Sugar Coated Sugar Has Become Notorious, with Countless Claims of Its Ill Effects on Health

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BULLETIN N o v . ’11 VOL.24 • NO.04

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Sugar Coated Sugar has become notorious, with countless claims of its ill effects on health. But not all sugars are bad for you. Consider fucose, an essential sugar the body needs. Without it, neurons can’t communicate, kidneys can’t

filter blood, and skin can’t stay hydrated. Chemical biologist Carolyn •

Bertozzi and her group are trying to learn more about the role of fucose in www.hhmi.org development. To do this, they injected modified versions of fucose into live, single-celled zebrafish embryos. As the embryos developed, the altered fucose molecules were incorporated into the sugars that coat cell surfaces. Using a simple chemical reaction, the team attached a labeled probe molecule to the altered fucose so they could visualize its location in the developing embryo. In this image of a 19-hour-old zebrafish embryo, labeled fucose (red) glows in the peripheral cells. Just one of many ways chemistry is helping answer biological questions (see “Living Chemistry,” page 12). Year of Chemistry Chemists fascinated by the complexity of biology are solving problems in neuroscience, immunology, and cell signaling. v ol. 24 / no. 04 Karen Dehnert and Scott Laughlin / Bertozzi lab In This Issue: Traveling Microscope / Lemur vs Mouse / Spotlight on Science Teacher Training cells—something thatbiologists havebeeneagertodo. the approachisparticularlysuited forimagingactivitywithin living spatial resolutionwithhigh speedandminimal light-induceddamage, plane byplane,untiltheentire volume isimaged.Combining 3-D light toilluminate asingle plane within aspecimenandthenrepeats, his teamatJaneliaFarm, themicroscope directsanarrowpencilof beam planeillumination microscopy. DevelopedbyEricBetzigand cancer cell,anosteosarcomacomesfromvideorecordedby Bessel Catching chromosomesintheact,this stillframeofa dividinghuman 24

Betzig lab

Emily Roberston for synthesizing acetylsalicylic acidwere developed by two chemists, sized akey derivative namedacetylsalicylic acidin1853. Refined methods of limited value. Charles Frédéric Gerhardt, a French chemist, then synthe- compared to salicin.Salicylic acid,however, causedguttoxicity, andsowas geous becausesalicylic acidwas easierto modifyinto other molecules Italian chemist, prepared salicylic acidfrom salicin,whichwas advanta - An active component of Willow tree extract issalicin.Raffaele Piria,an of combined approach isthediscovery offever-reducing drugs. to In many cases,extraction andsynthesis methodshave beencombined combine insometimes powerful andfar-reaching ways. Stockwell reveals how curiosity, persistence, andscientific know-how in anew bookonthescience behinddrugdiscoveries. Inthetelling, Brent Stockwell chosehisfavorites—including thestory ofaspirin— throughs that ledto innovative diseasetreatments. Chemicalbiologist The history ofscience overflows withcaptivating stories ofbreak Th Observati

make derivatives ofmoleculesfound innature. Anexample ofthistype e G i v i n o g ns

tree -

the Next Generation of Medicines, by Brent R. Stockwell, © Excerpt from TheQuest for theCure: TheScience and Stories Behind huge class ofbeneficialmedicinesthat are widelyusedaround theglobe. introduced, suchasibuprofen (now sold asAdvil). Suchdrugsrepresent a inflammatory drugs(NSAIDs) used.Subsequently, other NSAIDs were popular around the world. Itwas thefirst ofthenon-steroidal anti- coining thename“aspirin.” This fever-reducing drugquicklybecame company Bayer introduced acetylsalicylic acidasananti-pyretic in1899, molecules) were aggressively sought.The nascent pharmaceutical be damagingto the body. These so-calledanti-pyretics (fever-reducing medicines that could reduce fever, withtherationale that fever could At theendofnineteenth century, many researchers beganto pursue this moleculelanguished,withlittleinterest initsmedicinalproperties. Johann Kraut in1869 andHermannKolbe in1874, butthen,unfortunately, of theauthorand Columbia University Press. Stockwell, publishedby Columbia University Press. Used by permission

20 11 Brent

R. november ’11 vol. 24 · no. o4

Web Only Content Hear Eric Betzig talk about taking his new microscope to Woods Hole and see how it dazzled summer students and faculty.

Learn how Irv Epstein brings chemistry alive for students in the classroom.

Travel with Mark Krasnow to the rainforests of Madagascar to spy the mouse lemur in its native habitat.

Join us at www.hhmi.org/bulletin/nov2011.

24 30 Features Departments cover story PRESIDENT’S L ETTER Institute News Living Chemistry 03 Intellectual Ferment 40 Experiment Seeks to Create 1 2 As engineers of the molecular CENTRIFUGE Interdisciplinary Curricula world, chemists are making their 40 HHMI Offers International 04 Game Changer mark in biology. Student Research Fellowships 05 Stirring Debate 41 Getting Back to the Bench Calling a ll Teachers 06 The Peripatetic Postdoc 1 8 Everyone agrees that the U.S. needs Lab Book UPFRONT to train a new generation of inspiring 42 Unlocking the Interferon Puzzle 08 Creating Internal Maps science teachers. But how? 43 When Membranes Merge 1 0 Helping Preemies Have Microscope, Wi ll Travel 44 Bacterial-Viral Warfare PERSPECTIVES AND OPINIONS 24 Biology students and faculty A sk a Scientist 34 Changed Expectations immersed in science courses at 45 How fast would an object have to 36 Q&A—What was your first cool Woods Hole get their hands on a chemistry experiment—one that move to be invisible to the naked eye? remarkably powerful imaging tool turned you on to research before Nota Bene developed at Janelia Farm. you were a bona fide scientist? 46 News of recent awards and other S tar Search CHRONICLE notable achievements 30 Could the grey mouse lemur be the Science Education OBSERVATIONS next best model for human disease? 38 Room to Grow—and Learn The Giving Tree

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

teacher, Mrs. Otwell—a woman with sharp we spotlight the need in this country for intelligence and charismatic delivery who more, and better, science teachers in our taught me the “bus seat rule,” to illustrate schools. In other articles, we pay hom- the orderly manner in which electrons fll age to the increasingly powerful role that atomic shells, and the meaning of a quark. chemists play in biological discovery— I wasn’t the only one in my family chemists who no doubt got their start touched by Mrs. Otwell’s teaching magic. being fascinated by the fundamentals with One of my older brothers majored in chem- teachers like Mrs. Barnes and Mrs. Otwell. istry in college, and my sister, who as a Star Don’t miss the multimedia slideshows Student in high school named Mrs. Otwell and other extras in this issue, which can In the ffth grade, I won a blue ribbon at her Star Teacher, is now an academic be found online and in our iPad app. The my school’s science fair. Truth be told, it researcher studying bone genetics. digital versions of the Bulletin are proving wasn’t much of a project—I grew a “pop- Who’s to say what might have been had a great way to expand on the stories we corn plant” from an unpopped corn kernel. the early spark that Mrs. Barnes lit been offer in print—for example, fnd new details But my teacher, Mrs. Barnes, saw some- fanned into a fame during my later school of Matt Warman’s bone research, frst cov- thing there. years? After switching my college major ered in the May 2011 issue. The magazine’s I treasured that ribbon, and it could from English to biology, I eventually arrived stories continue to have lives long after be that Mrs. Barnes’s vote of confdence at a career in science, frst in the research they land in your mailbox, and we’ll use our launched me toward my graduate degree lab and now as a science writer and edi- website to update them as we go. in biology. Sadly, though, the rest of my tor. It was the right path for me, though I elementary, middle-, and high school years sometimes imagine how things might have were almost bereft of science, with few been different. good science teachers. The one excep- Clearly, those formative K-12 school tion was my eleventh grade chemistry years are critical. In this issue of the Bullet in,

HHMI TRUSTEES HHMI OFFICERS James A. Baker, III, Esq . Robert Tjian, Ph.D. / President Senior Partner / Baker Botts LLP Cheryl A. Moore / Executive V.P. & Chief Operating Offcer Craig A. Alexander Ambassador Charlene Barshefsky / V.P. & General Counsel Senior International Partner Sean B. Carroll, Ph.D . / V.P. for Science Education WilmerHale Jack E. Dixon, Ph.D . / V.P. & Chief Scientifc Offcer Joseph L. Goldstein, M.D . Mohamoud Jibrell / V.P. for Information Technology Regental Professor & Chairman / Department of Molecular Genetics Nitin Kotak / V.P. & Chief Financial Offcer University of Texas Southwestern Medical Center at Dallas Avice A. Meehan / V.P. for Communications and Public Affairs Hanna H. Gray, Ph.D. Gerald M. Rubin, Ph.D . / V.P. & Executive Director, President Emeritus & Harry Pratt Judson Janelia Farm Research Campus Distinguished Service Professor of History Landis Zimmerman / V.P. & Chief Investment Ofﬁcer The University of Chicago Garnett L. Keith HHMI BULLETIN STAFF Chairman / SeaBridge Investment Advisors, LLC Mary Beth Gardiner / Editor Former Vice Chairman & Chief Investment Ofﬁcer Cori Vanchieri / Story Editor The Prudential Insurance Company of America Jim Keeley / Science Editor Fred R. Lummis Andrea Widener / Science Education Editor Chairman & CEO Nicole Kresge Platform Partners LLC / Assistant Editor Maya Pines / Contributing Editor Sir Paul Nurse President / The Royal Society Additional Co ntrIButors Dame Alison Richard, Ph.D. Cay Butler, Michelle Cissell, Sarah Crespi, Professor / Yale University Mark Farrell, Heather McDonald Clayton S. Rose, Ph.D . VSA Partners, NYC / Concept & Design Professor of Management Practice Finlay Printing / Printing & Binding Harvard University Kurt L. Schmoke, Esq., Chairma n Dean / Howard University School of Law Anne M. Tatlock Director, Retired Chairman & CEO Fiduciary Trust Company International Telephone (301) 215.8855 • Fax (301) 215.8863 • www.hhmi.org ©2011 Howard Hughes Medical Institute

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2 hhmi bulletin | November 2o11 James Kegley California, SanFrancisco, rightlyobserves,someproblemscan’tbe cal questions andviceversa.AsKevanShokatoftheUniversity of divide aswellwhat’s changed forchemists interestedinbiologi- between chemistry andbiologyfromboth“sides” ofthedisciplinary try. We’re alookatthecomplexandexciting connections taking the endof2011andtheInternationalYear ofChemiswe near - interactions betweenbiologyandchem out thecountry. five-year mark,andwithgreaterfrequency atuniversities through- the time,atJaneliaFarm ResearchCampusas itapproachesthe that isproductiveandexciting. IseeitinmyUCBerkeleylaball cians together withbiologistsgenerateakindofintellectualferment we haveanalmostinfinite number toaddress. out isthebigchallengeforallofusinbiomedical researchbecause questionimportant worthyofyourtimeandenergy. Figuringthat or physicist—you willhaveasenseofwhatmakesprofoundly tions. Ifyouhave“biologicalintuition”—whetherareachemist so much aboutsolvingproblems as it is about asking the right ques - intuition orinstinct—whateverwordyouusetodescribeit—isnot have aninstinctivefeelforasubject?Doesitspeaktoyou?That about:intuition.Doyou colleagues canhaveahardtimetalking tems andchemists delightindiscovering biologicalphenomena. have becomeincreasinglyblurry:biologistsaremanipulating sys- happy to say that these disciplinary and philosophical distinctions on figuringouthow tomanipulate aprocessormakeitbetter. I’m the question ofhow somethingworkedbecausetheywerefocused the underlyingprocesses.Chemists, ontheotherhand,skippedpast were focusedondiscovering how thingsworkandlessinterestedin risk ofoversimplification,Iwouldsaythatformanyyears,biologists interested inworkingattheinterfaceofmultiple disciplines. Atthe scientist and these competing definitions can be vexing when you’re what moleculesaredoing andhow theyinteractwitheachother. major problems in biology,view: to attack it is essential to understand to biochemistry. Eversince,myresearchhasbeenshapedbyasingle work inthelaboflegendaryDaniel Koshlandthatdrewme tions. Instead, it was a fascination withbiology and the chance to synthetic organic chemistry thatturnedmythoughtsinnewdirec- Berkeley. Butunlikecountlessundergraduateseverywhere,itwasn’t arrived asafreshmanonthecampusofUniversity ofCalifornia, Chemistry was thefo Intellectual Ferment This issue of the Labs thatmix biochemists, engineers,physicists, andmathemati- For me,ithasalwayscomedown tosomethingthatmyscientist Every fieldhasa takestobeagood different definition ofwhatit takes special notice of theHHMI Bulletin takes c us ofmya c ademi istry—a fittingsubjectas c interestswhen I

tute ofBiochemistry, succeededindoing withsuchelegance. School ofMedicine, andFranz-Ulrich HartloftheMaxPlanckInsti- That iswhatArthurL.Horwich,anHHMIinvestigatoratthe Yale the complexregulatoryprocessesthatneedtohappenalong way. what actuallyoccursinlivingcellsamid tions oryoucanunderstand out how proteins ofexpectedatomic foldfromthestandpoint interac - this year’s LaskerAward forBasicMedical Research.You canfigure we havenobetterillustrationofitthanthediscoveries honoredby And makes theconfluenceofbiologyandchemistry soimportant. each otherinalivecellrealtime? at therighttime.Theproblemis,how to dothose100proteins talk reactions thatinvolvecloseto100polypeptidesdoing therightthing own work,Iaminterestedinthemolecularmechanism ofcomplex few—because youcan’tgettherebybeing purelydescriptive.Inmy engineering, computerscience, andbiophysics,tonamejusta tool atyourdisposal—that means genetics,cellbiology, chemical cal systems that underpin disease, you want to useeveryimaginable Fences MakeBetterNeighbors.” Chem might proposesomethingalongthelinesof“BetterBiologywith famous 1960s advertising slogan—this new breed of scientists chemistry. Instead of “Better Living through Chemistry”—Dupont’s addressed unlessyouharnessboththetoolsofbiologyandthose “ If youIf really want understand to tool at your disposal. you want useevery to imaginable that underpin systems disease, the function of complex biological Ro It’s solvingproblemslikethis,at theleveloflivingcell,that thefunctionofcomplexbiologi- If youreallywanttounderstand bert istry.” OrinavariationontheRobertFrost poem,“Lower T jian ” president November 2o11

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s letter hhmi

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3 4 hhmi O ported EXR Daley. “Ilike that!” off. “You hithard—really hard,” says Hospital Boston. investigator George Daley ofChildren’s partner andsummerlabmentor, HHMI student andslice toward herrallying off theracquet ofadark-haired biology campus. court ontheHarvard MedicalSchool tennis volleys echoesfrom asecluded thwok....thwok....thwok ofsharplyhit tail ofaBoston heat wave, thesteady On ahumidSunday morningonthe Game Changer pportunities Program) student, returns centrifuge Alana Van Dervort, anHHMI-sup- It’s the Bright yellow-green ballsexplode

bulletin f rst timethetwo have faced O P (Exceptional Research

November 2o11

comments knowingly to a the compliment. “He’s aplayer,” she so Imadeupfor itby becoming a change directions asneeded. bouncing ontheballsofher feet—to and acertain readiness—like aplayer and life—shows agrittydetermination her expenses. earning enoughprize money to cover professional women’s tennis circuit, South Korea, Mexico, andDubaionthe tr hood. Between 2003 and2006, she game shehonedsince earlychild- knocking therust offthepowerful aveled by herselfto places like China, “At 5-foot-5, I’masmallerplayer, Van Dervort’s approach to tennis— After alonglayoff, Van Dervort is

bystander. Association’s Women’s and even won theAmericanTennis tournaments. Shehadearlysuccess was four or was 10, started herontennis whenshe Dervort. “The NIH was my playground.” test tubesinthecentrifuge,” recalls Van of Health,withguidinghertoward care medicineat theNational Institutes research onsepticshockandcritical Dervort credits herfather, whodid years. Energetic andanimated, Van summer between herjuniorandsenior renowned stem cell biologist, for the selected to work inthelabofDaley, a logical sciences. Last June, shewas court for thelaboratory to train inbio- International She injuries, V of herentire body, notjust herarm. and powers hershotswiththeweight hits theballearlyinitsupward bounce meticulous technician,” shesays. She —Richard Saltus faster asoundernotion evolves.” actively engagingthequestion—the to aspeci travels. Today, sheappliesthe same to different cultures andlocalesinher tennis tacticswhenneededandadjust thing,” shesays. me con handed oruseafoam racket. Itgave I was serving,ormake meplay left- he would purposelydistract mewhile prepared for theunexpected. “Indrills strong work ethicandtaught herto be merly ranked No. 1intheworld. elite players, includingSharapova, for- Seles. Van Dervort trained dailywith Williams, Andre Agassi, andMonica an incubator of top tennis talent, years at thefamed NickBollettieri f ing MariaShar T scienc ennis Academy inBradenton, Florida, exibility to herscience. Her father, whodiedwhenAlana “He usedto letme‘help’himput At age22, inpartbecauseof “I Thus, Van Dervort could changeher Van Dervort’s father instilled inhera Van Dervort spentherhighschool

enrolled asafreshman at Florida f e andtennis. nd that theless Iamattached f dence that Icould handleany- an Dervort shifted gears. f c notion—aslongasI’m f ve, takingherto play in U apova, Serena andVenus niversity, trading the O pen at age17.

