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HHMI BULLETIN • Howard Hughes Medical Institute • www.hhmi.org vol. 24 / no. 01 Emi Takahashi Oki, Ellen Grant, and Elizabeth Engle Elizabeth and Grant, Ellen Oki, Takahashi Emi Brain Tease lead to eye disorders (see “Eyes Wide Open,” page 18). (see “Eyes Wide Open,” lead to eye disorders On a typical brain scan, the tangle of neurons in a mouse brain is the tangleOn a typical brain scan, brain is of neurons in a mouse for back to front, and blue for top to bottom. The new images help help images new The bottom. to top for blue and front, to back for in the resulting image, shown here in an 18-day-old mouse embryo, embryo, mouse 18-day-old an in here shown image, resulting the in individual neurons with more ease—and it produces wildly colorful colorful wildly produces it ease—and more with neurons individual relies on the fact that water molecules will move more quickly along along quickly more move will molecules water that fact the on relies researchers like Elizabeth Engle study how misplaced neurons can researchers like Elizabeth Engle study misplacedhow neurons can hard to decipher. A new technology lets researchers follow the paths of of paths the follow researchers lets technology new A decipher. to hard images. Called diffusion tensor imaging, or diffusion MRI, the method method the MRI, diffusion or imaging, tensor diffusion Called images. are color-coded based on direction of growth: red for left to right, green green right, to left for red growth: of direction on based color-coded are neurons extending downward than those growing sideways. The neurons neurons The sideways. growing those than downward extending neurons 4000 Jones Bridge Road Chevy Chase, Maryland 20815-6789 www.hhmi.org thousands ofproteinsontheDNA, mimicking whathappensinourcells. loads he when happens what wait see to hardly can Greene collisions, along and crash into, or hop around, nucleosomal barriers. A fan of fantastic DNA (green) and see the behavior of DNA-binding proteins as they motor tagged measure thedistributionoffluorescently nucleosomes (pink) on With this curtain of bright pinks and greens, biochemist Eric Greene can 24

Greene lab

VSA Partners Before they started writing their book book their writing started they Before Graspin relegated to the safely obscure. We fail to understand them at our peril, economists, lawyers, and meteorologists, genes are too important to be start. Butunlike thosetechnical details,whichwe cansafely leave to the World does, orwhy Bank tort reform isneeded, orhow tornados the same look that might surface in response to a question about what Most commonly, our requests to explain what a gene is were met with out of tenth grade biology. although thoseterms were fairly fuzzyto thosemore thantwo years was occasionally linked to concepts suchasDNAorchromosomes, they explain Johnny’s bigearsandMary’s quicktemper. The gene genes come from ourparents andgrandparents, andthenotion that traits oremotional characteristics, areflection of the realization that school biologyclassroom. Many associated thegenewithphysical to None of thepeoplewe queriedwhoweren’t biologists cameclose them. surprised results The friends. and family of poll informal an took they So, is. gene a what of understanding good a had public general the whether know to wanted Johnston Mark and Fields Stan investigator HHMI

i t a v r e s b O providing adefinition of thegenethat would pass muster inahigh g o

n the Fundamentals the s Genetic Twists of Fate of Twists Genetic , of The MIT Press. MIT The of Technology. permission byof Used Institute Massachusetts ©2010 From broccoli andbeets,chicken andcows, andapplesapricots. part of your body. Andnot just inyour body:they are inevery cell of and your liver cells, your brain andyour bonecells. They are inevery cell. Genesare found inyour skinand your stomach cells, your lung genes are present allover thebody—everywhere, invirtuallyevery Only aboutonethird of Lanie’s respondents gave the correct answer: heart, orbones,lymphnodesvarious other locations. eighth said“intheblood”;afew saidinthereproductive system, or a by AngelaD. Lanie, ascientist at theUniversity of Michigan.Nearly posed to Americansof varied ethnic and educational backgrounds question: where inyour bodyare genesfound? This was thequery But before we dealwithwhat genesare, let’s askaneven simpler lifespan, our mood, our insurability, and our food supply, to name a few. because they influence crucial aspects of our daily life: our health, our

quarter of therespondents saidgenesare “inthebrain”; aboutone Genetic Twists of Fate of Twists Genetic , by Stanley Fields and Mark Johnston, Johnston, Mark and Fields Stanley by , february ’11 vol. 24 · no. o1

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Web Only Content Explore Fred Alt’s “family album” of postdoctoral trainees.

