fall ’15 vol. 28 no. 3 bulletin - hhmi.org · 003 anewwchapatar6wwauios 3 james kegley...

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Fall ’15 Vol. 28 No. 3

GlobalChangemakers

Undergrads are learning about – and solving – real-world

health care challenges.

in this issue Meet the 2015 HHMI Investigators

Peter Walter’s Unpredictable JourneyScience Jam at Woods Hole

4000 Jones Bridge Road Chevy Chase, Maryland 20815-6789www.hhmi.org

Address Service Requested

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To Bead or Not To BeadThese droplets may look like rain beading on a freshly waxed car,

but they are actually a super-concentrated form of an RNA-binding protein called hnRNPA1. Newly minted HHMI Investigator J. Paul Taylor

discovered that hnRNPA1’s liquid-like properties help stress granules – membrane-free clumps of RNA and protein – form rapidly, and reversibly,

when a cell encounters unexpected stress, such as extreme heat. This quicksilver response allows the cell to temporarily switch up the genes it’s

expressing. Learn more about these granules and their surprising role in neurodegenerative and muscle diseases in “Problem Solvers,” page 24.

Go online to watch a video of these droplets assembling and disassembling at hhmi.org/bulletin/fall-2015.

34There’s more to this image of the mycobacteriophage Corndog than meets the eye – even more than its whimsical name. Look closely and you’ll see the faces of the student and faculty “phage hunters” from HHMI’s SEA-PHAGES program. Interwoven in this mosaic are snapshots of bacteria-infecting viruses, called phages, whose genomes are themselves a mosaic of modular components. Launched in 2008, SEA-PHAGES – Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science – has given thousands of undergraduates a taste of lab work by having them analyze the genomes of phages they find in local soils. Pooling that data has allowed a team led by HHMI Professor Graham Hatfull to compare the genomes of 627 different bacteriophages – including Corndog – found in the soil-dweller Mycobacterium smegmatis.

HHMI Bulletin / Fall 2015

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In the CrucibleA true Renaissance man, Antoine Lavoisier spent the years leading up to the French Revolution consumed with civic and scientific activity while immersed in the political crucible of the times. In 1788 alone, he held five important public posts at once, including the directorship of the Gunpowder and Saltpeter Administration and a seat on the board of the government’s central bank. At the same time, he was an active scientist, having built with his considerable fortune a state-of-the-art laboratory. There, he and his wife, Marie-Anne, a noted scientist in her own right, conducted robust research and participated in the race to identify the processes behind combustion. His theory on chemical reactions – published in a treatise in 1789, just four months before the fall of the Bastille – dispelled the last traces of medieval alchemic thinking and established the modern science of chemistry.

Lavoisier’s adaptation of Hales’s pedestal apparatus was nicely drawn by his wife as an illustration for his Opuscules physiques et chymiques, in which the results of these experiments were recorded. In his version, he set a porcelain crucible on a crystal pedestal, covered it with a bell jar, and controlled the water level with a siphon. A layer of oil on the surface of the water under the jar prevented any gases released from dissolving. In October of 1772, he put a lead oxide called minium [Pb

3O

4] into his crucible with a

small amount of charcoal and heated it through the bell jar with the burning glass, whose beam was narrowly focused on the contents of the crucible. This method, common for smelting metals from oxide ores, produced a significant release of gas of some description, or elastic fluid. Although (uncharacteristically) Lavoisier did not make an exact measurement of the gas, he recorded “a volume at least a thousand times greater” than that of the lead oxide used.

What actually happened in this experiment, though Lavoisier did not yet know it, was that the oxygen released in the reduction of lead oxide combined with carbon in the charcoal to form a large volume of carbon dioxide (fixed air). For his immediate purposes, the minium experiment demonstrated and confirmed an already known fact: the reduction of lead oxide released a gas. It also complemented the syntheses he had performed by combining air, phosphorus, and sulfur with an analysis where air was subtracted from a calx. Lavoisier’s

notion that air was fixed in the process of calcination (and released in the reduction of calces) was now supported at both ends.

Lavoisier was satisfied (or at least willing to claim) that these results had “Completely Confirmed my Conjectures.” The experiments on phosphorus, sulfur, and minium became the basis for the sealed note he deposited at the academy on November 1, 1772. The truth was that even though Lavoisier was convinced his discovery was “one of the most interesting that has been made since Stahl,” he still could not say precisely what had been discovered – nor did the discovery yet fit comfortably into his evolving theory. Not until February of the following year would he feel confident enough to declare, in that famous lab notebook entry, that he was going to bring about “a revolution in physics and chemistry.”

Excerpt from Lavoisier in the Year One: The Birth of a

New Science in an Age of Revolution by Madison Smartt

Bell. © 2005 by Madison Smartt Bell. Reprinted

with permission from W.W. Norton & Company,

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ContentsFall ’15 Vol. 28 No. 03

Web-Only Content

Trace the evolution of the Bulletin from a no-frills newsletter to an artful science magazine.

Learn what drives the newest cohort of HHMI investigators.

Travel to Africa to see how undergraduates are making an impact on global health.

Experience the windswept Arctic landscape that forms the cornerstone of David Marchant’s research program.

Go along with scientists as they collect stickleback fish from the lakes and streams that dot Vancouver Island.

Departments president’s letter03 ANewChapter centrifuge06 ACuriousMind07 IceBound benchreport08 ScienceJam10 SteadyOn perspectives&opinions30 Catalysis32 Q&A–Whatcareerlessonsdo youpassontoyoungscientists? chronicle34 Science Education PoweredbyStudents36 Up Close WildImmunology38 Lab Book Hangry?Here’sWhy Made-to-orderMolecules ATestTellstheTale observations IntheCrucible

Features04 Evolution of a Magazine AstheHHMI Bulletinretires, theeditorstakealookbackatits journeyfromnewsletterto widelyreadsciencemagazine.

12 World Class Globalhealthcurriculum initiativesencourage undergraduatestoembrace– andsolve–real-worldproblems.

18 Harnessing Serendipity Alongunpredictablepaths todiscovery,PeterWalterhas maintainedasure-footed approach–tothescienceaswell astothepeoplehementors.

24 Problem Solvers HHMI’s26newinvestigators willhavethefreedomtopursue thequestionsthatfascinate themthemost.

Harnessing Serendipity, page 18

www.hhmi.org/bulletin

Cover illustration:

Josh Cochran

This paper is certified by SmartWood for FSC standards, which promote environmentally appropriate, socially beneficial, and economically viable management of the world’s forests.Ja

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Editor’s Letter

Telephone (301) 215.8500 • Fax (301) 215.8863 www.hhmi.org© 2015 Howard Hughes Medical InstituteTheopinions,beliefs,andviewpointsexpressedbyauthorsintheHHMI Bulletindonotnecessarilyreflecttheopinions,beliefs,viewpoints,orofficialpoliciesoftheHowardHughesMedicalInstitute.

HHMI TRUSTEESKurt L. Schmoke, Esq., ChairmanPresident / University of BaltimoreJames A. Baker, III, Esq.Partner / Baker Botts. LLPAmbassador Charlene Barshefsky, Esq.Senior International Partner / WilmerHaleJoseph L. Goldstein, MDRegental Professor & Chairman Department of Molecular Genetics University of Texas Southwestern Medical CenterGarnett L. KeithChairman & CEO SeaBridge Investment Advisors, LLCFred R. LummisChairman & CEO Platform Partners, LLCSir Paul Nurse, PhDPresident / The Royal SocietyDame Alison F. Richard, PhDSenior Research Scientist & Professor Emerita Yale UniversityClayton S. Rose, PhDProfessor Harvard Business SchoolAnne M. TatlockRetired Chairman & CEO Fiduciary Trust Company International

HHMI SENIOR EXECUTIVE TEAMRobert Tjian, PhD / PresidentCheryl A. Moore / Executive V.P. & Chief Operating OfficerKathryn S. Brown / Head of CommunicationsSean B. Carroll, PhD / V.P. for Science EducationJennifer L. Farris / Head of Administrative ServicesHeidi E. Henning / V.P. & General CounselNitin Kotak / V.P. & Chief Financial OfficerErin O’Shea, PhD / V.P. & Chief Scientific OfficerGerald M. Rubin, PhD / V.P. & Executive Director, Janelia Research CampusKathy A. Wyszynski / V.P. for Human ResourcesLandis Zimmerman / V.P. & Chief Investment Officer

HHMI BULLETIN STAFFMary Beth Gardiner / EditorDana Cook Grossman / Story EditorJim Keeley / Science EditorNicole Kresge / Assistant Editor

ADDITIONAL CONTRIBUTORSElaine Alibrandi, Michelle Cissell, Mark Farrell, Heather McDonaldPentagram Design / DesignAllied Printing / Printing & Binding

Turning Pointshortlyafteri joined HHMIin2004,Iwasgivenawritingassignmentthatwouldchangemylife.NewlyhiredasassistanteditoroftheHHMI Bulletin,Iwassenttocoveranearly-morningbreakfastmeetinginLoudounCounty.Asthesunrosethatday,localteachers,schooladministrators,andbusinessleadersgatheredwithHHMIexecutivesandstaffmembersinanofficebuildingoverlookingthebusyconstructionsitethatwasthenJaneliaResearchCampus.Amidtheclatterofknivesandforks,HHMIformallyannouncedacommitmenttoinvest$1millionperyearinsupportofscienceeducationintheLoudounCounty

PublicSchoolsystem.Asifthatwasn’theadyenoughforthisnewbie,theeventwasalsowhereImetmyfuturehusband.

Tosaythatdaywasmemorableisnowanunderstatement.Butitsserendipitouseffectsweren’tyetevidentasIwentontowritethatstory,andmanymore,fortheBulletin.Then,twoyearslater,againstmywildestdreams,Iwasnamededitor.Andwhatarideit’sbeen.Themagazinehasbecome,asmybossputsit,“astorytellingmachine”–anorchestratedeffortbyacastoftalentedwriters,editors,illustrators,photographers,anddesignerstocapturetherichtextureofthestoriesbehindtheremarkablepeopleandworksupportedbyHHMI.Ourabilitytotellthosestorieshasgrownevermoredynamicovertimewiththeadditionofvideo,animation,andmultimediatoouronlineandiPadeditions.

Soforme,it’ssomewhatbittersweettoacknowledgethatthisissueoftheBulletin willbethelasteverpublished.Butaswemoveawayfromthemagazineformat,wepromisethatthestorytellingwon’tabate:weplantodiveheadlongintotheswirlthatistoday’scommunicationsfrontier.YoucanlookforcontinuingstoriesfromHHMI,bothonlineandthroughsocialandotherdigitalmedia.Andyourfavorite Bulletinarticlesfromthepastwillstillbeavailableaswell,archivedindefinitelyonourwebsite.Someofthemmayevenresurfacefromtimetotime,asthestoriesofscientificdiscoveryareoftenbytheirverynatureincrementalandevergreen.

Wehopeyou’llstaywithusaswemakethispivotintoamorenimblefuture.WithJanelianowapproachingits10thanniversary,andnewlyfundedscientists–suchasthelatestHHMIinvestigatorsintroducedinthisissue–comingonboardonaregularbasis,thereisadeepveinofstoriesyettomine.Wewilldoourbesttosharethetreasurewithyou.

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President’s Letter

A New Chapteri imagineevery generationofscientistsisstruckbythepaceofchange.Today,it’sdefinitelythecasethatHHMIresearchersarebreakinglong-heldscientificbarriers,fromlimitsinlightmicroscopyanddataanalysistowornpublishingdogmaandoutdatedfundingsilos.Since2009,it’sbeenmyprivilegetowatchthesewallscometumblingdown,andtoplaymypartindrivingscienceforwardasHHMIpresident.IthasalsobeenapleasureandhonortorecruitandworkwithasuperbexecutiveteamandothercolleaguesatHHMIheadquarters,theJaneliaResearchCampus,andinourfieldoperations.

AsIheadintomyeighthyearinthisrole,I’veannouncedmyintenttostepdownattheendof2016andreturntotheUniversityofCalifornia,Berkeley,whereIcandevotemoretimetoexcitingnewlabresearchopportunities.Inthiscolumn,I’dliketoreflectonsomeofthechangeswe’vemadeatHHMIinrecentyears.

CollaborationatHHMIisontherise–notonlyatJanelia,wheresmallteamsofscientistsworksidebysideasarule,butalsoinourphilanthropicsupportofscience.TocombataweakfundingenvironmentforbasicresearchandtoleverageHHMI’sinvestments,we’vedeepenedourpartnershipswithlike-mindedfunders.WorkingwiththeGatesFoundationandtheSimonsFoundation,HHMIissupportingearly-careerscientistsintheU.S.andinternationally.We’vealsopartneredwiththeGordonandBettyMooreFoundationtoshareournewlydevelopedadvancedimagingtechnologywithacademicscientistsandtofundplantscientists,whocontributemoretobiomedicalknowledgethanyoumightrealize.Inadditiontotheseresearch-fundingcollaborations,HHMIhasbegunpartneringwithothernonprofitstoincreaseoutreachtophilanthropistswhocaninvestinthenextgenerationofscience.Acrossallthis

work,ourgoalistodeepenandextendourimpactbysupportingbasicdiscoveryresearch,thebedrockofU.S.science.

Moresubtly,we’veworkedtoincreaseourimpactbyadaptingourprogramsandoperationstobeflexible,efficient,andsustainable.Forinstance,we’vedevelopeda“phase-out”optionforexperiencedHHMIinvestigatorswhoarepreparedtoleavetheInstitute.We’vealsoreshapedourfieldoperationstoensurethatwe’resupportingsciencesustainablyandconsistentlyinourlabs,coasttocoastaswellasinternationally.

Tocatalyzeacultureshiftinscientificpublishing,weprovidedfundstolaunchtheopen-accessjournaleLife,inpartnershipwithWellcomeTrustandtheMaxPlanckInstitute.Since2012,theonline-onlyeLife haspublishedmorethan1,000researchpapers,withanemphasisonthreeimportantprinciples:makingscientificresultsavailabletoeveryone;offeringafair,constructive,andexpeditedpeer-reviewprocess;andembracingthepowerofdigitalmedia.TheacceptancerateateLifeiscurrently15to18percent,andtheeditorshaveanambitiousagendaforgrowth,whichcurrentlystandsatover500submittedmanuscriptspermonth.

Onethingthathasn’tchangedduringmytenureinHHMIleadershipisourcommitmenttoidentifyandcatalyzeboldthinkers,allowingthemtodorigorousresearchthatrevealsfundamentaltruthsabouthowbiologyworks.Thiseffortextendsfromexperiencedscientiststopostdocs,andevenundergraduateandhighschoolstudents,whobenefitfromhands-onlabexperiencesandeducationalmediasupportedordevelopedbyourscienceeducationstaff.Wehavealsolaunchedneweffortstoenlightensocietyasawholeabouttheprocessofdiscoverybyproducingcaptivatingandscientificallyinformativedocumentaryfilms.

It’sbeenmyhonortoleadHHMI,workingcloselywithourBoardofTrusteesandotherseniorleaders.I’mconfidentthattheInstitutehasabrightfuture,fueledbypassionatescientistsandeducatorswhobelievedeeplyinthepowerofsciencetochangeourworld.Ilookforwardtodoingmypart,backatthebenchandinacademia.

“I’m confident that the Institute has a bright future, fueled by passionate scientists and educators who believe deeply in the power of science to change our world.”—roberttjian

Fall2015/HHMIBulletin

sinceitwasfirstpublishedin1988 ,theHHMI Bulletinhasassumedmanyguises.Themagazinestartedlifeasano-frills,four-pagenewsletter,meantsolelyfortheHHMIcommunity.Overtheensuing25-plusyears,itsappearancehasevolved;ithasexpanded(andoccasionallycontracted)insize;itscontenthasassumedamorenarrativetone;andthetexthasincreasinglybeencomplementedbyartfulillustrationsandcaptivatingphotographs.In2005,anequallyartful Bulletin websitewentlive,and2011sawthelaunchofaniPadedition–makingtheBulletin oneofthefirstsciencemagazinesofferedthroughtheiTunesstore.

Asthemagazineevolved,sodiditsreadership.IndividualsfromoutsideHHMI–includingscienceeducators,scientists-in-training,andscienceaficionados–begansubscribinginever-growingnumbers,drawnbythecompellingstoriesofscientificdiscovery.Morethan37,000copiesofthisissuewillcomeofftheprintingpress,tobemailedtosubscribersandpassedalongtootherreaders,andthemagazine’sonlineandiPadeditionswilleventuallybeseenbythousandsmore.

Now,withthislastissue,weareretiringtheBulletinaswemoveawayfromthemagazineasacommunicationsmedium.Butthatdoesn’tmeanthestorytellingwillend:LookforvibrantcoverageofHHMI’sworkandpeopleonlineandthroughsocialmediainthedays,weeks,andyearsahead.Scienceisongoing,andthewayit’sconducted–andcommunicated–willcontinuetoevolve.

August 1988Vol 1, No 1

May 1991

Evolution of a MagazineAs the HHMI Bulletin retires, the editors take a look back at its journey from newsletter to widely read science magazine.

Then...Topgraduate,

medical students win support

*thefirstHHMIdoctoralfellowships

inthebiologicalsciences

...NowFromthisfirstclassoffellows,three–Abby Dernburg,Julie Theriot,and Geraldine Seydoux–wentontobecomeHHMIinvestigators,andone– Scott Strobel–becameanHHMIprofessor.

