry about.” “Alicja has been invaluable to my career,” says Walker. “There In Rubin’s lab at Berkeley, Laverty played a supporting role is nobody in the world who can clone T cells better, and as my in more than 100 different research projects, including sequenc- lab manager she has not only set the highest standards for per- ing the Drosophila genome. Published in 2000, the sequence formance and integrity but has done it in the most collegial marked a scientific milestone because of the fruit fly’s pivotal way.” Today, Walker leads an international research effort to role as a model organism in research, in areas ranging from understand how some rare individuals, known as long-term non- aging and cancer to learning and memory. “There were hun- progressors—infected with HIV but never treated—can fight off dreds of people in the field who could do the same thing that the with their own immune systems. Insights into their biol- I was doing. But I had the opportunity to do it every day in ogy could lead to a vaccine or new treatments for the disease. the Rubin lab—and it was the Rubin lab that was sequencing Trocha supports this effort at the lab bench. “Tissue cultures the fly genome.” are like animals or kids,” she says. “You have to tend to them, not when you want, but all the time. My colleagues tease me that, since I was a veterinarian, I think of the cultures as my sheep. You i think of cultures may feed them twice a week, but some of them like to eat more, as my sheep. some less. I look at each flask and each culture individually, because they differ in their ability to proliferate. That variability in proliferation might be a clue to why some T cells are effective alicja trocha in inhibiting HIV in the body—and some are not.” research specialist III As a lab manager, Trocha also deals with the minutiae of making the impossible administration, regulatory requirements, and the exhaustive possible task of tracking a large repository of biological samples with bar codes. She documents growth and maintenance of the T cell clones (T cells derived from one “mother” cell that are 100 per- In 1989, Bruce Walker, an infectious disease specialist at Mas­ cent genetically identical), and she teaches fellows and postdocs sa­chusetts General Hospital, sifted through a tall stack of how to do the same. She also catalogs the clones and the details applications for a technician’s job in his lab. He immediately of how they were established, so that when clinical questions arise noticed the application from Alicja Trocha, a recent immigrant years after, she has the answers. from who had joined the anti-Communist Solidarity “I believe in myself because Bruce gave me that chance. I movement as a student in the 1980s. Trocha had worked in a lab would have never known what I could do if I hadn’t come here,” on the rabies virus—like HIV, a deadly pathogen. She had earned she says. That brimming confidence extends to the science. “It a veterinary degree. And she had done field work with farmers, is bigger than life to be with a group of people who have such suggesting a level of real-world maturity not always seen in hot- bold plans and high aspirations. But this is what I like: trying to housed science majors. make the impossible possible. An AIDS vaccine would change Walker interviewed Trocha in German, which she had picked the world.” up in an internment camp in Munich after fleeing Poland W –madeline drexler in 1986. Immediately impressed, he offered her the job. But Trocha, overwhelmed by Walker’s laboratory operation web extra: Read about other indispensable lab heroes from HHMI labs by visiting www.hhmi.org/bulletin/Fall2012. and by the technical terms she would need to master, initially

Fall 2o12 | hhmi bulletin 17

With an outsider’s perspective, Leslie Vosshall has changed thinking about the meaning of olfaction—for humans and insects.

by Robin Marantz Henig photography by Jon Moe measurement (like a wavelength for a particular color or musical note) from which to infer a particular smell. Her work on the mechanics of mosquito olfaction carries implications for global public health. Because mosquitoes detect their human targets by smelling them, her research might one day reduce the incidence of common and deadly mosquito-borne infections, such as and yellow fever. An Insects-Only Smell System Vosshall has been working in olfactory science since 1993, when hen Leslie Vosshall opens the door to her sprawling she became a postdoc in the laboratory of neuroscientist and apartment, I notice a child’s drawing on HHMI investigator Richard Axel of . Her the front door asking visitors to take off their shoes. Vosshall would first discovery was controversial, since it described an olfactory never ask me outright, but this crayoned request from her 10-year- receptor system that was unique to insects. This went against the old daughter Ophelia is too charming to ignore. I do as directed, conventional wisdom that most receptor systems are conserved and we conduct the interview in our socks. from worms to humans. Her work on the insect olfactory receptor, As it happens, Vosshall is wearing socks all over her body—thin called Orco, was originally done in the fruit fly Drosophila mela- nylon socks, one pair under her regular socks, and another pair nogaster. Later, Vosshall and her colleagues decoded an olfactory with the feet cut off on her arms. The extra layer of clothing is all sensory map in the fruit fly brain, through which the activation in the interest of science, specifically Vosshall’s decades-long fas- of a particular fly odorant receptor leads to a particular behavior. cination with the mechanics of the olfactory system. To generate In 2008, Vosshall’s lab group, which consists of six to nine post- enough samples of human scent for their insect experiments, the docs and about five graduate students, began to shift its attention people in Vosshall’s lab occasionally wear socks on their arms and to mosquitoes—which explains the socks in the freezer. In 2008 legs, while working up a sweat and foregoing deodorant or show- and in subsequent studies in 2011, her group elucidated the first ers. After 24 hours the socks are removed, rolled up, and thrown modern scientific explanation for how the popular anti-mosquito into a freezer until needed. Her team uses the aromatic power compound DEET works—it confuses the insects by jamming balls to investigate how human scent attracts female mosquitoes. their odor receptors. Ultimately, Vosshall says, she hopes to help Other scientists might have left such vaguely unpleasant develop more targeted, more efficient insect repellants, a crucial tasks to their assistants. But Vosshall, an HHMI investigator at weapon against mosquito-borne diseases like malaria. , engages in the stinky socks enterprise the way she engages in so many things—with a spirited and conta- E nticing aromas gious enthusiasm. After our chat in her apartment, which includes Reaching into her office fridge, Vosshall opens a vial and smells a tour of the artwork she collects from contemporary painters and it, then passes it to me. “This is violet,” she says, and I sniff. The photographers (as well as a quick hello to Ophelia’s pet tarantula), smell is luscious and a little heady, almost more food than flower. we head crosstown to her lab. There she opens the freezer to show Reluctantly, I give it back to her. (I probably couldn’t have contin- me where the socks are stored, and laughs at how many of the ued smelling with such pleasure even if I had held on to it; even labeled specimens are hers. a strong scent will pretty much disappear when you try to inhale The science of smell has intrigued Vosshall for years, and it a second time.) wearing odiferous nylons is just a small piece of it. In her office at She opens another vial, sniffs, and visibly shudders. “Gaaaah,” Rockefeller, where she is head of the Laboratory of Neurogenetics she says. “I didn’t realize what this was. Here, smell.” Foolishly, I and Behavior, several small refrigerators house rows of another sniff the vial that had thoroughly disgusted her. But I can’t smell kind of art she collects, high-end perfume (her personal favor- anything at all. Vosshall seems delighted. ites are two scents from the Parisian house of Frédéric Malle: “That’s androstenone,” she tells me. “It’s a component of male Lys Méditerranée for summer, Dans tes Bras for winter). She says sweat, and a small percentage of people are unable to smell it.” refrigeration keeps the scents fresher. Another fridge contains a Most people are totally grossed out by the scent, she says. Another strictly scientific collection of small vials of smell samples, part of 15 percent or so find it less disgusting—some even like it, describ- Vosshall’s attempt to categorize scents according to their chemi- ing it as smelling sort of like vanilla. And within that group is an cal structure, a kind of periodic table of smell. Eventually, she unknown minority of people who, like me, can’t smell androste- hopes—but this is a long way off—scientists will be able to do for none at all. The key is the gene for the olfactory receptor OR7D4. smell what is possible for vision and sound: provide an objective Vosshall probably has two good copies. I probably have two faulty

20 hhmi bulletin | Fall 2o12 copies. She’s doing some studies now to test the sensitivity of to devise an insect repellant that blocks the insect’s ability to smell. young women to these odors at the most fertile point in the men- The goal is to find a product as effective as DEET that is longer strual cycle. The women sniff from two vials of androstenone in lasting, less oily, less toxic, and safe enough to use on infants. different concentrations, as well as two control vials, while their Vosshall says she has always preferred working at the fringes sweat response and cortisol response are measured. Her “long- of science, where the questions are most interesting and least term dream,” she says, is to study the effect of OR7D4 and other explored. Her rule of thumb for whether to pursue a specific scien- receptors on general sociability or sexual responsiveness, but tific inquiry: unless precisely three laboratories are already working these studies are especially difficult to conduct. on it, forget it. More than three and the topic is already too popular “The only available experiments are very indirect,” she says. for her. Fewer and there aren’t enough colleagues who are knowl- Asking a person to sit in a laboratory and smell a sex-related odor edgeable about the subject with whom she can exchange ideas. and give a rating of how pleasant or unpleasant the scent is, she When she studied the function of insect odorant receptors, says, “is very far abstracted from human sexuality and does not for instance, the only other people she says were working on the really capture the biology well.” problem were Kazushige Touhara in Tokyo and Bill Hansson in Vosshall discovered OR7D4 with her Rockefeller collaborator Andreas Keller and a team led by Hiroaki Matsunami at . When they announced their finding of the androstenone-sensing receptor in 2007, there was a little ripple of amazement in the olfactory science world. A Newsweek report referred to some good-natured jealousy among other smell investigators. Working at the fringes “There are some people you meet and you know that they will do something very meaningful in science,” Vosshall’s postdoc advisor Axel told me in a phone conver- sation laden with superlatives. “She’s really strikingly dynamic, and that’s cou- pled with experimental fearlessness and thoughtfulness.” Axel said he is particularly impressed by Vosshall’s perseverance, no matter how many wrong turns she takes along the way. “Leslie is able to enter into new and dif- ficult experimental arenas with the knowledge that it’s going to take a depth of understanding and time to make a mean- ingful contribution.” Vosshall’s discovery of a unique olfac- tory system for insects was a bonanza, she says. “The fact that the target proteins are only present in insects is a huge conve- nience.” It means scientists will be able to prevent and reduce mosquito biting in a way that should have no effect on humans. To move in that direction, she is collaborat- With an eye for the uncommon, Leslie Vosshall’s life is imbued with art, enterprising ing with Bayer CropScience in Germany research, and community engagement—which feeds back into her science.

Fall 2o12 | hhmi bulletin 21 Germany, both of whom she eventually collaborated with. “When the Marine Biological Laboratory in Woods Hole, Massachusetts, the field gets very large,” she says, “collaborations become harder where she worked for her uncle, Philip Dunham of Syracuse to arrange, and secrecy is more of a barrier.” University, that she fell in love with science. Vosshall’s outsider status goes back to childhood. She was born “Mainstream was just taboo for Leslie,” says her sister. But in Lausanne, Switzerland, the eldest of three children of nomadic, even though Vosshall favored the punk scene and avant-garde adventurous parents. Before she was eight years old, she had music, she was an attentive student who graduated in 1983 as moved six times to four countries, going back to Switzerland every valedictorian at Kinnelon High School. She chose Columbia summer for family vacations crammed into a bare-bones shack over the other Ivy League schools she could have attended, partly high in the Swiss Alps. On the first day of third grade in suburban because she liked being in its pioneering first coed class, and New Jersey, where the Vosshalls finally settled, young Leslie didn’t partly because it was in New York, a city she always wanted to live speak a word of English. She picked it up quickly—she’s pure in and now can’t imagine leaving. New Yorker now—but she always held on to that feeling of being From Columbia, where she majored in biochemistry, Vosshall just outside the normal flow of things. went to Rockefeller University for her doctorate, where she “Even in high school she was fairly counterculture,” says her studied circadian rhythms in the fruit fly. “Even back then she sister, Nicki Dugan, a public relations executive in San Francisco. was fearless,” says Marina Picciotto, a close friend from graduate “We spent a lot of time poring through the Salvation Army men’s school who is now a professor of psychiatry, neurobiology, and department looking for ties and David Byrne–style big jackets. She pharmacology at Yale School of Medicine. “In every interaction tended to want to stand out.” you ever have with Leslie, she’s always herself, always speaks her Stylistically, Dugan says, Vosshall was into angular haircuts, mind.” Picciotto and Vosshall have remained close friends, both multiple ear piercings, and hair dyed colors that nature never married to neuroscientists and with children about the same age. intended. As a young teenager she spent weekend afternoons Sometimes the families attend scientific conferences together, so exploring Manhattan on her own, and took solo summer trips, first one of the parents can take the kids to the zoo while the other to and then to Cape Cod. It was during two summers at three attend the scientific sessions.