includ

Chris Silas Neal Shawn Records cal world andour place init,” says how we explain to ourselves the the Bushand and evolution, andtheuse ofscience in as toxic chemicals,intelligent design times heated, ontopics asfar ranging course, heleadsdiscussions, some- As director ofthehumanities-styled globe-trotting environmental activism. background intheliberal artsand his focus broadens to embrace his room of“BiologyandPolitics,” however, s probing themolecularevolution of Thornton isalaser-focused scientist In hisUniversity ofOregon lab, Joe Stirring Debate teroid hormonesandtheirreceptors. “Science isaform ofculture. It’s When Thornton enters theclass- O bama administrations.

physi- and Early Career Award for Scientists after hereceived a2006Presidential authority inculture.” ti assumptions aboutthenature ofscien- the way, they question theirmost basic politics inademocratic society. Along debate how science shouldinform social andpoliticalforce.” “That makes itanenormouslypotent T between scienti late different views oftherelationship and thehistory ofscience to articu- readings insociology, philosophy, hornton, an HHMI early career scientist. f c knowledge, hesays. “We explore Thornton created thecourse Students inThornton’s course Engineers. f c expertise and

tive Jim 1980s at Yale scientist. Asanundergraduate inthe ture shapethescienti saw theways inwhichpoliticsandcul- that science carriesinsociety. I also I saw theenormouspoliticalauthority ence changedtheway Ilookat science. natural systems,” hesays. “That experi- I becamefascinated withthestudy of molecular biologyandevolution. scientis rewarding for measateacher and tributing to culture. That’s extremely form ofself-expression—a way ofcon- see science asarigorous butcreative science,” Thornton says. “They come to tally changedtheway they thinkabout se new billinJuly. John each ofthelast three years. Senator ing themintroduced inCongress in with legislation aimed at address- chemicals hasgrown over 20years, the potential healthdangersofthese ogy andPolitics course. Recognition of good openingcasestudy for hisBiol- continues, henotes, makingtheissue a entered Columbia without formal training. At age30, he dreds ofreports andarticles,all before Congress, andauthored hun- groups around theworld, testi wildlife, heworked withcommunity on reproductive healthinhumansand endocrine disruptors andtheireffects Focusing ontheemerging issue of policies related to chemicalpollution. improve publicunderstanding of translating complex science to help peace, where hespentnineyears to politicalactivism. debate ontheenvironment, heturned ity,” hesays. Amidagrowing national it was divorced from any tangiblereal- “It was interesting andseductive, but English, withafocus onliterary theory. veral students say that itfundamen- “During my timewithGreenpeace, “Each timeIteach thecourse, The debate onendocrinedisruptors He worked asanactivist for Green- T hornton didn’tplanonbeinga

Kerry (D-Mass.) andRepresenta- t.” —JimBarlow

Moran (D-Va.) introduced a November 2o11 U niversity, hemajored in U niversity to study f c debate

hhmi f

bulletin itself.” 5 6 hhmi bemused by theinterest shown inhis south ofGloucester.” the hillsnearmy home, inatown just the Koreans. Iwas brought upwalking of peoples—theEnglish,the Japanese, he says. “That’s thecasefor anumber called my Ph.D. to gotten alate start; I’d hadalittlething waist-deep insnow,” Beeby laughs.“I’d “Because Iwas knee-and sometimes of thetrail’s end. came to astandstill just 60milessouth U quite madeitto thepointwhere the edge ofCanada.Beeby, however, never States from theMexican border to the which meandersthrough the that constitute thePaci had traveled 2,590 ofthe2,650miles O didn’t stop untilaTuesday afternoon in Monday morninginJune2007 and Morgan Beeby setoutonawalk one Postdoc The Peripatetic native nology, walking isjust apartofhis at theCalifornia Institute ofTech- with HHMIinvestigator Grant Jensen now apostdoctoral scholarworking .S. meetsitsneighbort ctober—four monthslater. By then,he centrifuge Perhaps that’s why Beeby seems “The Britishare anation ofwalkers,” Why stop, socloseto the For thisBritish-bornmicrobiologist, bulletin

culture.

November 2o11 f nish up.” f o thenorth.He c Crest Trail, f U nish line? nited

Paci a fantastic way ofgettingperspective.” something to be enjoyed in and of itself, tion, butthat’s notthepointofit.It’s it’s convenient that it’s alsotransporta- nice that it’s incidentallyexercise, and relaxation. Itjust is. tion noravocation, neithersportnor pieces. To him,walking isneithervoca- knife to cuthisfood into bite-sized given astanding ovation for usinga ramblings, reacting asifhewere being wher And onesummerhewalked for also hoofed 70 milesthrough Tasmania. of anassignment for amagazine. He tralia’s least-hospitable terrain aspart nearly 120milesacross someofAus- only one. Heandafriendtrudged longest trek, itwas by nomeanshis in Gloucester. “I in Birmingham,England,to hishome days from theuniversity heattended Although thetimespenton “Walking isaprocess,” hesays. “It’s f ever Icould pitch atent.” c Coast Trail was by far Beeby’s

camped in f elds f ve their precisely, to glideorswim—through that allow bacteria to travel—or, more that power thewhip-like appendages lar motors, themolecularmachines —Lori Oliwenstein he adds.“Whocanthinkat adesk?” and seetheworld isinvaluable to me,” ment ofanidea.Beingableto get out the process ofresearch anddevelop- pleasure andinvolvement Ihave with and bacteria move,” hesays. “It’s the not and research permits.Hestudies are shortweekend jauntswhenhis spent alotofmy childhoodbarefoot.” it’s becauseI’ve always walked and says withahalf-sheepishgrin.“Ithink train, andIalmost never getblisters,” he shoes onthemarket, however. “Idon’t tips oradiscussion ofthebest walking The onlylinkbetween hiswork These days, most ofBeeby’s trips Don’t count onBeeby for training

the surface similaritythat Imove his pastime istheprocess. “It’s

environment. f agel-

Chris Silas Neal upfront

08C reating Internal Maps Combining complementary skills, a team of neuroscientists studies how flies navigate their surroundings.

10 H elping Preemies Treating myelin injuries and tracking brain cell development to rescue the littlest patients.

web only content

a New Take on Retinoblastoma Basic research findings upend old thoughts on this childhood tumor. Read the story at www.hhmi.org/bulletin/nov2011.

When inspired people come together, even briefly, great things can happen. A developmental biologist pulls together a team of pharmacologists, chemists, and genomics wizards to build a comprehensive picture of a rare childhood cancer—and they find a drug to attack it. A pediatric neurologist partners with a veteran stem cell biologist and a young neurosurgeon to study brain tissues and they discover a pathway for neurogenesis. A Janelia Farm researcher hits it off with a visiting scientist, they pull in a postdoc, and voilá, fly behavior is illuminated. Teamwork par excellence.

November 2o11 | hhmi bulletin 7 upfront

Creating Internal Maps Combining complementary skills, a team of neuroscientists studies how flies navigate their surroundings.

Some collaborations click from the start. Take the chance meeting three years ago at Janelia Farm Research Campus between Michael Reiser, a group leader at Janelia, and Charles Zuker, an HHMI 20 centimeters across, with a clear glass lid. Most of the arena’s floor was a warm- investigator then at the University of California, San Diego (UCSD). to-the-touch 36°C. One tile, however, was The two had never spoken before, but within a day or two, Reiser says, only 25°C, pleasantly cool for fruit flies. Zuker was suggesting his graduate student as a perfect fit for the project. Each time the flies entered the arena, they typically wandered, but “once they found The partnership seemed so promising But how do neurons register this infor- the cool spot, they stopped and stayed that Zuker arranged to work with Reiser mation? Reiser believes it might be possible there,” says Ofstad. The flies were allowed through Janelia Farm’s Visitor Program, to dissect mapping of spatial memory by 10 five-minute trials to learn the location where scientists from around the world con- analyzing the process in fruit flies, where of the tile. To follow the flies’ movements, duct research of their own design for a few brain cells can be precisely targeted for the researchers were among the first to use weeks or several years (see Web extra side- manipulation. “The fly presents a real sweet software designed by Janelia Farm fellow bar, “Visitors Welcome”). “We all hit it off spot to try to answer this question,” he says. Kristin Branson that Reiser describes as “the beautifully,” he says. At the outset, Reiser brought his world’s best fly tracking program.” The researchers weren’t just simpatico. LED-based display that projects different The cool tile looked the same as the rest They brought together complementary background patterns, providing poten- of the floor, so the only landmarks in the talents and knowledge that enabled them tial navigation landmarks for flies. Zuker arena were patterns of bars projected on the to explore an important question: do fruit brought small, hot and cool tiles that his wall. To determine whether the flies used flies commit details of their surroundings lab had developed to study how the insects this background to guide them to the cool to memory? Humans and other vertebrates sense temperature. tile, the researchers rotated the floor and make spatial memories all the time. You The job of melding these technologies walls of the arena after each trial so that can return to your car in a crowded parking fell to the third member of the partnership, the location of the cool floor tile changed, lot, for example, by referencing landmarks Tyler Ofstad—Zuker’s graduate student and but its position relative to the wall patterns stored in memory. So-called place neu- an M.D./Ph.D. candidate at UCSD. After a stayed the same. rons in the hippocampus, a brain structure year of R&D in Reiser’s lab, handled largely The flies quickly learned to pinpoint crucial to memory, confer this ability. “In by Ofstad with what Zuker calls “devotion, the cool spot. After 10 attempts, the insects essence, the cells are creating an internal drive, and maniacal commitment,” the team could find the tile in under 60 seconds, less map of the outside world,” says Zuker. had built a shallow, circular arena, about than half the time of their first try, the group

8 hhmi bulletin | November 2o11 Mike Lemanski tions,” saysOfstad. “flies canformmemoriesabout spatialloca- evidence, they alsomadenoheadway. Giventhis the chancetofindcooltile inthedark, tile. Theflieswerebaffled.Whengiven corresponded to the location of the cool so that the background pattern no longer each trialbutleavingthewallstationary, the thermalpatternonarenafloorafter the visualbackground. where thetileshouldhavebeen,basedon arena withoutacooltile,theycongregated when thetrainedfliesencounteredan reported June 8,2011,inNature . Then the team tricked the flies, rotating Then theteamtrickedflies,rotating the researchers concluded that Moreover,

place neurons. first placetolookforthefly equivalent of isn’t clear,butZukersaysitwould bethe the insects.Theroleofellipsoid body ing orretrievingspatialinformation in this structuremight becrucial forstor- the fliescouldn’tnavigatearena.Thus, called theellipsoid bodywereshutdown, fied neurons.Whenneuronsinastructure smallgroupsofidenti- scientists to target lia Farm director GerryRubinthatallow genetic toolsdevelopedinthelabofJane- braincellsintheflies, using off certain location ofthecoolspot.Theyswitched which part of the fly brain remembers the Next theresearcherswantedtoknow

more ofit,” Zukersays. of exciting scientific problems,youwant ergy thathelpssomeofthemagiccomeout function. “Whenyoufindtheunique syn- behavior todecipher anotheraspectofbrain hatching aplantousefruitflyvisionand in New York City. The team, however, is versity CollegeofPhysicians andSurgeons has movedhislabtotheColumbiaUni - finish clinical workforhisM.D.,andZuker hasreturnedtoSan Diegoto ways—Ofstad The researchershavegonetheir separate bulletin/nov2011. Program at JaneliaFarm, visitwww.hhmi.org/ WEB EXTRA: November 2o11 To read more about theVisitor W

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L bulletin eslie 9 upfront

Helping Preemies Treating myelin injuries and tracking brain cell development to rescue the littlest patients.

Babies born prematurely—as much as three months too soon—have a better chance of surviving than they did just a decade ago. But they face serious neurological problems that HHMI investigator David Rowitch sees too often in his clinical rounds at the University of California, San Francisco (UCSF). Using tissue from a expression of the gene AXIN2. Wnt is well known as an important, complex signaling new neonatal brain bank, he is gathering clues to devise treatments for pathway involved in the development of brain-injured babies and perhaps also for adults with multiple sclerosis. most organ systems throughout the body. When the scientists injected an experi- “We routinely take care of babies in that offer clues to nerve cell repair as well mental drug that slows degradation of the the United States that are born at about as human brain development. Axin2 protein directly into patches of dam- six months of gestation, weighing about In earlier work, Rowitch and postdoc aged myelin in mice, it inhibited Wnt, a pound,” says Rowitch, a neonatologist. Stephen Fancy had noticed that white and the OPCs lining the wound rapidly “About 10–20 percent will develop cere- matter injuries in some premature babies differentiated into healthy, myelin-mak- bral palsy—an inability to move and talk look similar to the damaged patches of ing oligodendrocytes. The myelin injuries normally—and as many as 50 percent myelin in multiple sclerosis. Closer study healed 30 percent faster than similar inju- will develop learning, cognitive, or behav- of brain bank specimens revealed why: In ries in untreated mice. ioral problems.” At least some of those both cases, myelin-making cells known as Many questions remain. “We still don’t problems, Rowitch says, stem from dam- oligodendrocytes and the progenitor cells know enough about this particular drug’s age to the protective myelin coating that that give rise to them (known as OPCs) toxicity—especially in young children,” insulates nerve cell axons in the “white rush in to repair the initial injury. Mysteri- Rowitch says. “And, I think it would be sim- matter” of the baby’s brain. ously, they don’t complete their task. plistic to think this pathway is the only thing “Therapies to limit the damage or “The obvious question is, why aren’t going on in the inhibition of myelin repair.” enhance repair don’t exist,” Rowitch says. these cells—which are all showing up at Still, he says, the results suggest it might Answering even basic questions about the the right time in the right place—finishing be possible to speed mending of tattered developing human brain has been tough the job they are almost hardwired to do?” myelin with a drug soon after injury, before because of the lack of autopsied tissue Rowitch says. “We figured there had to be the underlying axon is permanently harmed. from young children available for study. some inhibitor present, right there in the Last summer, however, Rowitch and area of the lesion.” Where and When Development Occurs colleagues published two studies, con- Reporting in Nature Neuroscience in “Every baby’s brain contains a variety of ducted using tissue from the neonatal and June 2011, the team suggests one plausible immature precursor cells that could, in pediatric brain bank that he helped estab- reason for the blocked repair: overactiva- theory, be enlisted to help mend injuries,”

lish at UCSF in 2009 with HHMI support, tion of the Wnt pathway, as measured by says Rowitch. But first scientists need to lab / Rowitch Stephen Fancy

10 hhmi bulletin | November 2o11 know more about how and what these cells do. To that end, he has been collaborat- ing with UCSF neural stem cell biologist Arturo Alvarez-Buylla and neurosurgeon and postdoctoral fellow Nader Sanai, now at Barrow Neurological Institute in Phoe- nix, to map the trajectory of human stem cell activity emanating from a rich pocket of neurogenesis in the brain known as the subventricular zone (SVZ). The SVZ has been well characterized David Rowitch’s team improved remyelination repair in mouse models of demyelination in mice, in nonhuman primates, and, to a using a small molecule Wnt inhibitor. An injection of lysolecithin removed oligodendrocytes lesser extent, in human fetuses and older and myelin, while sparing the axons. In the mice that received the Wnt inhibitor along with the lysolecithin, remyelination was more rapid than in mice that received no inhibitor with adults. But no one knew if or how activ- the injection. Note the thicker black myelin around the axons on the electron microscopy ity in that region changed over the course image on the right. of brain development in newborns and young children. tal cortex,” says Sanai, who was an HHMI suggested the SVZ might churn out new Now, by carefully comparing the cel- fellow during his medical school training cells well into adulthood. The results were lular architecture of brain tissue from at UCSF. “That newly discovered pathway reported October 20, 2011, in Nature. 54 infants, young children, and teens, raises questions about the mechanics of The first year of life is a window of Rowitch, Sanai, and Alvarez-Buylla have how the brain developed and evolved.” particular vulnerability and opportunity begun filling that information gap—and Another dramatic twist: after a period of for the brain, says Rowitch. It’s a period turning up surprises. For one thing, at robust neurogenesis in the first year of life, of tremendous growth, organization, and least some of the stem cells arising from the human SVZ apparently slows down, flexibility, as fresh neural connections the SVZ travel to a different region in the sharply tapering production of brain cells are created, broken, and remade. A better human brain than in the mouse brain. by the time a child is 18 months old, and understanding of how things can go wrong “In humans we’re seeing streams of then slowing to almost zero by age two. in that critical period, he says, could ulti- cells from the SVZ moving not just into The finding should help settle conflicting mately improve the chances that things the olfactory bulb but also toward the fron- earlier reports, say Sanai and Rowitch, that will go right. W –Deborah Franklin