Flash ForwardFirst edition’s news still resonates today

Then...Institutescientists

receive national awards

...NowHHMIInvestigatorEric Kandel’s 1988 National Medal of Science (NMS)presagedhis2000NobelPrizeinPhysiologyorMedicine,whileNobelist Joe Goldstein,alsoanNMSwinnerthatyear,wentontobecomechairmanofHHMI’sMedicalAdvisoryBoardandlateranHHMITrustee,apositionhestillholds.

5HHMIBulletin/Fall2015

Spring 2005

July 2000

Fall 2013

Then...Newheadquarters

andconferencecentertobebuilton

“serenecampus”inChevy Chase,

Maryland

...NowHeadquartersopenedin1993,andanewwingwasaddedin2010.HHMIalsolaunchedtheJaneliaResearchCampus,nearAshburn, Virginia,in2006andhasestablishedfieldoperationssupportinglaboratoriesnationwide.

Then...Grantsgoto

44 liberal arts, historically

black colleges*amongthe

firstmajoreffortsofa10-year,

$500milliongrantsprogram

...NowScienceeducationgrantsprovided$77 million ofsupportinfiscalyear2014throughavarietyofprograms.Recentinitiatives,suchastheMeyerhoff Adaptation Project and Inclusive Excellence,aimtoencouragecollegesanduniversitiestoincreasethediversityofstudentsengagedinscience.

Then...Teninvestigatorsjoinresearchstaff

*raisingtotalnumberto178

...NowOutofthisgroupof10appointees,fivearestillHHMIinvestigators,andone–Tom Cech–wentontowintheNobel PrizeinChemistryandtobecomeHHMI’sfourthpresident.

February 1996

April 1998

To trace the evolution of the Bulletin from a simple newsletter to an artful science

magazine, go to hhmi.org/bulletin/fall-2015.

Centrifuge6 Fall 2015 / HHMI Bulletin

A Curious Mindcuriositymayhave killedthecat,butit’sAlejandroSánchezAlvarado’sraison d’être.“Idon’thavehobbiesperse,”headmits,“unlessthinkingcounts.I’vealwayswantedtounderstandwherethingscomefrom:music,language,ideas.It’swhatgotmeintotroubleasakidandwhatledmetolearntheclassicalguitar.It’sstilladrivingforce.”

Forinstance,herememberswonderingasaboywhydoorshavelocks,doingresearchatthelibraryabouttheoriginandhistoryoflocks,andthen–tosatisfyhiscuriosity–grabbingascrewdriveranddismantlingthelockonhisfamilyhome’sfrontdoor(notrealizingthat,like

HumptyDumpty,itcouldn’teasilybeputtogetheragain).Hisquestioningmindalsoledhim,uponseeingavanLeeuwenhoeksketch,tobuildhisownmicroscope,sacrificinghismother’shairpinsto“seetheunseen.”Spyinghisfirst“animalcule”–aParameciumorEuglena,herecalls–wasthrilling,evenif“nooneelseinmyfamilywasterriblyinterested.”(Tothisday,hismotherhasahardtimeunderstandinghowherson–anexpertinplanarianflatwormsatKansasCity’sStowersInstituteforMedicalResearch–makesalivingstudyingworms.)

SánchezAlvaradoisespeciallycaptivatedbythehistoryofscience.WhileteachingembryologythepastfewsummersattheMarineBiologicalLaboratory(MBL)in

WoodsHole,he’sspenttimeinMBL’sarchives,tryingtolearnwhocoinedtheterm“stemcell.”It’snoteveryone’scupofsummerfun,heowns,but“exceedinglyattractivetome.”He’sunearthedreferencesasfarbackasthemid-1800sandisintriguedthat“thisconceptlikelycamefrombotany,notanimalbiology.”

He’salsobeenponderingtheLophotrochozoasuperphylum,adiversegroupofanimalsthatincludesmollusksandflatworms.“Theyhavecomplex,plasticbodyplansthataregenerallyunderappreciated,”observesSánchezAlvarado,anHHMIinvestigatorwhoalmostsingle-handedlyestablishedthefreshwaterplanarianSchmidtea mediterraneaasamodeltostudyregeneration.“Iwanttoknow

more,”headds,sothelasttwosummershe’sconductedplanktontowsnearWoodsHoletounderstandthehabits,lifecycles,andnaturalhistoryofthisdiversegroupofanimals.“I’vebecomereallygoodatreadingtides,”hesays–floodtidebeingbestforcollectingsamplesoftheseorganisms(whichhe’snowcataloging).

Inmanyways,SánchezAlvaradowouldhavebeenrightathomeduringtheRenaissance,wheninductiveinquiry,orcuriosity-drivenobservationwithfewtonoassumptions,wasthenorm.“ImaginehowmuchfunitwouldhavebeentohavediscussedtheworldwithLaplaceandKepler,orLavoisier–hewasanengagedcitizenaswellasascientist.Allwerethinkerswhosawthingsothersdidn’tnecessarilysee.”

Thesedays,heworriesthathypothesis-drivenresearchhasallbutshovedasideinductiveinquiry.“Ifwepaidmoreattentiontothehistoryofscience,”hesays,“we’dseethatinnovationhasalwaysinvolvedboth.We’reabletogeneratedatalikeneverbefore,butit’smostlyknowledgewithoutmuchunderstanding.Howabouttakingastepback:Canwedistillnewfirstprinciplesfromthesevastdata?”

This,though,willrequirechangesinhowscientificproductivityisrewarded.“Iadorecuriosity-drivenresearch,butinthecurrentbiomedicalresearchclimateitdoesn’tnecessarilypaythebills,”SánchezAlvaradosays.“Still,sciencewillbebetterservedifweestablishmechanismstopromotesuchinquiry,aswillhumankind.”

Ashiftinthattidemaybeawhilecoming.Inthemeantime,he’llkeepdivingdownintellectualrabbitholes–perhapsremarking,likeyoungAlice,“Curiouserandcuriouser!”—Alissa Poh E

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7HHMI Bulletin / Fall 2015

Ice Boundbundledinfire-engine–red parkas ,ahandfulofresearcherspicktheirwayacrossaparched,high-altitudeAntarcticvalleysweptbyhowlingwinds.Beneaththeirpuffywhiteboots,theoldesticeonEarthliesburiedunderbouldersandsand.

LedbyDavidMarchant,ageologistwhodirectstheBostonUniversity(BU)AntarcticResearchGroup,theytakephotographs,collectsamplesofvolcanicash,andsearchforsiteswhereiceunchangedformillionsofyearsliesnearthesurface.SomecarryspadestoexposetheiceandthenusespecializeddrillstoretrieveicecoresforanalysisbackinMarchant’slab.

Thescientificprizethey’reafterisbubblesofatmosphericgasesthatweretrappedwithintheicecoresduringthePlioceneepochseveralmillionyearsago,whentheEarthwaswarmerandsealevelswere30to300feethigherthantheyarenow.Marchantexplainsthatmeasuringcarbondioxidelevelsinthebubblescouldhelppredictglobalresponsestotoday’srisingCO2levelsandtemperatures.

Thisfrigidsceneisdisplayedonwall-sizedmonitorsinthecomfortofMarchant’sBUlab.Thisandotherexpeditionvideosarealsopostedonline.Marchant,whobecameanHHMIprofessorin2014,placesahighpriorityonpublicoutreachaspartofacurriculumhecreatedforundergraduatesto“seedaculturalchangeinSTEMeducation”byemphasizingearlyandconsistentresearch,communication,andeducation.A

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Marchanthasagenialmannerandthelookofanoutdoorsman–beardedandtannedfrom20polarexpeditionssincebeing“captivated”byhisfirsttripsome25yearsago.“It’scoldandit’shardandit’sphysicallydemanding,”hesays.“Andtryingto‘read’thedynamiclandscapeisamentalchallenge.”Buthe’sdrivenbythethrillofdiscovery.“Weknowwecanfindthingsinasingleexcavationpitthathaveglobalsignificance,”hesays.

Marchant’sgroupispreparingforanotherfieldexcursion,fromNovember2015throughJanuary2016,theAntarcticsummer.Threeundergraduates

willjointheexpeditionforuptothreemonths’workontheWestAntarcticIceSheet,whichhasbeenmeltingsorapidlythatrecentscientificreportswarnitmaybedoomedtocompletedisintegration,raisingsealevelsbyseveralfeet.Theteamwillmapgeologicalfeaturesthatmarktheicesheet’schangingmarginsoverthepast18,000years.Theiraimistodevelopalong-termglacialandatmosphericrecord“thatcantelluswhattoexpectinthefuture,”saysMarchant.

StudentsremainingattheBUlabwillusehigh-resolutionphotosandvideostocreate“virtualfieldtrips”andanalyzelandscapepatternsandwillperformgeochemicalanalysesofthevolcanicandicesamples.They’llalsoworkwithmiddle-schoolteacherstotranslate

labresultsintolessonplansandproducecommunicationmaterialsforthepublic.

ForthosewhotravelwithMarchanttoAntarctica,hesays,theexperiencewillhavealastingimpact.“Whenthefirststormhits,thenewpeoplewillwonderifthey’regoingtomakeitthroughthenight,”Marchantsayswithagrin.Butthefastpaceandsteeplearningcurvetransformstudentsintoconfidentresearchersinafewshortweeks,hesays.“Youcanseeitwhenthey’rebackoncampus,too.There’snothingyoucangivethemafterthisexperiencethatthey’llfailat.They’lljustkeeptryinguntiltheygetit.”—Richard Saltus

To see more of David Marchant’s Antarctica, go to

hhmi.org/bulletin/fall-2015.

Bench Report

Science JamApop-uplaboratoryinWoodsHoletakesondaringbiologyresearchinanunusualsetting.overthewinter ,thescientistsgathergear,manufactureextraproteins,andboneuponobscureaspectsofbiochemistry.InJune,theydescendonthebeachtownofWoodsHole,Massachusetts–18,19,20ofthemfromaroundtheworld–forsixorsofeverishweeksofresearch.

Inasmall,sunnyroomoverlookingthegray-shingledMarineBiologicalLaboratory(MBL)quad,theydreamupexperimentsandperformthemthesameday.Theyswaptoolsandideasandresults.Atonepoint,somanypeoplewerebunchedaroundonemicroscopethatsomeonejokedtheyshouldsetupbleachers.“Idon’twanttousetheword‘vacation,’becauseit’snot,”saysgraduatestudentJamesMuller.“We’reworkingsuperhard.We’rehereverylateeverynight.Butit’slikeavacationforscientists.”It’sproof,sayspostdocLindsayCase,that“thisidealisticwaywewishsciencewasallthetimeactuallycanhappen.”

Theideaforthisflashmobofalab,calledtheHHMISummerInstituteatMBL,camefouryearsagotothreescientists–MichaelRosenoftheUniversityofTexasSouthwesternMedicalCenterandRonValeoftheUniversityofCalifornia,SanFrancisco,bothHHMIinvestigators,andJimWilhelmoftheUniversityofCalifornia,SanDiego.Theyrealizedthey’dallencounteredthesamephenomenonintheirresearch:large,mysteriousclustersofproteins.Atfirstglance,theclusterscouldbemistakenfordetritusfloatingaroundinthecell,butthey’renot.Theycoalesceinresponsetodiversecues,litteringthecellwithwadsofenzymes,signalingproteins,andevenRNA,andthendisappear.ThereweretantalizingcluesthattheyhelpedactivateimmunecellsandcontroltheproductionofproteinsfromRNA.

Studyingtheclustersdidn’tfallsquarelyunderanyoftheirresearchgrants,butaHughesCollaborativeInnovationAwardgavethetrioaplatformfromwhichtotacklethechallenge.Theawardsgotolarge-scaleprojectsofunusuallyambitiousscope;thisonecallsforthescientiststomeeteverysummer

forfiveyears–from2013to2017–tobroachanewaspectoftheproblem.Inbetweentheirsummersprints,theydiscussthetheme,inviteresearcherswhoseinterestsoverlapwithit,andginupexperiments.

Theapproachhasbeenfruitful.Thefirstyear,thegoalwastoseeiftheycouldgetclusterstoformonasyntheticmembrane.“Wethoughtitwasgoingtotakeallsummer,”Rosenrecalls.“Itwasthefirstweek.Ithinkitwasthefirstexperimenttheydid.Xiaolei[Su]andJon[Ditlev]camerunninguptomeandRonandwerelike,‘Hey–itworks!’”

Energized,thegroupthenembarkedonre-creatinginvitroacascadeofeventsyieldingclustersthatorganizeactinfilaments,aprocessinvolvingoveradozendifferentproteins.Su,Ditlev,andDariusKöster,allpostdocsindifferentlabs,putthefinalexperimentunderthemicroscopeat1:00a.m.justafewdaysbeforetheyweretoleaveWoodsHole.Inthemorning,theyhadavideothatshowsblueclustersappearingoutofthegloom,thenawebofredfilamentsbloomingandspreading.Itwasabeautifulvindicationofthesummer’swork.“Ikeptwatchingthevideoontheplane,insteadofmovies,”Susays.

Itwasanexperimentthey’dneverhaveattemptedbackhome.“Therereallyisalmostnowayyoucansaytoanewstudentorpostdocinyourlab,‘Hey,you’regoingtomake13proteins,andit’sgoingtotaketwoyears,anditprobablywon’tworkattheend,’”Rosensays.ButattheSummerInstitute,withafew

8 Fall2015/HHMIBulletin

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“We’re working super hard. We’re here very late every night. But it’s like a vacation for scientists.”—jamesmuller

proteinsmadebeforehandbyeachlabandeveryoneinthesameroomtotroubleshoot,itbecamepossible.

Lastyear,theyexaminedhowclustersthatincludeRNAform.Thisyear,thegoalwastounderstandhowtheassembliesmodulatesignalsandwhetherthesignalsthattriggerclusterformationarethesameindifferentkindsofimmunecells.Duringalabmeeting,resultsfrompastexperimentsandideasforfutureonesflew,whilesoundsoftouristsandseagullswaftedthroughtheopenwindow.Theynowhaveonlyhunchesaboutwhytheclustersexist.But,speculatesJayGrovesoftheUniversityofCalifornia,Berkeley,whentheirroleisfinallyunderstood,itmaypromptafundamentalchangeinthinkingaboutmolecularorganizationincells–ashiftakintoresearchers’realizationthatproteins’complexstructuresarekeytotheirfunction;Groves,anHHMIinvestigator,participatedinthisyear’sgathering.

It’shardwork,andtherearelowsaswellashighs.Noteverytackisassuccessfulasthefirst

year’sre-creationexperiment.Andifthere’saproblemwithmaterialsbroughtfromhome,it’snoteasytomakemore.

Butthescientists,bothjuniorandsenior,sayit’sworthit.GradstudentKyleBegovichtraceshisdissertationdirectlytohisworkattheSummerInstitute.Su,Köster,andDitlev,whoplantocontinuecollaborating,saythemodelforgeslastingrelationships.“Youcanmeetsomeoneataconference,andthat’sonething,”agreesMuller.“Buttomeetsomeonehereandtoreallygettoknowthem–tobreakbread,shareabeer,sharepipettes–thatleadstolong-lastingcollaborationsthatarenotjusttransientinteractions.”IthelpsthatthesessionsarehostedbytheMBL,whichhasacollaborativeculture,dorms,adininghall,andothervisitingresearchers.

Dotheyevermakeittothebeach?They’reonCapeCod,afterall.LindsayCaselaughsatthemereidea.She’sworkingsointentlyshe’slosttrackofthedayoftheweek.AftertheInstitute,shemighttakesometimeoff.Fornow,there’sworktodo.—Veronique Greenwood

Fall2015/HHMIBulletin10

Bench Report

Steady OnThroughout his decades-long career, physician-scientist Michael Welsh’s focus on cystic fibrosis has never wavered.whenmichaelwelsh wasamedicalstudent,inthe1970s,textbooksdescribedcysticfibrosisasalethalgeneticdiseaseaffectingchildren.

Cysticfibrosis,orCF,disruptstheabilityofcellsliningthebody’scavitiesandsurfacestomanagechlorideandbicarbonate,keycomponentsofsalt.Thishasparticularlydevastatingeffectsinthelungs,causingthick,stringymucustoclogtheairways.

ButthanksinparttoWelshandhiscolleagues,treatmentshaveimprovedandtoday’stextbooksreadverydifferently.“OurCFclinicnowhasmoreadultsthanchildren,”saysWelsh,anHHMIinvestigatorattheUniversityofIowa.

Asoft-spokennativeIowan,WelshispassionateaboutstudyingCF.Hehasfocusedonthedisease,whichiscausedbyinheritingamutatedCFTRgenefromeachparent,fornearlythreedecades.

Making HeadwayTheCFTRgenewasdiscoveredin1989.WelshwasalreadystudyingCFandcaringforpatientswiththedisease.Armedwiththenewgeneticknowledge,heandcolleaguesdiscoveredthattheCFTRproteinformsachannel,orpore,inthecell’soutermembranethroughwhichchlorideandbicarbonateflow.Theyalsoshowedthata“gate”inCFTRcontrolssaltflowbyopeningandclosingthechannel.

Bytheearly1990s,WelshwaslookingathowmutationsmangletheCFTRchannel.HeknewthattheCFTRgene’smostcommonmutation,foundinmorethanhalfofindividualswiththedisease,producesamisshapenchannel.Thecell’squalitycontrolmachineryrecognizesthemutantandrejectsit.Histeamshowedthatthemutantfailstoappearonthecellsurface,leavingnopathwayforchlorideflow.

SoWelshwaspuzzledbya1991paperbyFrancisCollins,thenanHHMIinvestigatorattheUniversityofMichigan.Collins’slabreportedthatthecommonmutantdid,infact,formachannelonthecellsurface.But,Welshnoted,CollinshadstudiedmutantCFTRinfrogeggskeptatroomtemperature,whilehisownlabhadstudieditinmammaliancellsatamuchwarmer37degreescentigrade.SoWelsh’steamrantheexperimentsagainatalowertemperature.