Vosshall’s arm offers a pleasing scent to this mosquito, which detects its prey through smell. She aims to block

that olfactory system to stop diseases like malaria, which kills up to 1 million people each year. lab Leslie Vosshall

22 hhmi bulletin | Fall 2o12 In grad school, Vosshall held on to a separate, bohemian life in addition to her workaday scientific world. She tried her hand at experimental filmmaking. “I made lots of really bad Super 8 nonnarrative films,” she says. “I lived downtown at the time—I was married to a musician and I had a lot of friends who were filmmak- Mainstream ers. I wanted to get into the action, too.” Picciotto remembers being cast in one of Vosshall’s films as Julia Child in the laboratory, whipping up a preparation of brain was just taboo specimen in a Sunbeam blender. That artsy phase was short- lived, Vosshall says. “You have to know your limits. Now I just buy a lot of art.” for Leslie. The Woman’s Role –Nicki Dugan Vosshall takes her role as a woman in science seriously, but she doesn’t put it at the forefront of her activities as some woman sci- entists do. “She’s not afraid of taking risks or of being perceived as exactly who she is,” Picciotto says, “which is an incredibly bril- liant scientist with an extremely strong aesthetic sense—and also a woman in a world dominated by men.” At age 47, Vosshall says she is lucky to be part of the bridge generation, when it became much easier to be a woman in sci- ence. “I felt like, with a few exceptions, people expected me to one cooked up for Vosshall’s lecture about smell was called the be a scientist and encouraged me.” She always had lots of female “Schnozmopolitan.” peers and colleagues, she says—that is, until recently. After their Through these public appearances, Vosshall is not only dissem- postdoctoral work, a “disappointing” number of women drop out inating scientific information to the public, she’s also indirectly of the tenure-track academic career path that she was on—mean- finding hundreds of volunteers for her smell studies. Her work on ing that now, as a full professor, she says she is “constantly the only mosquitoes was detailed in The New Yorker, which brought forth woman in the room.” hundreds of people willing to tell their mosquito-biting stories. It’s often the career-versus-family quandary that forces women Some people seem never to get bitten, others are mosquito mag- to leave science, but Vosshall says she managed to have a child nets, and everyone has a pet theory about what distinguishes the without breaking stride largely because Rockefeller made it easy. two in terms of what they eat, what color clothing they wear, what “There is terrific day care right here on campus,” she says. And their blood type is, or what cologne they use. her husband, Kevin Lee, executive director of the Ellison Medical Vosshall is aiming at a more scientific analysis, bringing those Foundation, is a hands-on father, taking Ophelia to fencing, art, volunteers to Rockefeller for a formal study involving blood anal- and rock guitar lessons so Vosshall can spend time in the lab, or at ysis, detailed medical histories, and follow-up to see if she can home at her desk in a corner of the expansive living room. find any genetic or other traits that make some people absolutely irresistible to mosquitoes. Public Talks and Schnozmopolitans She is also conducting a study of more than 1,000 volunteers Vosshall takes her public role seriously and is committed to who are brought in to give blood samples (for genetic analysis) and explaining her work to the public. She was featured last year at the to describe a battery of smells according to 146 standard descrip- World Science Festival, a three-day annual event in New York tors (such as smoke, soil, excrement, urine, , or rose). Her that brings together smart lay people and marquee-name scientists. goal, she says, is to “try to correlate their olfactory idiosyncrasies At the session called “The Science of Smell,” Vosshall entertained to their DNA.” her audience with tales of “strip club science” (studies showing With so many different projects grabbing her interest at once, that female strippers get more tips when they’re ovulating, possibly Vosshall is demonstrating the style and pacing that she’s main- because they’re sending off unconscious scent signals) and, as she tained her whole career. As her friend Picciotto says, “Leslie is put it, the “empirical” and “artistic” nature of perfumery. always thinking of next steps rather than last steps.” W She was also an early participant in the popular Secret Science Club, which meets monthly at a Brooklyn bar where people go FOR MORE INFORMATION: To see Vosshall speak at the 2011World Science Festival, visit www.worldsciencefestival.com/videos/how_do_we_smell. to talk science, ask questions, and drink thematic cocktails. The

Fall 2o12 | hhmi bulletin 23 THE FAT YOU CAN’T SEE

in growing numbers of people, the liver holds a hidden, dangerous store of fat. finding the triggers is step one.

written by Sarah C.P. Williams & illustrated by Graham Roumieu

a shiny, pinkish-brown triangle tucked under the right rib cage, a healthy liver is a marvel. nutrient- rich blood from the intestines pulses into one side, and the liver goes to work removing toxins, converting digested food to energy, storing vitamins and minerals, and controlling how much fat and is sent back out to the rest of the body.

Without the liver acting as a filter and energy producer, a person coming at the problem from different disciplines—genetics, endo- can’t survive, and no can perform all of its duties. crinology, immunology, and biochemistry—and their findings But in one in three Americans—and similar numbers in other show a complex, sometimes contradictory story of what pollutes developed nations—the liver has lost its luster. It is swollen, yel- the liver with fat. lowish, congested with fat, and doesn’t function up to par. Over time, this condition, called fatty liver disease, can lead to inflam- from food and genes to fat mation, scarring, and hardening of the organ, and eventually, Fatty liver disease is rarely detected because of symptoms. Most liver failure. In some people, it causes liver cancer. often, a patient gets a routine blood test and the doctor notices “Fatty liver disease is the number one liver disease in this altered levels of proteins made by the liver. Even then, there’s no country in both adults and children,” says HHMI investigator one test to give a definitive diagnosis of fatty liver disease. By ruling Gerald Shulman of the Yale School of Medicine. Rates of fatty out other causes of abnormal liver proteins in the blood—such as liver disease have risen dramatically over the past two decades. a hepatitis infection or tumor—a doctor may conclude that the “Furthermore, it is strongly linked to hepatic resistance patient has fatty liver disease. If the patient is not a heavy drinker, and type 2 ,” he says. Understanding these triggers and then the diagnosis is nonalcoholic fatty liver disease (NAFLD). how the disease progresses may stop the uptick in its occurrence. Today, more than three-quarters of fatty liver cases are NAFLD. Scientists know that fat buildup in the liver is more common “It’s an incredibly broad diagnosis,” says HHMI investigator in people who are overweight, have type 2 diabetes, or drink Helen Hobbs of the University of Texas Southwestern Medical excessive amounts of alcohol. But beyond that, not much about Center. “It can mean anything from mild fatty liver to severe fatty liver disease is well understood. Does the diabetes or fatty inflammation.” liver come first? Do certain genes predispose people to fatty liver As recently as a decade ago, not much more was known about disease? How can the disease be detected early and treated? Do the prevalence of NAFLD, says Hobbs. Clinicians had a poor other diseases contribute to fat in the liver? These are only some grasp of the overall incidence, how it progressed, or how to iden- of the questions that Shulman and others are pondering as they tify patients at risk for developing it in the first place. So when study who gets fatty liver disease and why. Hobbs launched the Dallas Heart Study, tracking the health “This is a slowly progressing disease,” says hepatologist Rohit of 6,000 individuals in the Dallas area, she and her colleagues Loomba of the University of California, San Diego, School of included questions about all aspects of cardiovascular and meta- Medicine. “If we want to prevent liver disease down the road, we bolic health. Among topics such as and diabetes, they need to act now.” According to a 2008 estimate, fatty liver disease also homed in on NAFLD. will be the leading reason for liver transplants by 2020, overtak- “One thing we were very curious about was whether nonalco- ing . holic fatty liver disease has a genetic underpinning,” says Hobbs. With a sense of urgency, scientists are pushing forward with As part of the study, Hobbs and her colleagues used a special studies on the basic biochemistry behind fatty liver. They are type of magnetic resonance imaging (MRI) scan to quantify liver

26 h h m i b u l l e t i n | Fall 2o12 Shulman: Brian Park Hobbs: David Gresham / UT Southwestern Medical Center Flavell: Yale University from differentperspectivesand findinguniqueroadsintothecomplexdiseaseanditscauses. HHMI investigators Gerald Shulman, Helen Hobbs, andRichard Flavellareeachstudying fatty liver disease suspected thatthevariantofPNPLA3stoppedprotein from down triglycerides, the main building block of fats. So Hobbs in theliver.” allele ofthegene,youtendtohavehighertriglyceridecontent been associated withfattyliver,” Hobbssays.“Ifyouhavetherisk between races. ofthedifferences inNAFLDincidencemore than70 percent Hispanics, andleastcommoninAfricanAmericans.Itexplained to fattyliver. Moreover,thegenevariantwasmostcommonin variant ofagenecalledPNPLA3seemedtopredispose people the different frequencies ofNAFLD.Theydiscovered thatone patients andtestedwhetheranygeneticmutationscouldexplain major differences intherateofNAFLDamongethnic groups. Even whentheyfactoredinobesityanddiabetes, therewerestill criteria, andonly24percentofAfricanAmericanshadNAFLD. But only 33 percent of European Americans met the diagnosis among races.” suspected itwouldbehigh,” saysHobbs.“Itwasthedifferences populationfitthe about one-thirdofthetotal diagnosis. the participant was classified as having NAFLD; 5.5 percent, fat in 2,349 participants. If theliver fat contentwasgreater than In theliver,PNPLA3prote “Within allpopulationsstud H Among Hispan “The biggestsurpriseforuswasn’ttheinc obbs andfrom her the colleagues delved into genetic data ics, herteamfound,45percenthadNAFLD. ied todate,thevariationhas in isresponsibleforbreaking idence—we had meal causes the liver to store —taken upfromtheblood meal causesthelivertostoresugars—taken the insulin produced by the pancreas after eating a the way the body deals with nutrients, including fat. Normally, patients ayear. says Loomba,whoseSanDiegoclinic seeshundredsofNAFLD an increaseinsugarconsumption—over thepast fewdecades, likely betrackedbacktochangesinpeople’s diets—particularly explain theincreaseinrates.Thechangeincidence canmost Even ifthere’s ageneticcomponenttoNAFLD,thatdoesn’t already going up.” you canscantheir liveragaintwoweekslaterandseefat givingthemthreecansofsodaaday,their liver,andthenstart

but it’s unlikelytoexplainthefullstoryoffattyliver. biochemical pathways involved in fatty liver disease progression, mechanism involved.Solvingthemysterywillhelpuncover tein causesfattyliver. Hobbs’teamisworkingtofleshoutthe her teamhasshown thatanexcessofthevariantPNPLA3pro- lead toanaccumulation offats.Inmousestudies, however, working, orfrombeing expressedatallintheliver,whichwould But ifyouhavethisgeneandyou’re obese,itisverylikelyyouwill.” have thisgeneandyou’re thin,youwon’thavefattyliverdisease. “If yout So “This isagene-environmentinteraction, da doesn’t have fat in it, but a diet high in sugar changes ake anynormal,healthypersonanddoanMRIof the diabeteslink ” says Hobbs. “If you ” saysHobbs.“Ifyou Fall 2o12