November 2o11 | hhmi bulletin 11

As engineers of the molecular world, chemists are making their mark in biology. by Sarah C.P. Williams illustration by Mario Hugo Ait ths very moment, your body is a living periodic table of elements. Chlorine atoms “There are chemists now that are indistinguishable from biol- combine with hydrogen and churn through your stomach, break- ogists at the cutting edge of biological discovery,” says Carolyn ing chemical bonds in the food you ate for lunch. Potassium Bertozzi, another HHMI investigator whose research overlaps pulses along your nerves, giving your fingers a sense of touch. the two fields. “And then there are chemists who collaborate Calcium makes up your bones and teeth; carbon is the back- closely with biologists.” bone of your DNA; and oxygen seeps into your bloodstream with As biologists and chemists learn to bridge the gap between every breath you take. their fields, with training programs and increased appreciation for If you are a chemist, you see the world in terms of these atoms. what the other has to offer, they are realizing just how comple- Not just humans, but plants, animals, bacteria, soil, computer mentary their skills can be. chips, telephones, and light bulbs. Each is made of unique mix- tures of the 118 elements posted on the wall of any high school Brain Chemistry chemistry classroom. Choosing where to apply his chemistry knowledge wasn’t hard for “Anything you see or touch or taste, it all comes down to Chang. “There’s nothing more complex or beautiful in biology these elements in different combinations,” says HHMI investiga- than the brain,” he says. Lucky for him, the brain is full of unique tor Chris Chang. chemistry that’s ripe for investigation. When Chang was launch- Both Chang’s undergraduate degree and his Ph.D. are in ing his research career, he discovered that the brain has at least chemistry. But now he studies the brain. His lab at the Univer- 20 times more copper than most of the body, and no one could sity of California, Berkeley, looks as much like a biology lab as a explain why. As a chemist, he saw an opportunity—copper is a chemistry lab, with microscopes and mice and cell cultures. He’s chemical element, the simplest building block of an organism. one of a handful of HHMI scientists—and a growing number By studying copper in the brain, Chang could fulfill his desire to of scientists around the country—who are applying their back- explore neuroscience and put his background in chemistry to use. ground in chemistry to biological problems. Biologists, however, had no way to visualize where the cop- These chemists are driven by a fascination with the complexity per was in the brain. They couldn’t track its movement or see of biology and a desire to work in a fast-moving field. But the way where it was being integrated into larger molecules. So Chang they approach problems is distinct from biologists—they break created a new kind of copper—a copper atom attached to chemi- organisms down to their most miniscule atomic parts to study how cal probes that offer a way to watch copper’s path in the brain. He they work. And they build those biological systems back up using engineered the copper so that the probes could light up under a new chemicals they create from scratch. fluorescence microscope or potentially be visualized in an MRI “Chemists are able to not only study things at this molecular of the brain. scale, but we can also reorganize things and build them from In an April 2011 paper published in the Proceedings of the the ground up,” says Chang. “It is this ability of chemists to cre- National Academy of Sciences, Chang’s team used the method to ate things that allows us to look at problems differently.” Like determine just how dynamic copper is in brain cells. They found structural engineers who design buildings and genetic engineers that when a neuron receives a signal—in the form of calcium who create new genes from scratch, chemists are engineers of molecules—a wave of copper moves from one end of the neuron the molecular world. to the other. Biology-interested chemists face no shortage of biological “We showed that copper is not this static building block of questions to answer. Chemical approaches are solving problems brain cells like many believed. It’s a dynamic, mobile signaling in neuroscience, immunology, cell signaling, and cancer biology. molecule,” says Chang. “And this is the first time that someone

14 hhmi bulletin | November 2o11 “Anything you see or touch or taste, it all comes down to these elements in different combinations.” Chris Chang

can watch it flow through brain cells in real time.” Next, the group added the synthetic molecules to cells to study the effect of aims to understand what this wave of copper movement triggers. specific sulfate clusters. By experimenting with blocking and Copper is far from the only dynamic chemical in the brain. unblocking different combinations of GAGs, the researchers Linda C. Hsieh-Wilson, an HHMI investigator at the Califor- began to decipher how the position of the sulfates offered molec- nia Institute of Technology, has used her combined knowledge ular instructions, telling the GAGs what functions to perform of organic chemistry and neuroscience to discover how a set of in the cell. molecules—glycosaminoglycans, or GAGs—influences neuron “What I think is cool about being an organic chemist is that growth. GAGs are long strings of carbohydrates that attach to pro- you can create molecules that are entirely new, that no one has teins and influence their behaviors. ever dreamed of, or molecules that only exist in minute amounts Each of the dozens of types of GAGs has a different function. in Nature,” says Hsieh-Wilson. “And then you can use these mol- At a molecular level, their distinction lies in the sulfate clusters— ecules to discover something new and exciting about biology.” groups of sulfur atoms—that decorate the carbohydrate strings. Although Hsieh-Wilson still has lots more to discover about For biologists trying to study each molecule’s effect on the brain, GAGs, she’s already found that the carbohydrates are involved in the sulfate groups were frustratingly similar. There was no way the growth and regeneration of nerve cells after injury. With this to isolate only one type of GAG at a time. Moreover, biologists fundamental insight, she and her team are working to create a couldn’t use genetics to study the sulfate clusters because DNA therapeutic approach to help treat spinal cord injuries. doesn’t directly encode carbohydrates. And blocking the addition of all the sulfates at once caused such chaos that it was hard to Body Chemistry tell what was what. Every organ in the human body functions through a constant “And so here’s where my chemistry background became very interplay of chemicals. By modifying those chemicals—to block important,” says Hsieh-Wilson. “We needed to be able to synthe- them, track them, or isolate them—chemists can add to the size and study the different GAGs one at a time. So, we used knowledge of how the body works. organic chemistry to design and synthesize these very complex Among the molecules constantly moving within cells is a large molecules from the ground up.” group of signaling molecules called protein kinases. There are Hsieh-Wilson’s group synthesized different GAG molecules more than 500 of them—and, like GAGs in the brain, they have and devised ways to block each one individually. Then, they widely varying functions but very similar chemical structures.

Stuart Schreiber and Linda Hsieh-Wilson create new molecules to test pathways

Schreiber: Jared Leeds Hsieh-Wilson: Darcy Hemley Darcy Hemley Leeds Hsieh-Wilson: Jared Schreiber: and circuits and, if they’re lucky, discover exciting new things about biology.

November 2o11 | hhmi bulletin 15 To figure out which kinases do what, HHMI investigator Kevan altered different parts of the immunosuppressant at a time. After Shokat developed a strategy similar to Hsieh-Wilson’s approach each chemical alteration, Crabtree tested whether the drug still to looking at GAGs. blocked immune function. Protein kinases work by binding ATP—a cellular source of “That collaboration allowed us to say which regions of the energy—and then using it to add phosphates to proteins, a modi- molecule were essential and to accurately order each of the steps fication that changes the function of those proteins. Biologists of the pathway,” says Crabtree. know how to block kinases from binding to ATP, which shuts the Despite being on opposite coasts of the country, the two con- enzymes down. But the action shuts down many different types of tinue to use small molecules designed by Schreiber to block protein kinases in a cell at once. chemical reactions within the cell. “Sometimes I’ll have a ques- “After six months of scrambling my brain on how I could tion about how a biological process works, and I’ll ask him how tackle this problem through chemistry, I realized that I could we can study this chemically,” says Crabtree. “Other times he’ll chemically engineer the ATP pocket of one kinase at a time be interested in a particular molecule he’s made and approach so that enzyme could be blocked specifically,” says Shokat, at me about studying what it does in the cell. Such molecules allow the University of California, San Francisco. First, the genes for biologists to order and test biological pathways and circuits. They kinases are removed from a human cell grown in a lab dish. also provide verification for mathematical models of how things Then, the newly engineered kinases can be added. work, an essential aspect of modern biology.” His method paid off: labs using his technique have discovered Schreiber is seeing more scientists embarking on this kind of the function of more than 70 kinases. His own lab is now focus- collaboration. He says that now is a defining time in the intersec- ing on the role of some of these kinases in cancer development. tion of chemistry and biology. He compares it, in fact, with the “I call the whole thing ‘chemical genetics,’” says Shokat, aftermath of Sputnik and the challenge by President Kennedy to “because neither chemistry nor genetics could have solved this send a spaceship to the moon. problem on its own. You take the best of both worlds.” “Kennedy didn’t propose that a group of very smart physicists The combination of chemistry and genetics is one that other come together to calculate the thrust required of a rocket to escape scientists have joined forces to explore. HHMI investigator our atmosphere. He brought many types of scientists—physicists, Gerald Crabtree, a developmental biologist at the Stanford engineers, mathematicians, even biologists—together. And he University School of Medicine, frequently collaborates with didn’t just have them calculate what would be needed to build Stuart Schreiber, a chemist and HHMI investigator at Harvard a rocket. He had them actually do it. Fly a rocket to the moon.” University and the Broad Institute. Crabtree studies how signals Biology without chemistry, Schreiber says, is like “hypothe- from other cells or the surrounding environment are transmit- sizing without testing things.” Together, biologists and chemists ted into a cell, eventually leading to changes in gene expression. might not be able to fly a rocket to the moon, but they can test Schreiber, with his organic chemistry training, can build mol- biological hypotheses—and do things—using compounds created ecules that block these signals at any step along the way. by chemists. Their first collaboration, in the 1990s, showed how an immu- “The marriage of biology and chemistry has never been more nosuppressant drug blocks immune cell functioning. Schreiber important than today,” he says. “We are in a position to use small molecules to test emerging concepts in human disease in physiologically relevant settings.” Learning from Biology There are biological mysteries that chemistry can help solve, and there are also chemical phenom- ena that the biological world can help explain. The ultimate goal of the field of chemistry historically has been to be able to synthesize any molecule in the most efficient way possible. And Nature often is the best teacher when it comes to efficiency. The ways that cells produce chemicals—whether they’re hormones, defensive molecules, or signals between cells—have been culled by billions of years of evolution. “Natural enzymes are generally really efficient and good at their jobs,” says Wilfred van der Donk, Chemists Chris Chang and Wilfred van der Donk say biologists and chemists have begun to understand what each can bring to the table to explore how the an HHMI investigator at the University of Illinois at

body works and to synthesize more efficient and cheaper drugs. Urbana–Champaign. Van der Donk, a chemist by ©HHMI der Donk: Darell Hoemann / AP, ©HHMI van Chang: Noah Berger / AP,

16 hhmi bulletin | November 2o11 “The marriage of biology and chemistry has never been more important than today.” Stuart schreiber

training, takes apart reactions that occur in the natural world to work, others stay specialized in chemistry and collaborate with learn how chemists can carry out the same reactions more effi- biologists. Neither path is easy. But with the right navigation, ciently in the lab. both routes can lead to success. Microbial cells naturally produce all sorts of antibiotics and For those who want to collaborate, the key is understanding antifungal chemicals, for example. His lab hopes to distinguish what each field has to offer. Carolyn Bertozzi, an HHMI investi- how cells do it and figure out which of these products have gator at University of California, Berkeley, believes that biologists potential as human drugs. In a paper published July 19, 2011, in and chemists have different motivations. Bertozzi, whose lab has Journal of the American Chemical Society, van der Donk pieced used chemical methods to track sugars within cells, has mentored apart how cells make one antibiotic that’s currently in clinical both biology and chemistry students (see Perspectives & Opin- development against cystic fibrosis. Understanding how the cell ions, “Changed Expectations”). makes the chemical could help him design related molecules “Biologists are very problem oriented,” she says. “They often that also fight cystic fibrosis. get frustrated if they can’t solve the problem they want to solve. And then there’s cellular chemistry that’s like nothing chem- But chemists like developing new technologies, even if it doesn’t ists can do in the lab. He wants to understand that too. get to the heart of a problem. It’s still a success if it works.” As a “There are enzymes that do reactions where, as a chemist, you mentor, Bertozzi tries to help biology students see that their work look at it and scratch your head and say ‘How can we do that?’” can be successful as long as it leads to a discovery. For chemis- Van der Donk cites one example that’s already made a dif- try students, she pushes them to take greater responsibility when ference. Many enzymes—proteins that carry out chemical tackling an applied problem. “I want them to think about what reactions—do their job by breaking a few bonds and creating a biological questions cannot be answered using current methods few others. Energy is transferred from bond to bond to rearrange and to focus their creative energies on technologies that really a compound. This means that to build a large compound from address that need,” she says. raw elements—either inside a cell or by industrial chemists in a These days, even a chemistry student who wants to stay lab—many chemical reactions are often needed. Each reaction focused on chemistry often works in a biology lab to get a feel shifts a few bonds, gradually building the desired molecule. for how to work with biologists, according to Schreiber. “You’ll But some enzymes in cells are more efficient, carrying out join a project where next to you, elbow to elbow, may be a devel- many bond rearrangements at once. Chemists have used these opmental biologist trying to differentiate a cell, and on the other enzymes as inspiration to design enzymes for industry. “This can side is a computer scientist trying to convert data to knowledge,” make drug synthesis, or material synthesis, more efficient and he adds. cheaper,” says van der Donk. This won’t necessarily teach chemists everything about devel- And sometimes it’s not learning directly from cells but being opmental biology, or everything about computer science, but it inspired by a biological problem that drives chemistry forward. will teach them how to work with those scientists. “The chemist Schreiber calls it “next-generation synthesis.” It’s the idea that simply needs to know what those fields are capable of achieving,” chemists faced with a difficult biological problem sometimes says Schreiber, “and how it connects back to their own skill set have to create new chemical methods to solve it. Schreiber, for and discipline.” example, developed a way to generate compounds with the abil- Crabtree’s biology lab frequently hosts chemistry postdocs. ity to modulate biological processes not otherwise possible. His “Occasionally these students do actual chemical synthesis,” says method, called diversity-oriented synthesis, allows scientists to Crabtree. “But mostly they’re there to learn biology. And I always discover chemicals that target, for example, proteins that cause hope they come away with an appreciation for what happens human disease. when you bring together the tremendous power of genetics with “In the same way that next-generation sequencing is transform- the tremendous power of chemistry.” ing genetics, next-generation synthesis is transforming molecular Biologists too, are gaining an appreciation for how chemistry biology,” says Schreiber. can help them, says Crabtree. “When you begin with a biological process that you want to understand,” he says. “One of the first Learning to Cross Boundaries questions you can now ask is, ‘Is there a chemical that prevents While some chemists dive into postdocs or other training oppor- this process?’ And if not, ‘Can it be synthesized?’” Such a question tunities focused on biology to help round out their own lab’s (continued on page 48)

November 2o11 | hhmi bulletin 17 Calling all Teachers Everyone agrees that the U.S. needs to train a new generation of inspiring science teachers. But how? by Dan Ferber | illustration by Sanna Mander

part 1 of 2: this article focuses on preservice training—training college students and graduates to be stem teachers. part 2 of the series, on training teachers once they’re in the classroom— in-service training—is coming in february 2012.

Lauren Miller planned to teach high school biology as well as health and nutrition. She knew that having hands-on research experience would boost her resume. So the 21-year-old secondary education major at Western Michigan University (WMU) signed up to work in a biology laboratory. To be honest, Miller says, she was not looking forward to it.