“Boom!Thereitwas–achannelthatconductschloride,albeitnotaswellasahealthyprotein,”Welshsays.“Toooften,researchersworrywhentheirresultsdifferfromthoseobtainedbyothersintheirfield.Itcanbegoodtoexplorewhyresultsdiffer,asthatcanleadtoimportantinsights.”

Today,thisdecades-oldresearchunderpinsworkonahandfulofemergingCFtherapeutics,includingOrkambi.Thedrug,whichmimicstheeffectsoflowertemperaturetofacilitaterepairoftheionchannel,wasapprovedbytheU.S.FoodandDrugAdministrationinJuly2015.

When Pigs FlyWelshalsosetthestagefornewwaysofunravelingpreciselyhow CFTR mutationscausethediseasein2008,whenheandcolleaguesreportedinSciencethatthey’ddevelopedapigmodelofCF.Untilthen,researchershadcreatedmicewithCFTRmutations;however,micedon’tdevelopthesamesymptomsashumans.

Pigs,muchclosertohumansintermsofbiochemistry,physiology,andsize,wereanattractivealternative.Butthemousewastheonlymammaleverengineeredtoreproduce

ahumandisease.TheideaofaCFpigseemedsofar-fetchedthatmembersofWelsh’steamhungawingedpigabovethelabbenchofthepostdocworkingontheproject.

Buttheideaworked.Now,Welshsays,“themodelislettingusasknewquestionsabouttheoriginsofthedisease.”It’sshownhowCFwreakshavoconthelung;inaJuly2012paperinNature,WelshandcolleaguesreportedthatCFthrowsoffthepHbalanceinthelung’sairways,cripplingthelung’sinfection-controlmechanism.Andit’srevealedhowCFdisruptsthelungs’naturalself-clearingaction;WelshandcolleaguesreportedinAugust2014inScience thatthisdisruptionisduetounusualacidityanddecreasedfluidproductioninthelung’ssubmucosalglands.

Welshsaystheseinsightswouldhavebeenimpossiblewithoutthepigmodel,whoseusefulnessseemslikelytoendure.

A Changing LandscapeWelshjokesthathechosethepigasamodel“becauseIamfromIowa.”Hebelievesthestatepossessesauniqueandsubtlebeautyoftenmissedbythosefromthecoasts.He’srestoredseveralacresofprairiesurroundingthefarmhousewherehelives,justminutesfromcampusbutoutofsightofanyneighbors.“Putthatinthearticle,”hesays,laughing.“ItmighthelpmerecruitpeoplefromBoston,theBayArea,andNewYork.”

Thelandhadbeenfarmedhardbeforeheboughtit.“Itwaslikelookingatahard,oldfacescarredbytheweather,”saysWelsh,afanofformerU.S.poetlaureateTedKooser,whooftenwritesabouttheMidwestlandscape.

Welsh’sacreagenowboastsprairiegrassesandwildflowers“thatwereherebeforewhitepeoplecame.”ItstransformationisnotunlikethechangeintheoutlookforthosewithCF.AccordingtotheCysticFibrosisFoundation,“TodaythelifeexpectancyofapersonwithCFis41yearsofage.Thisisadramaticimprovementfromthe1950s,whenachildwithCFrarelylivedlongenoughtoattendelementaryschool.”

Welshbelievesthedramaticimprovementswillcontinue.“Idon’tthinkCFhastobealethaldisease,”hesays.– Geoff Koch Lu

cyH

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“I don’t think CF has to be a lethal disease.”—michaelwelsh

Through genetics and porcine modeling, Michael Welsh is improving the lives of patients with cystic fibrosis.

World ClassGlobal health

curriculum initiatives encourage

undergraduates to embrace – and solve – real-world problems.

bymeganscudellari

illustrationsbyjoshcochran

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rebeccarichards-kortum couldn’tgetthefourtinynewborns,crowdedshouldertoshoulderinasingleplasticcrib,offhermind.

Itwas2005,andRichards-Kortum,abioengineerandHHMIprofessoratRiceUniversity,wasreturninghomefromMalawi,alandlockedAfricannationandoneoftheworld’sleast-developedcountries.Whilethere,she’dvisitedtheneonatalintensivecareunitatQueenElizabethCentralHospital.Itwasaninstitutionthatlackedsufficientspace,adequateresources,andequipmenttoperformeventhemostbasicmedicaltestsandtreatments.

WhenshegotbackhometoHouston,Richards-Kortumchallengedherstudentstohelpbabieslikethosefournewborns.JocelynBrown,aseniorbioengineeringmajor,

andfourotherundergraduatesacceptedthechallengeandspentthenextyearresearchinganddesigningadevicethatthepediatriciansatQueenElizabethhadrequested:abubbleContinuousPositiveAirwayPressure(bCPAP)system,whichblowsanoxygen-richairmixtureintothelungsofprematurebabiestohelppreventtherespiratoryproblemsthatoftenafflictpreemies.

HospitalsintheUnitedStatesusea$6,000bCPAPmachine,butthatpricetagwasn’tfeasibleforaMalawianhospital.Brown

andherteammatesconstructedaprototypeforlessthan$200thatofferedthesametherapeuticflowandpressureasthesystemsusedinHoustonhospitals.“Iknewstudentshadtheskillstodesigntechnologiesthatcouldtrulyimprovehealthcare,”saysRichards-Kortum.“Thatwasthestartofit.”

Today,RiceishometooneofseveralHHMI-fundedprogramsthatincorporateglobalhealthinundergraduate

curriculums.Theneedforsuchprogramsisgreat,saysHHMIProfessorMuhammadZaman,abioengineeratBostonUniversity(BU).Manyengineersandscientistshaveknowledgethatisdeepbutnotbroad,sotheymaybeunawareofhowtheirworkcanapplytoandaffecttherealworld,especiallyinresource-poorsettings.“Globalhealtheducationisanopportunitytounderstandhowpolicy,socialandculturalbarriers,religion,andthestructureofsocietyaffecthealth,”saysZaman.“Allofthesethingsareconnected,andthat’simportantforourengineersandscientiststoknow.”

Suchprogramsnotonlysupportthedevelopmentofsolutionstocriticalglobalhealthproblems,butalsoengagestudentsinreal-worldproblemsolving,saysDavidAsai,seniordirectorofundergraduateandgraduateprogramsforHHMI.“Giventheinternationalizationofeverythingwedothesedays,leadingschoolswillbethinkingmoreandmoreaboutwhat’sgoingoninthewholeworld.”

Breath of LifeBrowncontinuedtoworkonthebCPAPprojectaftergraduatingin2010.ShetraveledwiththemachinetoMalawianddemonstratedittophysiciansandnurses,whoofferedfeedback.Withthatinput,sheimprovedthedesignandthenreturnedtoMalawitoconductanine-monthclinicaltrialin89infantstotesttheeffectivenessofthemachine.

Thestudent-designedbCPAPdeviceimprovedtheaveragesurvivalofprematureinfantswithrespiratorydistresssyndromefrom24percentto65percent,saysBrown.“Itwasabsolutelyexcitingandvalidatingtoknowthatwehaddevelopedthisdevice,itcouldbeused,anditworkedwell.”

ThebCPAPdevicewasthefirstofmanytechnologiestocomeoutofRice’sBeyondTraditionalBorders(BTB)initiative,anundergraduatebiomedicalengineeringdesignprogramfoundedbyRichards-KortumandhercolleagueMariaOdenundera2006HHMIscienceeducationprogramgrant.

In2013,BTBwonthe$100,000Lemelson-MITAwardforGlobalInnovation.Richards-KortumandOdendonatedtheprizemoneytowardtheconstructionofanewneonatalwardatQueenElizabethCentralHospital.

Today,theBTBprogram–whichincorporatescoursework,designchallenges,internships,andoutreachprograms–hastrainedmorethan10percentofallRice’sundergraduatessincetheprogram’sinception.AndBTB

As an undergraduate at Rice University, Jocelyn Brown helped engineer a device to ease respiratory problems in premature infants.


undergraduateshavebuiltandtestedanestimated116prototypesforuseinthedevelopingworld.

Lastyear,forexample,agroupoffreshmendesignedahandhelddevicethataccuratelyandquicklymeasuresrespiratoryratesinchildren–acriticalparameterfordiagnosingpneumonia.“UsingjustamicroprocessorandacoupleofLEDs,theydidalotofgreatengineering,”saysRichards-Kortum.ThosestudentswereinMalawithispastsummer,demonstratingthedevicetonurses.Withtheirinput,thestudentswillspendthecomingacademicyearimprovingthedeviceandplanningaclinicaltrial.

Othertechnologiesunderdevelopmentintheprogramincludealiquid-medicinedosingsyringeforchildrenwithHIV/AIDS,asolar-poweredautoclave,ahand-poweredcentrifuge,andabattery-poweredfluorescencemicroscope.

AsforthebCPAPdevice,Ricelicensedthemachineto3rdStoneDesign,aCaliforniacompanywhereBrownnowworks.WithfundingfromtheUnitedStatesAgencyforInternationalDevelopment(USAID),thecompanydistributeddevicestoall27hospitalsinMalawiandnowispreparingtomass-produceittosellinotherdevelopingcountries.

“Formyselfandmyclassmateswhohavegonethroughtheprogram,itisreallyexceptionaltomakethingsthatwillactuallybeusedintheworld,”saysBrown.“Itiscompellingtoknow,asayoungengineer,thatIcanmakeahugeimpactonhealth.”

Leading by ExampleOnaquietstreettuckedbehindBostonUniversity’sbustlingurbancampus,MuhammadZamansaysgoodbyetofourundergraduatesandapostdoctoralstudentalsoeagertomakeanimpactonhealth.ThefiveareheadedtotheairporttocatchaplanetoZanzibar,anarchipelagooffthecoastofEastAfrica,wheretheywillspendsixweekslivingwithhostfamiliesandworkingwithlocalstudentstobrainstormhealth-caretechnologiesneededintheregion.

Afterseeingthemoff,Zaman,whobecameanHHMIprofessorin2014,walksbackthroughadoorleadingtohistwolaboratories.Inthelabtotheright,hestudieshowcancercellsinteractwiththeirenvironment.Inthelabtotheleft,hefocusesonglobalhealth.

Zamangrewupinadevelopingcountry,Pakistan,andexperiencedfirsthandthepovertyandlackofmedicaltechnologythatareendemictosuchsettings.Asaboy,Zamantaggedalongwithhismotherwhenevershetrekkedacrosstowntopickupmedications.Sheneverwenttothepharmacyonthecornerbytheirhouse,Zamanrecalls.Forthelongesttime,hethoughtthatwasjustthewayitwasdone–youtraveledacrosstownformedicines.“ThenIcametoAmericaandrealizedthat’snothowitshouldbe,”hesays.Zamanrealizedhismother’slongtripswerenecessitatedbyherdistrustofthequalityofthemedicinesatthecornerstore.

In2011,withfundingfromUSAID’sPromotingQualityofMedicineProgram,Zamanbegandevelopinganinexpensive,portablekitabletodetectcounterfeitandsubstandarddrugs.Anestimated10to30percentofthedrugssoldinpartsofAfrica,Asia,andLatinAmericaarecounterfeit,andawhopping30to50percentofallantimalarialsareestimatedtobesubstandard.Theprototypekit,whichZamancallsPharmaChk,isablackplasticcontaineraboutthesizeofacarry-onsuitcase.It’salaboratory-in-a-box,completewithtinytesttubes,fluorescentprobes,amicrofluidicschip,andmore.

In2013,Scientific American hailedPharmaChkasoneof10“WorldChangingIdeas.”Withthedevice,Zamanhopestoensurethatmedicinesaresafeatallpointsalongthesupplychain–frommanufacturerstodistributorstocornerstoresinPakistan.

AshewasbuildingPharmaChk,Zamandiscoveredthathisstudentswereaspassionateaboutglobalhealthashewas.“ThisistheFacebookgeneration;peoplearegettingmoreconnectedandaresociallyconscious,”hesays.Theinterestfromhisundergraduates,combinedwithhisownoriginsinadevelopingcountry,ledZamantoembraceandbecomeamodelforincorporatingglobalhealthintosciencecourses.InoneofhiscurrentundergraduatecoursesatBU,forexample,Zamanusesburninjuriesandpostpartumhemorrhagetoteachtheconceptsofheat,mass,andmomentumtransferinlivingsystems.

“It is compelling to know, as a young engineer, that I can make a huge impact on health.”—jocelynbrown

Today,ZamanisworkingtohelpotherprofessorsatBUdothesamething.Withstudents,hehasbuiltauniversity-wideonlinerepositorywhereanyone–studentorprofessoralike–canproposeaglobalhealthtopic.Onceanideaissuggested,histeamconvertstheconcepttouseful,bite-sizenuggets,suchasexamquestionsorprojectideas.Facultycanthenpullfromthatlistforlessonsandassignments,andZamanandotherswillhelpthemtailortheexampletotheirlesson–beitchemistry,history,literature,orsomeothertopic.

Thegoalistoincorporateglobalhealthexamplesintoasmanytypesofclassesaspossible,saysZaman.Fornow,theresourceisinternaltoBU,buthehopestoeventuallymakethesystemaccessibletootheruniversities.

Inadditiontoinfusingundergraduateclasseswithglobalhealthmaterial,ZamanisrampinguptheglobalizationofBU’sengineeringdepartment.AbiomedicalengineeringprogramcalledQuality,Exposure,Policy,InnovationandImplementationinContext,orQ-EPIC,includesabrandnew,spring2016course

calledEngineeringforGlobalDevelopment.Q-EPICwillalsoincorporateglobalhealthproblemsintoayearlongsophomorelabtakenbyeveryengineeringmajoratBU,andthesummerprograminZanzibarwillbeavailabletosevenoreightstudentsannually.

“Asstudentsgraduateandgointotherealworld,whetherornottheystayinengineering,theywillalwaysretainthisideaofhowengineeringtransformstherealworld,”saysZaman.“IfthereisonethingIwantthemtocomeawaywith,thatisit.”

Reaching Out to the WorldNotonlyarelargeresearchuniversitieslikeRiceandBUdevelopingglobalhealthprograms,butso,too,aresmallerliberalartscolleges.Forexample,threecollegesinPennsylvaniarecentlylaunchedHHMI-fundedglobalhealthprograms.

WhenAlleghenyCollegeinMeadville,innorthwesternPennsylvania,announcedanewmajoringlobalhealthforthe2013-14schoolyear,theresponsewas“ratheralarming,”saysLeeCoates,aprofessorofbiology.Witha2012HHMIeducationgrant,Coatesandcolleagueshadspentayeardevelopingthecurriculum;assoonasitwasannounced,ninegraduatingseniorsinstantlycameoutofthewoodworkandregisteredforthemajor.Freshmen,sophomores,andjuniorsenrolledintheprogramaswell.“Wehadfacultyinterest,andnowtherewasthis

incrediblestudentinterest,”saysCoates,projectdirectoroftheGlobalHealthStudiesprogram.

KevinCrooks,asophomorebiologymajor,immediatelysignedupforaminoringlobalhealth.“Itwasanewareaofstudy,andIknewIwantedtojumprightin,”herecalls.SoonCrookswasaddingclassesincommunityhealthassessmentandglobalhealthtransitionstohispackedscheduleofmolecularandcellbiologyclasses.

Thisyear,18seniorsareenrolledinAllegheny’sGlobalHealthStudiesprogram,andCoatesexpectsittosoonenroll25to30majorsperyear.ThatrapidgrowthisatestamenttotheinterestinthefieldandalsotoAllegheny’suniqueapproachtoglobalhealth,throughfour“pillars”:science,health,andtheenvironment;ethicsandsocialresponsibility;policy,resources,andeconomics;andculturesandsociety.

“Thisisaliberalartsapproachtoglobalhealth–it’sbiggerthanjustmedicaltreatment,”saysCarylWaggett,chairofAllegheny’sGlobalHealthStudiesprogram.“Usingthesebroaderwaysofthinking,students’skillsetsaremuchbetterrefinedwhentheygraduate.”

Inadditiontocoursework,manystudentsintheprogramparticipateineitherU.S.-basedorinternationalinternships.About40studentstookpartthisyearininitiativesrangingfromaprojecttoencouragebreastfeedinginPennsylvaniaworkplaces,conductedincollaborationwiththeWomen,Infants,andChildrenfederalnutritionprogram,tointernshipsinMysore,India,wheresixstudentsarecurrentlyworkingathealth-care–relatednonprofits.

CrooksspentsixweeksafterhisjunioryearatanorphanageinKenya,performingasystematicanalysisofbestpracticesatthatorphanageandtwoothersnearby.Hefoundthattheratioofcaregiverstochildrenhadahugeimpactonthechildren’slives.“Inthelargerorphanage,therewere90childrentooneortwocaregivers,”saysCrooks.“Itsetthechildrenback.”

Sincegraduating,manyofthefirstnineglobalhealthmajorshavetakenpositionswithserviceagenciesorentered

“A program that teaches science or engineering and neglects the social implications is an incomplete education.”—davidasai


Muhammad Zaman is spearheading an effort to incorporate global health studies into the curriculum at Boston University.

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lMor

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To see photos from Richards-Kortum and Zaman’s travels to Africa,

go to hhmi.org/bulletin/fall-2015.

medicalorpublichealthschool.Crookshadoriginallyplannedtogotomedicalschool,buthisexperienceintheGlobalHealthStudiesprogramchangedhismind.Today,heisworkingonamaster’sinpublichealthatTulaneUniversity’sSchoolofPublicHealthandTropicalMedicine,whilealsospendingtwoyearsinthePeaceCorps.“IknownowIcanmakeanimpact,notjustbeanobserver,”hesays.