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n i t e l l u b 27 Normal Energy Storage & Use

when you eat, insulin produced by the pancreas puts your body into storage mode to save all the energy you’ve ingested (left side of diagram). in the liver, glucose is converted to glycogen for long-term storage. in fat deposits around the body, molecules come together to form fats. and in muscles, the building blocks of proteins assemble. once you’ve digested the food, glucose and insulin levels drop and the molecules that have been assembled for energy storage start being broken down as your body needs them.

in the form of glucose and fructose—for later (see diagram). And interplay between sugar and fat metabolism in the liver. The criti- some of the glucose is repackaged into fat molecules. But a diet cal questions, he says, are what factors lead to the development high in sugar can lead to insulin insensitivity, or insulin resis- of NAFLD and how do alterations in the liver’s metabolism of fat tance. The body, including the liver, becomes less efficient at contribute to insulin resistance in the liver. responding to insulin’s signals. Eventually, it stops responding at Shulman’s lab group has been studying the development of all. And rather than send the fat molecules into the blood, the insulin resistance in muscle and the liver for nearly three decades. liver retains the fat it produces. They want to know the precise sequence of events that occur “The liver is clearly central to normal glucose homeosta- when patients develop muscle insulin resistance, liver insulin sis,” says Shulman, who is determined to sort out the intricate resistance, NAFLD, and type 2 diabetes. So they have developed

28 hhmi bulletin | Fall 2o12 novel magnetic-resonance scanning techniques to noninvasively with NAFLD lose a relatively small amount of weight, Shulman’s measure the concentrations of metabolites within liver and skel- team has found, their fatty liver and hepatic insulin resistance can etal muscle in patients who are prone to develop type 2 diabetes be reversed. and in those with well-established type 2 diabetes. Using this Hobbs’ and Shulman’s evidence of two different genes with approach, they have found that healthy, young, lean, insulin- profound effects on NAFLD hints at the complexity of this met- resistant offspring of parents with type 2 diabetes, who have a high abolic disease. More research will be needed to sort out how likelihood of developing type 2 diabetes, have insulin resistance these genes, and likely others, affect the development of this only in and not in the liver. devastating syndrome. “We have shown that selective insulin resistance in skeletal muscle—the earliest defect we can observe in these otherwise bacteria’s role young, healthy, lean individuals—can predispose them to hyper- Doctors in the clinic need a way to identify patients who are at lipidemia, NAFLD, and liver insulin resistance by diverting risk of developing worse forms of the disease—inflammation and ingested carbohydrate away from muscle, where it is normally scarring of the liver. After all, some people with fatty liver do stored as glycogen, to the liver, where it is converted to fat,” says just fine without treatment (although if Shulman is right, their Shulman. “By screening patients for muscle insulin resistance, fatty liver could be contributing to diabetes). In other patients, and understanding the progression to fatty liver and diabetes, however, the liver becomes inflamed, clogged with immune mol- researchers may be able to uncover new ways to stop these dis- ecules, and eventually begins to harden and stop working. eases in their early stages,” he says. “We need to find out who is at risk for developing full-on liver In a separate study, Shulman and his colleagues studied disease and who isn’t,” says Loomba. “And then we need to focus healthy, young, lean individuals in the New Haven, Connecticut, our energy on stopping liver disease in those at risk.” community from five different ethnic groups and found a strik- Patients with more risk factors—diabetes, smoking, poor diet, ing increase in the prevalence of NAFLD associated with insulin and alcohol consumption—are more likely to develop worse resistance in the lean Asian-Indian male volunteers. “Just about stages of liver disease. But even without those risk factors, some everyone will develop NAFLD if they become obese, inde- patients end up worse off than others. pendent of ethnicity,” says Shulman. “But there appears to be Now, a theory is emerging out of left field on why some something going on in the Asian-Indian men that predisposes patients may develop more severe inflammation in the liver. them to develop NAFLD and hepatic insulin resistance at a HHMI investigator Richard Flavell at Yale studies bacteria that much-lower body mass index.” inhabit people’s guts. He recently discovered problems in the lin- To further investigate this question, Shulman’s group teamed ing of the gut that lead to the body’s inability to control these up with HHMI investigator Richard Lifton at Yale and found types of bacteria in mice with susceptibility to inflammatory a different mutation than Hobbs’ team had uncovered. They bowel disease (IBD). pinpointed mutations in a gene called APOC3. While Hobbs’ “Once we had found this problem in the gut, it occurred to PNPLA3 is involved in triglyceride breakdown within the liver, us that it was unlikely to be limited to just the intestines,” says the APOC3 protein regulates the breakdown of triglycerides in Flavell. Researchers knew that the blood vessels between the the blood for storage in fat cells. Increased plasma concentrations intestines and liver of people with IBD often had leaks, letting of APOC3, which these gene variants have been shown to cause, unwanted material through. will predispose these individuals to both NAFLD and increased “The function of these blood vessels is to carry food to the triglyceride concentrations in the blood. liver,” says Flavell. “But we hypothesized that there could be a In transgenic mouse studies, Shulman’s team found that mice way in which the bad components of bacteria—or even whole overexpressing human APOC3 developed both fatty liver and bacteria—were traveling to the liver.” hepatic insulin resistance when fed a high-fat diet, supporting his So he took mice with mutations that predispose them to IBD theory that increased plasma concentrations of APOC3 predis- and put them on diets that usually lead to NAFLD. “We immedi- poses an individual to the development of NAFLD, and that fatty ately saw that if the mice don’t have this pathway in the intestines liver can cause hepatic insulin resistance and contribute to the working, they get much worse fatty liver,” he says. development of type 2 diabetes. The experiment, which included help from Shulman, was “I think the APOC3 variants that we describe predispose lean the first to suggest that NAFLD isn’t just a metabolic disease, but individuals to NAFLD and hepatic insulin resistance reflecting a could have a link to bacteria. The gut bacteria, while likely not gene-environment interaction. Just having high plasma concen- causing fatty liver in the first place, could explain the inflamma- trations of APOC3 will not do anything in itself, as reflected by tion that can lead—in a fraction of NAFLD patients—to more the lack of fatty liver and hepatic insulin resistance in the APOC3 severe liver disease. Flavell plans to study how the bacterial popu- transgenic mice fed a regular chow diet,” says Shulman. “But if you lations in the intestines of people with NAFLD vary from those in add a little of fat to their diet, they get fatty liver and hepatic healthy people. It’s an angle of the disease that may someday lead insulin resistance.” When the young, lean, Asian-Indian men (continued on page 48)

Fall 2o12 | hhmi bulletin 29

The View From

HUnbounded creativity—andere powerful computers—make possible the latest devices designed to peer into the deepest recesses of organs and cells. Written by Ivan Amato Illustrated by mitch blunt

Photography has come a long way in the two decades since digital cameras alL but relegated picture taking on film to a chapter in the history book of technology. Image-processing tools like Photoshop and mobile apps like Instagram have turned anyone with aspirations into a postproduction touch-up artist. Revolutionary, With phase 2 and the advent of digital cameras and -scan- yes. But it’s nothing compared to the evolutionary explosion ning techniques over the past few decades, “the image becomes in imaging techniques that the digital crossover has unleashed a set of measurements,” says Schnitzer. Each pixel has associated in laboratories. with it digital values of light intensity, color, or some other param- Every major advance in imaging technology precipitates a new eter. More than just a pictorial rendition of what is visible, he round of breakthroughs in cell biology,” says structural biologist notes, “the image becomes a numerical representation of reality.” Grant Jensen, an HHMI investigator at the California Institute of The camera’s automatic digital accounting of the images’ Technology. Seeing is the quickest route to understanding, says characteristics opened up a world of computer-assisted analyses Jensen, who has been using a technique similar to a computed of what once were only pictures. It also opened options for novel tomography (CT) scan to render visible the molecular machinery data syntheses, among them visual reconstructions of three- inside cells in three-dimensional splendor. dimensional biological structures from two-dimensional images By combining advanced , new-generation cam- of consecutive “slices” of a biological sample. eras, innovative methods of acquiring raw data, and computational “The third phase of biological imaging is where things have processing of the data, HHMI scientists and others are creating gotten really interesting,” Schnitzer says, adding that the ready unprecedented depictions of biology’s magnificent marriage of availability of powerful computers is as much the driver here as form and function. Think of the leaps from still photography to are the microscopes and cameras. Here, he notes, the meaning of movies, from black-and-white to color, and from silent to sound, the raw data is hard to interpret by eye until a computer processes and you begin to get a sense of how much more of life these and reconstructs it into, say, a two- or three-dimensional view with pumped-up imaging tools are allowing researchers to see. discernible cellular or molecular features. This is akin to the way Neuroscientist Mark Schnitzer, an HHMI investigator at today’s high-end sonography equipment can reconstruct images , has been working with colleagues to extend of a from sound echoing from it, or the way magnetic reso- the reach of their microscopes to watch ensembles of cells deep nance imaging machines convert electromagnetic signals from inside the brains of live, mobile animals. Schnitzer has been molecules in the body into portraits of internal anatomy. It takes thinking hard about the of imaging in biology. As he a lot of computing power to turn those raw signals into medically sees it, there has been a three-phase progression since the 17th useful pictures. century when the likes of Robert Hooke in England and Antonie van Leeuwenhoek in Holland first ushered microscopy into sci- The Third Phase entific investigations. Jensen has been pushing this third phase of imaging into the That first phase, based on what scientists could see in real time molecular domain. He combines a freeze-prep step—designed with their eyes peering through a microscope, lasted for centuries. to keep water inside cells from evaporating when inside an elec- First they recorded what they saw with hand drawings and then tron microscope’s vacuum sample chamber—with a multiple-view later with photographs. Their recorded images, says Schnitzer, reconstruction process. The process yields enough 3D clarity, he were essentially data in pictorial form. says, that the resulting images alone can provide sufficient evidence

