fall ’14 vol. 27 no. 3 bulletin - howard hughes medical institute · 2014. 6. 5. · hhmi...

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When Cells Divide

Errors in the process can disable cells— unless they’re cancerousA

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Fall ’14 Vol. 27 No. 3

in this issue Bacterial Comrades

Meet the New ProfessorsEco-friendly Fertilizer

Deadly BeautyThis slow-moving marine snail, Conus geographus, packs venom

so powerful that less than half a teaspoon can kill a person. Small fish within the striking zone of its venomous harpoon don’t stand

a chance. Paradoxically, components of the venom are extremely strong pain killers—up to 10,000 times more effective than morphine.

HHMI Professor Baldomero Olivera has spent his career teasing apart the hundreds of toxins in the beautiful cone snail’s venom, in

hopes of turning the meat-eating mollusk’s poison into medicine. One drug is already available for patients. Learn more about Olivera’s

research and his efforts to advance science education around the world in the HHMI Bulletin (www.hhmi.org/bulletin/summer-2014).

12Cell division involves intricate choreography. Pairs of chromosomes (red) line up center stage where thin spindle fibers (green) tug the couples apart, pulling individual chromosomes to opposite sides of the cell. But sometimes the well-oiled performance hits a snag, leaving one or more pairs united. Two aneuploid daughter cells result—one with too many chromosomes and one with too few. Aneuploidy can mean curtains for the cells. One standout exception is cancer, where cellular missteps in division can lead to wildly successful reproduction. H

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HHMI Bulletin / Fall 2014

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Mysteries of the MindThe seat of all our thoughts and emotions, actions and memories, the brain’s capacity and complexity seem impossible to fully grasp. Yet, thanks to advances in recent years, neuroscientists can now envision a comprehensive picture of the brain in action, from molecules to cells and circuits to behavior. In April 2013, President Obama launched the BRAIN Initiative to underscore and accelerate this vision. Details of the initiative’s plan are now available in a report released in June by a working group co-chaired by HHMI Investigators Cori Bargmann and William Newsome, whose poetic preamble sets a powerful framework for the effort.

We stand on the verge of a great journey into the unknown—the interior terrain of thinking, feeling, perceiving, learning, deciding, and acting to achieve our goals—that is the special province of the human brain. These capacities are the essence of our minds and the aspects of being human that matter most to us. Remarkably, these powerful yet exquisitely nuanced capacities emerge from electrical and chemical interactions among roughly 100 billion nerve cells and glial cells that compose our brains. All human brains share basic anatomical circuits and synaptic interactions, but the precise pattern of connections and interactions are highly variable from person to person—and therein lies the source of the remarkable variation we see in human behavior, from the breathtaking dance of a ballerina, to the elegant craftsmanship of a master carpenter, to the shrewd judgment of an expert trader. Our brains make us who we are, enabling us to perceive beauty, teach our children, remember loved ones, react against injustice, learn from history, and imagine a different future.

The human brain is simply astonishing—no less astonishing to those of us who have

spent our careers studying its mysteries than to those new to thinking about the brain. President Obama, by creating the BRAIN Initiative, has provided an unprecedented opportunity to solve those mysteries. The challenge is to map the circuits of the brain, measure the fluctuating patterns of electrical and chemical activity flowing within those circuits, and understand how their interplay creates our unique cognitive and behavioral capabilities. We should pursue this goal simultaneously in humans and in simpler nervous systems in which we can learn important lessons far more quickly. But our ultimate goal is to understand our own brains.

Excerpted from BRAIN 2025: A Scientific Vision, a

Brain Research through Advancing Innovative

Technologies (BRAIN) Working Group Report to

the Advisory Committee to the Director, National

Institutes of Health. Published June 5, 2014.

ContentsFall ’14 Vol. 27 No. 03

Web-Only Content

See what artist Daniel Kohn created when he spent eight years in a lab, painting alongside scientists.

Listen as HHMI professors talk about overcoming challenges in science education.

Go with Adam Cohen on a quest to jump-start science education in Liberia after years of civil war.

Watch cells move, shuffle, and divide in a growing fruit fly embryo.

Learn why an abnormal chromosome number might give cancer cells an edge.

www.hhmi.org/bulletin

Cover image:

atelier olschinsky

This paper is certified by SmartWood

for FSC standards, which promote

environmentally appropriate, socially

beneficial, and economically viable

management of the world’s forests.

Departments president’s letter03 ScienceForward centrifuge04 ArtistsintheBuilding05 LessonsfromLiberia benchreport06 ATwistofFate08 TheSilencer:MicroRNA10 APhosphateFix perspectives&opinions30 OrchestralApproach intheClassroom32 Q&A–Whatchallenges doeducatorsfacewhen tryingtoimplement hands-onundergraduate scienceclassesat universities? chronicle34 Science Education TheNewFacesofChemistry36 Toolbox AnOff-SwitchforNeurons38 Lab Book UntanglingaViralInfection KeepingTabsonDevelopment WhattheNoseKnows observations MysteriesoftheMind

Features12 Errors in Division Whencellsdivide, chromosomesaren’talways doledoutequally.The consequencescanbedire.

20 Bold Experiments The2014HHMIprofessorsare bringinginnovationfromthe labintotheclassroom.

26 Developing Relationships Twostudieshintatbacteria’s deep-rootedinfluenceon animaldevelopment.

Developing Relationships, page 26

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Contributors

Telephone (301) 215.8500 • Fax (301) 215.8863 www.hhmi.org© 2014 Howard Hughes Medical InstituteTheopinions,beliefs,andviewpointsexpressedbyauthorsintheHHMI Bulletindonotnecessarilyreflecttheopinions,beliefs,viewpoints,orofficialpoliciesoftheHowardHughesMedicalInstitute.

HHMI TRUSTEESKurt L. Schmoke, Esq., ChairmanPresident / University of BaltimoreJames A. Baker, III, Esq.Senior Partner / Baker Botts LLPAmbassador Charlene BarshefskySenior International Partner WilmerHaleSusan Desmond-Hellmann, MD, MPHChief Executive Officer / Bill & Melinda Gates FoundationJoseph L. Goldstein, MDRegental Professor & Chairman / Department of Molecular Genetics University of Texas Southwestern Medical CenterGarnett L. KeithChairman / SeaBridge Investment Advisors, LLC Former Vice Chairman & Chief Investment Officer The Prudential Insurance Company of AmericaFred R. LummisChairman & CEO Platform Partners LLCSir Paul NursePresident / The Royal SocietyDame Alison F. Richard, PhDProfessor / Yale UniversityClayton S. Rose, PhDProfessor of Management Practice Harvard UniversityAnne M. TatlockDirector, Retired 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 / Senior Director, Campus ServicesHeidi E. Henning / V.P. & General CounselMohamoud Jibrell / V.P. for Information TechnologyNitin Kotak / V.P. & Chief Financial OfficerErin O’Shea, PhD / V.P. & Chief Scientific OfficerGerald M. Rubin, PhD / V.P. & Executive Director, Janelia Farm Research CampusKathy A. Wyszynski / V.P. for Human ResourcesLandis Zimmerman / V.P. & Chief Investment Officer

HHMI BULLETIN STAFFMary Beth Gardiner / EditorCori Vanchieri / Story EditorJim Keeley / Science EditorNicole Kresge / Assistant Editor

ADDITIONAL CONTRIBUTORSElaine Alibrandi, Michelle Cissell, Mark Farrell, Heather McDonald Pentagram / DesignAllied Printing / Printing & Binding

Asmall,creativestudiobasedinVienna,Austria,atelier olschinsky(coverand“ErrorsinDivision,”page12)representstheworkofPeterOlschinskyandVerenaWeiss,artistswhooperateinvariousfields,includinggraphicdesign,illustration,photography,andartdirection.

Megan Scudellari(“ErrorsinDivision,”page12)isaBoston-basedfreelancejournalistspecializinginthelifesciences.Herworkhasappearedin Newsweek,Nature,and Scientific American,amongotherpublications.Whenshe’snotwritingaboutscience,Meganisbusychasingherownbiologyexperiments—hertwochildren,agestwoandahalfandsevenmonths—aroundthehouse.

IllustratorRuth Marten (“ATwistofFate,”page6)hasahistoryofdepictinghair.Havingworkedformorethanthreedecades,includingtattooinginthebad(good)olddays,shenowexhibitsherworkatVanderGrintenGalerieinKöln,Germany,andteacheswatercolorattheSchoolofVisualArtsinNewYorkCity.

Emily Shur(“TheSilencer:MicroRNA,”page8)isaphotographerlivinginanextremelyoldhouseinLosAngeleswithherhusbandandtheirgrumpybulldog,TheBaroness.SheisagraduateofTischSchooloftheArtsatNewYorkUniversity,andherclientlistincludesThe New Yorker, The New York Times Magazine,Entertainment Weekly,andESPN the Magazine.

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President’s Letter

Science Forwardif youarea regularreaderoftheHHMI Bulletin,youmayhavenoticedsomethingdifferentonthecoverofthisissue.It’sournewlogo.We’vefreshenedupouridentityatHHMI—amovethatwefeelbetterreflectstheInstitute’sspiritofinnovationandboldcreativity.Weacknowledgeandcelebrateourrichhistoryofachievement,yetwehavenotbeenstandingstill.Indeed,wehavebeenevolvingandareadifferentInstitutetodaythanwewerejust10yearsago.Westrivetocontinuebuildingourreputationandtobetterarticulateourmission—ournewvisualidentityreflectsagreateropennessalongwithourforwardmomentum.

Overthelastdecade,we’vemadenotablestridestoadvancescienceandscienceeducation.We’velaunchedanddevelopedanewframeworkofcollaborative,interdisciplinaryresearchattheJaneliaResearchCampus.We’vebroadenedourhorizonsbysupportingresearchersinnewfields,suchasplantscience,andnewcountries—fromSouthAfricatoSouthKorea.We’velaunchedascientificjournalandnewonlinechannels,andcreatedadocumentaryfilmproductionstudiotofosterscienceliteracyintheclassroomandbeyond.Andwe’re

partneringwithotherfundersinthescientific,education,andphilanthropiccommunities,collaboratingtoamplifyourcollectiveimpact.

Asweexpandandbroadenouractivities,IcontinuetobeinspiredbythenewknowledgethatcomesoutofHHMIresearchers’labs.InthecoverstoryofthisissueoftheBulletin,you’llreadabouthowsomeoftheresearcherswesupportaregettingattherootofaneuploidy—theunevendistributionofchromosomesthatcanoccurduringerrorsincelldivision.HHMIInvestigatorsAngelikaAmon,HongtaoYu,andothersarediscoveringthemoleculardetailsbehindhowtheseerrorscanleadtounexpectedconsequences,includingtumorformation.Understandingthebasicmechanismsofcelldivision—howitworksandwhathappenswhentheprocessgoesawry—isanecessarysteptowardeffectivetreatmentsforcancerandotherdiseases.

Alsointhisissue,you’lllearnaboutourlatestclassofHHMIprofessors—top-tierscientistswhoreceivesupportfromHHMItoapplythesamecreativityintheirclassroomsastheydointheirlabs.Weareexcitedtowelcomethisnewgroup,whichisnotableforitsdiversityofideasforinnovatingscience

education.AnneMcNeil,achemistattheUniversityofMichigan,isoneofournewHHMIprofessors.Sheplanstoenergizeherschool’sintroductoryorganicchemistrylabbycreatingreal-worldlabprojects,suchashavingstudentstransformusedvegetableoilfromrestaurantsintobiodieselfuelforlocalfarmers.AtBostonUniversity,bioengineerMuhammadZamanmakesabstractproblemsconcreteforstudentsbyaskingthemtosolveglobalhealthchallenges.Insteadofmeasuringstressesonabeam,forexample,studentsmightcalculatethestressonapairofcrutchesforadisabledchild—arealprobleminZambia,wheredisabilitiesarecommon.

Thesedynamicapproaches—inthelaboratoryandintheclassroom—arethehallmarkofHHMI,andtheessenceofwhatwewantedtocaptureinournewlogo.Wehopeitsfresh,modernlookwillsignalourdesiretoevolveandbuildmomentuminourcontinuingcommitmenttomovescienceforward.“Our new visual identity

reflects a greater openness along with our forward momentum.”—roberttjian

Centrifuge4 Fall 2014 / HHMI Bulletin

Artists in the Building steppingoffthe elevatoronanyflooroftheBroadInstituteinCambridge,Massachusetts,visitorsandscientistsaregreetedwithart:vibrant,colorfulcurves;thickblacklines;andgreenandorangespirals.Theinstallation,called Instance of a Dataset,consistsofsquarewatercolorprintsassembledinpatternsonawiregrid.Fromtoptobottom,itspanssevenfloors.

CreatedbythefirstBroadartist-in-residence,DanielKohn,itistheartisticfruitoftheeightyearshespentdiscussing,disagreeing,andcollaboratingwithscientistsattheBroadInstitute.

Kohnseeshiscollectionofpaintingsasametaphorforwhat

heobservedscientistsdoinginthelab:tryingtomakemeaningbymanipulatingandassemblingbanksofdata.

HHMIInvestigatorToddGolublaunchedtheBroadArtist-in-ResidenceProgramafterviewingaKohnpaintingattheUteStebichGallery,inLenox,Massachusetts.Itseemedtospeakofthecurrentstateofscience:someareasareknowningreatdetail,andothersremainverymuchamystery.GolubandKohnstartedaconversationaboutthesimilaritiesbetweenartandscience.

Fromtheirtalks,anideawasborn:Kohnwould“hangout”attheBroad—initiallyinanunfunded,informalway—andseewhatarthecreatedafterinteractingwithscientists.Afterthreeyears,Golubformalizedtheartist-in-residenceprogramandconvertedoneofthelabbaysintoaworkspaceforKohn.Theartistpaintedalongsidethescientistsastheyworkedwithtesttubesandgenesequencers.

“Iclearedoutsomelabtables,broughtinsomeplywood,andworkedinwatercolors,pencil,andcharcoal,”Kohnsays.Hisusualoilpaintsandturpentineweretooflammableforthelab.

TheresultoftheresidencywasKohn’sseven-storyinstallation.Healsodesignedadigitalappcalled“AssemblySpace”souserscouldarrangethesquaresintowhateverpatternstheydesired,saveandsharethem,andevenbuildoffothers’assemblies.Whenhemovedthesquaresonhiscomputer,hefoundtheycreatedasecondaryorderthatremindedhimofthewayscientistsworkwithdata.

Artandsciencearemuchcloserthantheymightatfirstappear,saysGolub,chiefscientificofficerattheBroadInstituteoftheMassachusettsInstituteofTechnologyandHarvardUniversity.Ratherthansittingateitherendofasubjective-objectivespectrum,bothare,ultimately,humanattemptstodescribe,understand,andrepresenttheworld.

“Ithinksomeofthemostexcitingadvancesinscienceamounttolookingatanancientprobleminanewway,”Golubsays.“Itseemstomethat’swhatartistsdo:theyreflectonwhat’shappeningintheworldthroughalensthatallowsbothartistandviewertoseeanoldproblemfromafreshperspective.”

Kohnagrees,“Theyarebothknowledge-generatingfields,andonceyoulookatitthatway,youseetheyareonparalleltracks,notoppositetracks.”

SinceKohn’sresidency,twootherartistshavespentmonths-longresidenciesattheBroad,creatingworksinspiredbytheirconversationswithscientists.SculptorMaskullLasserreistherenow.

Fromtheartists,Golubhaslearnedtokeepreinventinghisapproachasscienceevolves.He’salsoremindedthatwhatscientiststhinkarefoundationaltruthsareoftenjustassumptionsworthrevisiting.“Thepointisforartistsandscientiststoprovokeeachotherinnewdirections,”Golubsays.—Lauren Arcuri Ware

Go to www.hhmi.org/bulletin/fall-2014 for a slideshow of

Kohn’s artwork and studio.

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Lessons from Liberiawhenadamcohen wasahighschoolstudentin1994,henoticedhisscienceclubadvisorcollectingpensandpencilsdroppedinthehallways.Curious,heaskedwhy.AsumanaJabatehRandolphrepliedthathesentthemtoniecesandnephewsbackinLiberia,wherecivilwarmadeeverythingscarce.AsasophomoreatNewYork’sHunterCollegeHighSchool,CohenknewnothingaboutLiberiaotherthan“thatsuchacountryexisted.”WhenheaskedRandolphifhecouldvisitLiberia,Randolphsaidno—toodangerous.