SoutheastofAllegheny,anotherPennsylvaniacollegeboastsaglobalhealthinitiative.AtUrsinusCollege,locatedona170-acrecampusinsuburbanPhiladelphia,biologyprofessorRebeccaKohnandcolleaguessawaneedgreaterthanjustpumpingoutbiologymajorsandpremeds.“Wewanttomakesurestudentsarethinkingabouttheirimpactbeyondtheircareerasadoctororinaresearchlab,”saysKohn.“Wewantthemtothinkabouthowtheyimpactsociety,howtheyimpacttheworld.”

WithanHHMIeducationgrantawardedin2012,KohnandotherUrsinusprofessorsinitiatedtheCenterforScienceandtheCommonGood,aimedatencouragingsciencemajorstoreflectontheroleofscienceinsociety.Sinceitsinception,thecenterhasintroducednewcourses,internships,aspeakerseries,andstudentresearchprograms,infusingtheschool’straditionalsciencecourseswithethicsandglobalhealthtopics.

SeniorbiologymajorKathrynYooheardaboutthecenterfromateachingassistantinachemistryclassandthoughtitwouldgiveherachancetotravelinternationally.Itdidfarmorethanthat.“Iusedtogetsowrappedupintalkingscience,science,science–Ididn’tthinkabouthowitrelatestootherpeople,howitaffectstheirlives,”saysYoo.“Now,Ido.”Itwasthecoursesshetookthroughthecenter,shesays,thatmadethedifference.

Onesuchcourse,ScienceandtheCommonGood,examinestheethical,political,andreligiousimplicationsofcurrentscientificdevelopmentssuchasgenomesequencing.Anothercourseemphasizeshowsocial,economic,andpoliticalforcesinfluencesicknessandtreatmentsaroundtheglobe.StudentslikeYoocanalsobecomefellowsofthecenter,whichinvolvesintensiveadvising,asuiteofspecializedcourses,andinternshipfunding.YoospentfiveweeksinPeruworkingataclinicfordisabledchildren.“IntheU.S.,someofthesekidswouldliveathomeandjustgotophysicaltherapy,butbecauseofthestructureofPeru’shealth-caresystem,thesekidshavenochoicebuttoliveinthisclinic,”shesays.“Itwasshocking.”

Becauseofherexperiences,YoonowplanstopursueanMD-MPHdualdegreeratherthanjustanMD.“Inowknowit’snotjustthemedicalside,butalotofpolicy,thathasanimpactonhealthcare.Iwantabackgroundinthat.”

Almost200mileswestofUrsinus,atrioofprofessorsatJuniataCollege,aliberalartsschoolinthesmalltownofHuntingdon,Pennsylvania,hasdedicatedanentirearmoftheirHHMI-fundedGenomicsLeadershipInitiativetoscience’sbroadethical,legal,andsocialimplications–orELSI,astheycalltheprogram.

ELSIthrivesonbreakingdownacademicsilosatJuniatathroughinterdisciplinaryclassessuchastheSocialHistoryofMedicine,taughtbyahistorian,andDoctorsand

MedicineinLiterature,taughtbyJamesRoney,aprofessorofRussianliteratureandinternationalstudies,whoco-leadsELSI.“Alotofthesestudentsaremajorsinthescienceswhothendoindependentresearch,combiningtheirscientificknowledgewithworkonethics,globalhealth,andtheenvironment,”saysRoney.

Atallthreecolleges,thefocusisnotonlyonthestudentsbutalsoonthefaculty.AtJuniata,theELSIprogramhostswell-attendedfacultyluncheswhereprofessorsindifferentdepartmentstalkaboutissuesrelatedtogenomics.TheprogramalsohostedaJanuaryconferenceonteachingELSIintheclassroom.Andoverthelasttwosummers,12facultymembersattendedanintensivetwo-weeksummerworkshopthatinvolvedreadinganddiscussing10booksrelatedtoscienceandsociety,anddevelopinggenomicssectionstoincludeincoursesacrossarangeofdisciplines.

“Itcanbetooeasytositinyourownofficeandcritiquehowscientificresearchmightleadtosocialinequality,”saysRoney.“Thoseofuswhohavebeenthroughtheseworkshopstakesciencemuchmoreseriously.I’mpersonallyexcitedaboutthiskindofmodelforwhataliberalartseducationcanbe,forbothundergraduatesandforfaculty.”

AtAlleghenythissummer,theGlobalHealthStudiesprogramhosted38facultymembersfromotherschoolsintheU.S.andabroadtodiscussandshareglobalhealthcoursesandcurriculums.“Wehadtodevelopourmajorfromscratch,”saysCoates,“sowearealwaysinterestedinsharingideaswithotherfolksandlearningfromthem.”

Moreandmoreschoolsareclamoringforglobalhealthprograms,accordingtoRichards-Kortum,whoregularlyreceivesrequestsfromcollegesinterestedinstartingtheirown.Andtheyshould,addsHHMI’sDavidAsai.“Aprogramthatteachesscienceorengineeringandneglectsthesocialimplicationsisanincompleteeducation,”hesays.“I’mgladtoseethesetopschoolsengageandexposetheirstudentstotherealworld.”


After completing coursework at Ursinus College’s Center for Science and the Common Good, Kathryn Yoo is set on making a difference in global health care.

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byestherlandhuis

Harnessing Serendipity

Along unpredictable

paths to discovery, Peter Walter has

maintained a sure- footed approach –

to the science as well as to the people

he mentors.

photographybyjakestangel


Iit’s a creatureoflegend ,araresymboloftheinscrutableandunattainable.YetinPeterWalter’slarge,third-floorofficeattheUniversityofCalifornia,SanFrancisco(UCSF),adazzlingwhitespecimensitsinplainview.“She’sourlabmascot,”saystheGerman-bornscientist,gesturingatthestuffedunicornperchedonaswivelchairbesidebulgingbookcases.“Sherepresentsthemysticalthingswediscover.”

Theunicorn–aBigPlush.compurchase–standsthreefeettallandhasinksketchesofthegroup’smostbelovedmoleculestapedtoherchestandbrow.ThelabpresentedWalterwiththeendearingmonstrositylastfall,ataboatpartycelebratinghismostrecentawards.Walter’sprize-worthyresearchhasunveiledfundamentalpathwaysinthecellthatcontrolhowproteinsaremadeandwheretheygo.Imbalancesinthesesystemscanleadtoavarietyofdiseases.

Whyaunicorn?Theone-hornediconharkensbacktoanarticleWaltersharedwiththelab,asheoftendoes,tospurdialogueabouttopicsofinterestbeyondhisGenentechHallquarters.Thisarticle’sauthorwastakingajabatbig-datascience–likeningthehuntfordiscoverieswithinhugedatasetstothearcadegamewhereyoutrytograspsmalltoysbymaneuveringanelectronic“claw,”usuallytonoavail.Thestoryhadanamusingphotoofaclawmachineloadedwithplushunicorns–prizes“mostpeoplecannevergrab,”notespostdoctoralfellowMargaretElvekrog.“ButPeterdid.”

Walterdoesn’tcomeacrossasago-getter.Atarecentlabmeeting,thewhite-beardedbiochemistgreetedgroupmemberswithsmilesandanoccasionalhug.HisoutfitthatJulymorningconsistedofaloose,bluebutton-downwithkhakisandBirkenstocks.Duringbriefinterjections,theprofessor’stoneconveyedconfidenceandlight-heartedness.Buthisinterruptionswerefew.Formostofthepresentation,Walterpeeledanorangeandlistenedintently,browfurrowed.

AnHHMIinvestigatorsince1997,Walterhasatried-and-trueapproach:poseasingle,simplequestionandprobeitpainstakingly.Asagraduatestudent,Walterexploredhowacell’sproteinsknowwheretogo.Whathefound–themolecularmachinerythatbringsnascentlinearpeptidestotheintracellularfactorythatfashionsthemintothree-dimensionalproteins–helpedpropelhisadvisor,GünterBlobel,tothe1999NobelPrizeinPhysiologyorMedicine.

ThediscoveryalsolandedWalterhisownlabatUCSF.There,theyoungscientistcontinuedtostudyproteintraffickingbutshiftedhisgaze.

Hisnewfocus:thesignalsthattellthenucleuswhenthecell’sprotein-foldingfactory–amaze-likestructurecalledtheendoplasmicreticulum(ER)–isoverloaded.Bytheearly1990s,Walter’steamuncoveredthesetofmoleculesthattransmitsthisinformation.Calledthe“unfoldedproteinresponse”(UPR),thisquality-controlsystemsenseswhenmisfoldedproteinsaccumulateandspursthecelltomakemoreER.TheUPR“makeslife-or-deathdecisionsforcells,”saysWalter.Butifthingsgoawry,itcanpromptneuronstodieinappropriately,leadingtoneurodegenerativedisease,orkeepalivemenacingcells,causingcancer.

Througha2008HughesCollaborativeInnovationAward–aprogramdesignedtosupportteamprojectsofambitiousscope–WalterandcolleaguessynthesizedsmallmoleculesthatcanregulatetheUPR.NowtheresearchersareprobinghowtheUPRfunctionsinvariousdiseasemodelsinthehopeofonedaytweakingthesystemtohelppatients.Onecompoundmaderecentheadlinesbecauseitenhancescognitioninmice.ThismoleculeisundergoingfurtherdevelopmentatCalico,aBayAreabiotechfirmdevotedtofightingage-relateddiseases.

Walter’spioneeringresearchontheunfoldedproteinresponsehasearnedhimagrowinglistofaccolades–includingaShawPrizeandaLaskerAwardin2014,andthisyear’sVilcekPrizeinBiomedicalScience,whichrecognizescreativecontributionsofimmigrants.

Chasing FreedomWalter’spathtowardsuccessbeganinthe1960s,whenhewasacuriousladtinkeringwithchemicalsathisparents’Drogerie (astorethatsellsnonprescriptionmedicinesandhouseholdproducts)inWestBerlin.Thoseplayfulexperimentsproducedafewexplosions,admitsWalter,“someofwhichmyparentsneverknewabout.”

The“ignoranceisbliss”mantralikelyapplies.HisexplorationsinthefamilyshopledWaltertodecidebyage12thathewouldmajorinchemistry.However,thesciencetraininghegotasanundergraduateatFreeUniversityinBerlinwasunsatisfying.Thelabexperimentsweretooprescribed,Walterrecalls.

DeterminedtoimprovehisEnglishsohecouldreadimportantbiochemistrypapers,WalterappliedforaFulbrightscholarshiptostudyabroad.Hewasrejected.Butthankstoadifferentfellowship,WalterwasabletopackhisbagsandflytoNashville,Tennessee,wherehespentninemonthsworkingonthebiosynthesisofafungalalkaloidinTomHarris’slabatVanderbiltUniversity.“Igottwopapersoutofthat,”saysWalter.“AndIpickedupsomeEnglish.”

Butmostofall,herelishedtheindependence.“Asalowlystudent,Iwasgiventremendousfreedomtoplayandusesophisticatedinstruments,”saysWalterinhisliltingGermanaccent.“Iwasimmersedinrealresearchratherthanhavingtofollowacurriculumanddoexperimentsthatzillionsofstudentshaddonebefore.”

Thatappreciationforunbridledfreedomcarriesthroughtothisday,asWaltermanagestwodozentechnicians,students,andscientistsinhislabatUCSF.“Hegaveusfreedomtofollowourpassions,”saysCarmelaSidrauski,aformerPhDstudentandpostdocintheWalterlab.“He’snotscaredtogointoareashehasn’tyetexplored.Hewilltakethejourneywithyou.”

Waltercomparesthejourneyofascientisttothatofanartist.“It’snotenoughtodothesamethingoverandoveranddoitperfectly,”heexplains

For a video about Peter Walter – and a glimpse of his lab’s mascot – go to hhmi.org/bulletin/fall-2015.


“He gave us freedom to follow our passions. He’s not scared to go into areas he hasn’t yet explored. He will take the journey with you.”—carmelasidrauski

duringadriveacrosstowntohistwo-storybrickhome,whosegaragehe’sconvertedintoawoodshop.“Inscienceandart,theessenceisdoingsomethingnoonehasdonebefore.”

Thatprinciplepermeatesgatheringsofhislabteam.Yearsago,atoneofthegroup’sannualretreats,Walterbroughtcanvasesandacrylicsandhadeveryonepainttheirownproject.“Iwasn’tsureifthatwouldgodownlikealeadballoon,”hesays.“Buteveryonegotintoit.”HolidaypartiesattheWalterhomeincludea“SecretSanta”giftexchangewherelabmembersgiveeachotherhomemadebooks,boardgames,andsuch.Onetravel-heavyyear,WalterreceivedaWaldo-style“Where’sPeter?”map.

Nowthatgrantwritingandtravelingleavetheseniorscientistlittletimetotinkerinthelab,Waltertoolsaroundinhishomewoodshop.Somecreationsarewhimsical–forexample,agardensculptureofcubesgivingbirth,orasix-foot-longtwistedcopperfountain.Othersarehighlypractical–liketheclockheplanstogivehisyoungerdaughterforherOctoberwedding.“Ilikecreatingthingswithmyhands,”Waltersays.“I’mconstantlyinventinglittletricksandsolvingproblems.”

The Detergent TrickOfcourse,persistenceandingenuityalsopayoffatthelabbench.SixyearsbeforeWalterstartedhisPhDatRockefellerUniversityinNewYorkin1977,hisadvisor,Blobel,hadproposedacontroversialtheory.HehypothesizedthatproteinsdestinedfortheERcarryasignaturesequence–anaddresstagthatletsthecellknowwherethatproteinneedstogo.Theideawasintriguing,butwithoutdirectevidencemanyscientistsdismissedit.TheyfiguredproteinssimplydriftedtotheERbythermodynamicforces,notthroughaspecifictargetingmechanism.Toprovethelatter,Blobel,anHHMIinvestigatorsince1986,wouldneedtoisolatethistargetingmachinery.

Asafirststep,Blobelworkedoutasystemforstudyingproteinassemblyinatesttube.Thatwasquiteafeatinandofitself.Buttherewasanaggingproblem:whenWalter,asanewgraduatestudent,triedtopurifyanagentresponsiblefortransportingnewpeptidestotheER,itsactivityseemedtofizzleoutinoneofthewashsteps.

Puzzledbutcaptivated,Walterrepeatedtheexperimentagainandagain,adjustingtheconditionsmeticulously.Insteadofdiscarding“dead”washfractions,hestashedtheminthefridge.Hewas“waitingforthedaytheywouldwakeup,”Blobelsays.

Sureenough,Walterdiscoveredhecouldrevivethesampleswithadashofnonionicdetergent.NowhecoulduseconventionalprocedurestopurifythemolecularassemblythatbringsfledglingproteinstotheER.Dubbedthesignalrecognitionparticle(SRP),thiscomplexglomsontoasequenceofaminoacidsonsomenewlyformingpeptides.TheSRPthenferriesthepeptidestotheERbydockingataspecificsurfacereceptor.

Fast FameWalterdescribedthepurificationofSRPinalandmark1980paper.HisfindingsprovidedthefirstevidencethatproteinsreachtheERnotbychancebutthroughacontrolledprocessgovernedbydedicated

Given his travel schedule, Walter appreciates the fact that the succulents on his office windowsill tolerate erratic watering.

Fall 2015 / HHMI Bulletin

targetingmachinery.Hebecame“instantlyfamous,”Blobelsays.Waltersoonmadeanevenbiggersplash–andreeledinjoboffers–afteraserendipitousmishapliftedtheveilononeofSRP’smostintriguingfeatures.

WalterroutinelymeasuredtheconcentrationofhissamplesofpurifiedSRPonthelab’sspectrophotometer.Thismachineshinesultravioletlightthroughasolutionandcalculateshowmuchgetsabsorbed.AssumingSRPtobeaproteincomplex,Waltersetthespectrophotometertoreadat280nanometers–thewavelengthfordetectingproteins.However,onedayalabmemberdoingadifferentexperimenthadcalibratedthedeviceto260nanometersinsteadof280.WhenWaltercamealonglaterwithhisSRPsample,thesignalwastwiceashighashewasusedtoseeing.

“Hecouldhavesaid,‘Ohwell,thiswasanaccident,’”Blobelsays.Instead,Walterponderedthedataandrealizedsomethingelsewasgoingon.TheSRPisnoordinaryproteincomplex–itcontainsapreviouslyundetectedRNA.(Unlikeprotein-containingsamples,whicharereadat280nanometers,nucleicacidsolutionsare

measuredwiththespectrophotometersetto260nanometers.)

HappenstancemighthavenudgedtheSRP-RNAdiscovery.However,“luckisonlyrecognizedbythosewhoareprepared,”notesBlobel.Walter“isanincredibledetective,”hesays.“Fromthetiniestbitofevidence,hepursuesandeventuallyfindswhatisbeautifullyhidden.”

OneofWalter’scurrentgraduatestudents,AaronMendez,isgladnothingescapeshismentor’sscrutiny.“Oftenyougetblindedwhenyouseeanegativeresult,”Mendezsays,recallingaperplexingexperimentwhereamanipulationthatwassupposedtohelphiscellslivelongerinsteadmadethemdroplikeflies.“Itwasdemoralizing,”hesays.“Peterhelpedmegetoutofmytunnelvision.Sometimesit’sthethingsthatdon’tworkthatendupopeningnewavenues.”