32 hhmi bulletin | Fall 2o12 Jill Connelly / AP analysis willleadtoaqualitative leapin gatheringand quantitative leapindata other behaviors.Thehopeis thatthe tions onaggressionandcourtship, among approach sumshigh-throughput observa- one byone,thisautomaticmachine-based of making directtask observations of flies, ing someoneperformthetime-consuming recorded bythecameras.Ratherthanhav- are then embedded within the image files which iors withparticularpatternsofdata, computers toassociate specific flybehav- diverse fruitflies.Thescientists teachthe have usedtospyon300,000genetically behavior detectorthatsheandco-workers lance camerasystemintoanautomatic she transformedwhatamountstoasurveil- her computerscience backgroundtowork, fly behaviortoanindustrialscale.Putting era- andcomputer-basedobservationsof Kristin Bransonhasbeenrampingupcam- Extra sidebar,“EyeontheFly.”) and muscular controlsystem. (See Web the insects’less-visibleneurophysiological fromvideorecordings tured inthedata of dragonfly orientsitsheadandbody—cap- ofhow thehunting among them,details map the“microstructure ofbehavior”— turing preyduringflight?Intime,hewill ofcap- “guidance rules”toexecutetheacrobatic,high-speedtask one ofhisquestions: How dodragonfliesdeploybrain-encoded niques tohelpanswerquestions aboutwholeorganisms. Here’s has beenapplyingavarietyofsometimesHollywood-esque tech- “Embryogenesis inMotion.”) ogy’s performances.(SeeWeb mostspectacular Extrasidebar, with color-coding techniques tomakemoviesofsomebiol- erized trackingofcelllineage,proliferation,andmigration embryonic development of fruit flies. He combines comput- movies—theyliterallyevokegasps—ofthedaylong breathtaking technique hasallowed Keller,aJaneliaFarm fellow, toacquire Called simultaneousmultiview light-sheetmicroscopy, the computer-intensive technique into new biological territory. biologist PhilippKellerhasbeenpushingadifferent multiview, tion. (See Web Extrasidebar,“ACT Scan for Protein Complexes.”) complex inbacteriawhoseactionhadbeenamatterofspecula- aboutisthesyringe-likemechanism ofamoleculardefense talk erwise mysteriousmolecularcomplexes.Oneexamplehelikesto to choosebetweencompetingtheoriesaboutrolesplayedbyoth- In anearbylab,JaneliaFarm fellow Meanwhile, AnthonyLeonardo,agroupleaderatJaneliaFarm, At HHMI’s JaneliaFarm ResearchCampus,developmental of cells innear-native state. Helikens theresult to aCTscanfor protein complexes. Grant Jensenflashfreezes specimens to lockwater inplace thengets3Dimages of up to 100 fruit flies at once—both normal flies and those with of upto100fruitfliesatonce—bothnormalandthosewith formassivelyparallelbrainimaging to developinstrumentation image livingcellsandtissuethere. curved lens—needlesthatcanpenetratedeepintothebrainand lens that can magnify like a typical microscope’s much larger, mice. Centraltothesedevicesaremicro-optical needleswitha microscopes thatweigh afractionofanounceontotheheads at leastinlivingandbehavingmice. Schnitzer’s teammountstiny structures thathadbeeninaccessibletoconventionalmicroscopy, that enablesthemtoapplyfluorescence microscopy todeep-brain and co-workersalsohavedevelopedamicroendoscopy technique in thecerebellarcortexthatunderlieslearning andmemory. He hundreds ofbraincellsinlivemice to teaseouttheneuralcircuitry group has been developing techniques for simultaneously imaging Schnitzer is interested in virtual tours of inaccessible places. His Fly MeThrough behaviors. (SeeWeb Extrasidebar,“CapturingBehavior.”) understanding how genesorchestratenervoussystemsandrelated And in a project that complements Branson’s, Schnitzer aims t he Cell (continued onpage48) Fall 2o12

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Dianne Newman tools

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Darcy Hemley Medical microbiologists, whether studying tuberculosis or cystic fibrosis, often ignore the chemical environment of the tissues in which microbes naturally thrive. Dianne Newman argues that geobiologists like herself— who study how microbes have coevolved with the earth—have tools that could be applied to the medical sciences.

During a sabbatical at the last fall, So, what can geobiology offer the study of infectious dis- I spent hours in a beautiful 16th-century library. The shelves ease? To give just one example, my colleague Victoria Orphan included headings in Latin denoting the subject of the vol- combines fluorescence in situ hybridization and secondary umes in each row. One day, I did a double take at a heading mass spectrometry to study slow-growing bacterial that paired two fields rarely discussed together: MEDICINA populations in seeps on the ocean’s floor. These & HIST. NAT., or medicine and natural history. populations cannot yet be cultured in the lab, so she learns This pairing makes perfect sense. Both Earth and the about their metabolic activities by measuring their RNA and human body are complex ecosystems that depend on coevolu- isotopic composition. The same approach could be used to tion, where life impacts the chemical and physical properties study the metabolism of slow-growing pathogens inhabiting of the environment, and the environment, in turn, feeds back the mucus-filled lungs of patients with cystic fibrosis (CF). into life’s evolutionary adaptations. And for both, it is impos- By understanding the chemical composition of the mucus sible to do controlled experiments on the whole. Instead, in space and time, and how the organisms are coevolving we must perform creative but imperfect analog experiments with their environment, we could potentially devise better or make careful measurements of the natural system. ways to disrupt the microbes in their natural niches. Experimental Earth scientists, unable to reproduce the Geobiologists have much to learn from the mechanistic complexity of the natural world in a lab, have focused their approaches taken by medical microbiologists, as well. For efforts on developing analytically dazzling ways to measure example, a major question in Earth history is, when did dynamic environments. For example, geochemists have oxygenic photosynthesis arise? Although geochemists have dated Earth’s age by measuring radioactive isotopes of lead uncovered a wealth of molecular spanning vast time in meteorites and tracked the rise of carbon dioxide in the periods, they are limited in their ability to interpret them. atmosphere by analyzing trapped bubbles in ancient By studying the functions of their lipid counterparts in liv- cores. In my lab, we are collaborating with organic geochem- ing cells using the tools of molecular and cellular biology, ists to make sense of molecular fossils from bacteria in geobiologists could gain insight into the fossils’ evolution- billion-year-old sedimentary rocks. ary significance. Although they share an interest in , Building bridges across these two scientific cultures will medical and environmental microbiologists have separate take more than the buy-in of a few research labs. These scientific cultures: they don’t typically attend the same con- ideas should germinate in college and graduate school, ferences or publish in the same journals. As a consequence, when budding researchers are most open-minded. One of we know shockingly little about the chemistry of the places my graduate students, HHMI international student research in the body where microorganisms reside. fellow Sebastian Kopf, is using the isotope-measuring tech- Yet, the same methods geochemists apply to niques he learned as a geology student in Germany and at and ice cores can be tweaked for cells, tissues, and organs. Massachusetts Institute of Technology to measure bacterial Take the area of infectious disease. Medical researchers growth rate in sputum samples from cystic fibrosis patients. typically culture bacteria after isolating them from their nat- While I encouraged Sebastian to pick the CF lung as his ural microenvironments. While these scientists are adept “field site,” his strategy to study the microbial community at identifying genes, proteins, and pathways involved in lab in this environment is a product of his own creativity and models of disease, whether their findings extend beyond training in the geosciences. their specific model system is not always clear. What’s more, My ultimate hope is that future generations of scientists most pathogen studies have focused on the microbes’ early will feel comfortable pairing medicine and Earth science— rapid-growth stages, even though that represents only a just like the builders of that library in the 16th century. fraction of their life in the human host. Partly due to these artificial experiments, that work on organisms in Interview by Virginia Hughes. Dianne Newman is an the lab often fail in the clinic. HHMI investigator at the California Institute of Technology.

Fall 2o12 | hhmi bulletin 35 Q & A What part of your job would people find the most surprising? They do everything from making fly food to fixing centrifuges. Here, a few lab managers and research specialists describe some of the more unusual aspects of their jobs.

—Edited by Halleh B. Balch

Heike Pelka Matthew Adams Sarah Sarsfield Frank Wilson R esearch Specialist III R esearch Technician II Lab Manager Lab Manager II Danny Reinberg lab Christopher Plowe lab David Ginty lab Pietro De Camilli lab New York University University of Maryland Johns Hopkins University Yale University School of Medicine “I think what people will “Some of the procedures “I’m responsible for maintain- find most surprising is that, “The part of my job that I with mice—like checking ing the lab’s infrastructure as a lab manager who has find most surprising is our plugs—would probably be along with other operations- worked at the bench for challenge study. We give among the weirdest stuff related duties. People are 33 years, I do a lot of archi- patients malaria to study the I’ve done. We do develop- surprised to learn that, tectural work. I even have disease process and its mental , rather than call in a special- my own architectural ruler symptoms, and then we which means that we study ist, I often repair the lab’s now. The biochemistry cure them. It’s humbling embryonic development. So instrumentation myself. My wing at NYU was recently and interesting to me that we need to determine when father was adept at repairing renovated, and I designed people come to us to get mice have mated and then and constructing electronic a section of the labs. Of malaria. They’re sacrificing track the pregnant mice. devices, and in my early course, people sometimes a little bit of their health so The morning after you put a years I picked up a lot by say, “That’s not in your that we can learn something male and a female together, watching him at work in the job description.” Well, new to create a vaccine or you check for a plug. If the basement. I’m not afraid I don’t believe in job to learn about the parasite. mice mated, the female to open up an instrument, descriptions. You do what Our duty to them is to will have a plug. As a even if I don’t normally you are capable of.” make sure they aren’t sick scientist, I don’t really think operate it, and I can usually for too long.” much of it, but when people diagnose the point of failure ask what I do, I don’t usually if a system is faulty. I find it answer, ‘Oh, I spent yester- a welcome change from day morning checking tedious administrative tasks.” 80 female mice to see if they had sex the night before.’” Heike Pelka, Matthew Adams, Sarah Sarsfield, Frank Wilson Matthew Adams, Sarah Sarsfield, Frank Heike Pelka,

36 hhmi bulletin | Fall 2o12 chronicle

38 scIENCE EDUCATION 46 NOTA BENE Teaching Genomics, Plainly Fourteen Elected to National Academy of Sciences / Quake Receives Lemelson-MIT Prize / Horwich Awarded 40 INSTITUTE NEWS Shaw Prize HHMI Awards $50 Million to Colleges / Fifty International Students Get Support from HHMI / A tiny has just hatched from its egg. Under a micro- Medical Fellows Get a Chance to Try Research / scope, the slim, translucent lies motionless on its side, too 2012 Holiday Lectures on Science—Changing young even to swim. The only movement is its beating heart. Planet: Past, Present, Future At this early stage of life, the single ventricle of the fish’s heart is a hollow tube composed of only about 120 muscle cells. 42 LAB BOOK Within three months, those cells, called cardiomyocytes, will The Yin and Yang of Plant Defense / Like a Chinese replicate, morph, and spread to form a full-sized adult heart. Finger Trap / Wiring the Brain HHMI early career scientist Kenneth Poss recently visualized 45 ASK A SCIENTIST this dramatic transformation using a colorful new technique Why do we develop distastes for certain foods? to label heart cells like the ones seen here. To read more about this research, visit www.hhmi.org/bulletin/fall2012. Vikas Gupta / Poss Lab Gupta / Poss Lab Vikas

Fall 2o12 | hhmi bulletin 37 38 hhmi students boldlyadvanced.Through asemester—followed byayear are somegenesandalistofsymptoms. Pickoneandgo,” says Achilly. the mutationsincited problemsthatcouldexplain thediseases. “functional data,” observations in cells and animals confirming that caused theslewofneurologicalandothersymptoms.Thatrequired not havetheresourcestodetermine whetherthemutationsactually ment wastofindoutifthegeneswereculprits. diseases inAmish andMennonite patients.Thestudents’assign- Special Children hadrecentlylinkedmutationsinthosegeneswith list ofsevenmysteriousgenes.ResearchersatthenearbyClinic for mined project, aknown outcome,a100-point labreport. Marshall College(F&M),inLancaster,Pennsylvania: apredeter- follow thesamepathashispreviouslabexperiencesatFranklin & dumbfounded. Hehadsaunteredin,confidentthatthiscoursewould y oneo D Teaching Genomics, Plainly a science education Aided byanHHMIgrantandJinks’ steadyencouragement,the “Itwaslike,OK, here Jinks sent hisclassafterthat functional data. The clinic team, twophysicians andamoleculargeneticist, did But onthatfirstdayin2010,professorRobJinksstoodwaving a bulletin f neurochemistryclassle