In2009,Cohenaskedagain.Bythen,he’dearnedphysicsdoctoratesattheUniversityofCambridgeandStanfordUniversity,beenchosenbyMIT Technology Reviewasatopinnovatorunderage35,andwasteachingatHarvardUniversity.Thistime,Randolphsaidyes.

ThatsummerCohen,accompaniedbyhisfriendBenjaminRapoportwhowasanMD/PhDstudentandfellowHuntergrad,wenttotheWestAfricancountrytomentorscienceteachers.FourteenyearsofintermittentwarhaddestroyedmostLiberianschools.“Thequestionwas,howdoyoure-primetheeducationpump?”recallsCohen.

HeandRapoportbeganbyteachingthegermtheoryofdisease.TheyfashionedPetri

To see a movie of Cohen’s flashing cells, go to www.hhmi.org/bulletin/fall-2014.

Ad

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dishesbycuttingthebottomsfromwaterbottlesandfillingthemwithgelatinscavengedfromstewpots.Theyshowedlocalteachersthatstudentscouldculturemicroorganismsfromtheirfingersinthegelatinandthencompareculturesfromwashedandunwashedhands.

Toteachmath,thetwoworkedoutlow-techexperiments,“thingsyoucoulddowithnoelectricity,norunningwater—justyourbody,andcounting.”Forinstance,childrenmeasuredtheirheartratesbeforeandafterjumpingjacks.Cohenrememberstwochildrensoweakfrommalnutritiontheycouldn’tjump.“Thatwasquiteaneyeopener,”hesays.Themenaddednutritiontotheircurriculum.

Lessonsonelectricitycameaftertheyheardthatsomeonehadfriedthenation’sonlyx-raymachinebyconnectingittothewronggenerator.Theytaughtteachersandstudentstobuildbatteriesfromlimes,ironnails,

andcopperwire.“You’dfeelalittlejoltifyoutouchedtheelectrodestoyourtongue,”Cohenrecalls.“Itwasfun.”In2010,thetwomenreturnedtoleadaworkshopforscienceteachersattheUniversityofLiberiainMonrovia.

Sincethen,Cohen’sresearchhasrampedup,andhehasn’tbeenabletovisitLiberiaagain.AnHHMIinvestigatoratHarvardsince2013,Cohendevelopstoolstostudymoleculesandcells;forexample,hisgroupdevisedatechniquetoconvertelectricalimpulsesincellsintoflashesoflight.Theflashesallowscientiststovisualizehowdrugsaffectthecells,creating“aclinicaltrialinadish.”

ThescarcityhesawinLiberiaremindsCohentoappreciatehisowncircumstances.Heremembersthat,whenhevisitedin2009,theaverageLiberiansurvivedon$300ayear,while“we’lldrop300bucksforalittlemirrorwithoutthinkingaboutit,”hesays.“I’mmoreconscious,ofcourse,ofhowfortunatewearehere.”

Cohenaskshisstudentstoconsiderhowscienceandengineeringmightremedysuchinequities.“Sometimesthere’samisperceptionthattomakeadifference,youhavetogointoactivism,orlaw,orpolitics.ItrytoshowthemthatgoodengineeringandgoodtechnicalapproacheswillnotalwayssufficetofixproblemsliketheonespeoplefaceinLiberia,buttheycanmakeabigdifference.”—Cathy Shufro

Liberian science students learned the importance of collecting data.

Bench Report6 Fall2014/HHMIBulletin

A Twist of FateAchangeinoneregulatorygenedetermineshaircolorbutleavesotherimportantfunctionsintact.blondhairhas goneinandoutofstyleinWesternsocietiesforthousandsofyears.TheheroesandgodsofGreekmythologywereoftengracedwithgoldentressesasasymbolofyouthandbeauty.InancientRome,light-hairedwomendyedtheirhairdarktostayinvogue.Throughchangingfashionsandshiftingculturalperceptions,thebiologicalbasisofhaircolorhasremainedpoorlyunderstood.Now,researchthatbeganwithalittlefishcalledthethree-spinedsticklebackhashelpedansweralong-standingquestionabouthumanappearance:whatgivessomepeopleblondhairandothersbrown?

Sticklebackshavealotofstoriestotellaboutevolutionarybiology.Thefishhavebeenadaptingtofreshwaterhabitatseversincetheir

ocean-dwellingancestorsfoundthemselvesstrandedinnewlyformedlakesandstreamsattheendofthelasticeage.TheirphysicalandgeneticvariationsprovideHHMIInvestigatorDavidKingsleywithcluesabouthoworganismsadapttochangingenvironments.Becauseevolutionmakesrepeateduseofthesamegenetictools,followingcluesfromthefishhassometimesledKingsley’sresearchoutofstickleback-inhabitedwatersandintothegenomesofotherspecies.

In2007,Kingsley’steamatStanfordUniversitydiscoveredthatchangesaffectingasinglesticklebackgenehadgivenrisetopigmentationchangesthathelpedthefishblendintotheirsurroundings,improvingtheiroddsofevadingpredators.

Thegene,called Kit ligand, encodesasignalingmoleculethathelpscreatepigment-producingcells.Havingseenthatthegenewasusedoverandoveragainwheneversticklebacksevolvednewskincolors,Kingsleywonderedifsimilarchangesmighthavealteredpigmentationinotherspecies.

HisteamsoonshowedthatdifferentversionsofKit ligandwereassociatedwithvariationsinhumanskincolor.Aroundthattime,anothergroup’sgeneticanalysisofNorthernEuropeanslinkedaregionofDNAnearthehumanKit ligandgenetoblondhaircolor.Thesechangesdidnotalterthe Kit ligandgenedirectly,however.Instead,inbothfishandhumans,thealterationswereinregionsoutsidetheprotein-codinggenesequence,whereregulatoryelementsthatinfluencegeneactivityoftenlie.“Thekeymarkerthat’sassociatedwithblondhaircolorinNorthernEuropeansis350,000basesawayfromthegene,”Kingsleysays.Thus,aregulatorymutationwaslikelyresponsibleforchangingpigmentinfishandinhumans—consistentwithanemergingpatternofevolution-drivingalterationsthatKingsleyhasobservedthroughouthissticklebackresearch.

ButtheKit ligandgenedoesmuchmorethanpromotepigmentproduction.Kitligandisoneofthemostimportantsignalingmoleculesinvertebratedevelopment.Ithelpsguideformationofbloodcellsandspermandeggprogenitorcells,inadditiontopigmentcells.KingsleywantedtoknowhowamodificationtotheDNAsurroundingKit ligand coulddrivecommonchangesincolorationwithoutcompromisingtheprotein’sothercrucialfunctions.

CatherineGuenther,aresearchspecialistinKingsley’slab,pinpointedasnippetinhumanDNAnearKit ligandthataffectedhairfolliclefunction.Oncloserexamination,theteamrealizedthat,inNorthernEuropeans,asingleletterofgeneticcodeinthisregiondifferedbetweenblondsandbrunettes.Swappingoutthatletterconvertedtheregulatoryregionfromthebrunettesequencetotheblondsequence.

Placingthegeneunderthecontrolofthe“blond”switchreducedthegene’sactivityinculturedhumancellsbyabout20percentcomparedtothe“brunette”switch.Althoughthechangewassmall,KingsleyandGuenthersuspectedtheyhadidentifiedthecriticalpointintheDNAsequence.TheytestedthatideabyengineeringmicewithaKit ligandgeneunderthecontrolofthehumanbrunetteortheblondhairenhancer,sothatapairofmicedifferedonlybythesingleletterinthehairfollicleswitch.

Theotherwiseidenticalmicewereeasytotellapart:theanimalcarryingtheblondversionoftheswitchhadmarkedlypalerfur.“Sureenough,thatonebasepairisenoughtolightenthehaircoloroftheanimals,”Kingsleysays.“Thegeneticmechanismthat

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controlsblondhairdoesn’talterthebiologyofanyotherpartofthebody.It’satraitthat’sskindeep,andonlyskindeep.”HeandhiscolleaguesreportedontheregulatoryswitchintheJuly2014issueofNature Genetics.

The Kit ligandregulatoryswitchisnottheonlygeneticelementresponsibleforblondhairinhumans,however.Afewothergeneticassociationshavebeentrackeddowntoparticularmutations,butactualDNAsequencechangesresponsibleformanyhumantraitsremainpoorlyunderstood,inpartbecausesubtleregulatoryadjustmentsaredifficulttoidentify.“Alittleuporalittledownnexttokeygenes—ratherthanonoroff—isenoughtoproducedifferenttraits,”Kingsleysays.“Thetrickis,whichswitcheshavechangedtoproducewhichtrait?”

Kingsley’steamissearchingforotherpotentialregulatorsofKit ligand,whichtheysuspectmightalsoregulatethegene’sotherfunctionswithsimilarprecision.Buthehasn’tforgottenabouthisfavoritefish.“We’restillusingthesticklebacktoidentifyhowgeneralprinciplesofevolutionwork,”hesays.“Thelessonswelearnfromthefishturnouttoapplytolotsofotherorganisms,includingourselves.”—Jennifer MichalowskiR

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The Silencer: MicroRNATinyRNAshelpplantsthrivebystiflingotherRNAs.Wheretheydotheirworkandhowtheyavoiddestructionisbecomingclearer.anunusualarabidopsis plantwithdark,curlyleavesandclustersoftinier-than-normalflowersseededXuemeiChen’sinterestinsmallstrandsofRNAthatdobigthings.Only20to24nucleotideslong,microRNAsmakeanoutsizeddifferenceinhowplantsdevelop,saysChen,anHHMI–GordonandBettyMooreFoundationinvestigatorattheUniversityofCalifornia,Riverside.

“MicroRNAsarereallyshort,andtheydon’tencodeanyprotein,”explainsChenasshepreparesacupofherbalteaforavisitor.“Instead,theyregulatethefateofmessengerRNAs.”MicroRNAsfindandturnoffspecificmessengerRNAs(mRNAs)tofine-tunegeneexpression.

MicroRNAswereconsideredan“oddity”whenfirstdiscoveredinwormsinthe1990s,

saysChen.Herswasoneofthreelaboratoriestodetermine,in2002,thatplantshavethemtoo.Herstrange-looking Arabidopsis hadamutationinagene, HEN1,which,itturnedout,theplantneededtoproduceallmicroRNAs.Chen’spostdoc,WonkeunPark,showedthatthe HEN1mutantshadlowerlevelsofmicroRNAsthannormalplants.

“Whenheshowedme[thedata]Ithought,wow,hallelujah,”recallsChen.TheHEN1mutantsweremalformedbecausemanygenes,missingtheircorrespondingmicroRNAs,wereoutofwhack.ResearchersweresurprisedthatsuchteenybitsofRNA,whichtheyhadn’tevenknownexistedinplants,weresocrucialtotheorganism’sshape.

ChenspentthenextdecadestudyinghowmicroRNAsaremade,andsherecentlyturnedherattentiontotheirdegradationandwhereinthecelltheydotheirwork.Afteritssynthesisinthenucleus,theprecursormicroRNAmaturesasenzymescutoutunneededparts.Thefirsttrimmingstepstakeplaceinthenucleus;thenthemicroRNAexitstothecell’smaincompartment(thecytoplasm)andgetsitsfinishingtouches,includingtheadditionofsmallchemicaltagsattachedbyenzymeslikeHEN1.Readytogo,thefinishedmicroRNAteamsupwithagroupofproteinstofinditstargetmRNA,whichitidentifiesbyanucleotidesequencethatmatchesitsown.ThemicroRNAanditsproteinpartnersquashproductionoftheproteinencodedbythemRNA,eitherbyblockingtranslationorbydestroyingthemRNA.

SometimesaplantwantstogetridofamicroRNAsoitcankeepthecorrespondingmRNAsaround.ThefateofthemicroRNAcomesdowntotwoofthoselittlechemicaltags:themethylgroupaddedbyHEN1andanothertagcalleduridine.AnenzymecalledHESO1decoratesthemicroRNAwithachainofuridines,accordingtoapaperChen’steampublishedinCurrent Biologyin2012.Eachtagisasigntothecell:themethylsays,“Keepme,”andtheuridinessay,“Destroyme.”

Forawhile,ChenwaspuzzledastowhymicroRNAsneededa“Keepme”methylgroup;wasn’ttheabsenceofa“Destroyme”uridinetagsufficient?ShereportedthereasonintheApril29,2014,issueoftheProceedings of the National Academy of Sciences.HESO1could,potentially,addthesame“Destroyme”signal

tothemRNAs,whichsitrightnexttothemicroRNAsintheproteincomplex.TheonlywayHESO1cantellthedifferencebetweenmRNAsandmicroRNAsisthemethylgroup.ThemethylisthemicroRNA’sprotectivegear:itpreventsHESO1fromaddinguridines,therebywardingoffthemicroRNA’sdestruction.

Chen’salsobeenlookingatwhereinthecellmicroRNAsdotheirmRNAsilencing.ScientistspresumedthatmicroRNAsblockedmRNAsfloatingfreewithinthecell’swaterycytoplasm,butfewhadactuallychecked.SoChenandhercolleaguesusedfluorescentproteinstolabelsomeofthe

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Bench Report

Xuemei Chen studies small strands of RNA that do big things.


proteinsthatparticipateinmRNAsilencing.Undertheirmicroscopes,theysawthefluorescentgreenandyellowsignalsinthecell’sendoplasmicreticulum—aseriesofmembranetubulesinvolvedinproteinsynthesis.ThatdoesnotnecessarilyruleoutRNAsilencinginthecellinterior,ChenreportedinCell in2013;itjustshowsthattheendoplasmicreticulumisonesitewhereitdefinitelyhappens.

Thisfindinghasimportantramifications,Chensays.BecauseresearchersassumedthatRNAsilencingtookplaceoutsideorganelles,theyhaveoftendonetheirexperimentsintesttubeswithnomembranespresent.

Thatcouldbeamistake,Chensays,sinceitdoesn’tmatchthenaturalenvironmentofRNAsilencing.“IhopetheentireRNAsilencingfieldwillpayattentiontothemembraneconnection,”shesays.

ChenplanstolearnasmuchasshecanaboutthesecontrollingbitsofRNA.BecausemicroRNAsareimportantinanimalsaswellasplants,Chen’sworkcouldhavefar-reachingimplications.ScientistsalreadyknowthatmicroRNAsparticipateinsomehumandiseases,suchascancer.

“Atthemolecularlevel,peoplearenotthatdifferentfromArabidopsis,”Chensays.—Amber Dance

“I hope the entire RNA silencing field will pay attention to the membrane connection.”—xuemeichenE

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Bench Report

A Phosphate FixAnancientbacteriumprovidesthekeytoanovelplantfertilizationandweedcontrolsystem.

if youhopinto acarinthebordertownofEaglePass,Texas,anddrivesouthforfourhours,paststuntedmesquiteandblindingwhitegypsumdunes,you’llreachanisolatedcorneroftheChihuahuaDesertcalledCuatroCiénegas,orFourMarshes.It’snotyourtypicaldesert.Nestledamongthewhitedunesisanoasisofwildlifecenteredaroundaseriesofpoolswhosehuesofblueandgreenappearinstarkcontrasttothemonochromaticdesertsand.

Fedbyundergroundspringspercolatingupthroughthedesertfloor,thepools,orpozas,arehometocreaturesfoundnowhereelsein

theworld.Groupsofgrassshrimppopulatezonesrichwithalgaeandschoolsofinch-longpupfishthriveinthehot,saltywater.HHMISeniorInternationalResearchScholarLuisHerrera-EstrellaismostinterestedinPseudomonas stutzeriWM88,abacteriumthatmayholdakeytoplantsurvival,astheworld’seasilyaccessiblephosphorussupplyrunsdry.

Herrera-Estrellaandhislabteamhavemanagedtotapintothebacterium’sabilitytothriveinthepools,wherephosphate—asaltformofphosphorusthatoccursinnaturalenvironments—israre.

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Weareconsumingabout40to50milliontonsperyear.”Atthissamerate,phosphorusstoreswillbedepletedandunavailableforagricultureandindustrialuseinthenext70to200years,accordingtoestimates.

PhosphorusistheseventhmostabundantelementinEarth’scrust,butitschemicalpropertiesareitsdownfall.Itishighlyreactivewithsoil,quicklyforminginsolublecompoundsthatplantscan’tuse.Asaresult,aslittleas20to30percentofthephosphateappliedasfertilizerisactuallytakenupbycultivatedplants.Therestendsupasagriculturalrunoff,eventuallymakingitswaytoriversandoceanswhereitisabsorbedbyalgae,resultingintoxicalgalblooms.