Inthatcase,Walterguidedhisstudentthrougharoughpatchbyremindinghimofthebiggerpicture.Othertimes,Walterbringsfocustostudents’work.

“Peterizing” WhenSidrauskiwroteherfirstpaperasagraduatestudentinthelabtwodecadesago,sheappreciatedWalter’ssteel-trapmind.Scrollingthroughthemanuscriptlinebyline,“hewould‘Peterize’thetext–What does this mean? Why did you do the experiment?–translatingitsosomeonewithoutthebackgroundcouldunderstand,”recallsSidrauski,whonowworksatCalico.“YoucouldalwaystellwhenPeterhadrevisedamanuscript.”

Thoughlongandarduous,writingpaperstogetherwasoneofthethingsSidrauskilovedmostaboutworkingwithWalter.Shebroughtpaperstohishomeonweekends–theonlytimehewasn’tbooked–andtheywouldporethroughthemoveraglassofwine.“SometimesitgotsolateI’dstayfordinnerwithhiswifeandfamily,”saysSidrauski.

Waltermethiswife,PatriciaCaldera,atapartywhilebothwereworkingontheirPhDsinNewYork.AnativeofMexico,CalderahelpedcoordinateUCSF’soutreachtolocalscienceteachersuntilretiringafewyearsago.Thecoupleraisedtwodaughters;GabrielaisanarchitectinSanFrancisco,andSylviaisaschoolteacherinPortland,Oregon.

Peter Walter, who’s won both the Shaw Prize and a Lasker Award, has been on the UCSF faculty since 1983.


“It’s not enough to do the same thing over and over and do it perfectly. In science and art, the essence is doing something no one has done before.” —peterwalter

insensitivetoaparticularchemicalchange–phosphorylationoftheelF2molecule.Normally,thisphosphorylationeventputsabrakeonmemoryconsolidation.

NahumSonenberg,abiochemistatMcGillUniversityinMontrealandanHHMIseniorinternationalresearchscholar,hadamutantmouseinwhichthisphosphorylationeventispartiallyblocked.Thosemutantsoutperformednormalmiceintestsofcognition.WaltersurmisedthatgivingmiceISRIBwouldbethepharmacologicalequivalentofthegenetictamperingthatmadeSonenberg’smutantssmarter.Indeed,whentheteaminjectedISRIBintoordinarymice,theanimalslearnedbetter.

ISRIBactivatesacomplexofproteinsthat,ifmutatedinpeople,cancausearareandoftenfatalneurodegenerativedisorder.AtCalico,SidrauskiandhercolleaguesareconductingpreclinicalstudiestoexplorewhetheritmaybepossibletopreventneurologicaldeteriorationinpatientswiththisdisorderbyusingISRIBtoreviveactivityintheflawedproteins.

Walterstressesthattheydidnotbeginbyfocusingonaparticulardisease.“Wearetryingtounderstandthebasicwaysbywhichcellsoperate,”hesays.Thatknowledgecanthenguidetheresearchalongpathsthatleadtoanexplorationofwhatgoeswrongindiseaseandwhetherit’spossibletointerveneclinically.

TheunpredictablenatureofthisjourneyledWalter,ina2010commentary,todescribethepathtodiscoveryas“serendipity.”It’sthusnosurprisethatwhenheandhislabmatesbegandiscussingnamesfortheirunicornmascot,SerendipitywasWalter’sownsuggestion.Afterall,“sherepresentsthemysticalthingswediscover,”hehaspointedout.Justasmanyscientificquestionsremainunanswered,theunicorn’snamewasstillunsettled.Butshe’sduetobechristenedatthelab’sannualretreatthisfall.

Walterconsidersthelabhis“secondfamily.”Itsmembersareclose-knitandsupportive.Inbetweenexperiments,manybustlearoundtheloungethatjoinsthelabtoWalter’soffice,gulpingcoffeeorchattingoverlunch.Thegroupincludesmusicians,artists,andathletesfromallcornersoftheworld.Yetthediversecrewcarriesonlikeawell-oiledmachine,evenwhenWaltertravelsforweeksatatime.SomethinkthesecretisWalter’sknackforattractinghighlymotivatedfreespiritslikehimself.(Walterhimselfsayshelooksfor“endlesscuriosityandindependence”inprospectivelabmembers.)

“Eachpersonhasastrongpersonality,”sayspostdocDiegoAcosta-Alvear.“Alotofushavecreativepassions.”Acosta-Alvear,forexample,playstheelectricbass.He’salsobuildingone.OnsporadicweekendsAcosta-Alvearcarefullycuts,sands,andlaminateswoodpiecesinWalter’sgaragewoodshop.Constructionofthefive-stringfretless“baby”beganabouttwoyearsago,beforeAcosta-Alvear’swifegavebirthtoarealone–theirdaughterAnaSofia.

ThebassprojectgrewoutofconversationswithWalterduringapainfulturningpointinAcosta-Alvear’sresearch.“IhadtoleaveamainprojectI’dbeenworkingonforacoupleofyears.Itwasahardtimeforme,”recallsAcosta-Alvear.“Peterofferedhishome,hisshop,andhishelpsoIcouldhavesomethingtodooutsideoflab,tohelpmeregroupandrefocus.”

UPR and BeyondWhenWalterarrivedatUCSFin1983tosetuphisownlab,he,too,madeadeliberateshiftfromtheresearchhehadpreviouslypursuedatRockefeller.“Iwantedtostartsomethingnew,”recallsWalter,gazingouthisofficewindow.OnaknollbelowstandsDreamcatcher,a50-foot-tallsteelsculpturebyMarkdiSuveroinstalledbytheuniversitytoinspireinnovation.

Backinthe1980s,scientistsknewthatwhenmisfoldedproteinsaccumulate,thecellmakesmoreER.Itwasalsoclearthatthiscompensatoryactivityistriggeredbychangesintheexpressionofgenesinthecell’snucleus.Buthowdoesthenucleusknowwhat’sgoingonintheER?“Wewonderedhowthatinformationtravelsbetweendifferentcompartments,”Waltersays.

Tofindout,twoofhisgraduatestudents,JeffCoxandCarolineShamu,setupayeastgeneticscreen.TheywantedtoidentifymoleculesresponsibleforER-to-nucleuscommunication–apathwaynowknownastheunfoldedproteinresponse.TheydiscoveredIre1,asensormoleculeembeddedintheERmembrane.However,unlikeatypicalmembranereceptor–whichactivatesacascadebytransmittingasignaltoanotherprotein,whichinturnhandsitofftoanotherprotein,andsoforth,untilthesignalreachesthenucleus–Ire1behaveslikeabunchofdifferentproteinsbundledintoonepackage.Itssequenceofactionstriggersasplicingeventthatsignalsthenucleustoturnongenesthatwillboostthecell’sERresources.“Asthestoryprogressed,itbecamesuperexciting,”saysWalter.“Everybitofthispathwayisbizarre.”

Buthere’stheclincher–theessentialUPRfeaturesthatwerediscoveredinyeastarealsofoundinmammals.ThemammalianUPRismorecomplicated,though:ithasthreebranches,eachcontrolledbyadifferentsensor(Ire1,ATF6,orPERK),whereasyeastjusthaveIre1.

Collaboratingwithseveralgroups,SidrauskiandothersintheWalterlabidentifiedsmallmoleculesthatmodulatetheactivityofeachUPRbranchinmammals.Oneofthesemodulators,ISRIB,makescells

Problem Solvers

bynicolekresge

HHMI’s 26 new investigators will have the freedom to pursue the questions that fascinate them the most.

brittglaunsinger reubenharris

heninglin josephmougous

johnmacmicking tobiaswalther

squirebooker

doristsao

joshuamendell

portraitsby barryfalls

lorenfrankj.paultaylor

jaredrutter xinzhongdong

krishnashenoy

yifancheng jenniferzallen

kimorth

michaellaub pardissabeti

andreasmartin

jayshendure

joannawysockajobdekker

olgaboudker levigarraway suebiggins

Fall2015/HHMIBulletin26

Aasateenager , DorisTsaopickedupImmanuelKant’sCritique of Pure Reason,aninvestigationintotheoriginofhumanknowledge.Thebookisnotaneasyread.Tsaoadmitsshemadeitthroughonlythefirst60pages,buteventhatbriefdipintoKant’swritingsmadeahugeimpressiononher.Alreadysetonacareerinscience,Tsaohadhereyesopenedbythebooktothemysteriesofthebrainandspatialperception.Whilestillinhighschool,shesettledonthescientificproblemshewoulddevoteherlifeto:Howdoesthebraintranslatephotonsoflightintorecognizableobjects?

ScienceisfilledwithquestionslikeTsao’s.Howdoesthebraingenerateconsciousness?Howdidlifebegin?Howdoesaprotein’ssequencedetermineitsshape?Somescientists,likeTsao,findtheirquestionsatayoungage.Othersstumbleuponthemlaterinlife.Regardlessoftheirgenesis,suchquestionsaretheforcethatpushesscientificexplorationforward.Discoverydoesn’thappenwithoutinquiry,andeveryexperimentstartswithaquestion.

ThispastMay,HHMIannouncedthatTsaoand25othertalentedscientistswouldbegivenaninitialfiveyearsoffreedomtopursuethescientificquestionsthatkeepthemupatnight.TheInstitutehascommitted$153milliontosupportthisnewestcohortofHHMIinvestigators.Chosenfromamong894candidates,theresearchershailfrom19institutionsandrepresentavarietyofdisciplines,rangingfromcomputationalbiologytobiochemistrytoneuroscience.Andwiththem,theybringadiversearrayofproblemstheyhopetosolve.

Six Golden EggsTwentyyearsafterdippingintoKant,Doris Tsao,nowattheCalifornia

InstituteofTechnology,isstilltryingtogettothebottomofhowthebrainrepresentsvisualobjects.Herdream,

shesays,istounderstandthevisualsystemwiththesamemathematicalclaritythatphysicistsusetounderstandtheuniverse.

“OnereasonI’msointerestedinobjectperceptionisthatobjectsareessentiallyinformationfolders,”sheexplains.“Thecontentsofthesefoldersarereadindozensanddozensofvisualareasinthebrain,andI’mtryingtounderstandexactlyhowthisisorganized.”

Tsaomadeamajorsteptowardcrackingthebrain’sfilingsystemin2006,whenshewasapostdoctoralfellowatHarvardMedicalSchool.SheandHarvardelectrophysiologistWinrichFreiwaldcombinedtwoofthemostimportanttoolsinneuroscience–brainimagingandsingleneuronrecordings–torevealareasofthemonkeybrainwhosesolepurposeisrecognizingfaces.First,thepairusedfunctionalmagneticresonanceimagingtogetabird’s-eyeviewofthebrainandpinpointtheareas–sixinall–thatsawincreasedbloodflowasmonkeysviewedpicturesoffaces.Then,duringwhatTsaocallsoneofthemostexcitingdaysofherlife,theyprobedoneofthoseareasofthebrainwithelectrodesanddiscoveredthatalmosteverysingleneuroninthepatchfiredonlyinresponsetofaces.Thesamewastruefortheotherfiveareas.These“facepatches,”asTsaonamedthem,werethefirstconcreteevidencethattheprimatebrainoperatessomethinglikeaface-processingmachine.

“Thesepatchesarelikeahalf-dozengoldeneggs,andwe’retryingtounderstandhoweachoneisprocessingfacesindetail,”saysTsao.She’sonlyjustscratchedthesurface,butit’sclearthatthepatchesareworkingtogethertorecognizeanddiscriminateamongfaces.Eachfacepatchhasitsowntask;somerespondtocertaincharacteristicslikeamountofhairoririssize,whileothersareinchargeofrecognizingfacesfromspecificviews,suchasthefrontorside.

Next,Tsaowantstofigureouthowthebraintakesbitsofinformation–likefacialfeatures–andintegratesthemintoaperceptionofawholeobject.Tothisend,shehasrecentlyembarkedonacollaborativeprojectwithhermathematicianfather,ThomasTsao.They’reworkingonamathematicaltheorytosolveoneofthegreatestproblemsinvision–theinvarianceproblem,orhowobjectscanberecognizeddespitechangesinappearanceduetoperspective.

To learn more about the newest cohort of HHMI investigators,



Radical ResearchSquire Booker’spassionliesattheoppositeendofthespectrumfromTsao’s.WhileTsaoisafterthebig

pictureofbrainfunction,Bookerisfascinatedbytheatomicdetailsofchemicalreactions.

TheoriginsofhisresearchwerenotquiteasdeliberateasTsao’s,either.

“WhenIwasincollege,Ilikedalotofdifferentareasofscience,andIwantedtobeabletodoalittlebitofeverything,”heexplains.“ButoneofmyprofessorsatAustinCollegetoldme,‘Ifyouwanttodoresearch,you’regoingtohavetochoose.You’regoingtohavetodecidewhatyouwanttobe.’”Bookerchoseenzymology,adisciplinethatincorporateseverythingfromanalyticalchemistrytobioinformatics.“I’msortofajack-of-all-trades,”hesays.“Notnecessarilyamasterofanything,butabletoblendalotofscientificdisciplinesintoone.”

Thiscross-disciplinaryapproach,combinedwithanoseforimportantresearchproblemsandaknackforcleverexperimentaldesign,hasallowedBookertodecipherthechemistrybehinddozensofnovelreactionsinbiology.InhislabatPennsylvaniaStateUniversity,BookerstudiesalargefamilyofproteinscalledradicalS-adenosylmethionine(SAM)enzymes.Theenzymes,whicharefoundpredominantlyinanaerobicbacteria,harnesstheenergyfromanunstableformofS-adenosylmethioninetodrivereluctantchemicalreactionsforward.

Intruepolymathfashion,Bookercombinesavarietyofbiochemical,enzymological,andstructuraltoolswithsmall-scaleorganicsynthesisandfast-reactionkineticmethodstofigureoutwhatmakestheseradicalreactionsgo.

Oneofthosereactionsiscatalyzedlipoylsynthase,aradicalSAMenzymethataddssulfuratomstooctanoicacidinsidecells.Theresultingproduct,lipoicacid,isanimportantcofactorinvolvedinenergymetabolismandthebreakdownofanumberofdifferentaminoacids.“Ifyoudon’thavelipoicacid,youdie,”Bookerexplains.In2004,andmostrecentlyin2014,heworkedwithCarstenKrebs,oneofhiscolleaguesatPennState,toshowthatlipoylsynthaseusesanunstableSAMmoleculetoremovetwoofitsownsulfuratomstodonatetooctanoicacid.Interestingly,thisactionrenderslipoylsynthaseunabletocatalyzeanyfurtherreactions.“Inotherwords,theenzymekillsitselfafteritdoesaturnover,”Bookersays.“It’scompletelynovel,andalotofpeopledidn’twanttobelievethismechanismatthetime.”

AnotherradicalSAMenzymecalledCfrconfersantibioticresistance,mostnotablytosomestrainsofStaphylococcus bacteria.Cfraddsamethylgrouptothebacteria’sribosomalRNA,whichblocksantibioticbindingtotheribosome.Bookerandhiscolleaguessolvedthethree-dimensionalstructureoftherelatedenzyme,RlmN,andelucidatedthemechanismthatCfrandRlmNusetoaddthatmethylgroup.Becausetheatomthatreceivesthemethylgroupisinertandcan’teasilyacceptnewchemicalgroups,CfrhastotakeamethylgroupfromaSAM

molecule,stripitdown,andthenrebuildthemethylonthetargetRNA,ratherthanjusttransferringitwhole.NowthatheknowshowCfrworks,Bookerislookingatwaystostopthereactionandpreventantibioticresistance.

Booker’slatestendeavorisabigone.He’spartneredwithseveralotherlabstoassignfunctionstoradicalSAMenzymes.Oftheproteinfamily’salmost115,000members,thevastmajoritycatalyzeunknownreactions,soBookerandhisteamhavetheirworkcutoutforthem.

Granular InvestigationJ. Paul Taylorisalsointerestedinunknowns,onlyhisrelateto

neurodegenerativediseases.In2004,TaylorwasjuststartinghislabattheUniversityofPennsylvaniaSchool

ofMedicine.Atrainedclinicalneurologistwithaloveofresearch,

hewasinterestedinthegeneticbasisofmotorneurondiseasesbutdidn’thaveasetresearchprogram.“Ibasicallystartedmylabwithnoprojectsandjustfollowedwhatcameinthedoorattheclinic,”herecalls.

Whatcamethroughthedoorwerepatientswithoddversionsofcommonneurodegenerativeandmusclediseases:familieswithinheriteddiseasesthatdidn’tfitneatlyintoastandarddiagnosis,orpatientswithgeneticmutationswhodevelopedsomethingotherthantheexpectedsyndrome.Neurologistscallthesepatientsoutliers–casesthatcan’tbeexplainedbyknowndisease-causinggenes.“ThosearetheonesIwentafter,andwebegantofindawholeseriesofnewgenesthathavegivenuscompleteinsightintothebasisofsuchdiseases,”saysTaylor.

Bysequencingtheoutlierpatients’exomes,orexpressedDNA,Taylorandhiscollaboratorshavebeenabletopinpointthegenesresponsiblefortheirsymptoms.Surprisingly,hefoundevidencethatmanyseeminglyunrelateddegenerativebraindiseasesarecausedbymutationsinRNA-bindingproteinsassociatedwithso-calledstressgranules.TheseclumpsofRNAandproteinassemblewhenacellencountersunexpectedstress,suchasextremeheat,andneedstoquicklyswitchupthegenesit’sexpressing.BysponginguplooseRNA,thecell

Discovery doesn’t happen without inquiry, and every experiment starts with a question.


canpreventthenucleicacidfrombeingtranslatedintoproteinuntilthestressisover.Taylorandhiscolleaguesdiscoveredthatdisease-causingRNA-bindingproteinsfallintotwoclasses:thosethatarepartofthegranulesthemselves,andthosethatassistingranuleassemblyordisassembly.