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Fall 2o12 f t junior N a than A chill y

simply be learning content to solve problems rather than to pass a aprerequisitehad alreadytaken neurobiologycourse;theywould their teacherwouldhavetomanagesevendiverging projects. neuroscience content necessary to pass a standardized exam. And sleuthing asthefocus,studentswouldneedtofindtimelearn the wrinkled peasorextractcaffeine fromcoffee.Withreal-lifegene the typical college “canned lab,” in which students might count conditions plaguingthelocalcommunity. ONE, revealingthemechanisms behindsevenperplexinggenetic clinic group published their resultsonJanuary 17,2012,inPLoS cian KevinStrauss. Jinks,his13undergraduatestudents,andthe handed their evidencetotheclinicians. the alterations. In December 2010, over shared pizza, the students genes intocells,andcapturedimagesofhow thosecellsreacted to bases ofgenesequences, engineered bacteriatoshuttlemutated - of independentstudyforsome—pairsstudentssearcheddata Jinks wasn’t worried. The students taking thisupper-levelcourse Jinks wasn’tworried.Thestudents taking The audacious and controversial experiment was a far cry from “We justsattherewithourmouthsopen,” recallsclinic physi-

Naomi Wilkinson test. And he had experience managing several students doing inde- By searching bioinformatic databases, Willert hypothesized that pendent study projects at once. the normal gene, called CRADD, regulates how brain cells sprout Jinks knew he could do it—with HHMI support. Awarded in and maintain proper connections. Her cellular studies showed 2008, the $1.3 million HHMI grant was structured broadly to bolster that the mutated version of CRADD found in the Mennonite fam- genetic analysis and bioinformatics at F&M, allowing for the recruit- ily alters the ability of the CRADD protein to interact with other ment of instructors, the career development of current faculty, and proteins necessary to initiate programmed cell death. Thus, her outreach to high school teachers to help boost their understanding findings offered a potential reason for the patients’ cognitive and of bioinformatics. Jinks, who had long studied vision in horseshoe learning deficits. crabs, first tapped those HHMI funds in 2009, to embark on a With Strauss and team, Willert shared her scientific sleuthing sabbatical at the University of Pennsylvania. There he performed story with the family and at the annual meeting of the Society for protein experiments, learned DNA sequencing, and analyzed genet- Neuroscience in Washington, D.C., in November 2011. ics to better understand vision-related diseases in children. “We were looking for answers to whatever would cause this,” says When he returned to F&M, he approached the Lancaster clinic’s family member Geneva Martin, whose three sons, brother-in-law, research team to collaborate. Physicians Strauss and Holmes Morton, and sister-in-law are affected. “It helps just to know.” alongside molecular geneticist Erik Puffenberger, had already been Willert says that meeting the family helped her gain a better teaching an F&M course, describing in colorful case studies their focus in the lab. “I could put a name and on what I had been work with patients from the Amish and Mennonite communities. studying for so long,” she says, “and actually see the kids and how These so-called Plain People are named for their eschewing they interacted.” of cars, televisions, and other modern conveniences. Because the Now she can imagine how a mutation in a cell might 50,000 Amish in Lancaster County descended from only 50 to 200 translate into the behavioral changes that she saw. It also helped her original settlers, and because they tended to intermarry, they— better design the experiments that she conducted this past summer along with the Mennonites—have a high rate of certain genetic when she was hired by the clinic team to continue her work. disorders. The smaller gene pools and clear family histories make it Shaking off those first-day jitters, Achilly took to the project as easier for researchers to trace possible genetic causes. Since 2009, well. After two years uncovering how a mutation in an enzyme the clinic team has been discovering new genetic illnesses at a rate involved in protein synthesis might cause Usher syndrome type of 5 to 10 each year. Their success fueled Jinks’ bold and risky idea: to restructure his neurochemistry course to sup- “The critical thinking involved, port the clinic team’s genetic discoveries. “It was thinking of these things as puzzles, probably ambition coming off a really exciting sab- has been captivating. batical,” he says. “But it is a very unique population of patients and a great group of students.” nathan achilly ” Mutations and Behavior Changes Jinks went forward with the restructured course, teaching under- IIIB, characterized by hearing loss and progressive vision loss, graduates how to make strong connections between the bedside and Achilly, who graduated in May, has expanded his sights beyond a bench. Some students did so literally, by going to the clinic to meet medical degree. He now plans to pursue an M.D., Ph.D. in transla- patients and taking that experience back to the lab. Independent study tional neuroscience. student Rebecca Willert, for example, studied a Mennonite family in “The two years of experience that I gained from Rob’s lab have which five members displayed a form of intellectual disability charac- changed my life in many ways,” he says. “The critical thinking terized by learning delays. Through gene mapping and sequencing of involved, thinking of these things as puzzles, has been captivating.” family members’ , the clinic team had come up with a single W –trisha gura gene as the possible culprit. Puffenberger handed over that informa- FOR MORE INFORMATION: Among other colleges and universities, Franklin & Marshall tion to Willert, in addition to—with the patients’ consent—medical College recently won another HHMI grant to advance its work with the Clinic for Special Children records data detailing symptoms and onset. (see Institute News).

Fall 2o12 | hhmi bulletin 39 institute news HHMI Awards $50 Million to Colleges

Forty-seven small colleges and supported nearly 40 students and will undergraduate program. “We anticipate universities have accepted a challenge: to expand to help meet the needs of transfer that the theme-based programs will provide create more engaging science classes, bring students in the coming years. useful models that will inform other institu- real-world research experiences to students, “HHMI is investing in these schools tions, including larger research universities, and increase the diversity of students who because they have shown they are superb about strategies that might be replicated.” W study science. incubators of new ideas and models that With HHMI grants totaling more than might be replicated by other institutions to FOR MORE INFORMATION: To see a list of the 2012 $50 million, these U.S. institutions will dis- improve how science is taught in college,” awardees, visit www.hhmi.org/news/hhmicolleges20120524b.html. cuss strategies and share know-how with an says Sean B. Carroll, vice president of sci- eye toward eventually disseminating effec- ence education at HHMI. tive models more broadly. The Institute invited 215 schools to apply College I nitiative The expectation is that the four-year for the competition. Of those, 187 schools Strategic T hemes grants, ranging from $800,000 to $1.5 mil- submitted proposals. After two rounds of lion, will have a big impact on these small peer review, a panel of 23 leading scientists • Preparing undergraduates to become K-12 teachers who understand inquiry- schools, which should be more nimble than recommended that 43 awards be made to based learning. larger research universities and better able 47 schools (a joint award went to five under- • Creating curricula that emphasize to quickly develop and test new ideas. graduate schools in southern California learning competencies.

Hope College in Holland, Michigan, known as the Claremont Colleges). • Defining and assessing what it means for plans to use some of its grant money to Each school chose to work on one a student to be scientifically literate. fund a research program for incoming of six overarching objectives (see box). • Developing effective strategies that promote the persistence of all students in science. freshmen the summer before they enroll. “The strategic theme-based approach is • Creating course-based research experiences The grant will also provide continued fund- a new opportunity that enables the grant- that will help students learn science by ing for Hope’s Fostering a Community of ees to organize into smaller groups so that doing authentic research. Excellence in Science program, which faculty from schools can come together • Encouraging students to engage in pairs freshman and upperclassman minor- throughout the next four years to share research through one-on-one apprentice- based experiences. ity students to encourage them to stay ideas, challenges, solutions,” said David J. in the sciences. The program has already Asai, director of HHMI’s precollege and

Fifty International Students Get Support from HHMI

Elisa Araldi is studying in the United “Now in its second year, HHMI’s Inter- HHMI started the program because States to advance science in Italy. “The national Student Research Fellowships it recognized that international students reason I came to the U.S. for my graduate Program is supporting nearly 100 out- in the U.S. often have difficulty securing education was to train in the best scientific standing future scientists from 28 different funding to support their graduate stud- environment in the world and bring my countries,” says William R. Galey, director ies. “Being an international student, it is knowledge and expertise back to Italy,” she of HHMI’s graduate and medical education virtually impossible to find fellowships says. Thanks to an HHMI fellowship, she’s programs. “We anticipate that the program that fully support my stipend,” says Araldi, one step closer to her goal. will eventually support 150 outstanding bio- who is studying macrophage biology at Araldi is one of 50 graduate students medical science graduate students in the New York University’s Sackler Institute. from 19 countries who were awarded crucial years of their Ph.D. work.” Funding “Part of my project involves very sophis- HHMI International Student Research for the program this year is $2.15 million, ticated and expensive experiments, and Fellowships. The program provides $43,000 up from $2 million last year. this fellowship will allow me to perform a year to international science students Sixty-three Ph.D.-granting institutions more experiments.” studying in the United States. The fellow- were eligible to nominate their gradu- And more experiments for Araldi means ships fund the students during their third, ate students for the fellowships. Of the more scientific expertise for Italy. W fourth, and fifth years of graduate school— 19 countries represented in this year’s slate

a pivotal point in their studies when they of awardees, six—Australia, Bulgaria, , FOR MORE INFORMATION: The names of the must delve into intense laboratory research Italy, Latvia, and Switzerland—are new to International Student Research fellows can be found at www.hhmi.org/news/popups/isrf2012.html. for their doctoral dissertations. the program.

40 hhmi bulletin | Fall 2o12 Medical Fellows Get a Chance to Try Research

This past summer, 70 medical, dental, connectivity between the mouse motor and HIV and drug-resistant TB] at its epicen- and veterinary students put their courses barrel cortices. ter, and I look forward to working with and rotations on hold to focus on labora- “A year of research provides an avenue to my mentor and the K-RITH team of sci- tory research. The students, who came practice what should be an essential skill in entists to develop improved diagnostics from 27 schools across the country, are any scientific field: questioning ‘why,’” says for rapid TB drug-susceptibility testing,” part of HHMI’s Medical Research Fellows Wolman. “It is a thought [that will says Kalivoda. Program, a $2.5 million annual initia- teach] you to question why an unexplained This year HHMI also launched a tive to increase the training of future symptom in a particular disease constella- Summer Medical Fellows Program, provid- physician-scientists. tion occurs, and perhaps even help you ing opportunities for 27 medical students The program gives the students the develop the spark necessary to pursue that to do research for 8 to 10 weeks in the labs opportunity to spend a year doing bio- question to its answer.” of HHMI or Janelia Farm scientists. medical research at laboratories across the In a first for the program, one of the med- The yearlong Medical Research United States. Started in 1989, the fellow- ical fellows will be spending part of his year Fellows Program has an important impact ship has enabled more than 1,400 students in Durban, , at the KwaZulu- on the awardees. Seven of the 71 medi- to participate in research. Natal Research Institute for Tuberculosis cal fellows involved in the 2011–2012 When applying for the program, each and HIV (K-RITH). Eric Kalivoda, a program are continuing for a second student submits a research plan outlining student from the University of Vermont year, and ten students have decided to the work they will do with a mentor of their College of Medicine, will spend several pursue a Ph.D. in addition to their medi- choice. Dylan Wolman, a fellow from Tufts months in Durban, assisting HHMI inves- cal degree. W University School of Medicine, applied to tigator William Jacobs with his research on work at HHMI’s Janelia Farm Research tuberculosis. He will then spend the rest of FOR MORE INFORMATION: For more about the Medical Campus with JFRC fellow Davi Bock the year in Jacobs’ lab at the Albert Einstein Research Fellows Program and a list of the 2012–2013 fellows, go to hhmi.org/medfellowships. and group leader Karel Svoboda. Wolman College of Medicine in New York. will be spending his year using light and “K-RITH offers the unique perspective web extra: Go to www.hhmi.org/bulletin/fall2012 to hear from a medical research fellow alumnus. microscopy to study the neural to study and address [the co-infection of

2012 Holiday Lectures on Science— Changing Planet: Past, Present, Future

Just over 4 and a half billion years on Earth and the forces that have shaped, well as discuss his exploration of the geol- ago, a cloud of gas and dust came together and will continue to shape, our ever-chang- ogy and possibility of life on . Naomi to form our planet. Since then, it has under­ ing planet. Oreskes of the University of California, San gone massive change. In HHMI’s 2012 Andrew H. Knoll of Harvard University Diego, will present past scientific models of Holiday Lectures on Science, three lead- will use the -record geochemistry the forces responsible for shaping the physi- ing scientists will explore the history of life to explain the history of life on Earth, as cal features of our planet and describe the current understanding of plate tectonics. Daniel P. Schrag of Harvard University will discuss over geologic time and explain how understanding the past can help us comprehend the impact of our activities on current and future climate. HOLIDAY LECTURES The Holiday Lectures will take place November 15–16, 2012, at HHMI head- quarters in Chevy Chase, Maryland. You can sign up to view a live webcast at www. Changing Planet: Past, Present, Future holidaylectures.org. W

Fall 2o12 | hhmi bulletin 41 lab book The Yin and Yang of Plant Defense A plant’s response to infection is controlled by a concentration gradient of salicyclic acid.