Phosphateisalsoinshortsupplyinthesoilbecauseeveryorganismlivingthereneedsittogrow.

“Microbes,weeds,fungi,andcropsallcompeteforphosphorus,”saysHerrera-Estrella.Hespent15yearstryingtoengineercropsthatuselessoftheresourcebylookingathowplantsadapttolow-phosphateconditions.“We’vehadsomeadvancesbutnothingthatcouldreallyimproveefficiencyofphosphorususe,”hesays.“Sowewenttoaveryradicalapproach.Wedecidedtosearchfororganismsthatuseotherchemicalformsofphosphorus.”

ThissearchendedatthepoolsofCuatroCiénegas.Scientistsbelievethepoolsarerelicsofanancientseathatcontainedlotsofdissolvedoxygenbutnotalotofphosphate.Tosurviveinthepools,organismsevolvedtousealternativewaysofacquiringphosphate.P. stutzeriWM88didthiswithanenzymecalledphosphiteoxidoreductase(ptxD),whichconvertsphosphite—abundantinthepools—tophosphatebyaddinganoxygenmolecule.

Toseeiftheycouldencourageplantstousephosphitetomeettheirphosphateneeds,DamarLópez-Arredondo,thenagraduatestudentinHerrera-Estrella’slab,insertedtheptxDgeneintothegenomeofArabidopsis,amodelplantcommonlyusedinresearchlabs.Herrera-Estrellaisnostrangertoaddinggenestoplants.Hewasoneofthefirstpeopletomakeatransgenicplantintheearly1980s,andhe’sbeenusingthatknowledgetoimproveagriculturalcrops,especiallytheonesinhisnativeMexico.

“Ourfirstresultswereamazing,”saysLópez-Arredondo.Normalphosphate-usingplantsdiedunderthesameconditionsinwhichthetransgenicArabidopsisthrived.Moreover,thetransgenicplantsneededhalfthenormalamountofphosphorusfertilizer,whenappliedasphosphite,toachievemaximum

yield.Andphosphite’schemicalpropertiesareidealforfertilizer—itishighlysolubleandnotveryreactivewithsoilcomponents—twoattributesthatensuremostofitistakenupbythetransgenicplantsratherthanendingupasagriculturalrunoff.Asabonus,weedsandmicrobescan’tusephosphite,sotheydon’tcompeteforthemoleculeand,therefore,thesystemreducestheneedforherbicide.

Testsshowedthatphosphitelevelsinthetransgenicplantswereminimal,suggestingthatmost,ifnotall,thephosphitetakenupbytheplantswasindeedconvertedtophosphate.ThescientistspublishedtheirfindingsintheSeptember2012issueofNature Biotechnology.

Herrera-Estrellaisexcitedaboutthepotentialoftheteam’sdiscovery,pointingoutthatareductioninfertilizerandherbicideuseforfoodproductioncouldhaveapositiveecologicalimpactandwouldhelpproducefoodlesscontaminatedbyagrochemicals.

“TheoutcomeofwhatLuisandhiscolleagueshavedoneisnothingshortoffantastic,”saysHHMI–GordonandBettyMooreFoundationInvestigatorJeffDangl,aplantbiologistattheUniversityofNorthCarolinaatChapelHill.“OneofthethingsthatlimitcorngrowthinMexicoandCentralAmericaisphosphate-depletedsoils.Nowyouhavetheabilitytoaddphosphitetothosesoilsandtomaketransgeniccornthatcanusethatphosphite.Thisincreasestheoverallfertilityofthesystemandallowsyoutogrowmorecorn.”

Herrera-EstrellaandLópez-ArredondohaveformedacompanycalledStelaGenomicstodeveloptheirsystemandhavestartedfieldtestingtheptxDgeneincornandsoybeans.TheyalsohaveasmallgrantfromtheBill&MelindaGatesFoundationtodevelopthetechnologyforcornstrainsthatgrowinAfrica.Theirplanistomakethetransgenicsystemavailabletoeveryone.

“Iamconvincedthatthephosphitetechnologyhasgreatpotentialandcouldpromotemanychangesinagricultureworldwide,”saysLópez-Arredondo.“Iwanttobepartofthosechanges.”—Nicole KresgeM

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Plantsneedphosphorus.It’sanessentialcomponentoftheirDNA.Mostplantsobtainphosphorusfromphosphateinthesoil,butnearly70percentoftheworld’ssoilisphosphatedeficient,sofarmersmustusealotoffertilizertohelptheircropsgrow.Andthephosphorussupplyisshrinking.

“Phosphorusisanon-renewableresource,”explainsHerrera-Estrella,aplantbiologistattheCenterforResearchandAdvancedStudiesoftheNationalPolytechnicInstituteinIrapuato,Mexico.“Theplanethasacertainamountofphosphorus,andweareusingitveryrapidly.

The desert pools of Cuatro Ciénegas are home to many unique organisms, including bacteria that thrive in low phosphate conditions.

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When cells divide, chromosomes aren’t always doled out equally. The consequences can be dire.

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AAngelikaAmonhaswitnessedplentyofcelldivisionerrorsinhercareerasayeastgeneticist.Inyeast,theprocessofmeiosis—wheregermcellsdividetoformreproductivegametes—iserrorprone.Ascellsdivide,thread-likespindlefibersaresupposedtopullstubbychromosomepairsapartandsendthetwochromosomestooppositeendsofthecell.Sometimes,however,apairofchromosomesismistakenlydeliveredtoasingleside.Afterthecytoplasmdivides,theresultingtwodaughtercellsareaneuploid:onecarriesanextrachromosome;theotherismissingachromosome.

SittingatamicroscopetoexamineasetofaneuploidcellsinherlabattheMassachusettsInstituteofTechnology(MIT),Amonknewthecellswouldbesickly.Aneuploidyeastrarelyreplicate;theyoftendie.That’sbecauseorganisms—whethertheyhaveonesetofchromosomes(haploid,likesomeyeast),two(diploid,likemammals),or12(dodecaploid,liketheUgandaclawedfrog)—relyonbalancedgenomes.Anequalnumberofchromosomesassuresabalancedratioofgeneproducts.Whenthatbalanceisoutofwhack—whenanucleushasoneormoreextraormissingchromosomes—thecellalmostalwaysfailstodeveloporfunctionproperly.

Almostalways.Cancercells,whichareoverwhelminglyaneuploid,areanexception.Theythriveanddividewithafury.ThecontradictionnaggedAmon,anHHMIinvestigator,foryears.Howcouldaneuploidy—thekissofdeathformostcells—beahallmarkinthosecellswithanunparalleledabilitytoproliferate?Itdidn’tmakesense.

Whatwasworsewasthat,outsideofDownsyndrome(awell-studiedgeneticdisordercausedbyanextrachromosome21),aneuploidywasamystery.Despitetheprevalenceofaneuploidyincancercells—morethan90percentofsolidtumorsandabout75percentofblood

cancersdisplayit—scientistshadlittleunderstandingofhowaneuploidyaffectsthephysiologyofacell.

“Italwaysbuggedme,”saysAmon.“SoIdecidedtolookintoit.”Startingin2002,Amonsetouttodeterminethecellularimpactofhavinganabnormalnumberofchromosomesandtoresolvetheaneuploidyparadox.Beforelong,shehadalotofcompany.

Today,arosterofexperiencedcancerresearchersandmolecularbiologistsistacklinganeuploidy’seffectoncellsanditsroleincancer.Theireffortsarenotpurelyacademic:aneuploidycouldbeausefultargetfornewcancerdrugs.

Leaningforwardinachairinherfifth-storyoffice,Amonpropsherelbowsatopatable,firmlyclaspsherhands,anddeclares,“Iwanttoidentifygeneticorevenchemicalcompoundsthatkillaneuploidcellspreferentially.”Then,hervoicegrowingsoft,AmondescribeswatchingheryoungersisterwithbreastcancerperseverethroughnumerousroundsoftreatmentwithTaxol,acommonanti-cancerdrug.“It’sbrutal.Ifwecouldcombinepotentialaneuploidy-selectivecompoundswithTaxol,wecouldbemoreeffectiveandlowerthedoseofTaxol.Wecouldmakethelivesofpeoplewithcancersomuchbetter.”

Extra Gain, Extra PainAmon’sfirstforayintoaneuploidywasashotinthedark.“IhadatalentedtechniciannamedMonicaBoselli.SheandIusedtodocrazyexperimentsallthetime,”saysAmon.In2002,sheaskedBosellitomakeafewaneuploidcelllinessotheycouldgetagoodlookatthem—easiersaidthandone.First,Bosellilearnedanarcanechromosometransferstrategyusingmolecularmarkerstoselectandmoveindividualchromosomesfromoneyeastcelltoanother.Shecreated13strainsofhaploidyeast,eachwithoneortwoextrachromosomes.Then,Bosellicloselymonitoredthetransplantedchromosomes,asyeasthaveatalentforriddingthemselvesofextraneousgeneticmaterial.

Boselli’seffortsworked,andsheandAmon,alongwithAmon’sthenpostdocEduardoTorres,immediatelyobservedthattheextrachromosomewasnotdormant.Ineverycase,thechromosomewasactive:hundredsofgeneswerebeingexpressedfromitsDNA,and,Amonlaterconfirmed,thosegenetranscriptsweretranslatedintoproteins.

Next,Amonexaminedtheappearanceandactivityoftheaneuploidyeast.All13aneuploidcelllines,regardlessofwhichoftheyeast’s16chromosomeswasaddedastheextra,sharedcommontraits.Theyallhaddefectivecellcycles:theymultipliedmoreslowly—somecouldn’tevenformcolonies—andmanywere10-20minutesslowertoinitiatecellcycledivisionthantheirnormal,wild-typecounterparts.Thisconfirmedacommonassumptionthataneuploidyreducesacell’sabilitytoreproducenormally.Theyeastalsoexhibitedincreasedglucoseuptakeand

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sensitivitytogrowthconditionsthathinderedproteinfoldingandthebreakdownofproteins.

Allinall,thefindingssuggestedthataneuploidcellsrequireextraenergyforsurvival,andthattheystruggletofoldanddegradeproteins.Theproteindegradationpathwaysappearedtobeworkingatfulltilttryingtoridthecellofunfoldedandmisfoldedproteinsandpartsofproteins.Thesubunitsofmanyproteincomplexesareencodedacrossmultiplechromosomes,soanextraormissingchromosomewillresultinisolatedsubunitswithnopartners.Infact,workpublishedthisAprilinCellbyHHMIInvestigatorJonathanWeissman,attheUniversityofCalifornia,SanFrancisco,showedthathealthycellsproduceequalamountsoftheproteinsthatfunctiontogetherinacomplex.Thus,anychangeinthosecarefullymaintainedratiosislikelytocauseproblemsinacell.

“Itwasprettyobvious[aneuploidcells]hadmajorissuesintheproteinqualitycontroldepartment,”saysAmon.She,Torres,andBosellipublishedtheresultsin2007.Afewyearslater,Amonfollowedupwithimagesofaneuploidyeastchokedwithclumpsoffluorescentlylabeledproteinaggregatesshininglikegreenwartsinthecells.

Amonlovesyeast:thesmellofyeast,thepinkandivorycolonies,theteenybubble-likeyeastspores.Butafter

onetoomanycolleaguesinsinuatedthatheraneuploidyfindingswereapplicableonlytoyeast,Amonturnedtomousecellstodetermineifwhattheyfoundinyeastwasalsotrueinmammals.

Assheexpected,themousecellshadcellcycledefectsandstressedproteincontrolpathways.“Itwasthesame,”saysAmonofthemammalianworkpublishedin2008inScience.“Definitelythesame.”ApaperpublishedthisyearbyZuzanaStorchovaandcolleaguesattheMaxPlanckInstituteofBiochemistryinGermanyconfirmsAmon’sfindings,thistimeinhumancells:aneuploidhumancells,fromavarietyofsources,upregulatemetabolicandproteindegradationpathways.

Tug of WarThreemilessouthandacrosstheCharlesRiver,DavidPellman,alsoanHHMIinvestigatorandyeastaficionado,wassimultaneouslytryingtofigureouthowaneuploidyaffectsthefunctionofcellsandobtainmoredetailsabouthowitoccursinthefirstplace.

Inadditiontoanabnormalnumberofchromosomes,mostaneuploidcellshaveanabnormalnumberofcentrosomes—smallorganellesthatcontrolthepositionandactionofchromosomesonspindlefibersduringcelldivision.Healthycellshavejusttwocentrosomesduringmitosis—divisionofsomatic,ornon-germ,cells—butaneuploidcellsoftenhavethreeorfour.In2008,attheDana-FarberCancerInstituteandBostonChildren’sHospital,Pellmanandcolleaguesbegangeneratingcelllines(avarietyofmouseandhuman)differingonlyincentrosomenumber.Atthetime,itwaswellestablishedthatextracentrosomesgenerateaneuploidy,butthemechanismbywhichthatoccurredhadnotbeendirectlyobserved.

Angelika Amon is searching for the link between aneuploidy and cancer.

“It was pretty obvious [aneuploidy cells] had major issues in the protein quality control department.”—angelikaamon


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Watchingthecellsbyusingaliveimagingsystem,Pellman’steamfoundthatcellswithextracentrosomesdivideintotwo,justlikenormalcells,yettheextracentrosomesproduceadditionalspindlefibersthatpullchromosomesinthewrongdirections.Thistugofwarcanresultinlaggingchromosomesthatdon’tmakeittothecorrectsideofthecellpriortodivision.Thedaughtercells,therefore,areaneuploid.“Itwasanunexpectedmechanism,”saysPellman,butonethatconfirmedthatcentrosomesareactiveparticipantsinchromosomesegregationerrorsthatleadtoaneuploidy.

Aneuploidycanalsobecausedbyaweakenedordamagedspindlecheckpoint,thesecuritysysteminthecellthatensureschromosomesareaccuratelyseparated,saysHongtaoYu,anHHMIinvestigatorattheUniversityofTexasSouthwesternMedicalCenterinDallas.Ahostofspindlecheckpointproteins,suchasMad2andBubR1,monitortheattachmentofspindlefiberstokinetochores,stickyproteinhubsatthecenterofchromosomes.Inthecaseofincorrectfiber-kinetochoreattachments,checkpointproteinsbindandinhibitaproteincomplexthatwouldactivatethenextstageofcelldivision.

Completelossofthespindlecheckpointwhollykillscells,saysYu.Butlesserdefects,suchaslowlevelsordecreasedactivityofMad2orBubR1,resultinirregularattachments,continuedcelldivision,andchromosomemis-segregation.“Subtlechangesofthe

Hongtao Yu studies how subtle changes in spindle fiber proteins can cause chromosome mis-segregation.

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If extra chromosomes reduce cell viability, how and why do aneuploid cancer cells thrive?

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As chromosomes are partitioned during cell division, errors can occur along several pathways, resulting in aneuploidy.

spindlecheckpointsystemallowcellstolive,butcauseaneuploidy,”saysYu.

Paradoxically,itturnsoutthattoomuchofaspindlecheckpointproteincanalsocauseaneuploidy.OverexpressionofMad2inmousecellscausesaneuploidy,afindingpublishedbyRocioSotillo,anHHMIinternationalearlycareerscientistattheEuropeanMolecularBiologyLaboratoryinMonterotondo,Italy,in2007.Theexcessproteininitiallyarrestscellsinthephaseofthecellcyclewhenthechromosomesarelinedupalongthecell’sequator.Afewcellsmanageto“escape”thatblock,saysSotillo,andproceedwithmitosis.Buttheyoverwhelminglyescapewithbaggage—extraorfewerchromosomes.

Othercelldivisiondefectsandspindlecheckpointerrorscauseaneuploidyaswell,andevidencefromorganismssuchasDrosophilaandplantsreaffirmsthattheresultsofaneuploidyareslowedcellproliferation,sickness,and

death.Unfortunately,theseobservationsstillfailedtoanswerthequestionthatnaggedatAmon,Pellman,andothers:ifextrachromosomesreducecellviability,howandwhydoaneuploidcancercellsthrive?

Elephant in the RoomIn1902,whileobservingtheabnormaldevelopmentofaneuploidcellsinseaurchinembryos,GermanzoologistTheodorBoveritheorizedthatatumormightdevelopfromsuchacell.Laterscientistsindeedfoundthatmosttumorsareaneuploid,butmanycastthefindingasideasanoddity.Fordecades,theroleofaneuploidyincancerwaslargelyignored.