TaylorhasmovedhislabtoSt.JudeChildren’sResearchHospitalinMemphisandisnowfocusingonhowthesemutantRNA-bindingproteinsproducedisease.Helearnedthatthemutationscancausehyper-assemblyofgranulesorimpairgranuledisassembly.Butthemutantproteinsarealsoverypronetoformingamyloid-likefibrils,suchastheonesfoundinpatientswithamyotrophiclateralsclerosisorcertainillnessescausingdementia.“Wedon’tknowifthebadthingistheaccumulationofthesefibrils,orthefactthatyouareholdingthegranuletogethertoolongandtheRNAsarenotliberatedtobeused–orboth,”hesays.

AnotherpuzzleTaylorwantstosolveiswhytheseubiquitouslyexpressedRNA-bindingproteinscausediseaseonlyinneuronsandmuscles,andwhymutationsthatexistthroughoutlifedon’tcausediseaseuntilapersonis40or50yearsold.“ThesequestionshavebeentheresinceIwasborn,andforallIknow,theymaystillexistwhenI’mlonggone,”heexplains.“Butthey’realwaysinthebackofmymindeverytimewemakeanadvance.”

Chromosome Segregation

Inthelate1990s,Sue Bigginshadmutantsonhermindaswell.Shewas

apostdoctoralfellowinthelabofgeneticistAndrewMurray,whowasthenattheUniversityofCalifornia,SanFrancisco,andisnowanHHMIprofessoratHarvardUniversity,usinganewtechniquetotrackyeast

chromosomes.Lookingthroughamicroscope,Bigginsnoticedagroup

ofmutantcellsthatcouldn’tseemtosegregatetheirchromosomescorrectlyduringcelldivision.Whensheexaminedthosemutantsmoreclosely,shesawthatachromosomalstructurecalledthekinetochorewasaffected.“SoIstarteddiggingdeepintheliteraturetolearnmoreaboutkinetochores,andthat’swhenIrealizedhowlittlewasknown,”sherecalls.WhenitcametimetostartherownlabattheFredHutchinsonCancerResearchCenterinSeattle,Bigginswrotearesearchproposalonthekinetochore—whatshewantedtolearnaboutitscomponentsandhowtheyfunction.

Kinetochoresarecomplexmolecularmachinesmadeofhundredsofproteins.Theyconnectchromosomestothelong,thinmicrotubulesthattugthemtooppositeendsofadividingcell.Butthisisnoeasytask.Microtubulesareconstantlyinflux,growingandshrinkingatarapidpace,andkinetochoresneedtokeeptheirgriponthemwhilesimultaneouslybearingtheloadofthechromosome.Thisinteractionissocrucialtocelldivisionthatasurveillancemechanismcalledthespindlecheckpointimmediatelyhalts

thecellcycleifasinglekinetochoreisnotproperlyattachedtoitsmicrotubule.

In2000,justafteropeningherlab,Bigginsdecidedthatherbestshotatunderstandingthekinetochorewastoremoveitfromitscomplicatedcellularmilieu.Shechosetoisolatearelativelysimplekinetochore,acomplexofabout250proteins,frombuddingyeast.“Itwasverymuchtrialanderrorandbruteforce,butmygradstudentfigureditout,”saysBiggins.

Herresearchquicklytookofffromthere.Withpurekinetochoresinhand,Bigginsmadeseveraldiscoveriesaboutthemolecularmachines.WhensheandherUniversityofWashingtoncollaboratorCharlesAsburyaddedmicrotubulestothemix,theymadethesurprisingfindingthattensiondirectlystabilizeskinetochoreattachmentstomicrotubules.AswithChinesefingertraps,theharderthemicrotubulespullonthekinetochores,thestrongertheirgriponchromosomes.Herteamhasalsoidentifiedmanyofthemoleculareventsthatregulatekinetochoreassemblyandthespindlecheckpointpathway.

In2012,BigginsandTamirGonen,agroupleaderatJaneliaResearchCampus,publishedthefirst-everthree-dimensionalstructureofanisolatedkinetochoreattachedtoamicrotubule.Theirimagesrevealedakeyfactorinthemolecularmachine’sabilitytomaintainitsgriponthosedynamicmicrotubules:multipleattachmentpoints.“It’slikeyou’reclimbingaropeandsomeone’salwayspullingtheropeoutfromunderyou,”saysBiggins.“Onewaytostayattachedistohavemultiplecontactssothatifonereleases,theotheroneisstillthere.”

Ultimately,Bigginswantstounderstandwhat’sgoneawryincancerandotherdiseases,suchasbirthdefects,involvingthewrongnumberofchromosomes.“Aneuploidyisoneofthebiggesthallmarksofcancercells,”sheexplains.“Whetherandhowoftenitarisesduetoalteredkinetochorefunction,nooneknows.”Tofigurethatout,she’llhavetoisolatethehumankinetochore.Sofar,noonehasdoneit,butBigginsandherteamarealreadyworkingonthechallenge.

“These questions have been there since I was born, and they may still exist when I’m long gone. But they’re always in the back of my mind.” —j.paultaylor


A 3C ConceptJob Dekkerhasbeentryingtoansweradifferentquestioninvolving

chromosomesforalmost20years.AsapostdoctoralfellowatHarvard

University,hestartedthinkingabouthowgenomesandchromosomesworkfromadifferentpointofview.“Mostpeoplesee

chromosomesaslongmoleculesfullofinformation,”Dekkerexplains.“ButI’vealwaysbeendrivenbytheideathatifwewanttounderstandhowcellsworkwiththatinformation,wehavetounderstandhowchromosomesareorganizing,howtheyliveinsidecells.Whatdoesthelivinggenome–therealchromosome–actuallylooklike?”

Whatwedoknowisthatthechromosomeisextremelylongandverydynamic.Duringmitosis,itneedstofolditssixfeetofDNAintoanimprobablycompressedform.Atothertimes,theverysamechromosomemustreorganizeitselfinacompletelydifferent,lesscompact,fashiontomakeitsgenesaccessiblefortranscription.BothformsofDNAarephysicallydistinctandextremelycustomizedforthetasksathand.

Todeterminewhatachromosomelookslikeinthreedimensions,DekkerdevelopedatechniquefordetectingphysicalinteractionsbetweenDNAsegments.Theresultiscomparabletoamolecularmicroscope.“IrememberwhenIproposedthisinalabmeeting,Ijusthadaroughschemeofhowthiswouldwork.Almosteverybodysaiditwouldneverwork,”Dekkerrecalls.Butitdid.Inspades.Today,hundredsofscientistsaroundtheworldareusingDekker’schromosomeconformationcapture,or3C,methodtofindconnectionsbetweenfar-flungregionsofDNA.

Theconceptbehind3Cissurprisinglysimple.BecauseDNAisfolded,genesthatareotherwisefarapartalongthelinearmoleculecanendupextremelyclosetogetherinthree-dimensionalspace.Bycross-linkingneighboringareasofDNAandthencuttingthoseregionsintosmallpiecesforsequencing,Dekkerwasabletodecipherwhichpartsofthechromosomeinteractwitheachother.Themoreinteractionsbetweensegments,themorecloselythesegmentsareassociatedinspace.

SinceopeninghisownlabattheUniversityofMassachusettsMedicalSchoolin2003,Dekkerhasrefined3Ctovisualizeentiregenomes.In2009,hepublishedthefirstthree-dimensionalmapofthehumangenome.Themaprevealedalotaboutchromosomes,includingthefactthatloopsofchromatinareusedtoactivatetherightgenesattherighttimes,andthatDNAiscompartmentalizedinto“neighborhoods”ofactiveandinactivegenes.ThemapalsoprovidedphysicalevidenceforhowsomegenescanberegulatedbydistantbitsofDNAcalledenhancers.

AlthoughDekkerhasfinallycreatedthemaphedreamedofbackin1998,heisnowherenearreadytomoveontoanewproblem.“Ithoughtthatifwesolvedthestructure,wewouldgetalltheanswers,”headmits.“Wedidgetsomeanswers,butitalsoraisedalotofquestionsthatwedidn’teventhinkofaskingearlier.”Answersthatheintendstopursueduringthenextfiveyears,asanHHMIinvestigator.

Sue Biggins, PhDFredHutchinsonCancerResearchCenter

Squire Booker, PhDPennsylvaniaStateUniversity,UniversityPark

Olga Boudker, PhDCornellUniversity

Yifan Cheng, PhDUniversityofCalifornia,SanFrancisco

Job Dekker, PhD UniversityofMassachusettsMedicalSchool

Xinzhong Dong, PhDJohnsHopkinsUniversity

Loren Frank, PhDUniversityofCalifornia,SanFrancisco

Levi Garraway, MD, PhDDana-FarberCancerInstitute

Britt Glaunsinger, PhDUniversityofCalifornia,Berkeley

Reuben Harris, PhDUniversityofMinnesota,TwinCities

Michael Laub, PhDMassachusettsInstituteofTechnology

Hening Lin, PhDCornellUniversity

John MacMicking, PhDYaleUniversity

Andreas Martin, PhDUniversityofCalifornia,Berkeley

Joshua Mendell, MD, PhDUniversityofTexasSouthwesternMedicalCenter

Joseph Mougous, PhDUniversityofWashington

Kim Orth, PhDUniversityofTexasSouthwesternMedicalCenter

Jared Rutter, PhDUniversityofUtah

Pardis Sabeti, DPhil, MDHarvardUniversity

Jay Shendure, MD, PhDUniversityofWashington

Krishna Shenoy, PhDStanfordUniversity

J. Paul Taylor, MD, PhDSt.JudeChildren’sResearchHospital

Doris Tsao, PhDCaliforniaInstituteofTechnology

Tobias Walther, PhDHarvardUniversity

Joanna Wysocka, PhDStanfordUniversity

Jennifer Zallen, PhDMemorialSloanKetteringCancerCenter

2015 HHMI Investigator Competition

Winners

Perspectives & Opinions


CatalysisA new HHMI science education initiative reflects some of the same qualities – and rules – as a catalytic reaction, says David Asai, senior director of the Institute’s undergraduate and graduate programs.

acoupleofgenerationsago,studentsmajoringinwhatwenowcalltheSTEMfields–science,technology,engineering,andmath–fitahomogeneousprofile:mostweresingle,white,andmale;theyenteredcollegeat18withsolidacademicpreparation;andtheygenerallygraduatedinfouryears.

Today’sSTEMstudentsstandinstarkcontrasttothathomogeneity.Asnotedinthe2012reportfromthePresident’sCouncilofAdvisorsonScienceandTechnology,theyinstead“comefromdiversebackgrounds,havewidelydivergentlevelsofpreparation,maybereturningtoschoolafteryearsintheworkforceorservingintheU.S.military,andoftenareemployedwhileincollegetosupportthemselvesandfamilies.”ManySTEMstudentsnowadays–50percentofthoseearningbachelor’sdegreesand20percentofthoseearningPhDs–havetakenatleastonecourseatacommunitycollege,andabout30percentofundergraduatesdependoncommunitycollegesfortheirintroductorycoursework.Nearly25percentofundergraduatesarefirst-generationcollegestudents–meaningtheirparentsdon’tholdacollegedegree.Racialandethnic“minorities”(whosoonwillbeamajorityofthenation’spopulation,accordingtoU.S.Censusprojections)andindividualsfromeconomicallydisadvantagedbackgroundsaredisproportionatelyoverrepresentedamongtransferandfirst-generationstudents,butsignificantlyunderrepresentedamongthosestudentswhocompletethebaccalaureatedegree.

These“newmajority”students–atermcoinedbyCarolGearySchneider–arevitalforthefutureofscience.Theyarealargeandgrowingpartofthepoolthatwillsupplythenation’sfuturescientifictalent.Andtheybringtosciencethediversityofperspectivesneededforcreativeproblemsolving.Unfortunately,today’seducationalsystemfailstoenablethesestudentstorealizetheirpotential.Thebaccalaureatecompletionrateisnearlysix-foldbetterforstudentswhobegincollegeatafour-yearinstitutioncomparedtothosewhobeginincommunitycollege.1And,inastudyofalargecohortofstudentsfrom1992to2000,thebaccalaureatedegreecompletionrateforstudentswhoseparentshadabachelor’sdegreewasnearlythree-foldgreaterthanforfirst-generationstudents.2

AnewHHMIinitiative,dubbedInclusiveExcellence,challengescollegesanduniversitiestodoabetterjobatprovidingeffectivescienceeducationforallstudents,especiallythosewhocometocollegealongnontraditionalpathways.Ourgoalistocatalyzechangethatwillresultinlastinginstitutionalcapacityforinclusion,reaping

benefitswellbeyondthelifetimeoftheHHMIgrant.

Whatdowemeanby“catalyzechange”?Inmypreviouslifeasafacultymember,Ibeganmyintroductorybiologycourseeverysemesterbydiscussingasimplebiologicalreaction–thephosphorylationofglucoseinthefirststepofglycolysis,thecellularprocessthatbreaksdownsugartoyieldusefulenergy.Inthis

example,thereactionsubstrates(S)areglucoseandATP,theproduct(P)isglucose-6-phosphate,andthecatalyst(E)istheenzymehexokinase,asindicatedinthissimplifiedequation:

S + E S • E≥P + E

ThismetaphorremindsusofthreerulesrelevanttotheHHMIinitiative:

Rule 1: Theenzymeisnotconsumed;itisrecycled,availabletocatalyzethesamereaction

againandagain.TheHHMIgrantshouldbeacatalystandnotasubstrateforcampuschange.Asacatalyst,thegrantshouldenabletheinstitutiontochangethewayitdoesbusiness,continuingitsforwardtrajectorybyimplementinginclusivepracticesthatpersist.

Rule 2: Theenzymemakesthereactiongofaster,butonlyifthereactionisenergeticallyspontaneous.TranslatingthatconcepttotheInclusiveExcellenceinitiative,theinstitutionmustbereadyforchange.Thismeansasuccessfulideacannotdependononelonelychampion;ithastobeownedbytheinstitutionandengagealargenumberoffacultyandadministrators.

Rule 3:Wantingsomethingandachievingitarenotthesame.Theenzymeacceleratesthespontaneousreactionbyforming,withthesubstrate,thetransitionstate,duringwhichthereactantsaretwistedandcontortedunderenormousstrain.Thetransitionstateissounstablethatitcan’tbereadilyisolatedandsoisdenotedwithinbrackets.Nevertheless,forthereactiontogoallthewaytotheright,ithastogothroughthetransitionstate.ThereinliesathirdimportantlessonfortheInclusiveExcellenceinitiative.Becausethegoalistochangethewayaninstitutionthinksandbehaves,gettingtherewillrequiretheinstitutiontogothroughtransitionstates,timesofstrainanddifficulty.Indeed,iftheinstitutiondoes notgothroughdifficulttransitionstates,itwilllikelynotachievetheculturalchangesweseek.

Especiallyduringsuchtimes,institutionalleadershipandcollectivefocusarecriticallyimportant.Thegooddonebycollegesanduniversitiesdependsonpeople–facultyandadministrators–workingwithallstudents.Ourgoalisthat,throughtheHHMIInclusiveExcellenceinitiative,collegesanduniversitieswillundergothesedifficultbutnecessarytransitions.

1.Skomsvoldetal.,2011.NationalCenterforEducationStatistics.2.ChenandCarroll,2005.NationalCenterforEducationStatistics. P

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David Asai—David J. Asai is senior director of undergraduate and graduate programs in science education at HHMI.


David Asai likens HHMI’s new initiative, Inclusive Excellence, to a catalytic reaction.

32

Perspectives & Opinions


Tanya PaullHHMI InvestigatorUniversity of Texas at AustinChooseyourresearchquestionscarefully.Whatarethemostimportantquestionsthatneedtobeansweredinyourfield?Whatarethecriticalexperimentsthatcouldrevolutionizeyourareaofresearch?Isitpossibletoansweranyofthesequestions,andareanyofthemuniquelyansweredwiththeskills,information,andreagentsthatyouhave?

Erol FikrigHHMI InvestigatorYale UniversityIencourageyoungscientiststoenjoytheprocessofscientificinquiryforaslongastheycan.Itmightbeforasummer,ayear,adecade,or,insomecases,alifetime.Ascareersdevelop,therearecompetingchallengesthatdemandattention.Ifascientistgetstothepointwherelessthantwoorthreehoursofeachdayaredevotedtoconsideringscientificquestionsanddesigningexperiments,thenit’stimetoreflectand,hopefully,reorganize.

Vivian CheungHHMI InvestigatorUniversity of MichiganFindwhatyoulovetodo.ToquoteSteveJobs,“Keeplooking;don’tsettle.”Passiongivesyoustrengthtopersevereandreasonstocare.Investtimeandbegenuineinthesearch.Lifeisfullofunexpectedthings–somegood,somebad–thoughitisneverclearinthemomentwhatmaybegoodorbadintheend.

Ifyoulovewhatyoudo,youwilldiveinandaccomplishwhatisneeded,andyouwilldoitwell.Thisisparticularlychallengingtoday,whentheemphasisseemstobeonspeedratherthanperfection.Toachieveexcellence,youhavetocaredeeply.Theresultswillberewarding.