When a plant suffers a microbial infection, it produces salicylic cells from dying. Next, the team found that salicylic acid had opposite acid. But the role this hormone plays in protecting plants has been effects on these two protein-protein interactions. It stimulates NPR3’s somewhat of a mystery. A team of researchers led by HHMI-GBMF degradation of NPR1—but only with high levels of salicylic acid—and investigator Xinnian Dong has proposed a model to explain how prevents NPR4’s degradation of NPR1 in the presence of salicylic acid. salicylic acid controls both cell death at the site of infection and cell Dong’s group proposes that without infection, NPR1 levels are survival and immune activation in noninfected tissue. kept low by NPR4-mediated degradation. Upon infection, salicylic When exposed to infection, plant cells respond either by dying, acid forms a concentration gradient with higher levels at the infec- to protect the rest of the plant, or by activating resistance measures tion site and lower levels outward. A high level of salicylic acid in to survive. Salicylic acid and its signal transducer, NPR1, both influ- infected cells facilitates NPR3-based degradation of NPR1, and the ence the outcome, but they do not interact directly. Dong and her infected cells die. In cells distant from the damage, the lower salicylic research team at Duke University studied how two other proteins— acid level limits the binding of salicylic acid to NPR3 and NPR4, NPR3 and NPR4—interact with salicylic acid and NPR1 before and blocking degradation of NPR1, and those distant cells survive. after infection to modulate levels of plant defense. The team’s findings, published June 14, 2012, in Nature, may Observing mutants of the model plant Arabidopsis thaliana that be applied to both and medicine. “But our dynamic lacked NPR3, NPR4, or both, Dong’s team concluded that NPR3 and model has to be tested first,” Dong says. “That is not going to be easy.” NPR4 both promote degradation of NPR1, whose buildup prevents W –Nora Taranto

A gradient of the protein NPR1 (green) causes cell death near an infection site on an Arabidopsis leaf.

IN BRIEF

Memory Plays Muse Tsai, who is at the Massachusetts Insti- Amazingly, 147 regions in the genome An overactive enzyme called HDAC2 may tute of Technology, is eager to see whether were consistently altered across the 21 stick- be at the core of memory decline, accord- blocking HDAC2 is effective in humans. lebacks. The genetic regions are associated ing to HHMI investigator Li-Huei Tsai, “We need to test this hypothesis in humans with metabolism, developmental processes, whose lab team showed that blocking to see whether this concept holds up,” she behavior, and body armor formation, iden- the enzyme restores memory in mice with says. “While all the data look very promis- tifying a suite of changes that enabled the Alzheimer’s disease. ing in animal models, human studies are a formerly saltwater fish to survive in fresh HDAC2 switches off genes implicated completely different ball game.” water. More than 80 percent of the changes in learning and memory. When the enzyme were found in regulatory sequences rather was overexpressed in mice, memory func- Fow llo ing a Fish’s Evolution than protein-coding regions, helping to tion dropped and there was a significant After the last ice age, when melted answer a long-standing debate about the loss of synapses—the information transfer and fresh water streamed across land relative importance of regulatory and cod- stations between brain . When masses, many animals adapted to new ing changes during adaptive evolution. By the researchers reduced HDAC2 in neurons habitats. HHMI investigator David Kingsley studying the diverse stickleback genome, of mice exhibiting Alzheimer’s disease, and a team of international scientists have Kingsley says, “we can find the key genes they found a dramatic increase in the followed a fish—the three-spine stickle- that control evolutionary change.” number of active synapses. After only four back—to determine what genetic changes weeks, the HDAC2-blocked mice were allowed it to thrive in new environments in The Network indistinguishable from healthy mice in North America, Europe, and Asia. Scientists estimate that about one quar- memory tests. Kingsley’s team at Stanford University ter of autism spectrum disorders (ASDs) The researchers, whose work was pub- School of Medicine and scientists from the may be caused by mutations in the eggs lished February 29, 2012, in Nature, also Broad Institute of MIT and Harvard col- or sperm of parents who have no history of discovered what might put HDAC2 into laborated with international scientists to ASD. Tracking the origins of some of these overdrive. Two known Alzheimer’s indica- uncover the complete genome sequences so-called sporadic mutations, HHMI inves- tors, the protein amyloid- and oxidative of 21 members of the stickleback fam- tigator Evan Eichler and Jay Shendure, at stress—an excess of a reactive form of ily collected from around the world. As the , found that —can activate the protein gluco- described in Nature, on April 5, 2012, the many of the mutations affect a large pro- corticoid receptor 1, which in turn switches scientists looked for DNA sequences that tein network that functions in cell cycle on rampant production of HDAC2. had changed as the fish adapted. regulation and neuronal development. Nodoka Oka and Yasuomi Tada / Kagawa University, Japan, and Xinnian Dong / Duke University University, Japan, / Kagawa Tada Nodoka Oka and Yasuomi

42 h h m i b u l l e t i n | Fall 2o12 Like a Chinese Finger Trap Scientists zero in on disease-causing amyloid structure.

In neurodegenerative diseases like Alzheimer’s, the needle-like toxicity patterns similar to those fibers that accumulate in the brain are not the real damage-doers. in the major amyloid diseases. The culprits are intermediate protein structures, called small amy- Finally, using x-ray diffraction, loid oligomers, made of a few proteins that misfold and aggregate. Lagonowsky saw that the small But the oligomer’s fleeting existence—sometimes lasting only min- oligomer consists of a cylinder of utes before forming the longer fibers—make them nearly impossible six protein chains. They dubbed to study. HHMI investigator David Eisenberg has at last pinned the structure “cylindrin.” down the structure of an amyloid oligomer. “This cylinder looks sort of “We wanted to find the toxic agent,” Eisenberg, at the University like those toys you get in China- of California, Los Angeles, says about his research published March town, where you put your fingers 9, 2012, in Science. “You can’t design drugs if you don’t know the in and realize they’re stuck,” structure of the toxic agent.” says Eisenberg. “It has a struc- Though the oligomers in major amyloid diseases such as ture unlike any of the 70,000 Alzheimer’s, Parkinson’s, and even type 2 diabetes are short-lived, structures catalogued in the open- The toxic agents in many Eisenberg found one that lasts longer. The needle-like amyloid fibers source Protein Data Bank.” neurodegenerative diseases are intermediate structures that in some cataracts take decades to form, so the oligomer state of these Eisenberg hopes that under- form small cylindrical oligomers. misfolded proteins can be easily trapped. Eisenberg and graduate standing the cylindrin structure student Arthur Laganowsky took advantage of these unhurried aggre- may lead to new approaches to gates to study the cataract-forming protein, αß crystalline (ABC). studying the structures of the more elusive oligomers associated Lagonowsky used a computational to find the seg- with major diseases. “The fundamentals are absolutely critical to ments of the ABC protein responsible for forming the fibers. He understanding medicine,” he says. “Work in structure and com- then confirmed that the ABC oligomer had antibody affinities and putation of amyloid diseases is just starting.” W –Halleh b. Balch

IN BRIEF

Comparing autistic children’s genes use of the mineral. In one of these inter- “What we’ve discovered isn’t just the to those of their parents, the scientists actions, called phosphorylation, a kinase casein kinase,” Dixon says. “It’s a whole found more than 250 mutations unique enzyme affixes phosphates to proteins. new branch on the kinase tree that seems to the children. Some mutations had been With correct phosphorylation, proteins to play an important role in bone and linked to autism in past studies; others are able to bind calcium to form bones teeth formation.” were strong new candidates. and teeth. Analyzing the data further, the research- For over a century, scientists have known Fow llo ing CHI to Its Perfect Form ers found that the number of mutations that the milk protein casein contains phos- Joe Noel calls chalcone isomerase, or increased with the father’s age, and that phate. In a study published June 1, 2012, in CHI, the “perfect enzyme” because of its 39 percent of the mutations affected pro- Science, researchers led by Jack E. Dixon, extreme speed. teins within the same network. HHMI vice president and chief scientific Noel, an HHMI investigator at the Salk “I was surprised to see so many of them officer, found that Fam20C—a member Institute, wanted to know how CHI evolved as part of a highly interconnected set of of the seldom-studied Fam20 family of to catalytic perfection. He discovered that proteins,” Eichler says. Skeptical at frst, proteins—is responsible for the phosphory- CHI likely evolved from a noncatalytic the scientists sequenced the exomes (the lation of casein. protein that played a completely different protein-encoding genes) of 50 nonautistic Scouring old scientific reports, the role in plants, and that CHI and its noncata- siblings; none carried the mutations found researchers also discovered something lytic relatives coexist today. in the network. The research was published unexpected: mutations in Fam20C had CHI is crucial to production of favo- April 4, 2012, in Nature. been reported in patients with Raine noids, which customize plants to varied “Understanding how the mutations syndrome—a fatal disease in which bones terrestrial environments. Flavonoids pro- affect cells will require further experi- become too dense. Dixon’s team devel- vide UV sunscreens, for example, and colors ments,” Eichler says, “but converging on oped a cell line with the Raine syndrome that lure . a network is a step forward in the feld of mutations. “Every single one of these Noel and colleagues combed through autism genetics.” mutations inactivated the Fam20C kinase the genome of Arabidopsis and found that and prevented it from being secreted,” CHI shares genetic similarities with three It Does a Body Good says Dixon. The mutations affected phos- members of the FAP protein family. Milk may contain the calcium that helps phorylation of casein as well as several To learn how the two protein families build strong bones, but we rely on subtle other proteins involved in enamel and were related, the scientists introduced FAP biological interactions to absorb and make bone formation. genes into E. coli bacteria, and then studied David Eisenberg / University of California, Los Angeles