“Ifyoulookatoldcancerreviews,theyneverputaneuploidyinthere,”saysStephenElledge,ageneticistandHHMIinvestigatoratHarvardMedicalSchool.“Ithasalwaysbeentheelephantintheroom.”Thatmaybebecause,duringthe1970sand1980s,itwassignificantlyhardertoidentifythecellulareffectsofawholeadditionalchromosome,asopposedtoasingleoncogene,Elledgesuggests.“Itjusthurtpeople’sheads.”

Withtheadventofnewimagingandsequencingtoolsbeginningintheearly1990s,aneuploidyreceivedrenewedattention—butsoonbecamestymiedbycontroversy.Leadingcancerresearcherssuggestedaneuploidywassimplyaby-productofcancer,anunimportantconsequence.Othersvehementlyarguedthatitcouldbethesolecauseofcancer.“Therewasa


hugedebate,”saysPellman.Butitdidn’tscarehimawayfromthefield.

Priortoworkingfulltimeinthelab,Pellmanwasapediatriconcologist.LikeAmon,aviewthroughamicroscopedrewhimtothestudyofaneuploidy:overandover,heobservedabnormalstructuresinthenucleusthatindicatedaneuploidyinthecellsofhisyoungcancerpatients.“Ispentalotoftimelookingattheseabnormalnuclearstructures,”saysPellman.“Therewasanobviousconnection.”

SohedecidedtoputoneaspectofBoveri’shypothesis—thatwholegenomeduplication,whichcauseshighratesofaneuploidy,mightcausecancer—tothetest.Pellmaninstructedoneofhispostdocs,TakeshiFujiwara,toproducetetraploid(twicethenormalchromosomenumber)mousecells,whichhaveahighrateofchromosomemis-segregationandthusrapidlybecomeaneuploid.Then,Fujiwarawastoinjectthosecellsintomice.AlthoughPellmanthoughtitwasimportanttotesttheidea,hefeltitwasalmosttoosimple,“toogoodto

betrue,”forthetetraploidcellstocausecancer.Fujiwara’sinitialresultsshowedthatthecellsindeedcausedaggressivetumorsinthemice.“Itwaswhatwewereafter,butitwasneverthelessverysurprisingthatitworkedsowell,”Pellmanrecalls.Thediscoveryprovidedstrongevidencethattetraploidy,andtheresultinganeuploidy,promotestumordevelopment.

Sincethen,Pellman’slabhasbeenworkingtodeterminehowaneuploidymightcausetumors.In2012,histeamshowedthatinsidemicronuclei—smallmembrane-boundbodiesthatpartitionextrachromosomesawayfromthecytoplasm—chromosomesaresubjecttoextensiveDNAdamage.Thissuggeststhatonewayaneuploidycausescanceristheold-fashionedway:throughmutationsthatactivatecancer-causinggenesorinactivatetumorsuppressors.Additionally,Pellman’slabrecentlydiscoveredevidenceshowingthatextracentrosomes,independentofgeneratinganeuploidy,canleadtotheactivationofRac1,aproteininvolvedincancercellsignalingandtumorinvasion(publishedJune5,2014,inNature).

Moreevidenceismountingthataneuploidypromotescancerbyalteringoncogenesandtumorsuppressors.LastyearinCell,ElledgeandcolleaguesatHarvardreportedthatcancergenomesselectforextrachromosomesthatcontainpotentoncogenes,andselectagainstextrachromosomesrichintumorsuppressors(see“TheMethodinCancer’sMadness,”Spring2014HHMI Bulletin).AttheMayoClinicinMinnesota,molecularbiologistJanvanDeursenandcolleagueshave

Aneuploidy—an abnormal number of chromosomes—appears to help a normal cell transform into a cancer cell. But not by giving it an edge to grow. Evidence suggests that aneuploidy actually slows cell division. So how exactly does aneuploidy benefit tumors?

Scientists have two main hypotheses. The first is that aneuploidy helps cancer cells adapt quickly under extreme pressure. In 2012, geneticist Yitzhak Pilpel and colleagues at the Weizmann Institute of Science in Israel tested this theory in yeast cells by exposing them to high heat. The yeast that acquired chromosome duplications—especially of chromosome III, which contains special proteins that aid in heat tolerance—survived better than

yeast that did not. When Pilpel reduced the temperature back to normal for these chromosome III aneuploids, the cells quickly lost the extra copy of the chromosome during subsequent replication.

Interestingly, however, when Pilpel kept the aneuploids at a high temperature, they also lost the extra copy, but only after evolving a different, more efficient way to express the heat-tolerance proteins over time. Pilpel and his team concluded that having an extra chromosome is a “quick fix,” but not a permanent solution, to deal with stress. That ability to quickly adapt would be a great benefit to cancer cells during metastasis. When a breast tumor cell spreads to the bone, for example, it must survive in a completely different

environmental niche. “As the disease progresses, adaptation potential provided by aneuploidy could be very beneficial,” says Angelika Amon, an HHMI investigator and yeast geneticist at MIT. The hypothesis has yet to be tested in cancer cells, however.

Another hypothesis is that aneuploidy promotes structural abnormalities known to cause cancer. In studies of yeast, Amon’s team has shown that aneuploidy causes genomic instability—a high frequency of mutations in the genome, from small mutations of two to three nucleotides to larger structural changes. Amon assayed 13 aneuploid yeast strains in a series of tests for different types of genomic instability, such as increased mutation rates and increased rates

of recombination. “It was really remarkable. Every aneuploid strain we looked at scored in at least one assay,” says Amon, and most tested positive for multiple types of genomic changes. The finding suggests that aneuploidy, no matter which chromosome is duplicated, causes genomic instability. And that instability predisposes the cell to mutations that cause cancer.

Aneuploidy may help cancer cells adapt quickly to stress in the body and nudge cells toward mutations that directly promote tumorigenesis, according to this recent work. “But so far, all this work is done in [cultured] cells, and that’s not good enough,” says Amon. Her team and others are planning to test these two hypotheses in mouse models of aneuploidy. — M.S.

Stressed-Out Cancer Cells: The Benefits of Aneuploidy

“We’re at the point where there’s pretty strong trust that aneuploidy is driving cancer.”—stephenelledge

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foundthataneuploidypredisposesmicewithonlyoneworkingcopyofp53,insteadofanormalpair,tolosethatcopyofthesuppressorgeneanddeveloptumors.

Basedoncurrentunderstanding,aneuploidyappearstopromotetumorproductionthroughmultiplemechanisms,butnotbyincreasingacell’sabilitytomultiply.That,atleast,helpsresolvetheaneuploidyparadox.“Wethink[aneuploidy]offerstumorcellssomethingotherthanproliferation,somethingelsethatisgoodfortumorigenesis,”saysAmon.(Seesidebar,“Stressed-OutCancerCells:TheBenefitsofAneuploidy.”)

Butdoesaneuploidycausecanceronitsown?VanDeursen’sworksuggeststhatitdoesnot.Formorethanadecade,vanDeursenhasbeenengineeringmicetoproducelowlevelsofindividualspindlecheckpointproteins,includingBub1andBubR1(completelossofsuchproteinsislethaltoembryos).Someofthemicedevelopcancer,fromlungcancertolymphomatolivertumors,butnotall.What’smore,vanDeursencan’tpredictwhichcheckpointproteinthatheknocksdown—andhehastriedadozen—willresultinatumor.

“Ifitweremerelyaneuploidythatdrivesmalignanttransformation,thenwe’dexpectthatallthemicewouldhavecancers,andmanycancers.Butthatreallyisn’tthecase,”saysvanDeursen.“It’slikelytheanswerisaneuploidyplussomethingelse.Soyouwillhavetwo,three,orfourindependent,tumor-promotingactivities.”

Today,mostresearchers,includingAmon,agreethatoncogenesarethemaindriversofcancer,andaneuploidycontributesvariationandinstabilitytothetumorcells.Ifoncogenesarethespark,aneuploidyisthekindling.“We’reatthepointwherethere’saprettystrongtrustthataneuploidyisdrivingcancer,”saysElledge.“Thequestionis,howpotentisit?”

Targeting StressUntilthatquestionisanswered,mostaneuploidyresearchremainsfocusedonbasicmechanisms.Butafewinquisitivescientistsaredippingtheirtoesintotranslationalresearch,lookingforwaystotargetorexploitaneuploidytopreferentiallykillcancercells.

“Aneuploidyisdefinitelystressingthecells,andthecellsmustdependonstresssupportpathwaysmorethannormalcellsdo,”saysElledge.“Soifyoucantinkerwiththat,youcanpotentiallymakethecellvulnerableorkillit.Thiscouldcertainlyaugmentothertherapies.”

SomeofPellman’sworksuggeststhattargetingcellswithtoomanycentrosomesmightbeawaytoselectivelytargetcancercells.SeveraldrugcompaniesarepursuingsmallmoleculedrugstoinhibitaspecificmotorproteinthatPellmanidentifiedasessentialforthesurvivalofextracentrosome-containingcancercells.

AtUTSouthwestern,Yuandcolleaguesrecentlycompletedanexperimentinwhichtheysilencedeachofthe20,000+genesinhumancancercells,onebyone,andthentreatedtheresultingcellswithTaxol.TheirgoalwastoseewhichgeneshelpcellsavoiddeathbyTaxol,whichisbelievedtocausemassiveaneuploidy,andwhichgenespromoteTaxol-triggereddeath.

Manyofthegenestheyidentifiedencodecomponentsofthespindlecheckpoint,suggestingpotentialdrugtargetstohelpTaxolworkbetter,saysYu.ThosetargetscouldleadtothekindofdrugsAmonhaslongdreamedof,toimprovetheeffectivenessofcurrentchemotherapyregimensandreducesideeffects.

BackatMIT,Amon’stranslationalworkisinfullswing.IncollaborationwithaHarvardscreeningfacility,Amonhasbeensearchingthroughlibrariesofcompoundsforchemicalsthatpreferentiallypreventaneuploidcellsfrommultiplying.Shehasidentifiedseveral.Oneofthemisachemicalinvolvedintheformationoflipidsthatappearstotargethighlyaneuploidcells.

Amon’steamfoundthatbycombiningTaxolwiththenewcompoundatconcentrationswhereeachcouldkill10percentofcancercellsifgivenseparately,themixturewasabletodestroycancercellswithanefficacyof90percent.“Nowwe’reworkingtotreatmousemodelsofcanceranddeterminethemechanism,”shesays.“We’rereallyexcitedaboutit.”

Stephen Elledge has found evidence that aneuploidy alters the balance of tumor suppressors and promoters.

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BRIAN R. CRANESUSAN S. GOLDEN

MARK GOLDMAN AYDOGAN OZCAN

TRACY L. JOHNSON ARIEL D. ANBAR

The 2014 HHMI professors are bringing innovation from the lab into the classroom.

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MUHAMMAD H. ZAMANSUSAN K. MCCONNELL ANDREW MURRAY

JEFFREY S. MOORE JANE KONDEV DAVID R. MARCHANT

CHRISTOPHER D. IMPEY ANNE J. MCNEIL JOSEPH M. JEZ

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universityresearchscientists areexpectedtobepioneersintheirlabs.AnewgroupofHHMIprofessorswillbemeetingthosesamehighexpectationsintheclassroom.

Thetraditionalsystemsofrewardsandrecognitionandallocationofresourcesatresearchuniversitiesoftenencourageanimbalance:mostsciencefacultymembersarefarmorefocusedontheirworkasresearchscientiststhantheirworkaseducators.

“Ithasbeenagreat,missedopportunity,”saysSeanB.Carroll,vicepresidentforscienceeducationatHHMI.“Researchuniversitiesattractsomeofthebrightestyoungmindsinthenation,andtheyarehometosomeofthebestscientists.Theyofferapotentiallysuperbenvironmentforengagingstudentsinboththeclassroomandthelaboratory.”

Since2002,HHMIhasbeenpromotingabetterbalancebetweenresearchandteachingbysupportingsomeofthecountry’sleadingresearchscientistswhoalsoengagestudentsintheclassroomasHHMIprofessors.AtotaloffortyscientistsgivenHHMIprofessorgrantshaveappliedthesamekindofcreativeapproachesandrigorousmeasurementintheirclassroomsastheyhaveintheirlabs.Theyhavedemonstratedthattopscientistscanbetopeducators,byexpandingandenhancingstudentresearchopportunities,findinginnovativewaystooffermentoring,andencouragingotherfacultytoengageineffectiveteaching.

FifteenadditionalresearcherswerenamedHHMIprofessorsinJune.Eachwillreceiveagrantfor$1millionoverfiveyearstocontinuetopushscienceeducationforwardthroughprojectsasvariedascreativewritingaboutscienceandgroupresearchprojectsviaonlinecourses.

Witheveryapproach,theprofessorsstrivetohelpstudentsgrapplewith—anddeeplyinternalize—authenticresearchandscientificthinking.“TheHHMIprofessorspushhardattheboundariesofscienceeducation.Theyraisetheprofileoftheconversationabouteducation,”saysHHMIseniorprogramofficerSarahSimmons.“Thenewprofessorsleveragetheircrediblevoicesinthescientificcommunitytopulltogethertheeducationalandresearchsidesofscience.”

HerearethestoriesofsixofthenewHHMIprofessors—top-tierresearcherswhoseworkrangesfrombiologyandchemistrytogeologyandastronomy.TheirworkpromisestobringtheexcitementofscienceintotheclassroomandfuelanewgenerationofSTEMmajors.

anne mcneil University of Michigan

Project: Buildingmeaningfullabs—andcrowdsourceddata—intofirst-yearorganicchemistry.

AnneMcNeilknowsthealarmingstatisticthatmorethan60percentofstudentswhoentercollegewithaninterestinaSTEMdegreefailtoearnone.

Shewassuspiciousthatherschool’sdryintroductoryorganicchemistrylaboratory,takenby2,000undergraduatesattheUniversityofMichiganeachyear,contributedtothatfailurerate.“Thelabisreallybasic—thingsliketitrationsandseparations—withessentiallynoorganicchemistry,”shesays.“It’sde-motivatingforstudents.”Unfortunately,it’sanalltoocommonintroductorylabexperience.

McNeiliscommittedtotransformingherschool’slabfromloathedtoloved,andthatprocesswillstartwithbiodiesel.Studentswillusethefairlysimpletechniquesofrefluxingandseparationtotransformusedvegetableoilfromlocalrestaurantsintobiodieselforusebylocalfarmers.Thetechniquesaresimpleandtheresultsaremeaningful.Andthestudents,shehopes,willbehooked.

Theexperiencewon’tbeasinglepaint-by-numberslab.Afterfollowingastandard“recipe,”studentswillspendthenextlabchangingavariable—temperature,solvent,concentration—andhypothesizinghowthechangewillaffecttheoutcome.Byaddingtheirdatatoashared

spreadsheet,studentswillhaveaccesstoalargedatasettomakecomparisonsanddrawconclusions.

Aspartofherorganicchemistrylaboverhaul,McNeilplanstoincludeanarrayofotherexperiments,suchaslabsinwhichstudentsextractnaturalrubberfrommilkweed.

Concreteprojectscanbooststudents’enthusiasmfor—anddesiretocontinuein—science,shesays.Asafirst-yearstudentin1996,McNeil’spassionforsciencewaspropelledbyaprofessorwhodrewparallelsbetweenabstractconcepts,suchassubstitutionreactions,andtheirreal-worldapplications,suchasthechemicalweaponmustardgas.Today,McNeil’sresearchgroupdevelopssensorsthathelpcontractorsandinspectorscheckforharmfulleadinpaintatconstructionsites.Thesechemicaltools,knownasgelators,maysomedaybeusedtofindexplosivesatairportcheckpointsorenzymesinvolvedincertaindiseases.

Withthenewlabprojects,McNeilhopesthatherstudentswillseethatlabsareaboutdiscoveryandproblemsolvingratherthanlearningabstractconcepts.“I’mtryingtoreplicatetheresearchexperience—withintheconstraintsofthesystem—forasmanypeopleasIcan,”shesays.

“I want students’ initial lab experiences to inspire them to pursue other research opportunities.”


susan mcconnell Stanford University

Project: Developingandexpandingcoursesthathelpstudentsmergeartandscience.

Growingup,SusanMcConnellimaginedherselfasthenextJaneGoodall.Goodall’sgrandadventuresstudyingchimpanzeesinTanzania—andhercaptivatingstorytelling—crackedopenthejoyofscientificresearchfortheyoungMcConnell.