Learn Louisa Stark’s perspective on using Web-based tools to teach science.

See how scientist-sculptor Bertalan Andrasfalvy brought his “Butterfly” to Janelia Farm.

Watch the molecular effect of a genetic eye disorder on the brain and ocular nerves as revealed by Elizabeth Engle.

Join us at www.hhmi.org/bulletin/feb2011.

24 28 Features Departments cover story PRESIDENT’S LETTER Institute Ne ws The Next ge neration 03 TK 40 2010 Holiday Lectures on Science— 1 2 Experienced researchers have CENTRIFUGE Viral Outbreak: The Science of figured out how to find and train the Emerging Disease 04 Harboring Seals most promising postdocs. 41 SEA Reaches New Shores 05 Curved Wings 41 HHMI Launches Eyes Wide Open 06 Lost Mountain 1 8 Elizabeth Engle isn’t afraid to learn— International Competition for UPFRONT whole new fields, if necessary—to Early Career Scientists 08 When Worlds Collide find the cause of a group of rare Lab Book 1 0 Skin Sense eye disorders. 42 Forgetting Fear PERSPECTIVES AND OPINIONS Behind the Curtain 43 Releasing the Brakes on Cell Fate 34 Crucibles of Dynamism 24 Stringing molecules on threads 44 Warming Malaria 36 Q&A—Tell us something a postdoc of DNA gives a new view of their said or did during an interview A sk a Scientist interactions. that made you sure he/she wasn’t 45 How do internal stresses cause Hope Floats right for your lab. the external appearance of humans 28 With a new arsenal of robust models to change with things such as CHRONICLE wrinkles? Can appearance predict of ALS, drug development may move Science Education to the fast track. general health? 38 Road Warrior Nota Be ne 46 News of recent awards and other notable achievements

OBSERVATIONS Grasping the Fundamentals

VISIT THE B U L L E T I N ONLINE FOR ADDITIONAL CONTENT AND ADDED FEATURES: www.hhmi.org/bulletin COVER IMAGE: Micah Lidberg editor’s letter

I have to admit, I was a skeptic. The iPad seemed With this new format, we’re hoping to like one more way to spend serious money on reach an audience not currently familiar with a nifty electronic device. But receiving one as a the Bulletin. We’re eager to get our stories in Christmas present (my husband broke his vow the hands of what we think is a sizeable—and of no more gifts with an on-off button, sworn global—contingent of science-curious readers. to after seeing other digital gifts gather dust Given the iPad’s potential as a learning tool, on my desk) has made me a believer. The iPad we also hope the Bulletin app fnds its way into is a marvelous machine. the classroom. In January, a New York Times Witness “Star Walk.” Open this app on article reported escalating orders for iPads by your iPad, point the lightweight tablet toward public schools across the country, including the sky, and behold—every constellation and 2,000 in New York City alone. With upward major star in that part of the heavens is identi- of 5,400 educational apps available, of which fed. There’s Virgo, with bright Spica—the 15th nearly 1,000 are free, the tablet offers a way brightest star in the nighttime sky, you are told. “to extend the four walls of the classroom,” Swing the tablet to the right and the screen says one Long Island teacher. adjusts—there’s Leo, with bright Regulus twin- Science educators know that hands-on is kling on his chest. I’ve learned more about the the best way to teach science. Maybe ­tablet night sky in the last two weeks than I have in computers like the iPad will turn out to be my frst fve decades! second best. Time will tell. Meanwhile, I’ll be Now that I have this window into myriad trawling the iTunes store for more brilliant new worlds, it makes me even more proud and apps like Star Walk—and for more science pleased to announce that the HHMI Bulletin magazine apps like the HHMI Bulletin. I can’t is available to iPad users. Downloadable free wait to see what I learn next. from the iTunes store, the app is a new, interac- tive way to learn more about the cool science coming out of HHMI. We are having fun fgur- ing out creative ways to take you deeper into the scientifc discoveries the Bulletin reports.