“I came in thinking research was antisocial and I’d be sitting science teacher, she says, “You’ve got to know science and you’ve at a lab table by myself,” she says. She expected a long, lonely got to know effective teaching methods.” 10 weeks. Science and math teaching methods and standards are under- But Miller got caught up in her summer research project, going a major overhaul to include more “inquiry-based” learning, part of the university’s HHMI-funded program to give science in which students apply scientific thinking and experimentation teachers-in-training, also called preservice teachers, some real- to solve actual science problems (see Web extra sidebar, “A 21st life research experience. Often working alongside her advisor, Century Cookbook”). WMU biologist Chris Pearl, she prepared and stained slices Educators are still figuring out how to train teachers to teach of paraffin-embedded mouse testes to measure levels of a key science and math this way. There’s no one-size-fits-all approach estrogen-producing enzyme in normal and obese mice. And she to recruit teachers and get them up to speed on the latest science learned a lot more. and pedagogy. So, funders of teacher-training programs—includ- “I found there’s a lot of collaboration. You’re going to con- ing HHMI, the largest private funder of science education in the ferences and talking to people in the lab next door. The people nation—are experimenting. The particulars vary, but the goal in your lab are very willing to help with anything,” Miller says. remains the same: to train and put in place the talented science “Now that I have a glimpse of what research is, I’m eager to show and math teachers that the nation desperately needs. students that it’s fun to do.” To ensure future teachers have the training they require to Innovative teacher-training efforts like Western Michigan’s be comfortable and effective teaching science, HHMI is encour- could be one solution to what experts consider a national cri- aging undergraduate institutions to focus on ways to promote sis in science and mathematics education. In a 2009 study by high-quality science teacher training, says David Asai, director of the Organisation for Economic Co-operation and Development, HHMI’s precollege and undergraduate programs. “Just as good for example, American students ranked 17th of 34 developed pre-med programs provide a framework in which the student can and emerging countries in science literacy, and 25th in math demonstrate the competencies required for success in medicine,” literacy. To bring U.S. students up to the top of the pack in sci- he says, “so too should science teacher training engage the under- ence achievement and “enable our students to compete in the graduate in intentional professional development.” 21st century economy,” President Barack Obama has called for 100,000 new high-quality STEM (science, technology, engineer- Luring the Talent ing, and math) teachers in the coming decade. In the midst of a national shortage of qualified science and math Education experts agree. Some schools succeed at teaching teachers, school districts don’t always have the luxury of worry- science and math, but too many of the nation’s science teaching about educational fine points. Sometimes they have slots that ers know too little about their subject, about effective teaching need to be filled now. To recruit good science and math teachers, methods, or both, says Deb Felix, the senior program officer for school districts have offered signing bonuses, housing assistance, HHMI’s precollege science education initiatives. To be a great and tuition reimbursement. Policy makers have forgiven loans

20 hhmi bulletin | November 2o11 and created initiatives to lure science and math teachers to or many teachers teaching outside their field. As of fall 2010, districts that need them, especially high-need urban and rural Noyce had produced 4,148 new K–12 science or math teachers. school districts, where students are poor, academically struggling, Noyce scholars have all majored in a STEM discipline and or both, and teachers don’t stay long. taken upper-level science courses, including laboratory courses, A large supplier of STEM teachers nationwide is Teach For and many have conducted independent research. This gives America (TFA). Education’s version of the Peace Corps, TFA them “the confidence to teach, the excitement, and the passion takes recent graduates of elite colleges, puts them through a five- for the discipline that you might not find in a teacher who’s taken week boot camp on how to teach, and places them in high-need just one or two courses” in their subject, says NSF’s Joan Prival, districts for two years. During the 2010–11 school year, TFA’s who administers the Noyce program. corps included 2,980 middle- and high school STEM teachers. A University of Minnesota team surveyed 555 Noyce scholar- And more than 2,300 of the organization’s current corps of 9,300 ship recipients from 2002 to 2006 and found that their GPAs were teachers teach elementary school, which includes at least some high and the proportion of Noyce scholars who were minorities was science and math instruction, according to an overview of TFA’s higher (33 percent) than the proportion of minorities working as STEM initiative provided by spokesperson Carrie James. STEM teachers nationwide (up to 14 percent). And 22 percent of TFA relies on selectivity to provide good teachers: the 2011 Noyce scholars take on a leadership role in their first few years corps of teachers had an average undergraduate GPA of 3.6, and at a school, serving as a department chair, for example, or sitting only 2,980 of 16,850 STEM applicants were accepted. But critics on a committee that develops a new curriculum. argue that their training is too short. Julian Vasquez Heilig of the “Programs like Noyce have done a tremendous job in helping University of Texas at Austin and Su Jin Jez of California State raise the level of the teaching profession in the eyes of undergrad- University, Sacramento, reviewed 11 outside studies on TFA and uates,” says John Keller, a planetary scientist and director of the concluded that TFA teachers taught their students reading Center for Excellence in Science and Mathematics Education at and math as well as or better than other uncertified beginning California Polytechnic State University in San Luis Obispo. teachers but not as well as fully credentialed beginning teachers. Other preservice initiatives reach out to students with proven The TFA teachers, like others, got better with experience. But after science or mathematics chops and train them to teach. Prospective three years, 80 percent of them had left teaching. That’s about master’s degree students at the HHMI-funded Center for Science twice the attrition rate of conventionally trained teachers, the and Mathematics Education (CESAME) at Stony Brook University authors wrote in a 2010 report from the Education and the Public in New York need a bachelor’s degree in science with a B+ aver- Interest Center at University of Colorado and the Education Pol- age. Quite a few are health professionals or scientists—including, in icy Research Unit at Arizona State University. To be fair, however, recent years, four dentists, a medical doctor, and a research scientist. TFA teachers agree to teach for two years, and TFA’s own research shows that 61 percent of its corps continues to teach the year after the two-year commitment ends. Heightened teacher turnover does not serve students, says Francis Eberle, executive director of the National Science Teachers Association. “It generally takes several years for a person to get good at teaching. So students who keep getting new teachers are really disadvantaged.” The Noyce Scholarship Program at the National Science Foundation (NSF) takes a different approach. NSF provides funds for scholarships, stipends, and teacher training at colleges and universities that prepare undergraduate STEM majors and STEM professionals to teach. In exchange for each year of NSF support, Noyce recipients commit to teach two years (and receive a $10,000 salary supplement for each year) in a high-need school—one At Stony Brook University, David Bynum trains top-level science students to teach

Brian Park with high poverty, high teacher turnover, and requires that they spend lots of time observing and teaching in classrooms.

November 2o11 | hhmi bulletin 21 “Right at the beginning, if you attract talent, it makes a lot seminars to talk about teaching as a career and help interested of the problems go away,” says David Bynum, CESAME’s direc- students plan their coursework. They encourage academically tor. “The best districts lap up our graduates. That to me is a very successful biology majors to mentor their peers, watching them powerful indicator of success,” he says. And almost a third of for traits like leadership, perseverance, and patience that predict CESAME’s graduates teach in high-need districts. a successful teaching career, Cyr says. Promising students are Some programs focus on attracting that talent young. UTeach, invited to help a graduate teaching assistant instruct a laboratory launched in 1997 at the University of Texas at Austin, offers fresh- section of an undergraduate biology class; if they perform well, man science majors their first two education courses for free—a they are offered jobs as teaching assistants. significant recruitment tool in this age of rising tuitions. Students Many of the strongest programs, including UTeach, get also save thousands of dollars by completing their science and undergraduates teaching early, which tends to get them hooked. education training in four years with a bachelor’s degree that Kristyn Moloney, a master’s student at Penn State, says that after qualifies them for certification to teach secondary school sci- running an introductory biology laboratory section as a junior, ence or math in Texas, rather than the usual five or more years she knew science teaching was for her. Year-end course evalu- to get a bachelor’s in science and a master’s in teaching. UTeach ations from her students showed her how she had helped them. has graduated 675 teachers, and 82 percent of its graduate hires “That’s what set it in stone for me, that this is what makes me are still teaching after five years, compared with about 50 per- happy,” she says. cent of all teachers nationally. A nonprofit group called the National Math and Science Initiative is replicating UTeach at 28 Back to Basics universities in 13 states. Altogether about 4,700 more teachers- When students go out to teach, they need up-to-date knowledge in-training are enrolled at these sites, according to UTeach. Both of their discipline. So even though the prospective science and the National Research Council and the President’s Council of math teachers enter the Stony Brook program with at least a Advisors on Science and Technology, or PCAST, have recom- bachelor’s degree, half of their courses are still in their STEM mended further expansion. discipline, be it mathematics, biology, chemistry, physics, or At the new HHMI-funded program at Pennsylvania State Uni- geology, Bynum says. And the science-trained Noyce scholars versity, molecular cell biologist Richard Cyr and his colleagues and UTeach students have the grounding they need to teach bring working teachers and education professors into freshman STEM classes. But most science and math teachers still come through education schools, and their knowledge of the discipline they are THE CHALLENGE teaching may be outdated or sketchy, especially in the lower and middle grades. For example, a Department of Education survey in 1999–2000 found that 29 percent of middle-school biology total k–12 teachers in the u.s.: teachers and 41 percent of physical science teachers were not certified to teach their subject and did not major or even minor in 3.6 million it as an undergraduate. Certification requirements have tightened since then in many states, but the problem remains. total who are stem teachers: Maxine Singer, board president and founder of the Washing- 477,000 ton, D.C., branch of Math For America, a nonprofit dedicated to improving K–12 math education, recalls leading a training ses- estimated stem teachers sion for in-service elementary teachers at the Carnegie Institution who leave profession each year: for Science, where she is president emerita. According to Singer, 25,000 many struggled when converting all but the most basic fractions and decimals. Jeff Nordine, assistant professor of science educa- total new stem teachers requested tion at Trinity University, had a similarly disheartening experience by president obama: meeting with some in-service elementary school teachers. “It was 100,000 in 10 years news to them that water expands when it freezes,” he says. “I don’t remember not knowing that.” Many future elementary school teachers are education majors sources: who have taken a minimum of science during their under graduate years, Nordine says. “They are uncomfortable with National Center for Education Statistics (nces.ed.gov/fastfacts/display.asp?id=28) science, they don’t like it, and they feel dumb. Then they have to President’s Council of Advisors on Science and Technology, September 2010 (www.whitehouse.gov/sites/default/files/microsites/ostp/pcast-stemed-report.pdf) teach it to students.” Not surprisingly, the students lose interest in the subject.

22 hhmi bulletin | November 2o11 At Western Michigan University, Susan Stapleton (right) and colleagues require science teacher trainees to do a 10-week research project. The experience convinced Lauren Miller (left) that research is fun—enthusiasm she’ll share with future students.

Learning by Doing experiments to answer it, and to interpret the results,” says Susan When Nordine teaches elementary science education to future Stapleton, a biochemist who helps run the HHMI-funded preser- teachers, he tells them, “Listen, it’s OK to not know the answer; vice program at Western Michigan University. WMU is the sixth that’s what science is all about.” He helps them learn scientific con- largest U.S. preservice teacher training school. Most of its stu- tent, as well as where to find journals and other science-teaching dents go the traditional route: they major in education, including resources, from the National Science Teachers Association and a slew of pedagogy courses, and minor in their teaching specialty elsewhere that can help them on the job. (WMU produced 463 preservice teachers in 2010; 91 were sci- Even more important, Nordine and other leading science ence and math teachers). educators also show future teachers how to create inquiry-based That’s why she and one of the program’s codirectors, science science units, in which students learn by solving real-world prob- education professor Renee Schwartz, require science teachers- lems. For example, some preservice teachers in his elementary in-training like Lauren Miller to do a 10-week summer research science education class have created a unit in which kids learn project. But that’s just part of the program. “It’s one thing to give about density and buoyancy by investigating whether heavy them research experience. It’s another to translate that into teach- objects sink and light objects float. able units they can take into the classroom,” Stapleton says. So Such lessons build on two decades of work by cognitive scientists she and Schwartz will teach a class for preservice science teach- and education researchers on how students learn. In a landmark ers next spring on how to turn their research experiences into 1998 study, for example, Barbara White of the University of Cali- inquiry-based laboratory exercises. The trainees will then teach fornia, Berkeley, and John Frederiksen, now at the University of the exercises they’ve created to middle school students during a Washington, had students at an urban middle school learn physics two-week science camp the following summer. by doing it—by formulating a question, generating predictions, car- Giving preservice teachers tools like this helps them once rying out and analyzing experiments, and checking the results with they’re on the job. Laura Gurick, a 2010 CESAME graduate scientific models. Compared with grade 11 and 12 physics students of Stony Brook University, drew on her training last year for the who memorized facts and plugged through algebraic formulas, the 10th-grade chemistry class she taught at Herricks High School middle school students learned more physics (averaging 68 percent in New Hyde Park, New York. She could have taught paper on a short test of physics comprehension, versus 50 percent for the chromatography, a method to separate and analyze component high school students) and were better at thinking scientifically. chemicals from a mixture, using a conventional laboratory in Researchers have since honed their understanding of inquiry-based which the students were told exactly what to do. Instead she drew learning by determining which types of classroom exercises promote on a workshop she’d taken at Stony Brook on how to turn a con- real inquiry and which don’t, says K. Ann Renninger, an HHMI- ventional laboratory into one that’s inquiry based. funded educator and education researcher at Swarthmore College. Gurick told her students that there had been a kidnapping, Teachers can help students learn science by doing it, if the that one of them was the kidnapper, and that a ransom note and teachers have done the same. “Folks who want to teach need to a pen had been found at the scene of the crime. Several students

Lauren Miller: Peter Baker Susan Stapleton: Peter Baker Baker Susan Stapleton: Peter Lauren Miller: Peter know what it means to ask a good scientific question, to design (continued on page 48)

November 2o11 | hhmi bulletin 23

Heav Microscope, Will Travel

Biology students and faculty immersed in summer courses at Woods Hole get their hands on a remarkably powerful imaging tool developed at Janelia Farm.

By Jennifer Michalowski Photography by Jared Leeds i-Chang Chen spent the fifth day neer by training, Betzig listens carefully to biologists, and their top of his postdoctoral fellowship in a priorities have not changed since he began developing imaging rented van headed for Cape Cod. technologies more than 30 years ago. Biologists want to see smaller He’d barely had time to unpack in structures. They want to see them with more detail, with more Virginia before he was enlisted to speed, and deeper inside a tissue. And they want to see them in help take apart the very microscope healthy, living cells that are unperturbed by the tool they are using. he had come to Janelia Farm to Betzig and his team had created the Bessel sheet microscope work on. Its lenses, mirrors, lasers, to answer those demands, and after three years of development, and other components were now they were convinced the instrument could offer researchers fastidiously packed and stowed unprecedented views of dynamic subcellular processes. But many in the back of the van, traveling of the biologists at Janelia Farm are neuroscientists interested in north on I-95. Chen was about to understanding how neurons work together in complete circuits undergo what his new boss, Janelia in the brains of fruit flies or mice, and, Betzig says, Bessel beam Farm group leader Eric Betzig, was technology is not ideal for the size and thickness of the samples calling “trial by fire.” they want to image. “Our mandate is to develop new imaging Chen and his new colleague, Liang Gao, were transporting the technologies for biology, not necessarily just for systems neuro Betzig lab’s newest technology to the Marine Biological Laboratory science. So if we want to find users for these techniques, we have (MBL) in Woods Hole, Massachusetts—a seaside hub of scientific to look outside.” activity with an educational program that draws hundreds of stu- Word was beginning to spread about the power of the Bessel dents and faculty from around the world each summer. It would sheet, but the cultural divide between microscopists and biologists take a full day to reassemble its components into what the Betzig still frustrated the Betzig team. “It takes a surprisingly long time group calls a Bessel beam plane illumination microscope—a high- to get new microscopes to biologists,” Gao says. “So we decided to speed, high-resolution, three-dimensional imaging technology that take our latest microscope to Woods Hole to introduce it to them.” gives extraordinarily detailed views of cellular processes in action. The plan was for Gao and Thomas Planchon—developers of the new microscope—to guide MBL students and faculty R apid-Fire Days through the imaging process as they examined their specimens. The Marine Biological Laboratory is situated on a narrow, salt- Chen would have to learn quickly how to operate the microscope, swept piece of land in the far southwest corner of Cape Cod. because the team expected a steady stream of users, all demand- Tourists unload bikes at the nearby ferry landing; fried clams, ing expert attention. In exchange, the Betzig team hoped to learn homemade ice cream, and other indulgences of a beach vacation exactly what biologists need their microscope to do. are in ready supply. The tiny village of Woods Hole wakes up ear- The Bessel beam plane illumination microscope, or “Bessel lier than the usual beach town, however, and working scientists sheet,” was a work in progress. Betzig’s team had designed it to vastly outnumber vacationers. answer an obvious need of biologists—the ability to visually track Hundreds of scientists flock to Woods Hole in summer to movement of the tiniest structures inside living cells. In March immerse themselves in MBL’s unique culture for a few weeks or 2011, they had described the new technology online in Nature months. Distanced from routine distractions, most visitors find Methods, including as evidence of its power startlingly vivid por- the MBL experience gratifyingly intense. Between coursework, trayals of chromosomes sorting themselves in preparation for cell research, and discussions and debates, time in the lab routinely division and a lively cell surface sending out long, thin projec- stretches until 2:00 a.m., for students and faculty alike. “We’re not tions that quickly retract and reappear elsewhere. there to go to the beach,” Gao stresses. “There’s a vacationy feel The short movies had generated considerable excitement here; it’s nice outside,” says Betzig, who set aside two weeks during among biologists: there was no doubt that the new microscope sur- June and July to work with Bessel sheet users at MBL. “But you’re passed existing technologies in rapidly creating high-resolution, only here a short time, and everyone works really long days.” three-dimensional images without damaging living cells. But for So when Chen, Gao, and their microscope parts reached Betzig’s team, this acclaim was not the ultimate goal. “We’re not Woods Hole at the end of June, they wasted no time. They were developing technology for technology’s sake,” he says. “We want greeted by Jim and Cathy Galbraith, a husband and wife team to create technologies that will have a broad and deep impact on who have taught in the neurobiology course for seven years, biomedical research.” and a small crew ready to help maneuver an 800-pound opti- Maximizing the microscope’s impact had been foremost in cal table, on loan from Thorlabs, into a tiny, windowless room Betzig’s mind from its earliest development. A physicist and engi- in the basement microscope facility. The top of the table went