AfterreceivingherPhDfromHarvardUniversity,McConnellfoundherownwaytopursuescientificsuccess.Asaneurobiologist,shestudieshowneuronsinthedevelopingcerebralcortexareproduced,assignedspecificcharacteristics,andwiredtogetherintofunctionalcircuits.

Butevenfromherlab,McConnellfeltthetugofGoodall’slargervision.Greatsciencewasastartingpoint.Evengreaterpowercamefromsharingtheresearchinwaysthatinspireotherstopursueandsupportit.“[Scientists]can’tjustwritetootherscientists,”shesays.“Weneedtobeabletocommunicatetothegeneralpublic.”

ThatideaservedasthecatalystfortwonewclassesatStanford:“PersonalEssayinBiology”and“SeniorReflectioninBiology.”Bothcoursesallowstudentstobringanartisticsensibilitytothesciencetheystudy.

Inthefirstcourse,studentsspendatermworkingwithaward-winningwriterAndrewTodhuntertocompleteapersonal,deeplyresearchedscientificessayinthestyleofmagazinessuchasThe New YorkerorNational Geographic.Inthesecond,studentsuseavisualmediumoftheirchoice—photography(McConnell’sspecialty),painting,ormultimedia,forexample—andspendayearworkingcloselywithfacultymentorsinbothscienceandtheartstocreateandpolishtheirscience-linkedworkforviewinginacampusgallery.

Inpilotprograms,onestudentwroteagrippingpersonalessaythatcombinedresearchabouttheneurochemistryofmentalillnessandthestoryofherroommate’ssuicide.Anotherusedsandanimationtoexplore

theimpactofparasitesinlocalwatersourcesinGhana;shesharedaversionoftheprojectataTEDxeventandearnedastandingovation.

McConnellsaysthistwistonscientificthinking,throughprojectsthatshedescribesas“kindof‘out

there’alternativemodels,”hasthepotentialtotransformthewaystudentsthinkaboutthesciencetheydoandthewaytheysharethatworkwithothers.

AsanHHMIprofessor,McConnellplanstofurtherdevelopandexpandthepopularprograms,andaddhumanitiesstudentswhoareinterestedinusingscienceasthefoundationfortheirart.Communicatingscienceinbeautiful,accurate,andunexpectedways,shesays,canhelpstudentswrestlewithimportantproblems.

“We must present stories about science that are accessible, engaging, and informative.”

muhammad zamanBoston University

Project:Usereal-worldproblemstohelpstudentsunderstandglobalhealthissuesinthecontextofbiomedicalengineering.

MuhammadZamanbelievesitisnotenoughtogivehisstudentsthetoolstosolveimportantglobalhealthproblems.It’shisresponsibility,hesays,toimpressuponthemthevalueofthework.

Inhisownresearch,ZamanandhiscolleagueshavedevelopedPharmaCheck,atechnologythatcanquicklyandcheaplydetect

counterfeitandexpiredantimalarialandantibioticdrugs,inpartbyrevealingtheconcentrationofactiveingredients.Scientific Americanhailedtheinnovationasoneof10“WorldChangingIdeas”in2013.

Zamanwantstomotivatestudentstodevelopsimilarpracticalglobalhealthsolutions.He’sdevelopedacomprehensiveprogramatBostonUniversitytodothatindifferent,andreinforcing,ways.

Thefirstisanidearepository—adatabaseofreal-worldproblemsthatprofessorscancontributetoanddrawfromtohelpmakeabstractconceptscomealivefortheirstudents.Zamancitesasimpleexamplefromhisownclass:insteadofhavingstudentscalculatestressesonabeam,theycalculatestressesonawoodencrutchforadisabledgirl,orametalcrutchforamiddle-agedman.“ThisisarealprobleminZambia,wheredisabilitiesare[common],”hesays.

Thesecondisbringingtothecampusguestspeakerswhocandiscussglobalhealthpolicy.Finally,heplanstosendstudentstoabiomedicalengineeringsummerschoolatoneofseveralschoolsinAfricatogetfirsthandexperiencewithdifficultglobalhealthproblems.

Themostimportantaspect,hesays,istheintegrationofallofthesecomponentsintoacohesivewholethroughoutthestudents’collegecareers.Studentsdon’tjusttackleglobalhealthissuesinasinglecourseorsummer.“Wewantideastobereinforcedmultipletimes,”Zamansays.

Hisendgoalisfarmoreprofoundthancreatingtheworld’sbestengineers.“Myjobistomakethembettercitizensofsociety,”hesays.“Iwantthemtobepeoplewhoareabletocontributetothesocietyatlarge.”

“We want students to grapple with global problems that speak to their social consciousness.”


tracy johnsonUniversity of California, Los Angeles

Project:Developaprogramthatemphasizesmentorshipandcollaborativelearningwithascalable,research-intensivecourseonRNAsplicingasitscapstone.

It’snoteasyforfirst-yearbiologystudentstopicturethecomplexdanceofcellularprocesses.That’swhyTracyJohnsonneverreliesonlecturesashersoleteachingtool.

TohelpdescribeaclassicexperimentthatdemonstratedDNA’scompactformwithinacell,forexample,shepullsstudentsfromtheirseatstohavethemrepresenttheproteinscentraltothisformation,usesyarntorepresenttheDNA,andthenasksotherstudentstoplaytheenzymesthatcuttheDNA.“Doingitthisway,”shesays,“ledawholenewgroupofstudentstosay,‘ah,Igetit.’”

Participatorylearningworks,andthat’swhyshe’sdevelopinganewcoursethatallowsfirst-yearstudents—drawninpartfromhighschoolswithsizeablepopulationsofunderrepresentedminorities—tohelpherwithherresearch.JohnsonstudiesRNAsplicingandhowitisregulated.

Duringtheyear-longprogram,Johnsonandabout25studentswillworkwithSaccharomyces cerevisiae,yeastcellsthathavefastdoublingtimesandimportantsimilaritiestohumancells.Studentswillperformopen-endedgeneticscreenstohelpidentifymoleculesthatplayaroleinRNAsplicing.Theworkwillincludein-depthfacultyand

peermentoring—elementsthathelpsciencestick,saysJohnson.Whenstudentsworktogetherontheseprojects,theylearnmore

thanjustthemechanicsoftheproject.“Theylearnhowtoarticulateanddefendtheirideas,andhowtoworkcollaboratively,”Johnsonsays.

Usingonlinedataintegrationandanalysistools,studentswillconnectthedifferentdatatodeveloptestablemodelsthatdescribethemechanismsofRNAsplicing.Thestudentswillpresenttheirfindingsbeforeanaudienceofexperts.Iftheprogramgoeswell,Johnsonhopestosharethemodulewithotherschoolsinterestedinhavingtheirstudentsdoresearchduringtheirfreshmanyear.Fornow,shewantstomakesurethatherstudentsknowthatthey’redoingmorethanjustabsorbingknowledge:they’recreatingit.“Greatlabcoursesofferauthenticresearchexperiences,”shesays.“Studentsgeneratedatathatcanmakeanimpact.”

“Real science is collaborative.”

david marchantBoston University

Project: TobringafewundergraduatestudentstoAntarcticatostudyitslandscapes—andtogivethousandsmoreabackstagepasstothework.

GeologistDavidMarchanthasbeenstudyingclimatechangeinAntarcticafordecades,butuntilnow,he’sneverbeenabletobringateamofundergraduateresearchersalongtohelp—thatopportunityhastypicallybeenreservedforgraduatestudentsandpostdocs.

ButwiththehelpoftheHHMIprofessorsgrant,MarchantwilltakeuptothreeundergraduatestoAntarcticaeachyear.“I’mtaking

undergraduatesbecauseIwanttoinvestinthem,”hesays.

Studentsmayinitiallybeattractedtothesenseofswashbucklingadventurethatcomeswithstudying

Antarctica’sfrozenlandscape,butthey’reevenmoreenergizedbythepotentialimpactoftheresearch.

Amongotherthings,Marchantstudiestheworld’soldestglacialice.Hemeasuresatmosphericgassesovermillion-yeartimeframestounderstandEarth’snaturalvariabilityincarbondioxideandexaminesthegeologicrecordforiceloss.TheNationalScienceFoundation’sU.S.AntarcticProgramsupportshisfieldworkinAntarctica.

Hisnew18-monthprogramstartswithaclassofabout15students,fromwhichMarchantwillchoosehisresearchcompanionsforAntarctictripsofuptoeightweeks.Amongthetravelers’manyresearchresponsibilitieswillbetotakesuper-high-resolutionphotographsofglacialfeaturesandcollectsamplesofvolcanicashforradiometricdating.WhilestudentsareinAntarctica,theyalsogivetalksabouttheirworktodistinguishedvisitors,includingsenatorsandCEOs.

Studentswhoremainstatesidewillusethesuper-high-resolutionphotographstocreatevirtualfieldexpeditionsandperformreal-timelandscapeanalysis.MarchantwillalsodevelopaseminarcourseandalaboratorycourseinwhichstudentsconductgeochemicalanalysesonAntarcticsamples.Anewwebsitewillgiveanyoneintheworldavirtualtouroftheareaswhereheandhisstudentswork.

ForthosewhotravelwithhimtoAntarctica,hesays,thetripwillhavealastingimpact.Withtheirfastpaceandsteeplearningcurves,thesetripstransformstudentsintoconfidentresearchersinafewshortweeks,hesays.“Youcanseeitwhenthey’reback[oncampus],too.There’snothingyoucangivethemafterthisexperiencethatthey’llfailat.They’lljustkeeptryinguntiltheygetit.”

“The success of the entire expedition might lie in their hands.”


“They learn how to articulate and defend their ideas, and how to work collaboratively.”—tracyjohnson

Jane KondevBrandeisUniversityWaltham,Massachusetts

Tracy L. JohnsonUniversityofCalifornia,LosAngelesLosAngeles,California

Joseph M. JezWashingtonUniversityinSt.LouisSt.Louis,Missouri

Christopher D. ImpeyUniversityofArizonaTucson,Arizona

Mark GoldmanUniversityofCalifornia,DavisDavis,California

Susan S. GoldenUniversityofCalifornia,SanDiegoLaJolla,California

Brian R. CraneCornellUniversityIthaca,NewYork

Ariel D. AnbarArizonaStateUniversityTempe,Arizona

2014 HHMI Professors

Muhammad H. ZamanBostonUniversityBoston,Massachusetts

Aydogan OzcanUniversityofCalifornia,LosAngelesLosAngeles,California

Andrew MurrayHarvardUniversityCambridge,Massachusetts

Jeffrey S. MooreUniversityofIllinoisatUrbana-ChampaignUrbana,Illinois

Anne J. McNeilUniversityofMichiganAnnArbor,Michigan

Susan K. McConnellStanfordUniversityStanford,California

David R. MarchantBostonUniversityBoston,Massachusetts

christopher impey University of Arizona

Project: Bringinginteractivelearningandresearchtomassiveopenonlinecourses.

AstronomerChristopherImpeyhasbeentryingtoanswerbigquestionsabouttheuniverse:Howdidgalaxiesgrowtotheircurrentsizes?Howdosomeoftheuniverse’smostimmenseblackholesgrow?

Butintheyearstocome,he’llpursuehisbiggest,mostaudaciousvisionyet:harnessingthepoweroftensofthousandsofstudentscientiststomovehisresearchforward.

In2013,Impeylaunchedhisfirstmassiveopenonlinecourse(MOOC)throughthewebsiteUdemy.Thecourse,“Astronomy:StateoftheArt,”attractedastunning14,000studentsfrom175countries.

WhiletheenthusiasmforMOOCshasswunginrecentyearsfromred-hotardortocoolsuspicion,ImpeybelievesthatthepotentialofMOOCsisonlybeginningtobeexplored.Inhis27yearsasateacher,Impeyhasimplementedseveralinteractivetechniques,includingreal-timecomprehensionsurveysandhands-ongroupwork.He’sreadytobringthemostsuccessfulapproachestoonlinelearning.

Impeyplanstobuildstudentparticipationintohisonlinecoursesbyaddingrealresearchandcollaborativewebsitescalledwikis.Hewillreplicateclassroomlectureswithshortvideolectures.Smallonlinegroupsofstudentswillagreetomeetataspecifictime;they’llworktogetherinrealtimetofilloutwikisaboutthevideo’stopic,withthehelpofafacilitator.

Asstudentsprogress,Impeywillaskthemtodomodest—butreal—research,forexample,classifyinggalaxies,whichcomeindiverseshapesandsizes.“Studentsgetasetofarchetypestolearnfrom,”hesays.“Theylearnwhatmakesaspiral,whatmakesanelliptical,howtorecognizeimagery,whatsymmetriestolookfor,andsoon.”

Throughtheseprojects,Impeyhopestoleadhisstudentstothekindof“lightbulbmoments”thatturninteractionsintolearning.“There’satimeintheclassroomwhengroupsgetengagedindiscussions,evenarguments,astheytrytoassimilateunfamiliarmaterial.It’schaotic—amixtureofheatandlight—wherelearningtakesplace,”hesays.“Iwanttotrytotakethoselightbulbmomentsonline.”

“Students are capable of classifying galaxies [just] as well as PhD astronomers.”

Developing Relationships

Two studies hint at bacteria’s

deep-rooted influence on animal

development.by nicole kresge

illustration by mari kanstad johnsen


BBacteriaareeverywhere:floatingthroughair,driftinginwater,clingingtosurfaces.Soit’snotsurprisingthatmanyanimalsandplantshaveformedbeneficialrelationshipswiththemicroorganisms.

Wearesurroundedbyexamplesofbacteriahelpinganimalsandplants.Bacteriacanprotectplantsagainstextremedrought.Thebacterialmixlivinginananimal’sgutmakesdigestionpossible.Thegoodbacteriathatcoatskinfightoffharmfulmicrobes.Butasscientistsdelvedeeperintothetiesthatbindanimals,plants,andbacteria,they’refindingsomeunexpected,fundamentalconnections:insomecases,thechemicalsignalsreleasedbybacteriatriggerdevelopment.Theymayevenholdcluesastowhyorganismsbecamemulticellular.

Tworecentstudiesrevealthemolecularnatureofsomeofthesechemicalcues.Butwhatdothebacteriagetoutoftherelationships?“Animalsevolvedinabacterialworld,”saysDianneNewman,anHHMIinvestigatorwhostudiesbacteriaattheCaliforniaInstituteofTechnology.“Ithinkwe’rejustattheverybeginningofreallystartingtoappreciatethatandwhatitmeans.”

Bacterial Welcome MatThetubewormHydroides elegans beginsitslifeasatinylarva,floatingfreelythroughtheocean.Eventually,itneedstogrowup,settledownonahardsurfacesuchasarockorthehullofaboat,andbuildits“house”—acalcified,tube-likeoutershell.Thetriggerforthistransitionfromfree-swimminglarvatostationaryjuvenilecomesfromacarpetofbacteriacalledabiofilm.ThebiofilmcoversthesurfacewheretheH. eleganslandstosettledown.Thetransformationisfascinating,butit’salsoabanefortheshippingindustry.Thisaccumulationofbacteriaandmarineanimals,knownasbiofouling,createsextradragonboatsandincreasesfuelconsumption.

MichaelHadfield,abiologistattheUniversityofHawaii,hasspent25yearsstudyingthetubewormasitsettlesintoadulthood.He’sfocusedononeofseveralbiofilm-formingbacteriathattriggerthemetamorphosis—Pseudoalteromonas luteoviolacea,or P. luteo,whichisbyfarthemostefficient.In2012,Hadfield’sgraduatestudentYingHuangzeroedinonfourgenesinthebacteriathattriggertubewormtransformation.Butthespecificcuethatsparkedtheworm’slifestylechangeremainedunknown.

Twoyearslater,NicholasShikuma,apostdoctoralfellowinNewman’slab,collaboratedwithHadfieldtouncovertheproductsofthefourgenes.“Ithoughtthebacteriawereputtingoutapeptideorsomethingthatthelarvaewouldhavespecificreceptorsfor,”saysHadfield.Itturnsoutthetubewormswererespondingtosomethingmuchbiggerandmorecomplex:astructurecomposedofhundredsofproteincomponents.“Thisreallychangedourwholeperspective,”saysHadfield.

Big MACsShikumadiscoveredthatthesignalsproducedbyP. luteo wereactuallyneedle-likemacromoleculesthatheandhiscolleaguesdubbedmetamorphosis-associatedcontractilestructures,orMACs.EachMACconsistsofthreeparts:anarrowtubethatcanbeusedasaprojectile,ahollowsheaththatsurroundsthetubeandpullsbackwhentriggered,andananchoringbaseplate.Thestructuresbearastrongresemblancetothesyringe-liketailsfoundinsomebacteriophages—atypeofvirusthatinfectsbacteria(thevirusesusethenarrowtubecontainedintheneedlestopiercebacterialenvelopesandtheninjectapayloadofviralDNAinside).