Q&A What career lessons do you pass on to young scientists?Advicecanbebeneficial,especiallywhenitcomesfromsomeonewhohasbeeninyourshoes.Here,fourHHMIscientistsofferwordsofwisdomthatareequallyapplicableinsideoroutsidethelab.–Edited by Nicole Kresge F

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Vivek JayaramanGroup Leader Janelia Research CampusMyowntortuouscareerpathtookmefromaerospaceengineeringtoinsectneurobiology.Itellpeoplewhoareuncertainofwhattheywanttodototaketheirtimefiguringitout–acareerisn’tarace.Ifyou’regoingtospendmostofyourlifeworkingonsomething,ithadbetterbesomethingyoureallycareaboutandenjoydoing.Onceyouknowwhat“it”is,Ithinkit’simportanttoacquiretheconfidencetodothingsyourownway.Listentoexpertadvice,but,ultimately,honeandtrustyourownscientificinstincts.

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34 scienceeducation PoweredbyStudents36 upclose WildImmunology38 labbook Hangry?Here’sWhy Made-to-orderMolecules ATestTellstheTale

This40,000-year-oldhumanjawbonewasfoundinacaveinRomania.ThatplacesitsoriginatacriticaltimeinEurope’shistory,whenmodernhumansweresupplantingNeanderthals.Scientistshavebeenwonderinghowthistransitionhappened–archaeologicalevidencesuggeststhatthetwogroupsinteracted,butfewskeletalremainsexisttobackuptheevidence.AteamofscientistsanalyzedthetinybitofhumanDNAextractedfromthisjawboneanddiscoveredthat6to9percentofitwasNeanderthal,providingthefirstgeneticevidencethathumansinterbredwithNeanderthalsinEurope.Read more about the research in “Jawbone Reveals Neanderthal Origins” on page 39.


Chronicle / Science Education


Powered by StudentsTwo HHMI-supported scientists involve undergraduates by the hundreds and thousands in real, published research.evenaftercenturies ofscientificdiscovery,there’salotofmysteryleftinouruniverse.Inthelastsixyears,astronomershavefoundmorethan1,000previouslyunrecognizedplanets.HereonEarth,biologistsidentifyover15,000newspecieseachyear.Andtoday’sbiomedicalscientistsseekcluesabouthumanhealthanddiseaseingeneticdatasovastthatevencomputersarehavingtroubleparsingit.

Howtomakesenseofallthat?Byusingtechnology,ofcourse,butmeaningfulprogressalsorequiresscientists’discriminatingeyesandcreativeminds.

Educatorsworkingtoinspirethenextgenerationofscientistsarelearningthatengagingstudentsinresearch–notonebyone,butbythehundredsorthousandsonasingleproject–candrivediscoveryforward,propellingresearchinwaysthatwouldbeimpossiblewithoutamassivegroupeffort.

Thisspring,twoseparate,unusuallylargeteamsreportedfindingsonmicrobialdiversityandfruitflygenomicsinthejournals eLife andG3.Thepublicationsrepresentthework

ofhundredsoffacultyandmorethan3,500studentswhoconductedresearchthroughanHHMIprogramcalledtheScienceEducationAlliance–PhageHuntersAdvancingGenomicsandEvolutionaryScience(SEA-PHAGES)andtheGenomicsEducationPartnership(GEP).Bothinvolveundergraduatesinrealresearchaspartoftheircourseworkatinstitutionsaroundthecountry.

Delvingintogenuineresearch,whereoutcomesareuncertainandfalsestartsareinevitable,canbebothdauntingandempoweringforstudentsandfacultyalike.SEA-PHAGESandGEPfacultysaytheirstudentsgainconfidenceasthecoursesprogress,andbothprogramshavedatademonstratingthattheexperienceboostsundergrads’academicperformanceaswellastheirinterestinscience.Butthestudentsaren’ttheonlyoneswhobenefit.Theyoungscientistsmakelastingcontributionstotheresearchcommunity–collectingandanalyzingdata,sharingtheirfindings,andestablishingabaseofknowledgeuponwhichotherscientistscanbuild.

Connecting the DotsHHMIProfessorSarahElgin,directorofGEP,studiesthedotchromosome,asmallgeneticelementinfruitflies,inherlabatWashingtonUniversityinSt.Louis.DNAinthedotchromosomeappearstobetightlypackagedintoheterochromatin,aformatthatusuallyrestrictstheactivityofgenes,butgenesonthedotchromosomeworkjustfine.UnderstandinghowthosegeneshaveevolvedcouldhelpilluminatetherelationshipbetweenDNApackagingandgenefunction.

GEPstudentsatover110schoolshavebeenlearningaboutthepowerofgenomicsastheypiecetogethergenomicevidenceforhowthedotchromosomehasevolved.Eachstudentorpairofstudentsisresponsibleforasmallchunkofrawsequencedatafromafruitflygenome.Theirfirsttaskistofindandcorrecterrorsinthesequence,afterwhichtheyevaluateseverallinesofevidencetodeterminewhethergenesarepresentand,ifso,howthey’reorganized.

Thatdivide-and-conquerstrategyhasenabledElginandhercolleaguestocomparehigh-qualitysequencesfromthedotchromosomewithasecond,morelooselypackagedpieceofDNAacrossfourspeciesoffruitflies.Theyfoundmostofthedot

chromosome’sdistinctivecharacteristicsinallspeciesanduncoveredevidencethatgenesonthedotchromosomehavebeenlessaffectedbynaturalselectionthangenesinthemorelooselypackagedDNA.ThosefindingswerereportedMay1,2015,inG3,inapapercoauthoredby1,014researchers,including940undergraduatesfrom63institutionswhoworkedontheproblembetween2007and2012.

“Thisisnotalightning-likewaytodoresearch,”Elginacknowledges.ButwithoutGEP,itmightnever getdone.“Whenyouthinkabouttheman-hoursthatgointocarefulannotation,there’sjustnootherwaytodoit,”shesays.“Thecomputerprogramsaregettingbetter,butthey’renotasgoodasthehumanmind.”

Breaking GroundStudentsintheSEA-PHAGEScourseareinvolvedinasimilarlarge-scaleeffort.Theyareanalyzinggenomestheyisolatefrombacteria-infectingvirusesthattheyfindinlocalsoils.Theseviruses,calledbacteriophages,thrivejustabouteverywhere,outnumberingallotherlifeformsontheplanet.Theirimpactonecosystemsandtheenvironmentislikelyprofound,butlittleisknownabouttheirastoundingdiversity.

HHMI Bulletin / Fall 2015 35M

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HHMIBulletin/Fall2015

“This is all part and parcel of a whole classroom-based research movement.”—sarahelgin

Infact,relativelyfewphageshavebeenisolatedatall,letalonehadtheirgenomessequencedandmadeavailableforcomparativeanalysis.ButnowSEA-PHAGESstudentsarefillinginthemissinginformation,phagebyphage.SinceSEA-PHAGESwaslaunchedin2008,thousandsofundergraduateshavesequencedandanalyzedbacteriophagegenomesandsharedtheirresultsthroughacustom-builtonlinedatabase.PoolingthatdatahasallowedateamofscientistsledbyHHMIProfessorGrahamHatfullattheUniversityofPittsburghtocomparethegenomesof627differentbacteriophages,allofwhichstudentshadisolatedusingthesoil-dwellingbacteriumMycobacterium smegmatis.

Researchershadwonderedhowmuchgeneticdiversityexistsamongbacteriophagesthatinfectasinglehost.Basedonmorelimitedanalyses,suchphageshadbeensortedintoseveralclusterswithsharedgeneticfeatures–butwithfewgenomesrepresented,itwas

impossibletoknowwhethertheclustersweretrulydistinct.

“Youneedasufficientlylargecollectionofsequencedgenomestogiveyoutheresolutionyouneedtoaddressthequestion,”saysHatfull,whoisleadscientistfortheSEA-PHAGESprogram,nowrunningon95campuses.Whenheandhiscolleaguesanalyzedthevastnewdataset,whatemergedwasacontinuumofgeneticdiversity.

Hatfull’steamfoundthatphagesthatinfectM. smegmatisarerelatedtooneanotherincomplexwaysthatcannotbeexplainedwithdiscretegeneticgroups.“Wecouldn’thavegottenthatperspectivewithoutgettingthedatathewaywedid,asacollectiveconsortium,”hesays.ThegroupreportedthefindingsApril28,2015,inthejournaleLife,inapaperauthoredby199facultyand2,664studentsat81institutionsintheUnitedStatesandSouthAfrica.

Afterparticipatinginrealresearch,studentssometimeswonderwhyallscienceclassesdon’tusethatapproach.Butforeducators,implementingashiftfromtraditionallabcoursestotruediscoveryrequiresplanning,flexibility,andnewresources.SEA-PHAGESandGEPsupportthateffortwithtrainingforfaculty,aswellasbyfosteringcommunitieswherestudentsandfacultycanexchangeideas

acrossinstitutions;bothprogramscontinuetoseeknewschoolstojointheirventures.

Othereffortstointegrateresearchintoundergraduatecoursesareyieldingresults,too.

Forexample,studentsattheUniversityofCalifornia,LosAngeles,havehelpedidentifygenesthatdrivefruitflydevelopmentthroughtheUndergraduateResearchConsortiuminFunctionalGenomics,runbyHHMIProfessorUtpalBanerjee.Andthousandsofstudentshavecontributedtothefieldofsyntheticbiology,designingnewbiologicalcircuitsanddevices,throughtheGenomeConsortiumforActiveTeaching(GCAT),organizedbybiologyprofessorMalcolmCampbellatDavidsonCollegeinNorthCarolina.

Meanwhile,Elginhopestomakeiteasierforinterestedfacultytolaunchtheirownbioinformatics-basedcourses,creatingopportunitiestotiestudentactivitiesmorecloselytotheirownresearchquestions,bydrivingthedevelopmentofanew,user-friendlygenomebrowser.

“Thisisallpartandparcelofawholeclassroom-basedresearchmovement,andI’mhopingthat’samovementthat’sreallygoingtogrow,”Elginsays.“It’stheultimateactive-learningstrategy.”– Jennifer Michalowski

To read more about the SEA-PHAGES program, go to hhmi.org/bulletin/fall-2015.

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Chronicle / Up Close

Wild ImmunologyCollecting data in the great outdoors brings a fresh perspective to work in the lab.danbolnickhas asummerritual.Almosteveryyearforthepastdecade,he’smadethe2,400-miletrekfromhishomeinAustin,Texas,toacampsiteonVancouverIsland.It’snosecretthatBritishColumbia’smajesticsnow-cappedmountains,pristinelakes,andmossyold-growthrainforestsareperfectforoff-the-gridgetaways.ButtheHHMIearlycareerscientistisn’tafteralittleR&R.He’smoreinterestedinalittlethumb-sizedfishthatmakesitshomeintheisland’sremotelakesandstreams.

InhislabattheUniversityofTexasatAustin,Bolnickusesauniquecombinationofecology,evolutionarybiology,genetics,

andimmunologytounderstandhowthethree-spinedsticklebackfish,alsoknownasGasterosteus aculeatus,interactswithparasites.Hisgoalistouncoverthegenesandimmuneprocessesthefishusestoprotectitselfagainsthelminths–parasitictapewormsthatareacquiredbyeatinginfectedzooplankton.And,thankstothelasticeage,themyriadlakesandstreamsthatdotVancouverIslandprovidetheperfectsiteforBolnick’ssummertimefieldstudies.

“Ifyouwanttounderstandhowvertebratesgetridoftapeworms,whatyoureallyneedtodoisfindvertebratepopulationsthatdon’thavetapewormsandvertebratepopulationsthathavealotoftapeworms,andthenaskwhatthedifferenceis,”Bolnickexplains.

Twelvethousandyearsago,retreatingglacierscreatedcountlesslakesandstreamsonVancouverIsland–agulfislandaboutthesizeofBelgiumthatliesjustnorthwestofSeattle.Thesebodiesofwaterwereeventuallycolonizedbythestickleback’smarineancestors,whoprovedremarkablysuccessfulinadaptingtonicheenvironmentsintheirnewfreshwaterdwellings.Acrossthesedifferenthabitats,sticklebackstodayexhibitincrediblevariationinsize,behavior,skeletalmorphology,feedingecology,andbreedingcolor.

“Everywatershed,everyriversystem,everylakerepresentsareplicateofanunparalleledevolutionaryexperiment,”saysBolnick.

Theparasiticpopulationsalsodiffer,totheextentthatadjoininglakesandstreamsoftenhavedistinctparasitecommunities.Asaresult,somesticklebackpopulationshaveonlyafewparasites,whileothersareheavilyinfested.ThesevariationsprovideBolnick’steamwiththeopportunitytoseehowindividualsticklebackpopulationshaveevolveddifferentimmunologicalresponsestotheiruniqueparasiteloads.

Out and AboutBolnickestimateshe’svisitednearly100differentlakes,streams,andestuariesonVancouverIslandsincehestartedstudyingthestickleback15yearsago.Hisfieldtripsrangefromsixweekstotwomonthsandcaninvolveasfewasoneortwoscientistsorasmanyas25.Thedaysarefullandlong–inthesummertime,islanddaylightcanlastupto16hours,andtheteamtakesfulladvantageofit.

“OnedrawbackoflivinginTexasanddoingfieldresearchinBritishColumbiaisthelimitedtimethatwegettospendupthere,”saysBolnick.“Wetryandmakethemostofit,whichmeansalotofearlymornings.”Eachsummer,Bolnick’sgoalistocollectenoughfish,anddata,tosustainhisgroupuntilthenextyear’strip.

Mostdaysinthefieldstartwithsticklebackcollection.“Theterrainupthereisreallyphysicalincertainplaces,”explainsJesseWeber,apostdocinBolnick’slab.“Sometimesyouhavetohikeanhourjusttogettothelakethatyou’rehopingtosamplefrom,andthenyouhavetobeabletotransferallthosefishbackout.”Thefateofthosecapturedsticklebacksdependsontheexperimentdujour.

Ifthefisharedestinedforgeneticmappingstudies,theirtailfinsareplacedinethanolforDNAextractions,whiletheirbodies(includinganyparasitesonboard)arepreservedinformaldehyde;everythingisshippedbacktoTexasforanalysis.Bolnick’steamusesthedatafromthesespecimenstocomparetheresistancegenesandparasitesfoundindifferentpopulationsofsticklebacks.

Othersticklebacksaretakentoneighboringlakes,wheretheyareplacedin


For more about the Bamfield stickleback aquarium,



enclosures;theideawiththiscohortistoseehowtheyfareinadifferentecologicalniche.Bolnickwantstoknowifthetransplantsaremoreresistanttotheirnativeparasitesthantounfamiliarparasites.

Stillotherfishareplacedincoolersandtakentoafieldstation.There,theyarematedwithsticklebacksfromotherlakesandstreams.TheeggsproducedfromtheseencountersthengobycartotheBamfieldMarineSciencesCentre(seeWeb-Extrasidebar,“OpportunityKnocks”)–adriveaslongaseighthours–wheretheyareraisedtoadulthoodandthenbredtocreatesecond-generationhybrids.Ayearandahalflater,theBamfieldfishretracetheroadtrip,returningtocagesintheirgrandparents’nativeenvironments.Theseexperimentswill

helpthescientistsidentifygenesthatconferparasiteresistance.

Althoughcreatingaresearchprogramaroundafieldsitethattakesfourdaysofdrivingtoreachseemsimpractical,thedataBolnickandhiscolleaguesarecollectingmightonedayhelpcombatparasite-bornediseasesinhumans.ThetimeawayfromAustinalsogivesthescientistsafreshperspectiveontheirresearch.“VancouverIslandiswheresomeofourbestthinkinghappens,”saysWeber.“Aftersittingtherealldaylong,lookingatthefish,westarttoviewourdisciplineinawholedifferentway.Ithinkthatalmosteveryevolutionarybiologistwillsaythatthefieldiswheresomeoftheirbestideashappen,becausethat’swhereinspirationcomesfrom.”–Nicole Kresge

“Every watershed, every river system, every lake represents a replicate of an unparalleled evolutionary experiment.”—danbolnickJu

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Chronicle / Lab Book

I N B R I E F

TEASING OUT NEURONAL FUNCTIONThe brain holds a host of different kinds of neurons, each with its own job. Though you might think neuronal cells are highly organized, they are in fact intertwined in a colossal tangle. For scientists who want to study particular neuron types individually, teasing them apart is a major challenge.

Now, a team of researchers – led by HHMI Investigators Jeremy Nathans and Joseph Ecker, and Janelia Group Leader Sean Eddy – has devised a way to study individual cell types without getting mired in the tangle. Rather than trying to separate cells of a certain type from their neighbors, they’ve developed a way to isolate their nuclei. From there, they can study the cells’ DNA, which provides information

about the cells’ activity and history.

“We weren’t sure what to

expect. This was an exploratory,

discovery-level project,” says Ecker

of the study, published June 17, 2015, in Neuron.

But already, the method has revealed astonishing differences in cell types previously thought to be similar in function. “That means there’s a lot of additional information here,” says Ecker. Using the new technology, scientists will not only be able to delve even deeper into the secrets of the brain, but they might also gain greater understanding of other systems in the body as well.

RADICAL VACCINE HAMPERS HERPESThe herpes simplex virus infects millions of people worldwide, yet the

pathogen has for decades thwarted attempts to develop a vaccine.

Most efforts by scientists to create a herpes vaccine have focused on glycoprotein D (gD), a protein that triggers the production of protective antibodies. However, attempts to exploit gD in a vaccine have been futile.

“It was necessary to shake the field up and go another route,” says virologist and infectious disease physician Betsy Herold. So she and HHMI Investigator William Jacobs, both at the Albert Einstein College of Medicine, joined forces to take a radically different approach.