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

Paul Nurse, F.R.S. Additional Co ntrIButors President / The Rockefeller University Cay Butler, Michelle Cissell, Dame Alison Richard Nicole Kresge, Heather McDonald Professor, University of Cambridge VSA Partners, NYC / Concept & Design Clayton S. Rose, Ph.D . Finlay Printing / Printing & Binding Senior Lecturer, Harvard Business School Former Head of Global Investment Banking, J.P. Morgan & Co. 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

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

2 hhmi bulletin | February 2o11 James Kegley through NIH,theNationalScience Foundation (NSF),thedepart- fewer thanfivedozenreceived NIHresearch projectgrants. 24,000 scientists workingwithArabidopsis an exception.Atthe turn ofthemillennium, for example, of some grants throughtheNationalInstitutesofHealth(NIH),butshe is A highlyrespectedscientist likeChorymaysucceedinreceiving 2 percentofoveralllifesciences spending by thefederalgovernment. dedicated toappliedagriculturalresearch—andrepresentsabout of anafterthoughtintheU.S.—whereresources are substantial the U.S. DepartmentofAgriculture. gram withintheNationalInstituteofFood andAgriculture,partof horizon, including aplanfordevelopingcompetitivegrantspro- ers and academic leaders. Other positive developments are on the framework fordiscussingissuesamongpolicymak- these important “A NewBiologyforthe21stCentury,” providesamuch-needed able energysources.The2009NationalResearchCouncil Report, health, protectionoftheenvironment,identificationrenew- most pressingconcernsthatfacesociety: foodproduction,human possibly find solutions to—some of the help us understand—and time inourhistory. Plantscientists havetremendouspotentialto ics—but onecouldarguetherehasneverbeenamoreimportant study ofthehumblepeahelpedfoundmodernfieldgenet- a newgenerationofgraduatestudentsandpostdoctoralresearchers. will haveanoutsizedimpactontheir fields,particularlyinattracting to make analogous commitments. We also believe this core group plantscience andwillencourageothersintheUnitedmental States our joint of investing program in funda underscores the importance Moore Foundation overafive-yearperiod. We thinkthecreationof investigators and also receive grant support from the substantial scientists. Whenselectedin2011,theywilljoin theInstituteas identify upto15ofthisnation’splant mostcreativeandtalented Foundation announcedthatwewouldholdajoint competitionto this fall,HHMIandtheCalifornia-based GordonandBettyMoore (Mus musculus). ( cal colleagueshow much theycouldlearnfromthemouseearcress for Biological Studies has spent many anhour explaining to quizzi- within theHHMIcommunity, theinvestigatoratSalkInstitute study of any animal genome.” Asone of a handful of plantscientists might contributemoretohumanhealthandwell-being thanthe the pagesofHHMIBulletinthat“thestudyplantgenomes F Seeding PlantScience  Arabidopsis thaliana)—asdistinct fromthemammalianmouse o ur y The interagency National Plant Genome Initiative—funded For plantscience has been something toolong,fundamental Why now? Plantresearchproveditsvaluelongago—after all, Chory’s carefullycultivatedseedshavenow bornefruit.Earlier e ars ag o J o a nne Ch o ry mad e ab as their modelorganism, ol d stat e m en t w i th in -