“TheMACsarelikespring-loadedmoleculardaggers,”explainsHHMIInvestigatorGrantJensen,whocollaboratedwithShikumatogetanup-closelookinsidethebacteriabyusingatechniquecalledelectroncryotomography.“Theiroutersheathcontractslikeanaccordion,ejectingtheinnerrodanditschemicalpayloadintothetarget.”

Evenmoreintriguingwasthefindingthattheneedlesformedporcupine-likearraysthat,whenfullyextended,werelargerthanthecellsthatproducedthem.Atthebaseofthearray,theMACsaretightlygatheredlikethestemsinabouquetofflowers.Attheotherend,therodsprojectoutlikeabundleoftinyspring-loadedsyringes.

“Thistypeofassemblagewasstructurallyreallydifferentfromwhathadpreviouslybeenseenforphagetail-likeparticles,”saysNewman.“Andwhat’smore,unlikepreviouscaseswheresuchparticleswerelinkedtopathogenesis,theMACsmediateabeneficialinteraction.”ThegrouppublisheditsfindingsintheJanuary31,2014,issueofScience.

Onlyabout2percentofP. luteo cellsinagivenbiofilmproduceMACs,andtheygivethemselvesfullytotheprocess.TheyconverttheirentirecontentstoMACs,packingtheirinsideswalltowallwiththearrays.Eventually,theygetsofulltheyburst,releasingthearrays,whichspringopenlikeumbrellas.

Althoughthescientistsaren’texactlysurehowtheMACstriggermetamorphosis,theythinkthattheneedlesmayactlikemolecularguns,firingapayloadofwhoknowswhatintotheH. eleganslarvathatstartsthechangefrominnocuousorganismtoinvasivepest.

Alternatively,perhapsthetubesthemselvesactasarrowstopuncturethelarva’scells.“Tometheylooklikeawholebunchofcockedcrossbows,”saysHadfield.“Iftheyhittherightcell—asensorycellonHydroides—andpokeholesinit,itcouldbesufficienttotriggermetamorphosis.”

HowthebacteriabenefitfromthisrelationshipandwhytheyproduceMACsarealsounclear.Perhapsthewormsareprotecting P. luteo byingestingtheirzooplanktonpredators.Whateverthemechanismandtherelationship,it’sclearthatthebacteriaaresignalingtothetubewormsthatit’stimetogrowup.

A Quest for ColoniesMuchlikeH. elegans,thetinywater-borneorganismscalledchoanoflagellatesrelyonbacterialcuestoenteranewstageoflife.Choanoflagellatesspendtheirtimegorgingonbacteriainoceans,lakes,ponds,andevenpuddles.Generally,theyaresinglecelled.Butsomespecies,likeSalpingoeca rosetta,canalsoformlargecolonies.Asitsname


implies,as S. rosettacellsdivide,theyarrangethemselvesintoarosette,radiatingaroundacentralpoint.Littleisknownaboutthelifestyleoftheseorganisms,butsincetheyareamongtheclosestlivingrelativesofallanimals,theirbiologymayshedlightonhowandwhyourancestorsbecamemulticellular.

HHMIInvestigatorNicoleKingbecamefascinatedbychoanoflagellateswhenshewasapostdoctoralfellowin2000.Sincethen,shehasbeenonaquesttofigureouthowandwhytheyformcolonies.Inthewild,S. rosetta readilydevelopsintorosettecolonies.Inthelab,itwasadifferentstory.Foryears,Kingmanagedtocoaxtheorganismstodevelopintocoloniesonlyonceinawhile.

SoshedecidedtosequencethegenomeofS. rosetta,hopingforcluestothisdevelopmentalprocess.That’swhenundergraduateresearcherRichardZuzowmadeaserendipitousdiscovery.Topreparethecellsforsequencing,Zuzowneededtoremovecontaminatingbacteria.Sohetreatedthecellswithantibiotics.Certaincocktailsofantibiotics,henoticed,causedthechoanoflagellatestosticktogether,whileotherspreventedrosetteformation.

“Evenwhenwewashedouttheantibiotics,thecoloniesnevercameback,”explainsRosieAlegado,whoatthetimewasapostdocinKing’sUniversityofCalifornia,Berkeleylab.“Eithertheantibioticsweredirectlyaffectingchoanoflagellatesorwekilledoffsomethingintheculturethatwastriggeringthiseffect.”

A Simple SignalItturnedouttobethelatter.Zuzowfiguredoutthatcertainbacteria—Algoriphagus machipongonensis—werepromptingrosetteformation;theantibioticsusedtoprepthecellsforsequencingwerekillingoffthebugs.Alegado,nowattheUniversityofHawaii,teamedupwithJonClardy,anaturalproductschemistatHarvardMedicalSchool,topurifythesubstancethatwascausingtherosettestoform.

ItwasamuchsimplersignalthantheMACarraysthatspurtubewormmetamorphosis.A. machipongonensisreleasesalipidmoleculethatbelongstothesulfonolipidfamily.Similarcompoundshadbeenseenbefore,buttheirfunctionswereunknown.Theteamnamedthemoleculerosette-inducingfactor1,orRIF-1,andpublisheditsfindingsin eLife onOctober15,2012.

“Firstwefindthatabacteriumisactuallyregulatingwhetherchoanoflagellatesaresinglecelledorcolonial.That’sexcitingbecausechoanoflagellateseatbacteria,andthey’regettingcuesabouttheirenvironmentfromthebacteria,”Kingsays.“Thenwefindoutthatit’sthespecialclassofmoleculesthathasn’tbeencharacterizedbefore.”

Aswiththetubeworms,manyquestionsaboutthechoanoflagellate-bacteriarelationshipremain.AlegadoandKingthinkthatRIF-1isreleasedintothewaterviavesiclesthat“bleboff”thebacterialmembrane.TheselipidbubbleseitherfusewithhydrophobicmoleculesinS. rosetta’smembrane,ortheyareengulfedbythechoanoflagellate.Thentheytriggerrosetteformation—andthisiswherethingsgetmurky.

“Atthispoint,Ifeelverycomfortabletalkingabouthowthingsarehappening,”saysKing.“I’mjustlesscertainaboutwhy.”Forexample,shehasnoideawhyA. machipongonensisproducesRIF-1orwhy S. rosettarespondstoit.Onehypothesisforthelatteristhatcoloniesarebetteratcapturingbacteria,sothechoanoflagellatesformrosettestobetterexploitaresource.

Boththetubewormandchoanoflagellatestudiesillustratethat,insomecases,intricaterelationshipshaveevolvedbetweenbacteriaandtheorganismstheylivewith.Theyalsoraisemanyquestionsabouthowandwhytherelationshipsformed,andwhetherornottheyareexceptionsorthenorm.“Theyarebothanecdotesofhowbacteriaareintentionallyorunintentionallydrivingthebehaviorofmulticellularandtransientlymulticellularorganisms,”saysAlegado.“Thetwopapersindicatethatthere’sarichchemicaldialoguegoingonthatweknowverylittleabout.Itjustshowsthatwehavetocontinuetolook.”

“Animals evolved in a bacterial world. I think we’re just at the very beginning of really starting to appreciate that and what it means.”—dianne newman

Perspectives & Opinions


CarlWieman—Carl Wieman was associate director of science in the White House Office of Science and Technology Policy from 2010 to 2012.

Orchestral Approach in the Classroom Nobel-Prize-winning physicist Carl Wieman believes research-based science instruction trumps traditional lecture-style classes. Getting other scientists and research institutions to embrace active-learning methods and collect data on the impact of their teaching, however, is an uphill battle, says the Stanford University professor of physics and the graduate school of education.

Atamajorityofuniversities,scienceteachingmeanslecturinginfrontofacrowdofstudentswhoareoftensurfingtheweb,texting,orstrugglingtostayawake.Teachingshouldinsteadreflectthewayscienceisactuallydone—throughdynamic,small-groupworkonengagingandchallengingscientificproblems.Inthisapproach,theinstructoractsastheconductorofthestudentorchestra,providingthe“sheetmusic”alongwithfeedbackandguidance.

Thissortof“activelearning”yieldsbetteroutcomes.Amassiveanalysisofhundredsofresearchstudiesonundergraduatescienceinstruction,publishedintheJune10,2014,Proceedings of the National Academy of Sciences,showedsignificantlygreaterlearningandlowerfailurerateswithactive,research-basedteachingmethodsthanwithtraditionallectures(22percentversus34percentfailurerates).Whenstudentsactivelyapplyandprocessinformationduringclass—answeringquestionsusingelectronicclickers,completingworksheetexercises,andsolvingproblemswithfellowstudents,forexample—coupled

withfrequenttargetedfeedbackfromtheinstructor,theydevelopthecapabilitytothinklikeascientist.It’slikelearningtoplaymusic—beingintheorchestraismoreeffectivethanjustlisteningtoit.

ThoughIamaphysicist,Ihavespentthepasttwodecadesexploringthebeststrategiesforscience,technology,engineering,andmathematics(STEM)teaching.Scientistsrelyonresearchanddatatoadvancefieldsofstudy,andwemustrelyonresearchanddatatoadvanceeducationaswell.It’stimetostopdebatingwhetheractivelearningsurpassesthetraditionallectureformat.Thedataareconclusive.Let’snowmoveontotheroutine

useofactivelearningstrategiesandcollectingdataonwhichofthosestrategiesaremosteffective.Wecandeterminewhichtasksandmethodsoffeedbackworkbestatmotivatingstudentsanddevelopingtheirexpertise.

Fewresearchinstitutionsseemreadyforthisnextstep,however.Onmostcampuses,includingmyown,thetraditionallectureisthenorm.ButIhaveseenwhatcanhappenwhenacademic

departmentsandscientistsembracenewteachingstrategies.AttheUniversityofColorado,Boulder,andattheUniversityofBritishColumbia,whereIlaunchedScienceEducationInitiatives,STEMdepartmentsmadegreatprogresstowardswitchingfrompassivelecture-styleteachingtoresearch-based,activelearningapproaches.

Changingthosedepartmentsrequiredchangingtheincentives.Researchiswhatistraditionallymeasuredandrewarded,sothere’slittlemotivationforsciencefacultytofocusonteachingpracticesinstead.Topromptthosenewpractices,weprovidedfinancialincentivestodepartments,pluscoachingandincentivestofaculty,includingsummerstipendsandextrateachingorresearchassistantsupport,asprofessorslearnednewteachingtechniquesandmodifiedcourses.

Thesecarrotsprovidedsomemotivation,butwhatattractedfacultythemosttothesenewteachingtechniques,andkeptthemusingthem,weretheresults:Studentswerefarmoreengaged.Theycametoclass,paidattention,askeddeeperquestions,andincreasedtheirlearning.Itwasjustmorefuntoteach.

Forotherinstitutionstofollowsuit,afocusondataandincentivesiscritical.Usually,theonlywayaprofessorisevaluatedonhisorherteachingisfromstudentfeedbacksurveys,whichprovidelittleusefulinformation.Amoreeffectivealternativeinvolvescollectingdataontheteachingmethodsbeingusedineachcourse,andhowthosemethodstranslateintostudentlearning.Butfew,ifany,institutionsarecollectingsuchdata,letaloneincentivizingtheuseofthemosteffectivemethods.

I’mseekingaculturechangeinscientificeducation,andthatdoesnotcomeeasily.Universitiescurrentlyviewedastop-notchinSTEMbythecurrentresearch-focusedmeasuresareunlikelytolookasstrongifjudgedaccordingtotheeffectivenessoftheirteachingmethods.WhenItriedtoestablishfederalpoliciesthatwouldencourageinstitutionstomakeavailabledataontheirSTEMteachingmethods,therewassignificantopposition.However,I’veseensomeprogress.TheAssociationofAmericanUniversities—whichhasnotpreviouslybeeninvolvedinteachingissues—launchedaSTEMinitiativetobringaboutgreateruseofactive-learningmethods.HHMIandtheNationalScienceFoundationhavealsostartedfundinginstitutionalimprovementinSTEMteaching.Thisheadwayisencouraging.—Interview by Michelle R. Davis L

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31HHMI Bulletin / Fall 2014Carl Wieman is calling for a culture change in science education.

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Perspectives & Opinions

Fall2014/HHMIBulletin

Brian R. CraneHHMI Professor, 2014-presentCornell UniversityLargeclassesmakeitdifficulttoengagestudentsinapersonalwayandcreateenvironmentsinwhichtheyreceiveinteractionandfeedback.Technologymayhelpbridgethisgap,butforthemostpartwehaven’tdevelopedreallygoodtoolstosupplementandaugment(notreplace)theundergraduatescienceclass.Involvingstudentsinrealresearchearlyoncanbeverysuccessful,butinlargeclassesit’schallengingtofindprojectsthatcanbemassivelyparallelbutstilluniquetothestudent.

Thevariedbackgroundsofstudentsalsopresentachallenge.Some(maybeevenmany)studentscomingtoauniversitylackthequantitativereasoningskillsneededfordiscovery-basedlearning.Withoutsuchbasicabilities,eventhebestdesignedhands-onexperiencecanbelostonastudent.

Richard M. AmasinoHHMI Professor, 2006-2010University of Wisconsin-MadisonIt’spossibletohavehands-onundergraduatescienceclassesthatdon’tmanageto“turnbrainson,”andit’spossibletohavebrains-onundergraduatescienceclassesthatarenothandson,aslongasactivelearningisinvolved.Butideally,mosthands-onundergraduatescienceclassesshouldbebrainsonaswell.

Idefineactivelearningasusingone’sbraininanactiveway.Listeningtoalectureispassive.Studentssolvingproblemsposedtoaclassisactive,asisdefendingone’sanswertoaproblem.Hands-onlearningcanbepassive,however,ifitisanexerciseduringwhichstudents’brainscan“zoneout”whiletheyaredoingit.Activelearningisimportantbecausestudentsmustwork,andevenstruggleabit,withthesubjectmaterialtolearnitinameaningfulway.

Darcy B. KelleyHHMI Professor, 2002-2010Columbia UniversityThemajorchallengeincreatingamoreactivelearningenvironmentataprivateresearchuniversityisstimulatingfacultyinterest.Seniorfacultymemberswhocameintosciencethroughtraditionallecturesmaynotseeanyneedforchange.Lettingjuniorfacultymemberscreatecoursesfromscratchwillmotivatethemtouseorcreateotherapproaches.

Universityculturealsoplaysanimportantrole.Iflaboratoryresearchprogramsarethechiefcriteriaforfundingandadvancement[decisions],pedagogicalresearchwillbealowerpriorityforfaculty.TheHHMIProfessorsprogramhasraisedtheprofileofthecreativeeducationalapproachesoftopresearchers.Thechallengenowistobringtheseapproachestothesciencefaculties.

Q&A What challenges do educators face when trying to implement hands-on undergraduate science classes at universities?Hands-onprojectscantransformeducationbyfosteringcriticalthinkingandallowingstudentstoapplywhatthey’velearned.Butimplementingtheseprojectscanbedifficult.Here,fourHHMIprofessorssharesomeofthechallenges.–Edited by Nicole Kresge C

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Susan S. GoldenHHMI Professor, 2014-presentUniversity of California, San DiegoThebiggestchallengeisinertia.Academicscientistsaretryingtojugglemanydifferentjobs,allofwhichareimportant,andonlyoneofwhichisteachingsciencetoundergraduatestudents.Onceweestablisharhythmthatkeepsalloftheballsintheair,it’shardtocommittheenergyrequiredtochangethedirectionorspeedofoneofthoseballs.Amajorchangeinteachingmethodologywillaffecttheotherballs,too.ThebeautyoftheHHMIProfessorsgrantisthatitfacilitatesthatchange,byprovidingresourcesforteachingactivitiesthatarecreativeandfun—andthusworththedisruption—andbyintegratingsomeofthoseotheractivitieswiththeteachingcomponent.