26 hhmi bulletin | November 2o11 in first, suspended on a scissor lift until its vibration-eliminating Health (NIH). And throughout the following year, the Betzig lab supports were positioned underneath. From there, the team fol- hosted collaborators at Janelia Farm to advance projects initiated lowed Gao’s lead. Modular segments of the microscope were during those fervent weeks. unwrapped and bolted to threaded holes in the tabletop. A tower So when Betzig suggested they repeat the experience this past of electronic equipment—the control panel—was erected in the summer, Gao’s first thought was the challenge of transferring cramped room’s remaining space. Cables were connected; align- the delicate equipment to its temporary home. “It’s almost like ment measured; blue, green, violet, and infrared lasers tested. starting a new lab,” he says. But he knew it would be worth the Gao knew what he was doing: he’d built this version of the long drive and the long days that would follow, particularly if they microscope—a second-generation version, more compact and extended their stay to work with a wider group of biologists. portable than the original built by Planchon at Janelia. And last They chose a four-week period during which their microscope summer, he and Planchon had accompanied the Bessel sheet on could be integrated into two courses. Gao and Planchon made its first trip to Woods Hole, when it was so new Betzig was call- plans to helm the microscope in two-week shifts, while Chen ing it “bleeding-edge.” That visit had been grueling: two weeks would stay the entire four weeks to learn the intricacies of the of 18-hour days, imaging the very first living cells to be viewed Bessel sheet and become familiar with the language of its users. with the microscope, save one quick run-through back at Janelia Betzig would join the team for the weeks in the middle. Farm with the Galbraiths. But the benefits were enormous. Dur- During the first two weeks, the Bessel sheet would help ing the rapid-fire days, the team tested a panoply of samples and physiology students working with Jennifer Lippincott-Schwartz introduced the microscope to a range of users. The Bessel sheet’s from the NIH watch cells migrate or break down their unwanted early successes at Woods Hole became the vivid movies the team parts; in the second half of the microscope’s stay, neurobiology published in its Nature Methods paper, which is coauthored by students working with the Galbraiths could use it to visualize the Galbraiths, whose own labs are at the National Institutes of the processes that drive nerve cell function. Spare moments

In what Eric Betzig calls a “trial by fire,” postdoc Bi-Chang Chen spent a month at Woods Hole this summer,

Jared Leeds Jared familiarizing himself with the Bessel sheet microscope while helping students and faculty analyze their samples.

November 2o11 | hhmi bulletin 27 would be tightly scheduled with MBL faculty curious to see what collects the returned light. This approach confines the excitation the Bessel sheet might reveal about their own samples. much closer to the portion of the sample in focus. It’s an old idea—first proposed more than 100 years ago—that has recently been adapted to high-speed imaging of multicellular organ- The Photon Budget isms. Ernst Stelzer, who was at the European Molecular Biology The Bessel sheet was the newest imaging technology at Loeb Laboratory in Heidelberg, Germany, and is now at the Frankfort Laboratory, MBL’s educational hub, but it was not the only one. Institute for Molecular Life Sciences, resurrected the technique, The basement and first-floor hallways were crowded with bulky Betzig says, taking advantage of the reduction in light damage to crates emptied of sophisticated microscopes on loan for the sum- image living samples repeatedly over prolonged periods. mer. Course directors had collected commercial instruments The thick sheets of light that have made Stelzer’s technique a for super-resolution imaging (including Zeiss’s ELYRA, based success, however, obscure the tiny structures inside cells—a prob- on the concept of photo-activated localization microscopy, or lem that Betzig’s team addressed with a Bessel beam. At its core, PALM, invented by Betzig and Janelia Farm colleague Harald a Bessel beam is an extremely narrow beam of light that can be Hess), microscopes designed to peer deep into tissue, and high- swept across a sample to create a thin sheet well suited for imaging resolution methods for three-dimensional imaging of fixed tissue subcellular structures. The Bessel’s central beam is surrounded by to offer their students new perspectives on biological complexity. concentric rings of weaker light, however, which cause the same According to Cathy Galbraith, the two-week imaging section problems as any unwanted light sources do. So Betzig, Planchon, of the neurobiology course is designed not just to expose students and Gao devised a few tricks to minimize the contaminating to cutting-edge technology, but also to help them understand light. Rather than sweeping the beam continuously, they pulse which tools are best suited for particular questions, as well as how the beam rapidly to eliminate out-of-focus blur—a technique also the technologies are complementary. Likewise, physiology stu- used in super-resolution microscopy called structured illumina- dents experience firsthand how each tool has its strengths—but tion. They combined this pulsing with two-photon microscopy, none can do it all. a method in which weakly exposed regions generate very little It quickly becomes apparent how the Bessel sheet fits into fluorescence. Together, these tricks add up to a microscope that the imaging landscape. Like other fluorescence microscopes, collects unusually detailed images without damaging living cells. the Bessel sheet detects fluorescently tagged molecules within cells, letting biologists follow specific proteins and watch them interact with one another. The basic technique relies on fluo- 3- D Clarity rescent tags that absorb light—typically directed at a sample in Gao, Planchon, and Chen help students mount their samples so a focused laser beam—and rerelease the energy as fluorescence, they can receive the sheet of light created by the Bessel beam at which the microscope captures to create an image. Up to a point, the appropriate angle, then tweak the microscope’s parameters to brighter fluorescence contributes to a clearer image, but there is a accommodate variations in thickness, brightness, or background trade-off. Too much light exposure can make a cell sick, so living fluorescence. The Bessel beam sweeps quickly through each samples don’t survive long under the laser’s glare. What’s more, sample, collecting up to 200 images per second. As the micro- light destroys fluorophores’ ability to fluoresce, meaning even scope’s computer compiles the two-dimensional images into dead cells can be imaged only a brief time before their signal three-dimensional stacks and the first pictures begin to appear on begins to fade. So, fluorescence microscopy often ends up being the monitor, what is astonishing is the extraordinary detail appar- an exercise in compromise. ent in all three dimensions. Capturing fluorescence becomes increasingly crucial as new Clare Waterman, director of the MBL physiology course, says technologies push the limits of both spatial resolution and speed. she was blown away when she saw the Bessel sheet’s first images of Higher-resolution microscopes must extract information faster, her students’ cells. “I’ve been looking at light microscopy images more frequently, and from ever-shrinking segments of a sample. and 3-D reconstructions for 20 years,” she says. “When you rotate Ideally, a microscope would glean information from each photon a 3-D reconstruction, you always know what the z-axis is.” That of fluorescence a sample emits. In practice, however, plenty of is, even when a microscope produces crisp, detailed images in photons bounce off an illuminated sample and are lost forever. two dimensions, resolution almost always declines significantly Betzig and his team designed their new microscope to take in the third dimension. But the Bessel sheet images were differ- better advantage of what they call the “photon budget.” Most ent. “I could not tell what the z-axis was,” Waterman says. The microscopes illuminate a sample from the same objective lens cellular detail was clear from any angle. that collects light, directing a beam all the way through the The three-dimensional movies of migrating cells, which were sample even though only a single plane is in focus at a time. grown in a collagen gel so they could move freely in any direc- At high-resolution, where every photon counts, this is a problem tion, settled for Waterman what she says had been an unresolved because light in out-of-focus regions activates fluorescence and debate in her field. Waterman studies cell motility at the National damages cells, with no imaging payoff. Heart, Lung, and Blood Institute, and lately, she says, there’s been An alternative is to direct a sheet of light through the side of a big push to find out whether structures thus far observed only in a sample, via a lens that lies perpendicular to the objective that cells squashed flat between a microscope slide and a coverslip are

28 hhmi bulletin | November 2o11 left: Interacting with biologists helps Eric Betzig (right) and Thomas Planchon improve design of their microscopes. right: Three-dimensional imaging of live cells by the Bessel sheet microscope reveals remarkable detail, such as a cell’s ruffled edges and internal vacuoles.

physiologically relevant. But, she acknowledges, “There’s been a to encase the growing embryo. Chisholm says the movie, which reason we’ve been doing stuff on a coverslip for so long: because spans eight hours of early development, is “an order of magnitude that’s where optics are good.” Technologies that image in three better than what we can get away with using the last generation dimensions lack the spatial resolution to determine, for example, [of imaging technology]. It’s just beautiful.” whether migrating cells truly project the long, flat extensions thought to propel their motion. “Well, we could certainly see two- dimensional, flat lamellipods with this [Bessel sheet] system that U ser Feedback we could measure the thickness of, in every dimension.” By the time the weary team of postdocs disassembles the “It wasn’t like I was pining away for this,” Waterman says. microscope for the journey back to Virginia, they have imaged “I had accepted the limits of optical microscopy and I’d learned developing embryos, cells suspended in growth media, the ner- to interpret my data within those limits.” But once she saw what vous system of whole worms, cells embedded in collagen, dying was possible, she says, “I was doing backflips for a week.” cells, and dividing cells. Over the weeks, Chen says, they have taken every opportunity “to talk to biology people, to listen to what they are thinking. Because it’s really, really different from us.” Watching Embryos Develop They have heard users’ frustration about the microscope’s The Bessel sheet gets little rest at Woods Hole. A grid on the wall unconventional sample holder, which requires a fussy assembly blocks out time for faculty who want to squeeze into gaps between process to secure the sample in a vertical position—practical from student projects, but unexpected visitors stream in at all hours. Uni- an engineering perspective, but cumbersome for users. They versity of California, San Diego, developmental biologist Andrew know they need to adapt their optics to handle thicker samples, Chisholm, who visits MBL as faculty in the neurobiology course, which introduce aberrations in the imaging process. And there is says so many people were in and out of the tiny room that the an unrelenting desire, biologists have told them, for even better rising temperature sickened the C. elegans roundworm embryos spatial resolution, at even faster speeds. whose developing skin he wanted to image. With the confocal None of these requests are a surprise, the microscopists agree. microscopes Chisholm typically uses, he says, “you’re constantly And they are prepared to address them. The group plans to build balancing imaging quality with viability of the embryos. With a a third version of the Bessel sheet, so they can continue to tweak conventional microscope you really have to settle for images that the instrument and test out improvements while the original don’t look very good.” But since the Bessel sheet limits phototoxic- setups collect data. Chen will begin work immediately to add ity by using far less light, the dying worms were puzzling. additional Bessel beams to the microscope, which he says will Chisholm and the Betzig team considered other factors, and increase imaging speed while reducing phototoxicity. A new post- discovered that if they imaged the developing embryos in the doc in the Betzig lab, Kai Wang, will introduce adaptive optics morning—after a few idle hours had let the room cool down— into the system, and research scientist Lin Shao, who introduced they had better success. Working with Planchon, Chisholm the current methods of analyzing the data generated by the Bessel assembled a movie that shows skin cells forming, making junc- microscope, will continue to improve those algorithms. Thomas

Betzig and Planchon: Jared Leeds Science image: Betzig lab Jared Betzig and Planchon: tions with one another, and then forming a sheet that spreads out (continued on page 48)

November 2o11 | hhmi bulletin 29

have been the focus; introducing genetic changes, scientists have made great leaps in understanding disease and basic biology (see Web extra, “Model Redefined”). But mice can’t do it all. A 2008 analysis by University of Mich- igan scientists showed that in 40 percent of genetic defects known to cause human disease, researchers either do not see symptoms in mice or cannot identify an equivalent gene. “The mouse has revolutionized medical research, but it is necessarily limited by its biology,” Krasnow says. Physician-scientist Michael Welsh had been studying cystic he sat in a remote field station in Madagascar, surrounded by fibrosis (CF) for many years when it became clear that the field dense rainforests, Mark Krasnow realized that his journey halfway needed a new way to understand the disease. In humans, the around the world was worth it. The handful of biologists gathered single gene mutation that causes CF induces problems through- around him agreed that the mouse lemur could be the animal he out the body, especially the lungs and gastrointestinal system. In was looking for. mice, the mutations fail to produce typical CF disease. The HHMI investigator from Stanford University School of “To understand the pathogenesis of a human disease, a model Medicine was on a quest for a better animal model for human can be critical. If the model does not reproduce features seen in disease. The fruit flies and mice he’d been studying couldn’t help human disease, making progress can be a challenge. And if you him answer many basic research questions on lung diseases, and want to develop new therapies, and the model does not manifest he knew that scientists studying other disorders had similar expe- those key defects, you have nothing to correct,” explains Welsh, riences. He wanted to find a better disease model. an HHMI investigator at the University of Iowa. “It was frustration After a year of research into species worldwide, Krasnow had and the lack of an ability to make sufficient progress that led us to brought an unlikely team of high school students, molecular biol- develop another model of cystic fibrosis.” ogists, mouse lemur experts, and a veterinarian to the East African Welsh’s team settled on the pig, and their new CF model country to search for an animal that might be a closer match to develops disease like that of humans. “It is a very exciting time,” people than mice, the perennial lab favorite. Madagascar’s early Welsh says. “We are able to answer questions and approach per- separation from the continental land masses, some 80–90 million sistent problems that have been plaguing the field.” years ago, created an evolutionarily eccentric collection of plants Failure to replicate human disease isn’t the only problem and animals, including lemurs. “It’s like a biologist’s dreamland,” with mouse models of disease. “There have been some very says team member Sarah Zohdy, a doctoral student at the Univer- expensive long-term clinical trials based on mouse models that sity of Helsinki and one of a small number of scientists studying just didn’t turn out the way they did in mice,” says immunolo- mouse lemurs. gist Mark Davis, an HHMI investigator at Stanford University. The group spent several nights in the summer of 2010 scanning “The real test of a model is whether there is any predictive ability, the tall trees for all types of lemurs, but they were most interested in and I think there is often a disconnect between mouse data and the grey mouse lemur, Microcebus murinus (see Web extra, “Meet human disease.” Microcebus murinus”). The big-eyed, bug-eating lemur from Mad- Davis says scientists should make a more systematic attempt to agascar’s west coast is one of the world’s smallest primates. And, understand disease in people, which is the direction he has taken more importantly for Krasnow’s group, mouse lemurs’ DNA has his own research. For many diseases, he says, “We don’t know diverged from humans only half as much as the DNA of mice. enough about the human disease to know whether it is a good At the field station, in Ranomafana National Park, Krasnow model or not.” But he is enthusiastic about Krasnow’s attempt to talked with Malagasy biologists about the potential of mouse identify a better model. “We should rationally choose other models lemurs as a model for human disease. “They had grown up with that are closer to humans and therefore more likely to translate.” lemurs but had never thought about model organisms,” Krasnow says. They loved the idea that mouse lemurs could help cure dis- From Idea to Madagascar eases, he says, but they were concerned that the lemurs—and the Krasnow’s path to Madagascar began in 2009 when several Palo country—not be exploited in the process. Alto High School sophomores—Camille Ezran, Jason Willick, Krasnow’s daughter Maya, and, later, Alex Scholz—pestered him Moving Beyond the Mouse to work in his lab. After fending them off several times, he real- During the past half century, biomedical research has focused ized he could apply their growing knowledge of biology to the on a handful of model organisms, as research communities have mouse model problem. developed tools that make in-depth studies possible. The most “We spent the entire summer trying to understand what would widely used models include the mouse, the roundworm, the fruit make a good model, since we had never been exposed to genetic fly, and, more recently, the zebrafish. For disease research, mice model organisms before,” Ezran says. It had to be small and easy