­Chandler, chiefprogramofficerfortheMooreF in fundamental plantscience. Elsewhereinthisissue,VickiL.in fundamental supports manyplantscientists, hashadfewdedicated programs tools andknowledge overthepastdecade.ButNSF, which ments ofAgricultureandEnergy, andothers—hasgenerateduseful not flourish. and givesthescientists wesupportagreaterchancetosurvive—if symbiosis thatbenefitsbothorganizationsexample offacultative tions shareacommitment tosupportingexcellentscience. scientific advisory board,Ihaveseenfirsthandthatourorganiza- Chory helpedorganize. AsamemberoftheMooreFoundation’s potential newdirections inplantscience in a2008workshopthat andscientific interests,HHMIbeganexploring its environmental traditional scope.Just astheMooreFoundation soughttoconnect has historicallyviewedmuch of plantscience researchasoutsideits research withthepotentialtoimprovehumanhealth,Institute information sciences. GivenHHMI’s primaryfocusonbiomedical researchinphysical,life,and focused onsupportingfundamental conservation, has which has long been committed to environmental at firstglance,tobeobviouspartners.TheMoore Foundation, plant science researchbecauseourorganizations wouldnotappear, illustrates the extraordinary investment in potential for targeted the challengesandopportunities thatfacehercolleaguesinthefield. initiatives andanotedplantresearcherinherown right,describes “ Plant scientists have tremendous Ro face society. face of the most pressing concerns that and possibly solutions find to—some potential help to understand— us The resultissomethingthatecologistsmight recognize: an The collaborationbetweenHHMIandtheMooreFoundation bert T jian ” president February 2o11 oundation’s science

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California sea lions, elephant seals, She started working with sea lions and harbor seals, and then releases but switched to harbor seals. “Once I them back to the wild. From ­February got a taste of caring for the harbor seals, to August, volunteers also care for that was it,” she says. “With the sea lions abandoned harbor seal pups too young you have to concentrate all the time; to fend for themselves. Most of the they are really fast and really smart. animals are found by members of the They can twist around, and quickly bite. public, who call the center. A trained The harbor seals are a little slower and rescue team assesses the situation smaller, and more appealing somehow.” and brings in animals that are truly Last April 14, the rescue team ­distressed or in danger. brought in two harbor seal pups during Brejc and hundreds of other volun- Brejc’s Wednesday evening shift. One teers provide the abandoned pups with animal, offcially named Mairead, was food and warmth. “When the harbor just a day or two old and nearly pure seal pups frst come in—they are about white with big, doll-like eyes. Brejc and Harboring Seals a meter long—we feed them a fatty her crewmates nicknamed her Snow mixture of salmon oil and powdered White. She weighed 17.6 pounds. When Katjuša Brejc grew up in former milk through a tube,” Brejc says. As Brejc and the others kept regular Yugoslavia, she had pet parakeets. the animals put on weight, they get tabs on Snow White as the season pro- Later, when she moved to San Fran- solid food, fsh. Volunteers teach the gressed, though they try to minimize cisco, she knew she wanted to take animals to eat fsh by putting it directly their contact so the seals don’t become care of animals, but she had to be in their mouths, a task that takes two too comfortable around humans. “At picky. “Working with cats or dogs volunteers: one to hold the animal and the end of the day, they are wild ani- would be too dangerous,” Brejc says. another to feed it. Eventually, the seals mals,” Brejc admits. Two months later, “I’d want to take them all home.” So learn to catch fsh on their own. “By on June 23, the team celebrated when she signed on at the Marine ­Mammal the end of the season, we dump seven Snow White was released in Bodega ­Center in Marin County, California. kilograms of fsh in their pen and walk Bay at Scotty Creek, weighing 41.7 There’s no way she could take home away,” says Brejc, who’s been working pounds and ready to fend for herself. a seal. But that doesn’t mean she at the center for eight years. —Rabiya Tuma doesn’t get attached. “There are always a few animals that stand out,” says Brejc, a research “W orking with cats or dogs associate in HHMI investigator Barbara Meyer’s laboratory at the University of would be too dangerous. I’d California, Berkeley. want to take them all home. The Marine Mammal Center rehabili- tates sick and injured animals, including K aTJuša B rejc ” Illustration: Ping Zhu Photo: Courtesy of Katjuša Brejc