Chronicle

Thedevelopingembryoisawhirlwindofactivity.Itscellsareconstantlymoving,shuffling,anddividingastheycreateorgansandlimbs.Theabilitytowatchtheseembryoniccellsinaction—andseewherethingscangowrong—couldhelpscientistsunderstandandultimatelypreventdevelopmentalerrors.AteamledbyJaneliaGroupLeaderPhilippKellerhascreatedacomputerprogramthatcandojustthat.Ittracksthemovementsofeverycellinadevelopingembryobyminingdatacapturedbyusinghigh-resolutionmicroscopy.Theresultsarebothstrikingandinformative.Eachdotintheseembryosofafruitfly(topright)andazebrafish(bottomleft)isanindividualcell,colorcodedtorevealitsdevelopmentalorigins.Read more about Keller’s technique in “Keeping Tabs on Development” on page 39.

34 scienceeducation TheNewFacesofChemistry36 toolbox AnOff-SwitchforNeurons38 labbook UntanglingaViralInfection KeepingTabsonDevelopment WhattheNoseKnows

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Chronicle / Science Education

The New Faces of ChemistryBrief videos by student chemists hit their mark.it beganwith thewhiteguysinbeards.TeachingfreshmanchemistryattheMassachusettsInstituteofTechnology(MIT),CathyDrennannoticedthatthetextbookstaughtthebasics—butfromadusty,historicalperspective.

“Alotofstudentswouldlookatthepicturesandthink,‘Chemistryissomethingthatisdonebydeadwhitemen,’”shesays.“Studentsdidn’tseewhyitisusefulnow.”

SoDrennan,anHHMIinvestigatorandHHMIprofessor,launchedaproject.RatherthanresurrectDmitriMendeleevorAmedeoAvogadrofromthepagesofchemistry’shistory,Drennanenlistedyoungchemiststotalkaboutwhattheydotoday.Andshekepttheconversationsshort—lessthanthreeminutes.

BackedbyHHMI,Drennancreatedaseriesofshortvideostohelpeducatorsmakechemistryaccessible,desirable,andrelatable.

Theresultwassuccess—thestudentsfellinlovewiththechemistsalongwiththeirchemistry.

Theprojectbeganwithasearchfortherightchemists.Theyhadtobeengagingoncamera,diverse,anddoingresearchthatillustratesafundamentalchemicalprinciple.WiththehelpofchemistryinstructorBethVogelTaylor,Drennanqueried,cornered,andcajoledthebestcandidatesatMIT.Inthatsearch,thetwohappeneduponGeorgeZaidan,aformerundergraduatechemistrymajoratMITwithaknackforvideoproduction.TheyalsofoundPhDchemistMaryO’Reilly,whohasagiftforillustration,particularlymolecularabstractionsforvideo.Thetwobecamecrucialtotheproductionteam.

Duringtheinterviews,Drennanaddedathrowawayquestion:howthebuddingchem-actorsfirstgotinterestedinscience.Theanswersopeneddoorstomuchmorethanpurescience.

“WhenIwasyoungerIreadalotofcomicbooks,”saidpostdocNozomiAndoinhervideo.“Ireadaclassicseriesonninjas.Ireallywantedtobecomeone.”Andoexplainedhowshemodeledherscientificeducationafterninjatraining—alongapprenticeship,amentor,anddisciplineasanartform.Shealsodescribedtheprincipleofchemicalequilibriumasitplaysoutinunderstandingchemotherapeuticdrugtargets.

SamuelThompson,nowagraduatestudent,talkedaboutgrowingupasanartistic,intellectual,andgayteeninasmalltowninTexas.Healsoexplainedhowunderstandingacidsandbasesiscriticalforprobinglivingcells.Postdoc(nowassistantprofessor)HectorHernandez,borninHonduras,sharedhowhefirststudiedchemistryasacommunitycollegestudentatthealmostancientageof29.Then,hegotintosolubilityasitrelatestomanipulatingmicrobestocounteractclimatechange.Formergraduatestudent

LourdesAlemánconnectedchemicalbondingandstructuretotreatingdisease,andrevealedthatherinspirationwasherfather,ascientistinCubawhowasbannedfrompracticingsciencebecausehewasCatholic.

Thevideosmadetheirmark,firstonbuddingMITstudentsandthenonabroaderaudienceofuniversityandhighschoolstudents,someofwhomweresurveyedafterwatching.

“Itwasn’tlikethisissomegodlyresearcherthatwewillneverbecloseto,”saidoneviewerinafollow-upinterview.“Itwaslike,‘Okay.Thisisaperson.Icouldprobablytalktothispersonifwemetinreallife.’”

Measuring MotivationDrennan’steammeasuredimpactthroughexperiment.TheteamshowedaseriesofsixvideostoMITundergraduatechemistrystudentsoverthecourseofhalfasemester.Duringtheotherhalf,thestudentssawnovideos.Drennan’steamthencomparedstudentresponsestoquestionnairesduringbothhalves.Theydidthisthreetimes,fortwodifferentsemesterclasses.

Thestudentsrankedtheirmotivationonascaleof1(lowest)to7(highest).Thevideosappearedtosignificantlyboostdriveandinterestinchemistry.Theresultsalsoturnedupasurprise.WhileDrennanhadmadeaconsciousefforttoshowcasediversity,minorityandnon-minoritystudentsshowedequalenthusiasmforthevideos.


To watch some of the team’s videos, visit www.hhmi.org/bulletin/fall-2014.

Themaindifferenceoccurredbetweengenders.Afterviewingthevideos,femalestudents’motivationjumped1.3points(fromanaverage3.8to5.1),whilemotivationamongmalesrose0.7points(from4.2to4.9).

Whythegenderdifference?Althoughherteamdidn’texplorethisquestionexperimentally,Drennanhasobservedthatmorefemalestudentsthanmalesneedtofeelthesubjectisofrealworldvaluetowanttocontinue.Basically,Drennanexplains,chemistry,likeotherscientificsubjects,isademanding,lengthyinvestment.Womenarewillingtopursueit—andpossiblydelaystartingafamily,forinstance—iftheybelieveaspecificpursuitwillmaketheworldabetterplace—forexample,byimprovingmedicineortheenvironment.

“Someoftheculturalizationisthatwomen,iftheywanttohaveacareer,havetojustifywhythatisausefulthingtodo,”Drennan,herselfamother,sumsup.“Whereas,alotofthemenarejustlike,chemistrywashard,andIdidit.Yes!”

Thepassioncan—andshould—startmuchearlierthancollege,Drennanasserts.Sheandherteamareshowingthevideostohighschoolandmiddleschoolteacherstoencourageuseinscienceclassesandsparkthatpassionearlier.It’saneasysell,becausethevideosareunique:short,easilyinsertedintoaclass,andfullofdiverseandyouthfulcharacters,saysAniqueOlivier-Mason,atechnicalinstructoratMITwhoisheadingDrennan’soutreacheffort.Someteachers,shesays,arehandpickingcertainvideosforspecificstudents—forexample,showingtheHectorHernandezvideotoayoungHispanicmanwhoisthinkingofcommunitycollege.

“Eveninhighschool,noteverystudentisreadyforallthescience,”saysOlivier-Mason.“Butthepersonalvideosareapproachabletostudentsofalllevels.”

“Together,the12videospresentapictureofwhocontemporarychemistsare,”saysBethVogelTaylor.“Inspiringpeoplestudentscanrelateto.”—Trisha Gura

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“Together, the 12 videos present a picture of who contemporary chemists are: inspiring people students can relate to.”—bethvogeltaylor

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Chronicle / Toolbox

An Off-Switch for NeuronsNeuroscientists have built a light-sensitive switch for shutting down neural activity.whenfacedwith athornyproblem,researchersoftenturntonatureforasolution.Oneshiningexampleischannelrhodopsin,aproteinderivedfromgreenalgae.Thelight-sensitiveproteincan,withtheflickofalightswitch,instantaneouslyactivateneuronsinwhichitisgeneticallyexpressed.Givenlife’sspectaculardiversity,findingacomplementary

switch—onethatreliablyextinguishesneuralactivityinthesameway—seemedonlyamatteroftime.Butnearlyadecadeafterchannelrhodopsinbeganturningonneurons,asimilarmoleculeforturningoffneuronswithlighthaseludeddiscovery.

“So,”saysStanfordUniversityneuroscientistKarlDeisseroth,“wedecidedtotrytomakeone.”

Deisseroth,anHHMIinvestigatorandpracticingpsychiatrist,developedthefirstchannelrhodopsinon-switchesin2005.Channelrhodopsinsareessentiallyionchannels—tubularproteinsembeddedinneuronalmembranethroughwhichionscanflow.Inunicellulargreenalgae,theproteinsactasphotoreceptorstoguidethemicroorganisms’movementsinresponsetolight.Deisserothandhiscolleaguesdemonstratedatechniqueforgeneticallyinsertingthelight-sensitivechannelrhodopsinintorodentneurons.Shiningapulseofbluelightonthoseneuronstriggeredtheopeningoftheporesothatpositivelychargedionsflowedintothecell,causingthecelltofire.ThousandsoflabsaroundtheworldnowroutinelyusechannelrhodopsinstostudytheneuralbasisofawiderangeofdisordersrangingfromParkinson’sdiseasetodepressionandanxiety.

Ashelpfulastheyare,channelrhodopsinsprovideneuroscientistsonlyhalfthecontroltheyneedtofullymanipulatebrainactivity.Researchersneededareliablemethodtoswitchneuronsoffaswell.In2006,Deisseroth’steamfoundaworkablesolutioninhalorhodopsins,light-sensitiveionpumpproteinsextractedfromnature—thistimefromthemicroorganismhalobacteria,whichmakeopsins,orlight-sensitiveproteins,selectiveforthenegativelychargedionchloride.By2010,hislabteamhadsuccessfullyengineeredthesechloridepumpsintotoolsforinactivatingneurons.However,unlikechannelrhodopsins,whichallowhundredsofionstopassthroughperphotonoflight,allopsinpumpsmoveonlyasingleionthroughperphoton.Putsimply,ifachannelisafirehose,apumpisadrippingfaucet.“Youstillgetinhibition,butit’sinefficientinhibition,”saysDeisseroth.

Afterseveralmorefruitlessyearsofsearchinggenomicdatabasesforaninhibitorylight-sensitivechannel,Deisserothdecidedtoreengineerchannelrhodopsintomakeitselective

fornegativeions.Heknewhe’dhavetochangethepolarityofthepore’sliningfromnegativetopositive,sothatnegativeions,suchaschloride,couldbeshuttledthrough.OnewaytodothatwastointroduceDNAmutationsthatwouldswapoutnegativelychargedaminoacidsintheporeliningforonesthatwerepositivelycharged.Fortunately,histeamhadbeentinkeringwiththegeneticsofchannelrhodopsintomakeitmorelight-sensitiveandtokeepthechannelopenforlongerperiodsoftime.So,theyknewsuchgeneticmanipulationswerepossible.Theyjusthadtofigureoutwhichofthehundredsofaminoacidstotweak.

Startingin2010,Deisseroth’steam,alongwithbiophysicistsattheUniversityofTokyo,committedtosolvingthestructureofachimeraoftwochannelrhodopsins,calledC1C2,usingx-raycrystallography.Aftertwoyears,theypublishedacrystalstructurethatofferedaroadmapofaminoacidstotargetwithmutations.Still,therewerehundredsofpossibilities,whichtookanothertwoyearstotest.Severalmutationsconferredselectivityforchloride,butthechannelsfailedtoconductcurrent.So,Deisseroth’steam,ledbypostdocAndreBerndt,screenedmorethan400combinationsofmutations,andthroughasystematicprocess,ultimatelyconstructed

Fall2014/HHMIBulletin

Deisseroth says he is particularly pleased with how his lab was able to weave together years of projects to derive the channelrhodopsins.

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achannelwithnineaminoacidmutationsthatconductedchloridecurrents.

Thenewchannel—dubbedinhibitoryC1C2,or“iC1C2,”anddescribedintheApril25,2014,issueofScience—inhibitsneuronfiringintwoways:chloriderushinginmakesthecellmorenegativelycharged,keepingitfromreachingitsfiringthreshold,and,moreimportantly,allthoseopenchannelsmaketheneuron’smembraneleaky.“Bymakingthemembraneleaky,youmaketheneuronhardertofire,”saysDeisseroth.“Youcan’tdothatwithionpumps.”

Withonefinalmutation,Deisseroth’steammadethenewchannelmuchmoresensitivetolightoverall.Themutationalsogavetheresearchersgreatercontroloverthechannel.Bluelightcanopenthisadditionalswitchingtool,calledSwiChR,forminutesatatime;redlightmakesitclosequickly.Suchcontrolhasprovenusefulinlong-termstudieswhereeventssuchasneuraldevelopmentandplasticityplayoutoverminutestohours.Theextendedchannel-opentimesalsomeanlesslightisneededtoinhibittheneurons.Usingaweakerlightsourcereducestissuedamage,increasestheabilitytoreachdeepbrainstructures,andopensthepossibilityofcontrollingbrainfunctionsinvolvinglargeregionsofthebrain.AccordingtoDeisseroth,thesecapabilitiesshouldfacilitatetheuseofinhibitorychannelsinanimalswithlargebrains,suchasprimates.

Deisserothsaysheisparticularlypleasedwithhowhislabwasabletoweavetogetheryearsofprojectsinvolvingcrystallography,geneticengineering,andbehavioraltestingtoderivethechloride-conductingchannelrhodopsins.“Itwascertainlyahigh-riskproject,”hesays,“andintheend,itwassurprisinghowwellitworkedandhowmuchwelearnedabouttheseamazingproteins.”– Chris Palmer


Chronicle / Lab Book

I N B R I E F

TURBO SPEEDWhen a fruit fly detects a looming predator, it can launch itself into the air and soar to safety in just a fraction of a second. But what happens if even a fraction of a second is too long? According to scientists at HHMI’s Janelia Research Campus, flies can employ an even quicker escape response that helps them evade their swiftest predators.

Janelia Group Leaders Gwyneth Card and Anthony Leonardo and their lab teams recorded the reactions of more than 4,000 flies exposed to a looming dark circle that simulated the approach of a predator. They discovered the flies have two distinct responses: a slow and steady takeoff in which they take time to raise their wings fully, and a quicker, clumsier escape that eliminates this step. “The fly’s rapid takeoff is, on average, eight milliseconds faster than its more controlled takeoff,” says Card. “Eight milliseconds could be the difference between life and death.”

By monitoring neurons in the flies’ brains, the scientists learned

that different neural circuits control the two types of takeoff. Any sort of threat will activate the slow, controlled escape neural circuit. But if the threat is closing in quickly—for example, a swooping damselfly—the speedy escape circuit will kick in and override the slow one.

The findings, published in the July 2014 issue of Nature Neuroscience, help shed light on the neural circuits animals use to select one behavior over another.

SHARPER IMAGEA big problem in microscopy is that biological samples bend and distort light in unpredictable ways. The larger and more complex the specimen, the more erratic the light—and the fuzzier the resulting image. To circumvent this obstacle, Janelia Group Leader Eric Betzig created a new microscopy technique that borrows from

astronomy and ophthalmology.Astronomers correct for

atmospheric distortion by shining a laser skyward in the direction they plan to observe, and then measuring the distortion of the returning light. Betzig and his colleagues duplicated this process on a smaller scale by figuring out how a tissue sample distorts infrared light. They corrected for aberrations in the returning light with a method ophthalmologists use to adjust for the movement of a patient’s eyes when capturing retinal images.

The techniques allowed Betzig and his colleagues to bring into focus

the subcellular organelles and fine, branching processes of nerve cells deep in the brain

of a living zebrafish. “The results are pretty eye-popping,”

says Betzig, who published the method in the June 2014 issue of

Nature Methods.“We kept on pushing this

technology, and it turns out it works,” explains Kai Wang, a postdoctoral fellow in Betzig’s lab. “When we

compare the image quality before and after correction, it’s very different. The corrected image tells a lot of information that biologists want to know.”

Y IS HERE TO STAYThe human Y chromosome has been shrinking. Over hundreds of millions of years, it has shed about 97 percent of its original genes. Could the loss of a few more genes tip it into extinction? Not according to HHMI Investigator David Page of the Whitehead Institute for Biomedical Research. He believes that the jettisoning of genes has stopped.

In an April 24, 2014, Nature paper, Page and his colleagues compared the sequences of Y chromosomes from eight mammals, including humans, to reconstruct that chromosome’s evolution. Their results showed that, although there was a period of rapid degeneration and gene loss during the early days of its evolution, the Y chromosome retained a subset of ancestral genes that have remained P

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Untangling a Viral InfectionA host cell enzyme is commandeered by a knot-like structure in flavivirus RNA.flavivirusesareresourceful .TheagentsbehindWestNileanddenguefevertricktheirhost’sinvader-fightingenzymesintohelpingthevirusinfectmorecells.HHMIEarlyCareerScientistJeffreyKieftisresourcefultoo.He’sfiguredouthowthesepathogensperformtheirtrickeryanddevisedapotentialwaytoputanendtoit.