Instead of using gD, the researchers used a mutant strain of the virus lacking gD. “Once we had this mutant in our hands,” says Herold, “it was a logical, scientifically driven hypothesis to say, ‘This strain would be 100-percent safe and might elicit a very different immune

response than the gD subunit vaccines that have been tried.’”

The study, published March 10, 2015, in eLife, tested the hypothesis in mice. The new vaccine completely protected the mice from the most common herpes infections, without any adverse effects.

If the vaccine works in humans as well as it does in mice, it could have a profound impact on the global prevalence of herpes.

A COMPASS FOR FLIESIf you’ve ever made your way through a dark room, you’ve relied on neurons to help maintain your balance and bearings without vision. A fly’s brain is much less complex than a human’s, yet flies, too, can keep a sense of direction in the dark,

scientists at Janelia Research Campus have found.

Group Leader Vivek Jayaraman

and postdoc Johannes Seelig

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Hangry? Here’s WhyScientists unravel why feeling hungry can also mean feeling angry.let’s behonest ;dietingisrough.Hungercandeflateadieter’sspiritandrenderfriendsandco-workersunbearable.

Still,hungerisevolutionarilybeneficial,asitsignalswhenourbodiesneedfood.Eatingactivatesrewardsystemsinthebrain,butscientistshavepuzzledfordecadesoverwhyourmoodturnsbleakwhenhungerhits.

ScottSternson,agroupleaderatJaneliaResearchCampus,decidedtotacklethatquestioninmice.Histeamstartedbylookingatthebrain’sagouti-related

peptide(AGRP)neurons,which,whenactivatedinmiceoptogenetically,elicitvoraciouseating.

Theresearcherspresentedwell-fedmicewithtwoflavoredgels;themiceshowednopreferenceforoneovertheother,andneitherhadnutritionalvalue.Wheneverthemicenibbledatoneofthegels,scientistsactivatedtheirAGRPneurons.Surprisingly,themicebeganavoidingthatgel.

Tofurthertestthelink,Sternson’steamactivatedtheAGRPneuronseverytimethemicewenttoacertainpartoftheircage.Sureenough,themicebeganavoidingthatarea.

Whenthescientistspeeredintotherodents’brains,theyobservedthatAGRPneuronsareindeedactivewhentheanimalsarehungry.Buttheneuronsshowedlowactivityduringeating.Infact,they’reinhibitedassoonasfoodissensed.

Thus,itappearsthatAGRPneuronsencourageustopursuefoodtoavoidastateofphysiologicalneedfornutrients.Basedonhisteam’sfindings,publishedApril27,2015,in Nature,SternsonthinkstheunpleasantfeelingassociatedwithAGRPactivationpromptsthedrivetofindfood.Thisisimportantevolutionarily,asanimalsoftenfacerisksinseekingfood.Ifhungerisunpleasant,animals

The brain’s hunger-sensitive AGRP neurons (green) are responsible for the unpleasant feeling that drives us to snack.

aremorelikelytotakethatrisk,ensuringtheirsurvival.

Whilethatworksforanimals,it’stoughondieters.“Whenpeopletryaweight-lossdietandfindittobeunpleasant...it’sprettylikelythattheelevatedactivityoftheAGRPneuronshassomethingtodowithit,”Sternsonsays.

Withthatinmind,scientistsarelookingathowtheymightinterferewithAGRPneuronactivity.Iftheneuronsbehavesimilarlyinhumans,helpindroppingthoseextrapoundsmaynotbefaroff.– Anzar Abbas

39

in a virtual reality arena to observe the insect’s neurons as it walks. The study, published May 14, 2015, in Nature, focused on a part of the fly brain called the ellipsoid body, a donut-shaped structure suspected to be involved in directional movement.

The researchers saw a strong relationship between the fly’s orientation relative to its visual surroundings and the neurons activated in the ellipsoid body. When the fly changed direction, even in total darkness, neuronal activity shifted from one part of the ellipsoid body to another, much like the needle of a compass.

“We think we have a window into the fly’s internal model of its world,” says Vivek, who believes ellipsoid body neurons may share characteristics with human head direction cells. “We’re starting to see increasing evidence that the fly may have a lot to tell us about how our own brains work, even when it comes to more complex aspects of cognition.”

RARE MUTATION MAKES FLU FATAL While catching the flu might be an inconsequential annoyance for many of us, the flu virus can prove life threatening in some people. Research led by HHMI Investigator Jean-Laurent Casanova at Rockefeller University tackled the question of why some patients respond differently to the virus than others.

The study, published April 24, 2015, in Science, describes a two-year-old girl who had been treated for a severe case of the flu at the Necker Hospital for Sick Children in France. The researchers sequenced her exome to hunt down the reason for her immune system’s weakened response to the virus.

What they found was a rare mutation in her IRF7 gene, known to be responsible for the production of antiviral molecules called interferons. Without the functional protein, a patient would have an inadequate response to the flu virus.

“Now we have proof that life-threatening flu, an infectious disease, can also be a genetic disease,” says Casanova, whose past work has identified other mutations that make patients more vulnerable to a variety of infectious diseases.

Understanding IRF7’s role in fighting the flu virus may allow doctors to consider other treatment options, such as administering interferons, when faced with severe unexplained flu.

JAWBONE REVEALS NEANDERTHAL ORIGINSScientists have successfully retrieved and examined DNA from a 40,000-year-old bone.

And not just any old bone. This human jawbone, found in 2002 in a Romanian cave

called Peștera cu Oase, dates back to a critical period of Europe’s history when modern humans were replacing Neanderthals. Scientists have always wondered how this transition happened. Now, the bone’s DNA indicates that it belonged to a modern human whose recent ancestors included Neanderthals.

On average, humans today living outside Sub-Saharan Africa owe about 2 percent of their genes to Neanderthal ancestors. The study, published August 13, 2015, in Nature, shows that 6 to 9 percent of the Oase bone’s DNA came from Neanderthals.

“The sample is more closely

related to Neanderthals

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Made-to-order MoleculesA new invention acts as a molecular 3-D printer.whenchemistfriedrichwöhleraccidentlymadesyntheticureaabout200yearsago,hestumbleduponafeatthathasoccupiedscientistseversince:thesynthesisofsmallmolecules.

Today,weusesmallmoleculeseverywhere.Youcanfindtheminmostmedicines,foods,scientificresearch–evencoffeesweetenersandlightbulbs.Yetwhenitcomestothevastpossibilitiesarisingfromsmallmoleculeproduction,we’vebarelyscratchedthesurface.

“Thebottleneckissynthesis,”saysMartinBurke,anHHMIearlycareerscientistattheUniversityofIllinoisatUrbana-Champaign.Todate,makingsmallmoleculeshasrequiredacustomizedapproachachievableonlybyhighlytrainedspecialists.

Butnow,Burkeandhisteamhavedevelopedaninventionthatextendsthat

abilityfromaselectfewtoanyonewithacomputer.“We’vecreatedamachinethatcandoon-demandsmallmoleculesynthesis–kindoflikea3-Dprinterforsmallmolecules.”

Burkesaysthemachine,describedinScience onMarch13,2015,wasinspiredbylivingorganisms.“Naturemakesmostsmallmoleculenaturalproductsthroughverysimplebuilding-blockchemistry....Soinasense,natureisalreadytellingustheanswer.”

Themachinetakesbasicchemicalmodulesandstitchesthemtogethertocreatesmallmolecules.Whenmixedandmatchedindifferentcombinations,thesebuildingblockscangenerateaplethoraofnewsmallmolecules

–madeautomaticallyandusingrelativelylittleeffort.

“Historyspeaksstronglytothemajorimpactthatcanbeachievedwhenyoutakeapowerfultechnologylikemoleculemakingandputitintothehandsofeveryone,”saysBurke,whoselong-termvisionistohaveawebsitewhereanyoneintheworld–achemist,biologist,engineer,orhighschoolstudent–canordersmallmoleculestobemadeandshippeddirectlytothemselves.Fornow,themachineisalreadyenablinganewbiotechcompanytoenhanceitsdrugdevelopmentefforts;ithasthebroaderpotentialtoexpandpossibilitiesinmanyfieldsofscientificresearch.– Anzar Abbas

Taking cues from nature, this molecule-making machine couples chemical building blocks to create small molecules.

40

Chronicle / Lab Book

Reich, an HHMI investigator at Harvard Medical School, who co-led the study with Svante Pääbo at the Max Planck Institute in Germany.

The data suggest that the Oase individual had a Neanderthal ancestor as recently as four to six generations back. “It’s an incredibly unexpected thing,” Reich says. “In the last few years, we’ve documented interbreeding between Neanderthals and modern humans. But we never thought we’d be so lucky to find someone so close to the event.”

LESSONS FROM PARROTSIf you’ve wondered how parrots can imitate humans so well, you’re in good company – many scientists have marveled at the behavior. Among them is HHMI Investigator Erich Jarvis of

Duke University, who studies how certain birds mimic humans.

Scientists have known that the brains of certain vocal-learning bird species have specialized neurons involved in learning to produce sounds, but they did not know why parrots are better at imitating compared to other rare vocal-learning bird groups. In a study published June 24, 2015, in PLOS ONE, Jarvis and his postdoc Mukta Chakraborty found that parrots have a “shell system” of vocal-learning neurons not found in other species. This shell surrounds a “core system” found in songbirds and hummingbirds.

By comparing nine different parrot species, the team learned

that the larger this shell was in a particular species’ brain, the better those birds were at imitating spoken language. This suggested the shell might play a role in the skill.

Jarvis hypothesizes that the shell emerged from a

duplication of the core language region millions of years ago, developing a more complex function as it evolved. “Maybe in the human brain we have multiple duplications of an ancient pathway that’s controlling our complex speech abilities.”

COMPLEX SENSORY CIRCUITSWe rarely use just one sense at a time. Even when we eat, our experience is affected by a food’s look, feel, and smell, as well as its taste. Other creatures’ brains appear to be wired similarly.

Fruit fly larvae seem to integrate cues from multiple senses, too. For example, a larva is more likely to roll over to defend itself from a predator if it’s sensing a noxious stimulus – stinging, for example – and physical cues at the same time, according to findings from scientists at Janelia Research Campus.

Janelia Group Leaders Marta Zlatic and Albert Cardona led a

team that mapped the neurons involved in this behavior. In a study published April 20, 2015, in Nature, the researchers mechanically stimulated fruit fly larvae while activating their nociceptor, or injury-sensing, neurons to understand the circuits involved from the point of stimulation to when the larva rolls over.

Surprisingly, they found that the circuits for nociceptive and mechanical stimulation were integrated on multiple levels, resulting in a very sophisticated structure. “Initially, I would have thought this circuit would be simpler, but the complex network could really allow the animal to do a complex computation and react to very particular combinations of cues,” says Zlatic.

The team has made its electron micrograph information freely available, with the hope that it will help in mapping the insect’s entire nervous system.


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A Test Tells the TaleOne drop of blood reveals a history of viral infection. stephenelledgeand hisresearchteamatBrighamandWomen’sHospitalinBostonhavedevelopedatechniquethatwillallowdoctorstolearnaboutapatient’sentireviralinfectionhistoryfromjustasingledropofhisorherblood.

Thetechnique,calledVirScan,isagiantleapforwardfromcurrenttestsdesignedtohuntforindividualviruses.VirScan,whichcostsonly$25,searchesforall206speciesofvirusesknowntoinfecthumans.Evaluatedinmorethan500peopleonfourcontinents,thetestisprovingbeneficialinbothhealthcareandmedicalresearch.

Withamorethoroughpatientclinicalhistory,adoctorcanmakebettertreatmentdecisions.“Youcouldgotothedoctoronce

ayearandgetallyourviruseschecked,”saysElledge,anHHMIinvestigator.“It’scheaptodoit,it’sroutine,andyourdoctormightpickuponnewinfections...beforetheydoalotofdamage.”

Knowingpatientviralinfectionhistoriescanalsohelpscientistsstudyingdiseasesunderstandassociationspreviouslyunknowntothem.“Wehaveanabilitytonowask,‘Okay,whataboutautoimmunediseasesliketype1diabetes,’”saysElledge.“Isthereanassociationbetweenthatdiseaseandaparticulartypeofviralinfection?”

VirScanworksbyexploitingthefactthatwehavememoriesofpastviralinfectionsfloatinginourblood–immuneparticlesthatwillattackagivenvirusifitdecidestoreturn.Thetestintroducesahostofvirus-mimickingmoleculesintoapatient’sbloodsampletoseewhichoneselicitaresponse.Ifaparticularvirusmoleculeisattacked,itislikelythepersonwasexposedtothatvirusinthepast.TheteampublisheddetailsofthetestonJune5,2015,inScience.

ElledgethinksVirScanmightseeitsgreatestpotentialindevelopingcountries,wheredoctorscouldusethetesttotracktheextentofnewviralepidemicsinentirepopulations.– Anzar Abbas

Using a single drop of blood, a new test can detect antibodies against more than 200 species of virus, including this influenza virus.

34There’s more to this image of the mycobacteriophage Corndog than meets the eye – even more than its whimsical name. Look closely and you’ll see the faces of the student and faculty “phage hunters” from HHMI’s SEA-PHAGES program. Interwoven in this mosaic are snapshots of bacteria-infecting viruses, called phages, whose genomes are themselves a mosaic of modular components. Launched in 2008, SEA-PHAGES – Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science – has given thousands of undergraduates a taste of lab work by having them analyze the genomes of phages they find in local soils. Pooling that data has allowed a team led by HHMI Professor Graham Hatfull to compare the genomes of 627 different bacteriophages – including Corndog – found in the soil-dweller Mycobacterium smegmatis.

HHMI Bulletin / Fall 2015

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In the CrucibleA true Renaissance man,Antoine Lavoisierspent the years leading up to the FrenchRevolution consumed with civic and scientificactivity while immersed in the politicalcrucible of the times. In 1788 alone, he held five important public posts at once, including the directorship of the Gunpowder and Saltpeter Administration and a seat on theboard of the government’s central bank. At the same time, he was an active scientist, having built with his considerable fortune a state-of-the-art laboratory. There, he andhis wife, Marie-Anne, a noted scientistin her own right, conducted robust researchand participated in the race to identify the processes behind combustion. His theory on chemical reactions – published in a treatisein 1789, just four months before the fall of the Bastille – dispelled the last traces ofmedieval alchemic thinking and established the modern science of chemistry.

Lavoisier’s adaptation of Hales’s pedestal apparatus was nicely drawn by his wife as an illustration for his Opuscules physiques et chymiques, in which the results of these experimentswere recorded. In his version, he set a porcelaincrucible on a crystal pedestal, covered it with abell jar, and controlled the water level with a siphon.A layer of oil on the surface of the water under the jar prevented any gases released fromdissolving. In October of 1772, he put a lead oxide called minium [Pb

3O

4] into his crucible with a

small amount of charcoal and heated it throughthe bell jar with the burning glass, whose beamwas narrowly focused on the contents of the crucible. This method, common for smelting metals from oxide ores, produced a significant release of gas of some description, or elastic fluid. Although (uncharacteristically) Lavoisier didnot make an exact measurement of the gas, he recorded “a volume at least a thousand times greater” than that of the lead oxide used.

What actually happened in this experiment,though Lavoisier did not yet know it, was that the oxygen released in the reduction of lead oxide combined with carbon in the charcoalto form a large volume of carbon dioxide (fixed air). For his immediate purposes, the miniumexperiment demonstrated and confirmedan already known fact: the reduction of lead oxide released a gas. It also complemented the syntheses he had performed by combining air, phosphorus, and sulfur with an analysis where air was subtracted from a calx. Lavoisier’s

notion that air was fixed in the process ofcalcination (and released in the reduction of calces) was now supported at both ends.

Lavoisier was satisfied (or at least willing to claim) that these results had “CompletelyConfirmed my Conjectures.” The experimentson phosphorus, sulfur, and minium became the basis for the sealed note he deposited at the academy on November 1, 1772. The truthwas that even though Lavoisier was convincedhis discovery was “one of the most interesting that has been made since Stahl,” he still could not say precisely what had been discovered –nor did the discovery yet fit comfortably intohis evolving theory. Not until February of the following year would he feel confident enough to declare, in that famous lab notebook entry, that he was going to bring about “a revolution in physics and chemistry.”

Excerpt from Lavoisier in the Year One: The Birth of a

New Science in an Age of Revolution by Madison Smartt

Bell. © 2005 by Madison Smartt Bell. Reprinted

with permission from W.W. Norton & Company,

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Fall ’15 Vol. 28 No. 3

GlobalChangemakers

Undergrads are learning about – and solving – real-world

health care challenges.

in this issue Meet the 2015 HHMI Investigators

Peter Walter’s Unpredictable JourneyScience Jam at Woods Hole

4000 Jones Bridge Road Chevy Chase, Maryland 20815-6789www.hhmi.org

Address Service Requested

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To Bead or Not To BeadThese droplets may look like rain beading on a freshly waxed car,

but they are actually a super-concentrated form of an RNA-binding protein called hnRNPA1. Newly minted HHMI Investigator J. Paul Taylor

discovered that hnRNPA1’s liquid-like properties help stress granules – membrane-free clumps of RNA and protein – form rapidly, and reversibly,

when a cell encounters unexpected stress, such as extreme heat. This quicksilver response allows the cell to temporarily switch up the genes it’s

expressing. Learn more about these granules and their surprising role in neurodegenerative and muscle diseases in “Problem Solvers,” page 24.

Go online to watch a video of these droplets assembling and disassembling at hhmi.org/bulletin/fall-2015.

fall ’15 vol. 28 no. 3 bulletin - hhmi.org · 003 anewwchapatar6wwauios 3 james kegley...

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