Fall 2o12 | hhmi bulletin 43 44 hhmi b D Brain the Wiring to the striatum, and silencing the indirect pathway increased the pathway preventedtheformationofconnectionsdeliveringinput silenced, thesynapsesgrewnormally. However, silencing thedirect receiving neurons.Instead,evenwiththestriatum’s outputsignal stop them from forming connections between the striatum and incapable ofreleasingthechemical messengerGABA. whose indirect ordirect pathwayswereturnedoffbecausethey Sabatini andhiscolleaguesatHarvardMedical Schoolbredmice ment. To activityaffectsneuronaldevelopment, learnhow striatal stimulates movementandanindirect pathwaythatinhibitsmove - trates movementthroughtwopathways:adirect pathwaythat sory andsocial contexttodirect movement. of synapsesinthebasalganglia,aregionbrainthatusessen- self-reinforcing loopsofneuralactivitymaydrivethedevelopment its wiringshortlyafterbirth? doesn’t receive inputsfromtheexternalworld,sohow doesitbuild sounds, andexperiences.Butonepartofthebrain,basalganglia, synapses—connections betweenneurons—inresponsetosights, y evel lab booklab IN BRIEF The scientists expectedthatsilencing theseneuronswould The basalganglia’s maininputcenter—thestriatum—orches- Research byHHMIinvestigatorBernardoSabatini suggeststhat A newborn’s braindevelopsbyforming andstrengthening new

in Nature. 2012, 13, May published waswork The CHI. to precursor immediate the FAPsare that FAPs.these on Based on rely ancestors, plant early of example modern-day the algae, Evenchloroplasts. in regulation and biosynthesis acid fatty in role a play they that found team the tallography. the expressed FAP proteins with x-ray crys- scientists had been unable to resolve their Medical Center. the at Takahashi,says clock,” biological the of of these proteins. has solved the three-dimensional structure Now, HHMI investigator Joseph S. Takahashi sure, and metabolism on a 24-hour schedule. pres blood patterns, sleep our regulate that rhythms circadian the for sponsible TwoCL proteins, Wha into plant way,similar a it turn grabstochalcone CHI In bacteria. the from molecules fatty-acid to tightly held that FAPs in pockets saw ne bulletin Despite the proteins’ important role, important proteins’ the Despite CL Tracking FAP proteins in TrackingproteinsFAP u o t ral O pment U Ma CK and BMAL1 are “the batteries “the are BMAL1 and CK niversity of Texasof niversitySouthwestern f kes

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O c . f n sinit can scientists Science, CK and BMAL1 proteins BMAL1 and CK o y embryo. These are the ts’ Home ntr O CK, and how gene how and CK, to revealhow perturbationsaffectwiringlaterinlife. continue to engineer mice, activating and inactivating specific neurons disproven bythestudy,” says Sabatini. Readyformoresurprises,hewill state.” Sabatini’s team published its results May 31, 2012, in itselfbydrivingitsown maturationintotheright thing canestablish positivefeedbackloopwheresome- development “ofaveryimportant the basalgangliaduringearlydevelopmentcanhavelastingeffects. gesting thatwiringchangesin striatum thannormalmice, sug- neuronal connectionsintheir hood, their brains hadfewer When thesemice reachedadult- striatum during development. neurons providing inputtothe the group reduced the activity in development ofinput. itself—output controlled the The circuit wasbasicallywiring growth oftheseinputsynapses. O o In afollow-up experiment, “We wentintothestudywithhypothesesthatwerecompletely This research,saysSabatini, revealstheexistenceinbasalganglia CK is entwined is CK lled Vid eo

Clock O CK.

in Nature Methods. are the precision, to angled mirrors and start to embryo, the of side everyoccurs—from it as processdevelopmental the of view a is four directions at the same time.” The result from it at look “wesays, Keller do, scopes sample from one direction” like most micro- resolution videos. “Instead of looking at the high- the achieveto calibration perfect in be must chamber sample the straddling The end. on hours for embryo the overforth and back scan that light laser of sheets two on rely images The detail. unprecedented with unfold biology tal developmenwatch- to scientists allowing images, of millions captures microscope the microscopy, sheet light multiview cist PhilippKeller. biophysi- by designed microscope new a development. embryo’sthe throughout divide moveand cell each watch to Campus Research Farm Janelia HHMI’s at colleagues his and Keller allowing illumination, laser the to response in light emit cells labeled cently O The results were published June 3, 2012, ae SMiw fr simultaneous for SiMView, Named f awlessly aligned, and the two cameras n a large table f nish. nish. phore to helpmeasure itsgrowth. pathway withared fluoro- An fillsanindirect f lled with optical lenses W – N ora taranto f uores- Nature.

Bernardo Sabatini / Harvard Medical School ask a scientist q A We all have Our genes and the environment influ- did not have the food luxuries we have ence our food preferences. Our taste buds today. Food was scarcer, and an active foods we like distinguish between bitter, sour, sweet, lifestyle kept them from developing umami (savory), and salty flavors, and we . While the genetic variations and dislike, may even have a “fat” taste receptor. Sci- underlying the preference for sweetness but from an entists have identified some of the genes are still being studied, one can imagine responsible for these different receptors that these variations could have arisen evolutionary and believe that variations within these based on the availability of food sources standpoint genes may affect our individual food pref- for a particular population. Overall, erences. Environmental pressures that preference­ for sweetness is a complex it seems like we are no longer an issue probably caused trait—one influenced by genetics and our taste buds to evolve, leading to pref- the environment. shouldn’t turn erences that may not make sense in the Umami food—that is, food with a up our noses at modern world. savory, meaty flavor—is another taste For example, scientists believe that that appeals to humans. Since the body anything that the ability to detect bitterness evolved uses similar molecular processes to to prevent consumption of poisonous— detect sweet and umami foods, our affin- helps us survive, and often bitter—plants. Unfortunately, ity for this high-energy food group is and we shouldn’t some healthy plant-based foods, such not surprising. as broccoli, also trigger the same bitter Our preference for seems to be have different taste perception and associated nega- influenced most by environmental fac- tastes from other tive reaction. The ability to perceive the tors, mainly childhood exposure to salty bitterness of a chemical called phenyl- foods. Studies suggest that people with people living thiocarbamide (PTC) reflects a particular lower sodium exposure as infants have genetic variation affecting the range of a less fondness for salty foods as adults, in the same person’s bitter taste recognition. Interest- compared with those who had higher environ­ment. ingly, different populations have different exposure to sodium in infancy. sensitivities to PTC. One study showed Recent research indicates that mice Why do we that only 3 percent of West Africans do recognize and prefer fatty foods. A recep- develop distastes not perceive PTC as bitter, while about tor on the tongue called CD36 appears to 30 percent of Caucasian North Ameri- control how mice perceive fat. Though for certain cans do not (see Further Reading). One humans have a version of CD36, its can imagine that populations in West role in human fatty-taste perception is foods? Africa may have developed this advan- unknown. As with sweet and umami tage based on greater exposure to certain taste preferences, an attraction to fatty Asked by a college student from Maine bitter-tasting poisonous plants. foods would have maximized survival Sour taste may also serve as a protec- chances of our ancestors by directing tive mechanism. Most animals reject them to eat high-calorie foods. sour-tasting foods. This reaction prob- We’d likely be better off if we were less ably evolved to protect against eating quick to choose the sweet or meaty, high- spoiled food or unripe fruit. calorie foods that supported our ancestors’ Our preference for sweet foods may survival and, instead, went for the bitter- be due to the fact that sweet foods are tasting broccoli or mustard greens. usually high in energy, and our pre- FURTHER reading: historic ancestors would have needed Answered by Roxana Daneshjou, Garcia Bailo B, Toguri C, Eny KM, El-Sohemy, A. a 2011 HHMI medical fellow at Genetic variation in taste and its influence high-energy meals to survive. The many on food selection. OMICS 2009; 13:69–80. generations of humans preceding us Stanford University School of Medicine.

Science is all about asking questions, exploring the problems that confound or intrigue us. But answers can’t always be found in a classroom or textbook. At HHMI’s Ask a Scientist website, working scientists tackle your tough questions about human biology, diseases, evolution, animals, and genetics. Visit www.hhmi.org/askascientist to browse an archive of questions and answers, fnd helpful Web links, or toss your question into the mix. What’s been puzzling you lately?

Fall 2o12 | hhmi bulletin 45 nota bene

spotlight

Fourteen Elected to National Academy of Sciences

top row: NANCY M. BONINI, GIDEON DREYFUSS, EVAN E. EICHLER, K. CHRISTOPHER GARCIA, RACHEL GREEN, GREGORY J. HANNON, LIQUN LuO bottom row: roy parker, nikola p. pavletich, louis J. ptÁČ ek, alexander y. rudensky, , xinnian dong,

Twelve HHMI investigators, an HHMI-Gordon and Betty Moore Foundation investigator, and an HHMI early career scientist were elected to the National Academy of Sciences. The investigators are Nancy M. Bonini, University

of Pennsylvania; Gideon Dreyfuss, University of Pennsylvania School of Medicine; Evan E. Eichler, University of Quake: George Nikitin / AP

Washington School of Medicine; K. Christopher Garcia, Stanford University School of Medicine; Rachel Green, Johns Hopkins School of Medicine; Gregory J. Hannon, Cold Spring Harbor Laboratory; Liqun Luo, Stanford University; Roy adilla

Parker, University of Arizona; Nikola P. Pavletich, Memorial Sloan-Kettering Cancer Center; Louis J. Ptáček, University Hartshorn arker: Margaret P of California, San Francisco; Alexander Y. Rudensky, Memorial Sloan-Kettering Cancer Center; and Xiaowei Zhuang, Harvard University. The HHMI-GMBF investigator is Xinnian Dong, Duke University, and the early career scientist is Karl Deisseroth, Stanford University. Deisseroth: Darcy P

Luo: Charlene Liao

Nine HHMI investigators and one HHMI Science and Engineering Visualization Chal- a variety of disciplines ranging from the arts professor are among 220 new members and lenge. Baker’s free game allows players to fold to the physical sciences. Dong: Jim Bounds A/P 17 foreign honorary members elected to the proteins for fun while contributing to scien- / AP k Seckler

American Academy of Arts and Sciences. tific research. The Norwegian Academy of Sciences and HHMI’s newly elected members are James Letters awarded its 2012 Kavli Prize in Neu- Hannon: Zac

J. Collins, Boston University; Brian J. HHMI investigators Cornelia I. Barg- roscience to Cornelia I. Bargmann, an Druker, Health and Science mann of the Rockefeller University, HHMI investigator at the Rockefeller Uni-

University; Sarah C. R. Elgin, HHMI pro- Bonnie L. Bassler of Princeton Univer- versity; Winfried Denk, a senior fellow at aul Fetters Zhuang: Cheryl Senter / AP

fessor, Washington University in St. Louis; sity, and J ack Szostak of the Massa- Janelia Farm Research Campus; and Ann Green: P

Susan Ferro-Novick, University of chusetts General Hospital were elected to M. Graybiel of the Massachusetts Institute California, San Diego; T yler E. Jacks, the American Philosophical Society. The of Technology. The three scientists, who Massachusetts Institute of Technology; APS is the oldest learned society in the are recognized for elucidating basic neuro- Richard P. Lifton, Yale School of Medi- United States; its members are selected from nal mechanisms underlying perception Liqun Luo ettering Cancer Center cine; , Stanford University Garcia: Barbara Ries

School of Medicine; Danny F. Reinberg, spotlight New York University School of Medicine; Bre nDA A. Schulman, St. Jude Chil- dren’s Research Hospital; and Steven A. Quake Receives Lemelson-MIT Prize

Siegelbaum, Columbia University. David / AP hler: Ron Wurzer Rudensky: Memorial Sloan-K HHMI investigator Stephen Quake of Stanford Univer­- Eic

W. Oxtoby, a member of the HHMI Sci- sity was awarded the 2012 Lemelson-MIT Prize, ence Education Advisory Board, was also which honors outstanding midcareer inventors dedi- elected to the academy. cated to improving the world through technological aul Fetters

invention. Quake is being recognized for his work in Fetters ek : Paul č

drug discovery, genome analysis, and personalized Ptá

Dreyfuss: P Foldit, an online game created by HHMI medicine. His group was the first to use microfluidic investigator of the University technology in the determination of protein structure of Washington, took first place in the inter- through x-ray crystallography. active game category in the National stephen quake avletich: Paul Fetters Paul avletich: P Science Foundation’s 2011 International Fetters Bonini: Paul

46 h h m i b u l l e t i n | Fall 2o12 Jerry Domian D tor atBrighamandWomen’s has Hospital, The Award fromtheBaylorCollegeofMedicine. 2012 Rush and Helen Record Neuroscience Reemtsma Foundation inGermanyandthe Neuroscience PrizefromtheGertrud also received the2012KlausJoachimZülch to studyneuralcircuit function.Deisseroth development and application of Massachusetts InstituteofTechnology fortheir with EdwardBoydenandFeng Zhangofthe Neuroscience Prize. Deisseroth shares the prize University of North Carolina’s 12th Perl-UNC University,scientist atStanford wasawarded the H e S Ka HHMI investigator million dollars. and decision, willshare anaward ofone and online. film andvideoproductions,both broadcast tion andAdaptation.Theawards aregivento film recently wontwoTelly Awards for the short in theHHMIscience educationdepartment HHMI investigator ress inindustryandresearchestablishments. for leading scientific andtechnologicalprog- researchand contributions tofundamental members gainmembershipinthesociety for bers oftheRoyalSociety. Fellows andforeign presented The AmericanPhytopathologicalSociety in responsetochangestheenvironment. mechanisms plantsusetoaltertheir growth genetics forthelast15years.Chorystudies the ica Medal for outstanding contributions to awarded the2012GeneticsSociety ofAmer- Salk InstituteforBiologicalStudies was to discriminate betweenfriendandfoe. underlying theplantimmune system’s ability research onthemolecularmechanisms Allen Award. Dangl was honored for his Carolina atChapelHill,withthe2012Ruth GBMF investigator at the University of North dent andchiefscientific officer Princeton University andHHMIvicepresi- t i xo r p The Making of the Fittest: Natural Selec- l Edu n De e

have beenelectedasforeign mem- n c i

Je sserot J. a t ff E i ll o ery L.D nal e d h Bo NN Jo g ,

an HHMI early career anHHMIearlycareer R e, a nni eso anHHMIinvestiga- an e L.B e u g rces C l h , an HHMI- o a ry s J s G a l ro ck of the er up of of E .