“Scientistsdiscoveredalongtimeagothatwhenflavivirusesinfectacell,theyproduceasubgenomicRNAmoleculethatisessentialfor

viralinfection,”explainsKieft.Themolecule,calledsmallflaviviralRNA(sfRNA),isactuallycreatedbyahostenzymenamedXrn1.Ironically,Xrn1canhelpdefendthehostbydestroyingforeignRNA.Butinthiscase,ithelpstheinvaderattack.

Toitscredit,Xrn1managestochewupmostflavivirusRNA,butthenitstops,andthefragmentthatremainsisthedamage-inflictingsfRNA.KieftandhisteamattheUniversityofColoradoDenvercharacterizedthespotontheviralRNAthatblockstheenzymefrommovingalongtheforeignRNA.Itturnedouttobeaknot-likefoldintheRNAthatactsasablockade.

“Xrn1ischewingdowntheRNA,progressingreallyeasily,anditrunsintothistangled-upRNAstructureandjustcan’tgetby,”explainsKieft.“Itcan’tfigureouthowtountiethe‘knot.’”

Thescientistsalsolearnedthatiftheydisrupttheknot-likestructurebychangingcertainnucleotidesintheRNA,Xrn1cansuccessfullychewthroughtheRNAandpreventproductionofthepathogenicsfRNA.Theypublishedtheirfindingsintwopapers—oneintheApril1,2014,issueofeLifeandtheotherintheApril18,2014,issueofScience.

IfresearcherscanfindawaytopreventviralRNAfromformingtheknottysnarl,

theywillhaveatreatmentforflavivirusdiseases.“Nowthatwe’vegotafullpictureofthestructureandhaveamodelforhowitstopsXrn1,wecangetseriousabouttryingtotargettheblockadewithsmallmoleculestodisruptitsstructure,”saysKieft.– Nicole Kresge

A knot-like fold in flavivirus RNA helps the pathogen trick host cell enzymes.


remarkably stable for the past 25 million years.

Moreover, the nature of the surviving genes hints that a Y chromosome may do more than just dictate the gender of its owner. Most of the genes have little to do with sex determination or sperm production. Instead, they play roles in protein synthesis, RNA splicing, and gene regulation. What’s more, they are expressed in the heart, lungs, and other tissues throughout the body. Page thinks these genes could be contributing to the ways in which disease affects men and women differently.

“This paper tells us not only that the Y chromosome is here to stay, but that we need to take it seriously—and not just in the reproductive tract,” says Page.

CLUE TO LANGUAGE DEVELOPMENTThe human brain has different regions with different functions: vision in the occipital lobe, hearing in

the temporal lobe. But how are these specialty regions formed? A study by HHMI Investigator Christopher Walsh at Boston Children’s Hospital shows that selective regulation of a particular gene may control brain development on a section-by-section basis. Their findings may be relevant to understanding human brain evolution.

In a study published February 14, 2014, in Science, Walsh and his colleagues looked at five people with abnormal folds near a deep furrow in the brain known as the Sylvian fissure, a region that includes the brain’s primary language center. As expected, the five subjects had impairments in cognition and language, yet none had mutations in the protein-coding regions of genes associated with brain function or formation.

All of them, however, were missing 15 nucleotide base pairs in a noncoding segment of their DNA. The mutations had inactivated a stretch of DNA that was promoting the expression of GPR56, a gene critical

for normal brain fold development. “The mutation caused the gene to be deficient, but only in the parts of the brain that did not develop properly,” Walsh explains.

Interestingly, evolutionary studies have shown that, around 100 million years ago, placental mammals acquired some additional DNA in the very area where Walsh’s team discovered the inactivated element. Because those nucleotides determine whether or not GPR56 will create brain folds around the Sylvian fissure, and may even account for the language center’s existence, Walsh believes that it may have helped set the stage for humans to develop language.

A SWELL DISCOVERYBy its nature, a cell’s membrane is permeable to water. So if water levels in the cell’s environment increase, the cell will swell. If it can’t pump out the excess water, the cell will burst. But most cells don’t burst, and HHMI Investigator Ardem Patapoutian of the

Scripps Research Institute has identified a

gene that helps explain why.

Because water tends to follow solutes—the ions and other chemicals dissolved in water—a cell can manage its water content by managing its solutes. In the 1980s, scientists discovered that a cellular ion channel—called volume-regulated anion channel (VRAC)—opens in response to swelling to allow the outflow of negatively charged ions, which take excess water with them.

“Although scientists have known about the activity of VRAC for almost 30 years, its molecular identity has remained a mystery,” says Patapoutian. To find the VRAC genes, his team created fluorescent cells whose glow was muted when VRAC channels opened. The researchers inactivated more than 20,000 genes, one by one, and watched the effect on the glowing cells. Silencing of only one allowed the glow to continue, P

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To see Keller’s cell tracking in action, visit www.hhmi.org/bulletin/fall-2014.

Keeping Tabs on DevelopmentNew software simplifies cell tracking as an embryo grows.therearetens ofthousandsofcellsinafruitflylarva.Recentadvancesinimagingtechnologycanprovidesnapshotsofeachofthesecellsastheydivideandmigrateduringdevelopment.

Capturinganimageofagrowingembryoevery30secondsorsoduringthecourseofaday,however,producesterabytesofdata.

AteamledbyJaneliaGroupLeaderPhilippKellerhasfiguredoutawaytoanalyzethedatabyallowingcomputerstoidentifyandtrackdividingcellsasquicklyashigh-speedmicroscopescancollecttheimages.

Thecomputerprogramisbasedontheideaofclusteringthree-dimensionalpixels,calledvoxels,intolargerunitscalledsupervoxels.Usingthesupervoxelasthesmallestunitallowedtheresearcherstoreducecomplexitybyathousand-fold.Thecomputerscansgroupsofconnectedsupervoxelsforshapesresemblingcellnuclei.Thatinformationisthenusedtolocatethosenucleiinsubsequentimages.

Kellerandhiscolleagues—includingpostdocFernandoAmat;GroupLeaderKristinBranson;andformerJanelialabheadEugeneMyers,nowattheMaxPlanckInstituteofMolecularCellBiologyandGenetics—alsoincorporatedafinalstepthatallowsscientiststochecktheaccuracyofthecalculationsandfixanymistakes.

Totesttheirprogram,theteamcollectedimagesofentirefruitfly,zebrafish,andmouseembryosduringdevelopmentandcomputationallyfollowedthedynamicbehavior

ofthemanythousandsofcellsinthesedatasets.Theyalsousedthesedatasetstoanalyzethedevelopmentoftheearlynervoussysteminafruitflyembryoatthesingle-celllevel.AstheyreportedonlineonJuly20,2014,in Nature Methods,theywereabletotrackalargefractionofearlyneuroblasts—cellsthatwilldevelopintoneurons—andcouldevenpredictthefuturefateandfunctionofmanycellsbasedontheirbehavior.

Kellerhopesthatotherswillusetheprogram,whichworkswithdatafromseveraltypesoffluorescencemicroscopes,tolearnmoreaboutearlydevelopment.Histeamhasmadethesoftware,whichcanrunonadesktopcomputer,freelyavailableonhiswebsite(www.janelia.org/lab/keller-lab).– Nicole Kresge

A new computer program helps track cell movement in images like this one, of a developing fruit fly embryo (left).


Chronicle / Lab Book

I N B R I E F

implying that VRAC had been inactivated. They named that gene SWELL1 and published their findings on April 10, 2014, in the journal Cell.

“When cells swell, the SWELL1 protein is activated and pumps chloride and other solutes out of the cell, which initiates the process to shrink a cell back to original volume,” says Patapoutian.

Now that the team has a molecular understanding of VRAC, they plan to investigate how the channel senses volume change and the role SWELL1 plays in physiology and disease.

LEGO FOR THE LAB Synthesizing a molecule is a lot like doing a jigsaw puzzle. You start with many pieces, figure out how they fit together, and eventually, after a lot of trial and error, you’re done. HHMI Early Career Scientist Martin Burke has come up with a way to

simplify the process using Lego-like building blocks that take the puzzling out of synthesis.

Burke and his team at the University of Illinois at Urbana-Champaign analyzed almost 3,000 polyenes found in nature. These molecules—commonly used as drugs, pigments, and fluorescent probes—contain chains of carbon atoms connected by alternating single and double bonds. The scientists realized that more than three-quarters of the natural products could be created with only 12 different chemical building blocks joined by a single type of coupling reaction. Like 12 pieces of Lego that can be combined to make just about anything, from a house to a dinosaur, the researchers mixed and matched the basic polyene building blocks to produce several different molecules.

The discovery, reported in the June 2014 issue of Nature Chemistry, provides chemists with a simple

way to build polyenes that are challenging or too expensive to

extract from their natural sources. Burke eventually hopes to expand his chemical Lego set to include more than just polyenes. “This paper covers about 1 percent of all natural products isolated to date,” he says. “We want to determine how many building blocks it takes to reach most of the remaining 99 percent, and to create a highly optimized machine that can automatically stitch those building blocks together.”

CLIPPING CONTROLWhen a strand of DNA in a yeast cell breaks, one of the first responders is the endonuclease Sae2. The enzyme’s job is to trim a little from the damaged ends of the DNA in preparation for repair. But if Sae2 lingers around too long, it might end up clipping some perfectly good DNA as well. HHMI Investigator Tanya Paull of the University of Texas at Austin has figured out how cells keep the enzyme in check.

Paull’s team discovered that Sae2 normally forms nonfunctional,

insoluble protein aggregates in the cell. But after DNA damage occurs, an enzyme called cyclin-dependent kinase adds several phosphate molecules to Sae2. This causes the protein clusters to break apart, and the now-soluble single molecules of Sae2 become active. The DNA damage also triggers the degradation of Sae2, ensuring the cellular “clipper” is only transiently available. The findings were published March 2014 in Molecular and Cellular Biology.

“Sae2 is an endonuclease that is potentially very toxic to cells when unregulated,” explains Paull. “So this strategy is ideal for sequestering the protein into a form that is not toxic, yet is available for immediate activation through phosphorylation.”

Paull recently discovered that CtIP—the human version of Sae2—is an endonuclease with even more phosphorylation than Sae2. The results, published in the June 19, 2014, issue of Molecular Cell, have prompted her to investigate if CtIP is also regulated by changes in solubility.

What the Nose KnowsHumans can tell the difference between at least a trillion smells.everyday,we’re confrontedbyamultitudeofsmells,goodandbad:perfume,bodyodor,bakingcookies,ripegarbage.Buthowmanysmellscanthehumannoseactuallydistinguish?AccordingtoarecentstudybyHHMIInvestigatorLeslieVosshall,it’smorethan1trillion.

Fordecades,peoplebelievedthatthehumannosecoulddiscriminatebetween10,000differentsmells.Thatestimate,neverempiricallytested,didn’tsitrightwithVosshall.“Thenumberwasfromtheoreticalworkinthe1920sthatcametobeuncritically

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Italsodidn’tmakesensethathumanscoulddetectfewersmellsthancolors.Thehumaneyecanperceiveatleast2.3milliondifferentcolorsusingthreetypesoflightreceptors.Bycomparison,thehumannosehas400olfactoryreceptors.Surelyweshouldbeabletosmellmorethan10,000odors.

AndreasKeller,aseniorscientistinVosshall’sRockefellerUniversitylab,decidedtodetermineamoreaccuratenumber.Heselected128differentodorantmoleculesthat,whensniffedindividually,couldevokesmellssuchasmintorcitrus.Butwhenmixedincombinationsof10,20,or30,theodorants’smellswereunfamiliar.

Twenty-sixvolunteerswerepresentedwiththreevialsofthesescentcocktails;twowereidentical,thethirdwasdifferent.Itwasthesniffer’sjobtopinpointtheoutlier.Eachvolunteerdidthismorethan250times.Onaverage,theycouldeasilydistinguishbetweenmixtureswithfewerthanhalftheircomponentsincommon;abovethat,discriminationbecameharder.

Fromthedata,theteamextrapolatedhowmanydifferentodorstheaveragehumancandetect.Vosshalllikenstheprocesstoasurvey—ratherthanaskingtheentirecountrywhatpresidentialcandidatetheywillvote

for,youtelephoneafewthousandvotersanduseyourfindingstomakeanestimateoftheentirepopulation’spreferencesbasedonthissampling.Thenumber,publishedMarch21,2014,inScience,was1.7trillion—aconservativeprojection,astherearemanymorethan128odorantsintheworld.

Nooneencountersatrillionsmellsinaday,sotheabilitytodistinguishbetweensomanyodorantmoleculesisn’treallynecessary.Butbeingabletodiscriminatebetweensimilarsmells,suchasspoiledmilkversusfreshmilk,iscertainlyuseful.– Nicole Kresge

Volunteers sniffed 250 different scent cocktails to help determine the limits of human odor detection.

12Cell division involves intricate choreography. Pairs of chromosomes (red) line up center stage where thin spindle fibers (green) tug the couples apart, pulling individual chromosomes to opposite sides of the cell. But sometimes the well-oiled performance hits a snag, leaving one or more pairs united. Two aneuploid daughter cells result—one with too many chromosomes and one with too few. Aneuploidy can mean curtains for the cells. One standout exception is cancer, where cellular missteps in division can lead to wildly successful reproduction. H

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Mysteries of the MindThe seat of all our thoughts and emotions, actions and memories, the brain’s capacity and complexity seem impossible to fully grasp. Yet, thanks to advances in recent years, neuroscientists can now envision a comprehensive picture of the brain in action, from molecules to cells and circuits to behavior. In April 2013, President Obama launched the BRAIN Initiative to underscore and accelerate this vision. Details of the initiative’s plan are now available in a report released in June by a working group co-chaired by HHMI Investigators Cori Bargmann and William Newsome, whose poetic preamble sets a powerful framework for the effort.

We stand on the verge of a great journey into the unknown—the interior terrain of thinking, feeling, perceiving, learning, deciding, and acting to achieve our goals—that is the special province of the human brain. These capacities are the essence of our minds and the aspects of being human that matter most to us. Remarkably, these powerful yet exquisitely nuanced capacities emerge from electrical and chemical interactions among roughly 100 billion nerve cells and glial cells that compose our brains. All human brains share basic anatomical circuits and synaptic interactions, but the precise pattern of connections and interactions are highly variable from person to person—and therein lies the source of the remarkable variation we see in human behavior, from the breathtaking dance of a ballerina, to the elegant craftsmanship of a master carpenter, to the shrewd judgment of an expert trader. Our brains make us who we are, enabling us to perceive beauty, teach our children, remember loved ones, react against injustice, learn from history, and imagine a different future.

The human brain is simply astonishing—no less astonishing to those of us who have

spent our careers studying its mysteries than to those new to thinking about the brain. President Obama, by creating the BRAIN Initiative, has provided an unprecedented opportunity to solve those mysteries. The challenge is to map the circuits of the brain, measure the fluctuating patterns of electrical and chemical activity flowing within those circuits, and understand how their interplay creates our unique cognitive and behavioral capabilities. We should pursue this goal simultaneously in humans and in simpler nervous systems in which we can learn important lessons far more quickly. But our ultimate goal is to understand our own brains.

Excerpted from BRAIN 2025: A Scientific Vision, a

Brain Research through Advancing Innovative

Technologies (BRAIN) Working Group Report to

the Advisory Committee to the Director, National

Institutes of Health. Published June 5, 2014.

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Fall ’14 Vol. 27 No. 3

in this issue Bacterial Comrades

Meet the New ProfessorsEco-friendly Fertilizer

Deadly BeautyThis slow-moving marine snail, Conus geographus, packs venom

so powerful that less than half a teaspoon can kill a person. Small fish within the striking zone of its venomous harpoon don’t stand

a chance. Paradoxically, components of the venom are extremely strong pain killers—up to 10,000 times more effective than morphine.

HHMI Professor Baldomero Olivera has spent his career teasing apart the hundreds of toxins in the beautiful cone snail’s venom, in

hopes of turning the meat-eating mollusk’s poison into medicine. One drug is already available for patients. Learn more about Olivera’s

research and his efforts to advance science education around the world in the HHMI Bulletin (www.hhmi.org/bulletin/summer-2014).

fall ’14 vol. 27 no. 3 bulletin - howard hughes medical institute · 2014. 6. 5. · hhmi...

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