32 hhmi bulletin | November 2o11 Krasnow: Ramin Rahimian “For decades Madagascar has endangered animals. the of themouselemurcouldhelp humansaswellpreserve about thegeneticsandphysiologyMark Krasnowthinkslearning “Social groupings,behavior,andbehavioraldiseases, havebeen could helpstudygeneticlinkstobehavior,theteamrealized. tofieldbiologiststhere.Thoseexperts emerged astheytalked Alzheimer’s-like disease. for thecolony’s history, including theanimals’ tendencytogetan scientists records and tissue samples had been keeping detailed could do,” Albertellirecalls.Whatexcited Krasnow wasthatthe a smallcastle.“Thatconvinced methatthiswas somethingwe mouse lemurs at a 40-year-old colony housed on the grounds of tothescientists. to talk of mouselemurs, Krasnow decided histeamneededtovisitone that severalEuropeanresearchcentershaddecades-oldcolonies the mouselemur asamodelorganism. Afterthegrouplearned but then she heard Krasnow describe the biological argument for Megan Albertelli.Atfirst,shethoughttheideawasfarfetched, organism andembracedtheideaofmouselemur,” hesays. leagues. “Theyagreedwiththeneedforanewgeneticmodel discussingwhen Krasnow starting itwithotherscientists andcol- narrowed toadozenexamine inmoredetail. a spreadsheetoftheworld’s smallestmammals,whichtheythen weeks inthelibraryandonInternet,studentsconstructed to bemorecloselyrelatedhumansthanmice were.Spending those inhumans.Ithadtoreproducefairlyquickly. Andithad to workwith.Itsbrain,lungs,andotherorganshadresemble Alison Richard hotspot Their next stop was Madagascar, and more research paths The group went to Europe, where they saw their first live veterinarianandgeneticistNext, Krasnow turnedtoStanford The mouselemur rosetothetop.Theideagainedtraction f o r b i odiversity, and rightly so.” ted tostudyingmouselemurs without sacrificing them,instead was neattoseewhatthecollaborativelandscapemight looklike.” versity, asanctuarythatstudies lemur behaviorandconservation.“It says AnneYoder, whorunstheDukeLemur CenteratDukeUni - be inthesameworkshopwithsomanyothertypes of researchers,” gists, and model organism experts. “I had not had the opportunity to withgeneticists,Europe, andtheUnited conservationbiolo- States Campus, bringingtogetherfieldbiologistsfromMadagascar, ever mouselemur meeting,at HHMI’s JaneliaFarm Research move ahead.InJune 2011,Krasnow andAlbertellihostedthefirst On their planning return,Krasnow how andhisteam started to C students,” shesays. ing mouselemurs asamodelorganism couldinvolveMalagasy - worked on the island for decades. “Much of the work establish ard, anHHMITrustee andprofessoratYale University whohas fortraining,great opportunity sayslemur biologistAlisonRich- itsvalue.”time wewouldliketoprotectourforestmaintain for theConservationofTropical Environments,“butatthesame Madagascar,” saysBenjamin Andriamihaja oftheisland’s Institute done in Madagascar. “We would like more researchers coming to and conservationefforts,asmuch researchaspossibleshouldbe already being doneinmouselemurs.” very hardtostudyinmice,” Krasnow explains.“Thosestudies are reating a One outcome is that Krasnow’s group and others have commit- This newfoundinterestinmouselemur researchoffersa The visit made clear to Krasnow that, to help local scientists b turning to genetics, imaging, and other noninvasive lemurs,” Rogerssays.“Theopportunity to combineyears investigators focusedondoing research onmouse conserved betweenmouselemurs andhumans. and help to identify what DNA sequences are highly the Alzheimer’s-like syndromefoundinthese animals, samples forgeneticconnectionstodisease, including researchers analyzethethousandsofexistingtissue Genome Sequencing Center. Thatcouldhelp Rogers oftheBaylorCollegeMedicine’s Human effort to complete the mouse lemur genome, says Jeff and genomics. TheJune meetingspurreda renewed and lemurs alike,” Krasnow says. lab colonies andfieldstudies, forthebenefitofhumans to beartoday’s researchtoolson existingsamplesfrom organisms. “Therearehugeopportunities inbringing techniques honedthroughthestudyofothermodel e “It issobeneficial forustohaveacommunity of The biggest area for immediate impact is genetics en seen a as C olla b orative

November 2o11 L andscape (continued onpage48)

| hhmi bulletin 33 perspectives & o pinions

Carolyn Bertozzi C hanged Expectations chemists trained in biology were once a rarity— now they’re becoming the norm. Ramin Rahimian

34 hhmi bulletin | November 2o11 After Carolyn Bertozzi finished her Ph.D. in organic chemistry in 1993, she did something risky. She accepted a postdoctoral fellowship in a cell biology lab, not a chemistry lab. In the two decades since, chemists have embraced the value of studying biology by total immersion. Bertozzi, an HHMI investigator at the University of California, Berkeley, who uses chemical approaches to tackle biological problems, reflects on this shift.

What was it like in the 1990s for chemists who wanted to both departments. Many medical centers—for example, tackle biological problems? at the University of California, San Francisco—host chem- A handful of us were in the same boat. We had been ical biology training programs. Stanford Medical School trained broadly to design chemical tools for use in biology has renamed its Molecular Pharmacology Department but didn’t know enough biology to identify the problems in “Chemical and Systems Biology.” The basic coursework urgent need of such tools. We were contemplating doing for a Ph.D. in chemistry hasn’t changed much, but students postdocs in biology labs to gain such insights. But many of are learning to integrate their chemistry skills with biology us received negative feedback from senior professors. It was systems in research settings. considered maverick to leave your field and pursue total immersion in another. Is industry also embracing chemists who are trained in biology? If we left our circle of familiarity and went off into a In a big way, but it’s a fairly recent trend. Until about 5 years strange land, the “chemistry establishment” would lose track ago, to land a job as a chemist in a big pharma company, of us and we’d have a hard time securing jobs. One advisor you had to do as much hardcore chemical synthesis as pos- even went so far as to use the phrase “career suicide.” sible. I would even venture to say that if a chemist revealed more than a superficial understanding of biology during an You went for a biology postdoc anyway. Did their predictions interview, it might be considered a bad thing. come true? That has completely changed. These companies are Not at all. When I applied for faculty jobs in chemistry under considerable pressure to find new and better drug tar- departments, I’m sure some people wondered how to judge gets. Hiring managers recognize that the people most likely my postdoctoral work. Contrary to the earlier warnings, to break out of the tired old mold are the ones with inter- people valued that I had spent time in a pure biology labora- disciplinary training. I receive regular e-mails from pharma tory. I was hardly an expert, but relative to other bioorganic companies looking for chemical biologists—people who are chemists, I was in a much better position to identify important comfortable engineering proteins, doing chemistry on large biological problems that chemistry could uniquely address. molecules in aqueous environments, designing systems far off the typical path of small molecule drug development. Is it easier today for chemists to follow the path you took? This is a very good sign, for the industry and for our trainees. It wasn’t too much later that it became fashionable for chemistry Ph.D.s to postdoc in a biology lab. By the In what areas are biology-focused chemists making an impact? early 2000s, when the first wave of students from my lab Everything from drug development to materials science. graduated, most went on to postdoc in labs that were even A big one is medical diagnostics for developing countries— more biological than mine. Now, if students interested in they need to be portable and cheap and still accurate. That working at the chemistry–biology interface do not take that problem will be solved by clever chemical engineering. The route, they may find themselves at a disadvantage later on. interface between physical chemistry and biology has led to Nonetheless, there are still many scientists who fear that all sorts of new ways to image molecules. There is a space cross-disciplinary training will produce neither the best for drug discovery—nanoparticles or big molecules—that chemists nor the best biologists. But this opinion is waning. pharmaceutical companies have been reluctant to pursue because of the difficulty of getting these drugs into the body. How are colleges and universities changing their curricula to But as chemists find ways to engineer new delivery systems, meet this new expectation that chemists know more biology? that space is opening up. Some schools are doing a phenomenal job of creating programs tailored to training at the juncture of biology and chemistry. Several schools, including Berkeley, sup- Interview by Sarah C.P. Williams. Carolyn Bertozzi port programs that span the life sciences and chemistry is a distinguished professor of chemistry and a professor of departments, and graduate students rotate through labs in molecular and cell biology at UC Berkeley.

November 2o11 | hhmi bulletin 35 36 hhmi

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Torii: Stephen Brashear / AP, ©HHMI Urban: Rosanna Baker Tsien: Paul Fetters Looger: James Kegley 38 science EDUCATION chronicle Room to Grow—and Learn

40 institUTE NEWS Experiment Seeks to Create Interdisciplinary Curricula / HHMI Offers International Student Research Fellowships / Getting Back to the Bench

42 LAB BOOK Unlocking the Interferon Puzzle / When Membranes Merge / Bacterial-Viral Warfare

45 ask A SCIENTIST How fast would an object have to move to be invisible to the naked eye?

46 nota BENE Horwich Wins Lasker Award / Keio Prize Goes to Beachy

Bacteria are under constant attack by viruses and phages. To defend against repeat offenders, bacteria display bits of their invader’s RNA on a surveillance complex called Cascade. When an invader returns, Cascade recognizes its nucleic acids and calls over another molecule to destroy the offending genetic material.

In this artist’s imaginative rendition of Cascade’s role, a bacterial cell wrapped in a protective layer of barbed wire made from invaders’ RNA fends off a hover- ing T4 phage. An enlarged silhouette of the Cascade complex can be seen within the cell.

Learn more about how researchers figured out Cascade’s structure and role in Lab Book, page 44. Gabriel Lander and Blake Wiedenheft

November 2o11 | hhmi bulletin 37 38 hhmi appear onuniversity campuses,changingthe wayscience courses courses,” says Wessler. something verydifferent fromtraditional, impersonallecture machine. “For manystudents, thiswillbetheir firstbiologycourse— ics laboratory, down tothe radio playingmusic andthecoffee give incoming freshmentheexperienceofworkinginarealgenet- science. Itaimsto to integrateteachingandhands-onexperimental at theUniversity ofCalifornia, Riverside,inearlyJuly, isdesigned room andcomputerlab,withnewMaclaptopsfor25students. ics researchlabonebuilding away. Just acrossthehallisadiscussion wet labwithmostofthesameequipment foundinherplantgenet- tory withamixture ofprideandanticipation. Susan Wessler gazesaroundthebrand-newscience learning labora- experience G Room toGrow—andLearn iven science education Special spacesdevotedtoexploringscience arebeginning to The CampbellScience Learning Laboratory, whichopened On onesideoftheblue-and-whitecheckeredhallway, there’s a bulletin

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lab Wessler developedacourse thatreplicatedherresearchprogram engaged inscience. the laboratorygotherthinking aboutbetterwaystokeepstudents were bouncing off the walls.” engagement in Seeing the instant wouldn’t beparticularlyexcited. Buttheundergraduatesinlab in herresearchlab:“Iwouldwalkoutoftheclassroomandpeople when shesaw theminlecturesandwhentheyworkedonprojects pointing,” shesays.Shenoticedsomethingpeculiarinthestudents experience wasnotwhatshehadhoped.“To behonest,itwasdisap- at theUniversity of Georgia morethan two decades ago,the who haslaunchedtwoHHMI-supportedlabspaces. says RichardLosick,aprofessorofbiologyatHarvardUniversity interested inmajoringsciences becauseofbiglecturecourses,” “Weare organized andtaught. werelosingalotofstudentswhoare . , With support from an HHMI professor grant, awarded in 2006, When Wessler began teaching undergraduate biology courses st u dents

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Owen Gildersleeve in an undergraduate classroom laboratory, allowing students to Losick spearheaded the design of the new science learning analyze transposable DNA—small pieces of DNA that can jump spaces with help from HHMI professor grants, starting in 2002. from one location to another inside a cell’s genome. At the same His aim was to move away from formulaic science teaching where time, she spearheaded the design of a special place to teach the students go through the motions without really learning. “There are unusual class—with all the elements of a working lab space. When two features that make for a successful hands-on experiment: owner- Wessler made the move from Georgia to UC Riverside last year, ship and discovery,” he says, adding that science is not just a series of bringing the lab and the class were part of the deal. The Riverside facts but an active process. lab is named after the late Neil Campbell, an alum and coauthor Of course, designing courses so that every student can discover of the biology textbook used in many high school and college something novel is not easy. Losick has created two teaching spaces introductory courses. to take on the challenge. The Jeremy Knowles Teaching Lab, which The crossover between discovery and practice in such learning opened at Harvard in December 2009, is a highly flexible space that spaces means that concepts get put to work immediately, and lab can accommodate different science classes, from molecular biology isn’t just an add-on to lecture-based learning. “Rather than going to a new course on the science of cooking. to the lab the next day, we can do experiments at the same time we Around 120 students can simultaneously use the 7,000-square- discuss concepts,” says James Burnette, a researcher who coordinates foot laboratory for the research component of different lecture Wessler’s class laboratory. Even more importantly, students have the courses, thanks to engineering tricks like moveable benches and a opportunity to repeat experiments if something doesn’t work—just false floor that serves different equipment. The space can be divided like a research lab—and they must master concepts before moving up with sound-proof walls, creating two or four smaller spaces. In on to the next project. this setting, rote-learning science labs are out and true experiments The investment in infrastructure isn’t small—Wessler says her are in: small teams of undergrads tackle a semester-long project. One space cost $700,000, with nearly three-quarters of that coming from course, for example, trains students to work with a protein impli- Rochelle Campbell, Neil Campbell’s widow. Now that the lab is cated in cancer and then has them look for other proteins involved. paid for and in place, however, Burnette notes that it can be run The second space Losick designed is a 50-person, interdisci- with nearly the same student lab fees as a typical undergraduate plinary laboratory used solely for research-based classes. In one science course. project, students built their own confocal microscope and then For undergraduates who have the opportunity to do high-level used it to study neuronal firing in zebrafish. In another project, research, the experience can be unforgettable. Paris Stowers, who students stud ied samples of cheese from a gourmet store, identify- took Wessler’s course at the University of Georgia, says the class was ing microbes in the cheese and rinds. “The projects are changing all one of the most influential of her college career. “We were guided the time, and the course is entirely devoted to research,” says Losick. through the process of designing an experiment, writing a grant pro- “It’s like working in a real lab with a team of five or six students who posal, and presenting the results.” The class cemented her plans are tackling some question of current research.” to pursue a career in medical research. Starting in September, Back at Riverside, Susan Wessler would love to see the model Stowers will spend a year conducting research on neuroblastoma of project-based science classes grow—for the students and for through Baylor College of Medicine’s medical student research slightly more selfish reasons. “When we started, I thought that we’d track program. be bringing ideas from my research lab to the classroom, to design and deconstruct complex projects to their fundamentals. But I’ve Ownership and Discovery been surprised that the learning goes both ways—some of the user- Rich Losick believes that labs and classrooms have the potential to friendly computer software we’ve developed in the classroom has work symbiotically for students—and professors. “For me, teaching moved back to my research lab,” she says. “The lesson is: if you and research go hand in hand, and I’d like to think I’m a better teach students what’s out there in science and give them the right teacher for being a researcher and vice versa,” he says. “It leads me tools, they can do real experiments.” And she’s betting they’re mak- to see the big picture and get to the heart of the matter.” ing discoveries for life. W –Katharine Gammon

November 2o11 | hhmi bulletin 39 institute news

members will present the NEXUS proj- Experiment Seeks to Create ect at various educational conferences to Interdisciplinary Curricula expand its visibility and to solicit feedback. “There are many conversations heading M ost people associate experiments run on a larger scale than one discipline or in the same direction, addressing how young in science with test tubes and beakers. How- one institution,” says Sean B. Carroll, HHMI’s people should be trained to participate in bio- ever, HHMI is trying a new type of science vice president for science education. medicine and medical practice in the future,” experiment—one that involves education. The four schools are working together says Cynthia Bauerle, who oversees the The Institute has brought together an expert to ensure that the modules meet common NEXUS project and is a senior program offi- in student evaluation with faculty mem- goals and that the courses are designed and cer in HHMI’s precollege and undergraduate bers from four universities with one goal measured in a unified way. They are devel- program. The hope is that NEXUS will be a in mind: to create interdisciplinary science oping assessments that move beyond just hub for that broader national conversation. W courses easily implemented in any under- testing students on factual knowledge to FOR MORE INFORMATION: Learn more about this initiative graduate classroom. assess their ability to demonstrate scientific at www.hhmi.org/news/nexus20110608.html. The four-year, $1.8 million National competencies and apply their knowledge to Experiment in Undergraduate Science complex problems. Education, or NEXUS, involves Purdue HHMI has hired David Hanauer, an The N exus team University; the University of Maryland, Bal- evaluation specialist at Indiana University of Purdue University is revising its introductory timore County; the University of Maryland, Pennsylvania, to help coordinate the teams’ chemistry curriculum to include more biological chemistry, with a focus on active learning approaches. College Park; and the University of Miami. assessment work and develop their capac- The University of Maryland, Balti- Each is focusing on a specific topic, with ity to tackle competency-based assessment more County, is infusing mathematical modeling the aim of creating undergraduate educa- approaches. This past summer, Hanauer led into its introductory biology course, including quantitative reasoning skills and mathematical approaches to under- tional modules that integrate biology with a two-day workshop, with representatives stand biological processes and living systems.

physics, math, and chemistry (see box). The from the four institutions in attendance, to The University of Maryland, College teams are pilot launching their modules this discuss strategy for assessment development. Park, is revising its introductory physics course for biology majors to present physics concepts in a biological context. fall and hope to have them ready to share The Institute has appointed a steering The University of Miami is developing with other institutions in a few years. committee and an interdisciplinary advisory biomedical case studies that will challenge students to use “We really believe in the word ‘experi- board of leaders in education reform. In the scientific inquiry to analyze the biology, physics, chemistry, and math involved in human health and disease. ment,’ and here is an experiment that is being coming months, many steering committee

Sixty research institutions with estab- HHMI Offers International lished relationships with HHMI were eligible Student Research Fellowships to nominate between one and 10 graduate students for the fellowships, depending on When Amanda Valeta came to the year International Student Research Fellow- the size of their graduate programs. A panel United States, she had trouble finding finan- ships. The support will allow them to devote of top scientists and graduate educators cial support for graduate school. “There are their full attention to research at a critical reviewed applications from 385 students. very limited sources of funding for non-U.S. time during their professional development. Institute leaders were particularly pleased citizens to train in the United States,” says “For my research project on cancer and with the broad distribution of countries rep- the Zimbabwe native. “This greatly limits the immune system, I need to carry out resented by the awardees. Students from the ability of foreign students like myself to some very expensive studies,” says Valeta, a China and Canada received the most awards, bring back the education and expertise that graduate student at the New York University but Turkey, Israel, Slovenia, and Colombia are needed to address the complex health School of Medicine. Now, with her salary also are represented. The new fellows come problems facing our native countries.” covered by the HHMI fellowship, she has from a wide variety of disciplines, including To encourage universities to take a more money for those experiments. physics, chemistry, and engineering, in addi- chance on the best international graduate HHMI originally planned to give 35 fel- tion to the biomedical fields that HHMI has students, HHMI established a fellowship lowships in this pilot year but increased traditionally supported. program to support science and engineer- the number to 48 because the quality of HHMI has committed to continue funding students during their third, fourth, and the applicants was so high. “The applicant ing the program; planning for next year’s fifth years of graduate school. pool was spectacular,” says Sean B. Carroll, competition is already under way. W

Recently, the Institute selected Valeta and HHMI’s vice president for science educa- FOR MORE INFORMATION: Visit http://www.hhmi.org/ 47 other graduate students from 22 countries tion. “We hope, through these fellowships, news/intlresearchfellows20110804.html to learn more about the to be the inaugural recipients of the $43,000 a to identify future scientific leaders.” International Student Research fellows.