Award. Kandelstudies thebasicmolecular Psychiatric Association’s 2012AdolfMeyer cians and Surgeons,received theAmerican the Columbia University College of Physi- investigators The GruberFoundation presentedHHMI levels ofcholesterolintheblood. factors thatcontributetovariationsinthe Hobbs’ researchfocusesondefining genetic Gotto Jr. PrizeinAtherosclerosisResearch. sclerosis Society’s inauguralAntonio M. Center received theInternationalAthero- University ofTexas SouthwesternMedical E sented The NationalHemophiliaFoundation pre- in geneanddrugdiscovery. development of genetic technologies to aid the cellcycle and isalso interested in the Medicine. Elledgestudies theregulationof tion’s 2012 Prize for Scientific Excellence in CancerFoundawon theAmerican-Italian - J HHMI investigator ing disorders. novel therapeuticsforthetreatmentofbleed- blood coagulationandthedevelopmentof Award. Highstudies themolecularbasisof Philadelphia, with itsLeadershipinResearch investigator attheChildren’sof Hospital cialize duringembryonic development. activity andhow braincellsdiversify andspe- channels control brainon how potassium The scientists wererecognized fortheir work Francisco, with its2012 Neuroscience Prize. an r i spotlight c , bothoftheUniversity ofCalifornia, San arth Horwich Awarded ShawPrize R . Ka Kand u r t

h h L o er il e rwich y l in , anHHMIinvestigatorat Y He e A.H . J l an e n and H.Ho i g fold, away from outsideinterference. proteinsforprovidesplaceto safethat a “machine” foldingcage-like a as acts chaperoninprotein the that determined Hartl and Horwich folding. tein pro- of mechanism molecular the understanding tocontributions their for Biochemistry of Institute Franz- with award million $1 the shares He Medicine. and Science Life in PrizeShaw received 2012 Medicine, the of School Yalethe investigatorat HHMI an Arthur Horwich , h , an HHMI Yuh bb s N of the ofthe un g sense andadapttochangingoxygenlevels. icine forresearch on how tissues and organs the JohnsHopkinsUniversity SchoolofMed- University ofOxfordandGreggL.Semenza shares theprizewithPeter J.Ratcliffeofthe Foundation’sScientific GrandPrize.He recipient of the 2012 Lefoulon-Delalande of theDana-Farber CancerInstituteisa HHMI investigator ory inanimals. mechanisms underlyinglearning andmem- Jeremy N HHMI investigator of themammalianretinaandembryo. genetic approachestostudythedevelopment dation ofPittsburgh.Nathansusesmolecular Muse Prize,givenbytheEyeandEarFoun- icine, istherecipient ofthe2012AlbertC. the JohnsHopkinsUniversity SchoolofMed- by molecularmotorsinsidecells. University forexplaining how cargoismoved versity andJamesSpudich atStanford prize withMichaelSheetzatColumbia Uni- California, SanFrancisco. Vale sharesthe an HHMIinvestigatorattheUniversity of Sciences wasawarded to The 11thannual WileyPrizeinBiomedical the preventionandcureofcancer. association’s mission toaccelerateprogressin bership and board of directors to further the role, Sawyers willworkwiththeAACRmem- can Association forCancerResearch.In this Center was elected president of the Ameri of theMemorialSloan-KetteringCancer U lrich Hartl of the Max Planck Max the of Hartl lrich a t han s, Willia Fall 2o12 Cha an HHMI investigator at anHHMIinvestigatorat r R l o m es L.

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47 continued from page 29 (THE FAT YOU CAN’T SEE)

to ways to identify patients at risk for severe liver disease, or to distinct There are multiple drugs in clinical trials for treating later treatment methods from those targeting obesity and blood sugar. stages of liver disease—the inflammation and scarring—but no pill For now, though, scientists agree on the best way to treat—and to cure early NAFLD. And because of the complex interconnec- reverse—NAFLD: weight loss, exercise, and a balanced diet. tions between diabetes, weight, and liver fat, a single cure-all drug In the same way three cans of soda a day can quickly lead to fatty targeting only the liver is unlikely to be discovered. But with each liver, Loomba says, weight loss and exercise can rapidly reverse it. discovery of genes, molecular pathways, and bacteria that contrib- He’s seen patients, within weeks of beginning an exercise regimen, ute to the disease, scientists feel they are getting closer to being show improvement in both liver fat levels and insulin resistance able to identify patients most at risk and help lessen the severity in liver cells. of their disease. “If we get patients with type 2 diabetes to lose relatively small “I think we have probably just moved from the infancy to amounts of weight by diet alone, we can cure most cases of fatty the adolescence of understanding this disease,” says Loomba. liver, hepatic insulin resistance, and type 2 diabetes,” says Shulman. “The hope is that our understanding of fatty liver is really going to “But unfortunately getting patients to lose weight and keep it off is explode in the next five years. I think we are on the cusp of some- one of the most challenging clinical endeavors.” thing big.” W

continued from page 33 (THE VIEW FROM HERE)

genetically induced changes. He aims to learn how neural circuits so they decline treatments that could help them,” says Jensen. “Our associated with those genetic variations produce and control specific animations of HIV’s molecular transformations will help them animal behaviors. understand that we are not making this up.” Jensen is pushing computational reconstruction of reality in As researchers move through the early part of Schnitzer’s third pursuit of scientific understanding in yet another direction. He and phase of biological imaging, Jensen is already imagining what might visualization experts in his laboratory have been transforming their be a fourth phase. “The ultimate would be a microscope where you electron cryotomography data into mechanism-revealing anima- could see down to individual while they were being arranged tions. Says Jensen, “If a picture is worth a thousand words, then an and rearranged inside a cell in its living state,” Jensen muses. “If you animation is worth a million.” could develop an imaging tool like that, the study of cell biology “We have done movies where we fly into cells and look at things would be all but over,” Jensen says, noting, however, that it would from different points of view,” says Jensen. “We have tried to illus- take a century or more to digest such a comprehensive portrait of trate mechanisms of how things work inside cells.” He believes life. An outlandish vision for revealing biology’s deepest structures animations can be powerful educational tools. “Some people still and mechanisms, to be sure, but that is just the sort of thinking it don’t believe that HIV is the causative agent of AIDS, for instance, takes to unveil molecular biology in all of its elaborate minutiae. W

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48 hhmi bulletin | Fall 2o12 30 start to finish at www.hhmi.org/bulletin/fall2012. at finish to start embryo’s the of from development video his See Campus. Farm Research at Janelia hedeveloped technique microscopy a using over time cells of movement and origin the tracks Drosophila a in cells fly. color-coded fruit By following a flight-ready become hours within will balloon studded brightly this that believe to It’s hard things. great come beginnings From small embryo, such as the one seen here, Philipp Keller Keller Philipp here, one seen the such as embryo,

Keller lab / Janelia Farm Research Campus

Owen Gatley 14-member committee included Leemor Joshua- to thecareerstheyarelikelyfind.HHM modifying trainingprogramstoincludediverseexperiencesrelevant biomedical Ph.D.sintenure-trackfacultypositions,andsuggests director forextramuralresearch,theworkinggroupnotesadecline in without reducing theproductivity oftheresearch enterprise. Staff permanent staff to trainees could have abeneficial effect onthe system The working group believes that even amodest changeintheratio of number ofresearch-oriented jobsinacademia,government andindustry. future scientists are beingproduced eachyear, well inexcess ofthe carried outby trainees. This creates asystem inwhichalarge number of number ofpermanenttechnical staff, withthemajorityof research The typicalacademiclaboratory consists ofaPIandoneorsmall more importantrole inbiomedicalresearch (one that may become scientists—individuals withmaster’s orPh.D. degrees—could play a by PrincetonUniversityPresident One ofthoseoptions—thestaffscientist—coulduseaboost.Co-chaired a Junereportbythe trainees shouldbeintroducedtomultiplecareerpaths,according of T t o prepareandretainatopnotch,diversescientificworkforce, Observati S h cience,” e trainin HHMI Bulletin,May2011)and NI o H ns B iomedical Workforce Working Group. iomedical WorkforceWorkingGroup. g

p S hirley i p e T S I ally investigatorsonthe ilghman (see“ l ine R T ockey, orr and NI R T H deputy H deputy ichard Lifton. he Future he Future

I A E position categories that reflect the value and stature ofthese researchers. applications that includestaff scientists andurges institutions to create The working group encourages NIHstudy sectionsto bereceptive to grant increasing over thelast few years. successful competition for research funds,acategory that hasbeen “soft money” scientists, whoseemployment dependsupontheir Center andProgram Project grants. They shouldbedifferentiated from apply for theirown grants, butare supported by research project, research program. Intheextramural program, thesescientists donot staff scientists constitute anessential partoftheNIHintramural wide variety oftitlesandemployment conditions. Asanexample, important functionsaspartofinstitutional core facilities, buthave a Today, thesescientists bringstability to many labsandprovide strengthens outside oftheUnited States incoming years). increasingly necessary ifthemarket for biomedicalresearchers nstitutes ofHealth, June14,2012. xcerpted fromBiomedicalWorkforceWorkingGroup Report, WorkingGroupof the A dvisory Committee totheDirector, N ational HHMI

BULLETIN F a l l ’12 V o l .25 • N o . 03

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Out of Africa •

This beauty is Aedes aegypti, a mosquito that can transmit www.hhmi.org vol. dengue and yellow fever viruses, among others. Originally from Africa, it is now found in tropical and subtropical regions around the world. While this mosquito prefers to feast on animals over humans, it lives in close proximity to blood-hungry relatives that will choose a human meal every time. HHMI investigator Leslie Vosshall and her lab group are studying the evolutionary changes behind the insects’ diverse dietary habits. Their research may help reduce mosquito-borne illnesses. Read about Vosshall and the arc of her scientific career in “Avant Garde Scientist,” page 18.

perils of fatty liver vosshall on the scent über cameras 25 / no. Leslie Vosshall 03