40 hhmi bulletin | November 2o11 where I thought, ‘Either I get back to the lab Getting Back to the Bench now or I will never be able to get back,’” he Janelia Farm offers researchers the time and says. “I don’t really know yet what I’ll be doing resources to focus on science. at Janelia—and I find that exhilarating.” All Janelia Farm group leaders, fel- After several years as an independent we see in academia is that scientists are lows, and junior fellows actively engage in researcher, David Stern says the demands of forced to become full-time managers, instead research. They work in small interdisciplin- running a lab of 12 people, combined with of spending their time focusing on their sci- ary teams to address two broad scientific teaching and administrative duties, simply ence. Janelia Farm offers an alternative.” goals: discovering the basic rules and mech- became too much. In an effort to get back Stern and structural biologist Tamir anisms of the brain’s information-processing into the lab on a regular basis, last year the Gonen, who was an HHMI early career sci- systems and developing biological and com- HHMI investigator took a “sabbatical” at his entist at the University of Washington, are putational techniques for creating and home institution, Princeton University. Janelia Farm’s newest group leaders, along interpreting biological images. During that one-year break, Stern threw with Michael Reiser, a Janelia Farm fel- Group leaders direct research groups of himself into lab work—doing experiments low who was promoted to group leader this two to six lab members and receive an ini- and building hardware to study evolution year. Gonen and Stern will anchor two new tial appointment of six years. Fellows, who and development of the nervous system in research programs: structural biology (with receive five-year appointments, are indepen- the fruit fly. “The most important things I a focus on cryoelectron microscopy), and dent researchers who lead labs with up to realized during that time were that I missed the evolution and development of the ner- two additional members. Junior fellows are doing research with my own hands and that vous system. In the past 18 months, Janelia postdoctoral fellows who develop their own my efforts in the lab could make a differ- Farm has recruited two group leaders, four research programs and are appointed for up to ence in advancing our work,” he says. fellows, and four junior fellows (see box). three years, with a possible two-year renewal. So when the opportunity presented Stern says Janelia Farm appeals to him Rubin notes that recruitment of new itself to make a fresh start at HHMI’s Jane- because he will be able to focus on the evo- scientists continues, and researchers from lia Farm Research Campus in Ashburn, lution of behavior, a relatively new area of a variety of disciplines—including bio- Virginia, Stern wasted no time in deciding inquiry for his lab. “I started this work about chemists, biologists, chemists, computer to move south—even though that meant three years ago when I became an HHMI scientists, engineers, mathematicians, neu- uprooting his family and giving up tenure investigator,” he says. “The work has been robiologists, and physicists—can apply for at Princeton. He knew that at Janelia Farm, challenging and fascinating. I thought it laboratory head positions through a com- he’d spend less time on the administrative would be wonderful if I could do this work petition that closes December 15, 2011. duties, teaching, and grant writing that had close to other labs that are struggling with the Applications in the competition for junior been consuming his days. same sort of challenges in studying behavior.” fellow positions (an independent postdoc- “At Janelia Farm, scientists have the Gonen’s decision to move to Janelia Farm toral position) close December 1. Further time and resources to actually do their own was motivated by his realization that if he information is available at www.janelia.org/ research—not just manage it,” says executive wanted to do his own experiments in the lab professional-opportunities/research-positions. director Gerry Rubin. “One of the problems again, it was now or never. “I reached a stage W –jim keeley

Janelia’s N ew S cientists

Group Leaders diversity in fruit flies. He believes that a Viren Jain is attempting to map the Stephen Huston is a neuro Tamir Gonen uses molecular electron thorough understanding of the molecular network of connections in the brain. He scientist who has worked on the neural microscopy to study structures of large pro- basis for diversity may lead to a revised develops computational techniques for auto- basis of flexible sensory-motor transfor- tein complexes that function as molecular view of how developmental mechanisms mating image analysis and applies them to mation in the fruit fly. He is continuing machines. His research addresses two fun- influence evolution. studying neural circuits. work on understanding how the outputs damental questions in cell biology: How do of the visual system are transformed into cells interact with each other and with their FELLOWS Na Ji develops imaging tools capable of motor actions. environment? How do they obtain the nutri- Meng Cui wants to develop robust, peering deep inside animals’ brains to better ents essential for cell survival? ready-to-use tools for biomedical imaging. comprehend the function of neural circuits. Stefan Pulver wants to uncover He plans to use ultrasound as a virtual She is focused on improving the speed and fundamental operating principles behind Michael Reiser studies sensory light source, allowing him to visualize resolution of in vivo brain imaging, and the neural circuitry that controls locomotion mechanisms that drive innate behaviors in deep tissues. applying the resulting techniques to existing in fruit fly larvae. He plans to study motor the fruit fly, such as the ability to sense gravity problems in neurobiology. networks in the larva’s locomotor system. and visual motion. He uses molecular genet- Adam Hantman seeks to understand ics to uncover the functional organization of how the central nervous system uses sensory JUNIOR FELLOWS Koen Vervaeke has been exploring neural circuits that orchestrate behaviors. input called proprioception to inform and P arVEZ Ahammad seeks to improve how networks of neurons can produce optimize circuits involved in motor control. current methods and develop approaches to both synchronizing and desynchronizing David Stern is trying to identify He is using an approach that integrates tackle a fundamental challenge in neuro behavior via electrical activity at the synapse. the genes—and ultimately the individual genetics, physiology, optical-based circuit science: linking specific behaviors to specific At Janelia Farm, he will study the roles of nucleotides—that generate phenotypic tracing, and behavioral assays. neural activity in defined circuits. specific inhibitory neurons in attention.

November 2o11 | hhmi bulletin 41 lab book Unlocking the Interferon Puzzle Scientists show that interferon signaling depends on bond strength.

How can different interferon molecules bind to the same recep- amino acids responsible for binding to the receptor and found tor and elicit vastly different responses? This conundrum has long that although the locations of most contact points are constant puzzled scientists who study these signaling proteins. A study led from one interferon to another, the strength of the bonds varies. by HHMI investigator K. Chris Garcia suggests the key may lie in Thus, the receptor differentiates between interferon molecules how tightly the interferons bind to that receptor. by how avidly they attach at certain positions. The punch line is Interferons are protective chemicals that cells produce to that chemistry, rather than ultrastructure, appears to functionally combat cancer, viruses, and infections. It takes the combined differentiate interferons. effort of many different interferon molecules to get the job done, As Garcia reports in the August 19, 2011, issue of Cell, manipulat- and each one activates a particular component of the body’s ing the chemistry of the binding surfaces can endow one interferon defense systems. with the functional properties of Garcia wanted to figure out how the 16 varieties of type I inter- another. For example, replacing feron trigger different cellular actions through just one cell surface a single amino acid in IFN with receptor. He and his postdoctoral fellow Christoph Thomas at the one found at the same posi- Stanford University School of Medicine used x-ray crystallogra- tion in IFNa2 boosts the mutant phy to deduce the three-dimensional structures of the receptor’s IFN’s cancer-fighting ability, two subunits, IFNAR1 and IFNAR2, bound to two kinds of type I making it more like IFNa2. interferons, IFN2 and IFN. These findings provide an Surprisingly, both interferon varieties bound the subunits in a alternative to the long-standing similar fashion. The finding countered the prevailing notion that “lock-and-key” model of recep- each kind of type I interferon would bind in a unique way. tor binding in which there’s only The interferon receptor (blue To dig deeper, Garcia teamed up with researchers from the and green) can distinguish one way a molecular key can Weizmann Institute of Science in Israel and the University of different interferons (brown) bind to, and activate, its receptor by how tightly they bind. Osnabrück in Germany. Collectively, they mutated the interferon lock. W – Nicole Kresge

IN BRIEF

Detecting Prostate Cancer the absence of prostate cancer, higher ney, gut, eyes, brain, skin, muscle—were The days of uncertainty in prostate can- levels of the gene do suggest a larger and regenerated. It all came from one original cer diagnosis may be numbered: HHMI more invasive prostate tumor. starting cell.” scientists have developed a simple urine “We think of this as the frst-generation Since most planarian genes have human test to help determine the presence of version of this test,” says Chinnaiyan. “We counterparts, the fndings, described May 13, the disease. hope to add to it in the future by test- 2011, in Science, could provide insight into In 2005, HHMI investigator Arul M. Chin ing for additional gene fusions that we human regenerative medicine. naiyan and colleagues at the University know about.” of Michigan Medical School identified a Genetic Insight into Head fusion between two genes that occurs in Rebuilding a F latworm and Neck Cancers approximately half of all prostate cancers. How do planarians regenerate themselves, Two independent studies by teams of When TMPRSS2 and ERG combine to form cell by cell, when sliced into the tiniest of HHMI investigators have revealed genetic TMPRSS2:ERG, the new gene drives pros- slivers? By exposing the fatworms to ion- mutations often present in squamous cell tate cell growth out of control, leading izing radiation that destroyed all but a few carcinoma, the most common form of head to cancer. of the animals’ neoblasts, researchers have and neck cancer. In their latest work, published August 3, come closer to answering that question. Todd R. Golub of the Dana–Farber 2011, in Science Translational Medicine, the HHMI early career scientist Peter Red- Cancer Institute looked at the genetics of researchers recruited 1,312 men scheduled dien and his colleagues at the Massachu- 74 tumors diagnosed as head and neck for a prostate needle biopsy. They collected setts Institute of Technology discovered squamous cell carcinoma (HNSCC). Bert the men’s urine before the biopsy and that some of the surviving neoblasts Vogelstein of the Johns Hopkins University compared TMPRSS2:ERG levels in samples seemed to possess all the qualities of a School of Medicine analyzed 32 HNSCC from patients whose biopsy revealed can- stem cell. So, they put these cells, called tumors and validated the results in an addi- cer with levels in men whose biopsy was clonogenic neoblasts, to the ultimate test: tional 88 tumors. The results of the studies negative for cancer. they transplanted a single clonogenic neo- appear in two separate papers published in Around 50 percent of the men con- blast into an irradiated worm lacking any Science on August 26, 2011. firmed to have prostate cancer tested other dividing cell. Both studies compared the tumor positive for TMPRSS2:ERG in their urine; “Tissues of the host were slowly but exomes—the part of the genome that fewer than 5 percent of men whose biopsy surely replaced with descendant cells from encodes proteins—with a noncancerous did not detect cancer had the gene. While the transplanted donor cell,” says Reddien. sample from the same patient to identify lack of the fusion gene does not indicate “All the various parts of the body—kid- mutations unique to the tumors. A high Garcia lab

42 hhmi bulletin | November 2o11 Laguna Design / Photo Researchers, Inc. Berkeley, donorvesiclecontentswithgreenself-quenching tagged University andtheUniversitycolleagues atStanford ofCalifornia, tofinish.”show theprocessfromstart the calcium concentrationconstant,” saysBrunger. “Sotheydidn’t the wholepicture. strates thatwhilelipidmixing isnecessaryforfusion,it’s farfrom the as ananalogoffusion.Thenewassay, reportedJuly 19,2011, in dyes, and lipid mixing (from two distinct membranes) was used withfluorescingIn thosesystems,membranelipidsweretagged previous assaystoilluminate theprocesstoldamisleading story. contents intothesynapticcleft—thegapbetweenneurons.But naled vesiclestofusewiththeneuron’s membraneandspilltheir in. Researchersknewthisflashfloodofcalcium somehow sig- nels in the cell membrane open, allowing calcium ions to rush tor AxelT. Brunger. to apowerful tooldevelopedbyresearchersledHHMIinvestiga- ofthisfraction-of-a-millisecond steparenowDetails clearer,thanks neurotransmitters into the space between one neuron and the next. Neurons communicate byreleasingthecontentsofvesiclesfull S When MembranesMerge cientists IN BRIEF To mimic fusion andneurotransmitter release,Brunger and “Those assaysshowed onlypartoftheprocess,andthey kept As anelectricalimpulsetravelsthroughanervecell,chan- i wf Jnie Drel n ohr col other and Darnell Jennifer wife his with together Darnell, investigatorRobert to a tumor before developing therapeutics. speci mutations understanding of tance squamous speci into cells stem of tiation differen- the pathway: molecular one in involved genes in were discovered ers ing whenit’s activated. form - from tumors HNSCC keeping gene, suppressor tumor a as acts it case this in NOTCH1was downregulated, that meaning however,HNSCC, In types. cancer other in mutations had tumors the of percentage rti’ seii RA agt andmechanism of targets RNA specific protein’s the about consensus little is there but cells,in (mRNA) RNA messengerto binds FMRP that know Researchers (FMRP). protein retardation mental X Fragile the encoding gene the in mutations from results disability, intellectual inherited of cause leading the syndrome, X Fragile Unreg Linke Proceedings of the National Academy of Sciences , a gene upregulated in severalin upregulated gene NOTCH1a , hs rsls nesoe h impor- the underscore results These research- the mutations other Many In the July 22, 2011, issue of issue 2011, 22, July the In d ul to Fragi

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| l hhmi i f y bulletin 43 44 hhmi molecule Cascade. RNA (green) onthesurveillance by displaying aninvader’s own wardBacteria off recurring attacks S Bacterial–Viral Warfare nia, Berkeley, andWageningen University intheNetherlands,used itfordestructionbyanuclease.complex grabsholdandtargets totheCRISPRsequencethat iscomplementary it’s carrying,the called Cascade.WhenCascadeencountersapieceofforeign DNA as RNAanddisplayed onamultisubunit surveillance complex interspaced shortpalindromic repeatsorCRISPRs,aretranscribed of confiscatedDNA,whichareintegratedintoclusteredregularly eah lab booklab IN BRIEF Nogales, Doudna,andcolleaguesattheUniversity ofCalifor- on August 5,2011, in was launched. The team reported its results response immune no cells, in aggregation MAVSblocked they when that found also activating immune reactions. The scientists in effective highly were that aggregates into clumped had mitochondria the on mitochondria.Withinminutes,every MAVS toMAVS aggregates added team Chen’s this,aggregates.” Toforform testalso to tors onhumancells. recep - to binds and recognizes that area mutate—the doesn’t virus influenza the system.However,of immune part the one rapidly,evademutateto virus the allowing f glycoproteinfacespeci ognizes multiplestrains ofthe rec- that antibody an unusual: something enza virus vaccine when he stumbled upon in receivedthe had who subjects from antibodies scanning was School, Medical Harvard and Boston Hospital Children’s at investigatorHHMI an Harrison, C. Stephen A a few copies ofavirus. only senses it evenif says, Chen response, antiviral full-blown a launch to cell the

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c f c o to one strain of strain one to mplex A ntibo f u virus. without harming their own. their intruder’starget genome scripts fromthesebitsofDNAto of how bacteriausetheRNAtran- have deducedmoleculardetails Nogales and Jennifer Doudna HHMIinvestigatorsEva attacks. genome tohelpcombatfuture and integrateitintotheir own some of the invader’s DNA with avirusorphage,theytake When bacteria survive a run-in pr In

oteins d helps Escherichia coli,thepieces y f u- more than 100 different genes, fewerthan genes, different 100 than more of one any in mutations by caused be to gressive vision loss. The disorder is thought pro- in result that conditions eye genetic of group a is (RP) pigmentosa Retinitis S antibodies to produce. which chooses system immune the how would like to use CH65 to learn more about endeavor,an Harrison such on embarking antibody.BeforeCH65 of production lates stimu- that vaccine a developto used be of theNational Academy of the in 2011, 23, August lished blocked 30 of them. The research it was pub- that found and strains flu 36 against CH65— antibody—dubbed the tested Collaborators mutations. surrounding by to the receptor pocket that it isn’t affected however,tightly isolated, so leagues binds bodies wouldn’t bind. anti- the mutated, area surrounding that if Thus, areas.” changeable surrounding, recognize also would it but area, binding receptor that target might antibody “an receptors,”Harrison, saysvirus most than area contact larger a have antibodies

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ba complex beforeandafteritboundtobitsoffore cryoelectron m surrounding degradationofthe foreign DNA. between Cascadeandthenuclease tolearnmoreabouttheevents enemy isafriend.” ing their defensecapabilities,” saysNogales.“Theenemyofour we haveapotentialwaytocontrolbacterialpopulationsbyreduc- by whichabacteriumisabletosurviveviralinfectionmeansthat issue of Nature, may provide a way for humans to combat harmful signal foranuclease todestroytheinvading nucleic acids. conformational change in the Cascade molecule that may serve as a helical segmentsreducetheoveralllengthofcrRNA,causinga crRNA bindstothem,forming severalduplexregions.Theseshort cient exposuretosurveytheenvironment. thecrRNAfromdegradationwhileallowing itsuffi- that protects it displays itsCRISPR-derivedRNA(crRNA)inalonggroove entists discovered thatCascadeisshapedlikeaseahorseand Bl cteria. “Anything that allows us to understand the mechanismscteria. “Anything that allows us to understand Next, NogalesandDoudnawanttolookattheinteraction The structure,whichwasreportedintheSeptember22,2011, When the complex encounters invading nucleic acids, the in

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path half of which have been identi been have which of half the scientists were able to able were scientists the testes, the in predominantly studied been had previously gene this Although RP. for identifyingmany gene to this list and have devised a method more one added havecollaborators with Shef C. Val and Stone M. Edwin investigators 1 about in found also was mutation the Sciences, of AcademyNational the of ings the in 2011, 23, August reported As gene. kinase) associated germ-cell patient’s the of copies both in mutation a found team the RP, with patient a proteins—of encodes that DNA genes asthey can. RP new many as identify to technology cell stem pluripotent induced and ing next-generationsequenc- of combination protein at all. MAK full the make to unable were cells mutant These skin. patient’s RP the from ating retina cells out of stem cells obtained cre- byeye the on mutation the of effects cells aswell. version of the MAK protein in human retina

o per Sequencing the exome—the portion of exome—theportion the Sequencing Now, the group plans to apply the same investigatedthe then researchers The gens f et f neae idvdas with individuals unrelated of cent eld of the of eld . U niversity of Iowa along Iowa of niversity

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q A How fast would The short answer is yes, Dash could run Dash were moving fast, photons bouncing fast enough to be invisible. Exactly how off him would be scattered across many an object have fast he would have to run depends on cones, and each of these cones might be many factors. insufficiently activated, so Dash would to move to be For an object to be visible, light par- be invisible. If there were just a little more invisible to the ticles (photons) must bounce off the activation, he would appear as a blur. object and into your eye. There must be The less light there is, the more Dash naked eye? enough light that specialized neurons can afford to take it easy. At noon when Could Dash from in the eye—the rod and cone cells that there is a surplus of photons, he has to be form the photosensitive pixels of the at his speediest to be invisible. “The Incredibles” retina—are activated to a level that trig- Other factors are at play. One is eye gers awareness. If Dash zipped through movement. We never look steadily at a really run so fast your field of view so quickly that too single point in space. We are not aware of that we could little light from him reached your retina, it, but our eyes constantly dart from one you would not see him. location in the visual scene to another. not see him? What is the minimum amount of light They make small jumps that last about required? In a classic experiment, people a fifth of a second. These jumps are Asked by John, a high school in complete darkness were exposed called “saccades,” during which our student from Virginia. to flashes of light. Only the rod photo visual system is suppressed. If Dash shot receptors were sensitive enough to detect past during a saccade, you would not see the light intensities used in this experi- him. If he ran past a crowd, chances are ment. At the minimum flash brightness that at least some people would be in required to trigger visual awareness, only midsaccade and would miss him. a handful of rods each absorbed just The bottom line is, a complete answer one photon. The implication is striking: to your question does not exist. How much single cells, capturing single particles of light is required for a good cone signal, light, can trigger perception. how activity across the array of cones is However, at best, the rods can provide assembled into an image, how the visual only a low-resolution image. To see and system shuts down during a saccade, and recognize Dash requires cone photo- other factors such as attention are active receptors. Cones allow high-resolution research areas. color vision in brighter light. Unlike rods, individual cones must absorb many photons to generate a sizeable response. And since each cone contributes a single Answered by Michael Tri Do, an assistant pixel to the final image, many cones are professor at Children’s Hospital Boston, FURTHER reading: Webvision: webvision.med.utah.edu. required to “draw” Dash on the retina. If Harvard Medical School.

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

November 2o11 | hhmi bulletin 45 46 are recognized fortheir formidable and sc are among the oldest and most prestigious Sc the 2012Benjamin Franklin MedalinLife ence education at HHMI, has been awarded hhmi S Davi regeneration. and nanotechnologytotissuerepair research focuses on the application of micro- of participating inthesociety. Bhatia’s biomedical engineering and have a record demonstrate exceptionalachievementsin isawardedstatus tosociety members who ing Society’s class of 2011 fellows. Fellow was elected to the Biomedical Engineer of theMassachusettsInstituteTechnology HHMI investigator useful functions. and to design molecules with new and tures ofnaturallyoccurringbiomolecules methodstopredictcomputational thestruc- excellence in biochemistry. Baker uses nizes scientists fortheir achievementsand Award. Theinternationalaward recog- the Biochemical Society’s 2012Centenary the University ofWashington, received ean ience awards in the world, and recipients nota bene iences. TheFranklin Institute Awards s A Horwich Wins LaskerAward p

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El Davi H parts and patterns. development shape the evolution of body changes inthegenesthatcontrolanimal versity ofWisconsin–Madison, studies how Carroll, anHHMIinvestigatorattheUni- ground-breaking contributionstoscience. Organization awarded The HumanFrontier Science Program locations inthe body. ity allows cellstoknow andremembertheir looks athow thecoordination ofgeneactiv- tributions todermatologicscience. Chang Marchion of Medicine, wasawarded the2011Alfred Universityscientist School attheStanford tor at the University of California, Santa expression asasourceofbiological variation. ofstochasticity,tance or“noise,” ingene selected forhisworkthatshowed theimpor- breakthroughs inlifesciences. Elowitz was Nakasone, honorsscientists whohave made for formerJapanesePrimeMinister Yasuhiro HFSP Nakasoneaward. Theaward, named California InstituteofTechnology, the2011 o o w w ar d research, andpublicservice. the world—are given annually for basic medical research, clinical medical LaskerAwards—considered in respectedprizesmostscience the among Theactiveforms. convertedbiologically be their proteinstointo made newlyfor place a providesthat “machine” folding cage-like a as acts chaperoninproteincalled a that Theythemselves.determinedby cells werediscoveringinsideforhonoredHartl fold proteins andcannot that Franz- awarded the 2011 Albert Lasker Basic Medical Research Award along with investigatorHHMI Yalewasan at Medicine, Horwich, of L. School Arthur itz

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ini ResearchPrizeforhiscon- Y , anHHMIinvestigatoratthe u . C ss U hang lrich Hartl of the Max Planck Institute of Biochemistry.of Institute Planck Horwich Max the of Hartl lrich l er , anHHMIinvestiga- , an HHMI early career chae M i l

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honors internationally respected American the AmericanDream.Theannual award Education from the Merage Foundation for National Leadership Award in Science and cians and Surgeonswasawarded the2011 the Columbia University College of Physi- HHMI investigator interactions. inmacromolecular the roleofelectrostatics opment of software tools used to analyze sciences. Honig washonoredforhisdevel- that enhancesresearchinthemolecularlife sible and innovative computer technology given toscientists whohavecreatedacces - Biosciences. Theannualputational award is Molecular BiologyDeLanoAward forCom- American Society forBiochemistry and Columbia University received the 2012 HHMI investigator vertebrate genomes. the molecularevolutionofhumanandother tistical andalgorithmic methodstoexplore problems inbiology.- Hausslerdevelopssta methodsthatcanbeappliedto statistical for thedevelopmentofmathematicalor of Oxford. The annual prize is awarded don MemorialPrizegivenbytheUniversity Cruz, wasselectedtoreceive the2011Wel- E B ric arry R . K H an onig d e l of of of of

Chris Jones Bill Denison HHMI investigators the endoplasmic reticulum. ognized forhisresearchonprotein folding in contributions toglycobiology. Parodi wasrec- scientists whohavemadewidelyrecognized Glyco 2011 KarlMeyerAward bytheSociety for Foundation, wasselectedtoreceive the tional research scholar at the Leloir Institute A HHMI investigator memory inanimals. immigrants. Kandellooksatlearning and leaders who came to the Unitedas States mond andBeverlySacklerInternational of HarvardUniversity sharedthe2011Ray- of secretedligands. pathways that are activated by the Wnt family tion. Moonstudies thesignaltransduction such ashealth,energy, andscience educa provides scientific analysis on issues in areas Academy of Sciences. The academyState Medicine waselectedtotheWashington of theUniversity ofWashington Schoolof Stanford University and Stanford rman s P Keio PrizeGoestoBeachy p hilip biology otli d o J. o A.B . Theannual award isgivento g eachy P ht aro

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HHMI investigator for Microbiology. Research Award fromtheAmericanSociety with the2011PromegaBiotechnology of gene expression and virus–cell inter tion imaging methods to study the regulation develops single-moleculeandsuperresolu- biological and medical interest. Zhuang tion and applies these tools to problems of Quake inventsformsofbiologicalautoma- Prize in Biophysics from Tel Aviv University. a School ofMedicine, withthe2011 an HHMIinvestigatoratEmoryUniversity Stress Studies honored The InternationalSociety forTraumatic their shape. and maintain across membranesandhow organellesform his researchonhow proteins aretransported in cellbiology. Rapoportwashonoredfor every other year for outstanding discoveries of Sciences Leopoldina. Theaward isgiven Schleiden MedalfromtheGermanAcademy of HarvardMedical Schoolwonthe2011 standing Scientific Achievement.Ressler Laufer, Ph.D.,MemorialAward forOut- ctions. Quake was also recently honored tor investigaHHMI - awardedto was Prize Science Medical Keio 2011 The discovering theproteasome andelucidating its physiological functions. Tanakaapplications. discoveringmedical and forits selected ment, was receivedforhonor keythe a Hedgehog, identifying develop-in molecule sciences.Beachylife the or contributionstooutstandingmedicine made Keioby annually given is prize The Science. TanakaMedicalTokyo of of InstituteMetropolitan P of Stanfordof Beachy A. hilip T om K erry J. A . R apoport R Robert ess U niversity in Japan to researchers who haveresearcherswho to Japan in niversity l er S. , U

niversity School of Medicine and Keijiand Medicine of niversitySchool of post- is giventoscientists with10yearsorless istry and Molecular Biology. The award from theAmericanSociety forBiochem- ScholarAwardEarl andThressaStadtman beenselectedtoreceiveogy, has the2012 at theMassachusettsInstituteofTechnol- HHMI investigator regulates growth. ing themTORsignalingpathway, which received thehonorforhisworkonelucidat- type 1. Rett syndrome and spinocerebellar ataxia several neurologicaldisorders including genetic andmolecularmechanisms of was honored for her work elucidating the progress inknowledge and culture. Zoghbi awards givenbythePeter and Patricia prize is one of five annual international the 2011GruberNeuroscience Prize.The Baylor CollegeofMedicine wasawarded Gruber F Davi based disorders. develop therapiesforanxietyandotherfear- studies themolecularneurobiologyoffearto d

M postdoctoral experience.Sabatin . oundation forworkthatfacilitates S aba November 2o11 tini Hud , anHHMIinvestigator a Y

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47 continued from page 17 really talking to one another more than we ists on biological problems. And they’ve (Living chemistry) used to. As a result, biologists understand only just begun. W can launch career-changing collaborations, better what chemists can bring to the table.

as Crabtree and Schreiber have learned. And chemists understand better the ques- FOR MORE INFORMATION: See other articles on researchers “The important thing,” says van der tions that biologists really care about.” This, applying chemistry to biological questions throughout this issue, Donk, “is that biologists and chemists are he says, has led to a bigger impact of chem- in print, online, and on the iPad.

continued from page 23 100 hours each observing teachers—in mid- faculty lead professional development initia- (Calling all teachers) dle schools and high schools, in ordinary and tives for the teachers at each school. were suspects, she added, and each suspect high-need districts, and teaching different Back in Kalamazoo, Lauren Miller will used a characteristic brand of pen. The subjects. Many preservice teachers also help do her student teaching next spring, and students figured out how to use paper chro- teach in the university’s unique biotechnol- next summer she’ll teach eighth graders matography to distinguish the inks in Bic, ogy, chemistry, physics, and earth science the unit she develops on sex hormones RoseArt, and other pens. Most were able to teaching laboratories. Science teachers from and obesity. Beyond that, she plans to finger the guilty suspect. “I wanted them to 80 percent of Long Island’s school districts teach family consumer science, which understand the concepts more deeply than bring their students for half-day laboratories. includes personal nutrition, reproductive they would if they had just been given the Establishing strong ties with local schools health, and parenting, to high schoolers. instructions,” Gurick says. can pay off for much smaller teacher-train- She’ll take her newfound enthusiasm for ing programs. At Trinity University, aspiring science with her. “Science is asking ques- Getting in Practice science teachers do a year-long internship tions—you ask one question and you’ve Stony Brook’s curriculum, like all good at one of three “professional development got 10 more after that,” Miller says. “I want teaching programs, also requires preservice schools”—elementary, middle, or high to take that to my students and get them teachers to spend plenty of time in schools, school—in San Antonio, where they are excited about science.” W watching and teaching. Before they’re mentored by an experienced teacher. In

allowed to student-teach in the third and exchange, the university appoints these men- FOR MORE INFORMATION: To learn about new science final semester of their master’s course, pre- tors as clinical faculty for a year, complete and math standards and to see a comparison of preservice service teachers at Stony Brook must spend with library and other privileges, and Trinity programs, visit www.hhmi.org/bulletin/nov2011.

continued from page 29 capabilities with the super-resolution of Betzig team continues to improve the Bes- (Have microscope, will travel) PALM, a project that the Galbraiths—fre- sel sheet. Because what they really learned Planchon, now an associate professor at quent collaborators at Janelia Farm who at Woods Hole, Gao says, is how urgently Delaware State University, plans to develop brought their own custom-built PALM with biologists await those improvements. W similar microscopes to look at live multi- them to Woods Hole this summer—are urg-

cellular organisms and continue working ing forward. web extra: Hear Eric Betzig talk about the microscope closely with biologists. Ultimately, Betzig’s The long days at MBL will transition and see how it dazzled Woods Hole students and faculty in group would like to merge the Bessel sheet’s into long days back at Janelia Farm, as the an audio slideshow. Go to www.hhmi.org/bulletin/nov2011.

continued from page 33 tional samples and setting up collaborations Richard says. “But it is welcome to see that (STAR SEARCH) with Malagasy scientists and other lemur recognition translating into a broader sci- of background information concerning both biologists around the world. They think that entific interest in mouse lemurs—primates wild and captive mouse lemurs with new learning about the genetics and physiology found nowhere else in the world.” W genetic and genomic data is very exciting.” of mouse lemurs could help preserve the

At Stanford, Krasnow and his group endangered animals. web extra: Travel with Mark Krasnow and his team are pushing forward with mouse lemur “For decades Madagascar has been seen as they explore the rainforests of Madagascar. See the research, starting with seeking out addi- as a hotspot for biodiversity, and rightly so,” slideshow at www.hhmi.org/bulletin/nov2011.

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

48 hhmi bulletin | November 2o11