4 hhmi bulletin | February 2o11 Curved Wings “I always wanted to do something with ing leftover granite or marble salvaged thick, from Vermont. Over a year of my hands,” says Bertalan Andrasfalvy, from graveyard and construction sup- weekends, working in a studio owned with a quick grin. That much is easy to pliers and weekdays doing research by stone carver Malcolm Harlow, he believe. His long fngers seem perpetu- and crafting tools for scientists study- took a diamond-disc saw to the slab, ally busy—tracing the white granite ing the brain. He recently developed, transforming it into a modern, milky edges of his butterfy sculpture at with Janelia Farm physicist Alipasha white butterfy, with curved wings HHMI’s Janelia Farm Research Campus, Vaziri, an optogenetic technique for 7 feet tall and 3 feet wide. poking the air in philosophical empha- precisely activating neurons. A butterfy is ftting, he says, given sis, or pointing out the lab where he “My philosophy is that there are HHMI founder Howard Hughes’ love works with Janelia Farm group leader only two things you can do to keep of fight. The smooth, rounded piece Jeffrey Magee. creative, like a child: art and science,” also softens the spare architecture and Born in Hungary, Andrasfalvy is 40, Andrasfalvy says. “In these felds, you the metallic sculptures on campus. with swift dark eyes, a chiseled jaw, and can follow your curiosity. How does this “Besides, with Rubin’s developmental a casually athletic frame that stretches work? What does it look like? Every- biology work inside, half the building well over six feet. He exudes a quiet thing else is a job.” is working on fies,” jokes Andrasfalvy. restlessness. He holds an M.D., a Ph.D., Andrasfalvy has worked in academic “This is such a nicer insect.” and two curricula vitae—one that lists research labs in Budapest, Tokyo, and Today, the butterfy sculpture sits eight peer-reviewed publications on New Orleans. In 2006, he arrived at high on the horizon, just outside the neuronal physiology, and another that Janelia Farm to work with Magee, who main building, watching over a cluster describes 20 sculptures, several of studies how neurons work. He also acts of willow oaks and feathery grasses. them commissioned and many gifts. as a consultant to the physics group It rests on a giant rock, evoking a quiet The pivot between art and science at Janelia. And as resident artist. energy, as though—with the right started early. When Andrasfalvy was In 2008, he approached ­Janelia wind—it might take to the air. 10 years old, his father gave him a Farm director Gerry Rubin about —Kathryn Brown woodcarving set. By age 20, he had creating a sculpture for the campus. completed his frst stone sculpture— Rubin agreed, and Andrasfalvy placed WEB EXTRA: For a photo slideshow and was on the path to medical school. his order for raw stone: a massive of Andrasfalvy’s butterfy sculpture, visit www.hhmi.org/bulletin/feb2011.

Andrew Cutraro Ever since, he’s spent weekends sculpt- 15x5-foot slab of white granite, a foot

February 2o11 | hhmi bulletin 5 6 hhmi centrifuge bulletin

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February 2o11 upward, huggingtheinnerwall couldn’t seethesummitabove us.” pons didn’twork. Itwas sofoggy we “The snow turnedsoft andourcram- of thebrain’s cortex at Columbia ologist whostudies themicrocircuitry became threatening. Yuste, aneurobi- a attached to theirbootsoles—canget hard, andtheircrampons—metal spikes ascent whenthesnow isstill packed ing, they start outfresh andmake the f at amountainhutbefore makingthe (Lost Mountain),stopping overnight two days to scaleMonte Perdido a heartattack andslideoffthecliff.’” ‘I’m going to fall from exhaustion or have beating outofmy chest andIthought, memory. “Iwas deadtired; my heart was of Rafa,’” herecalls, still shivering at the isgoingtoI thought‘this betheend didn’t thinkIwas goingto make it— their deaths here inthepast 30years. account, some60peoplehave fallen to the slopelast July. By onelocalnews and avid mountaineerwhonegotiated Rafael Yuste, anHHMIinvestigator you getspit down thecliff,” explains steep andtilted sideways, soifyou slip La Escupidera—the Spittoon. “It’s very track alongasheerrock drop-off. that corkscrews like an half-mile-long inclineofsnow andice Pyrenees, climbersface atreacherous, summit of Monte Perdido in the Spanish In thefinalpushto the11,000-foot Lost Mountain were it was gettinglate andconditions uphill for more thanseven hours, turned back.“We hadbeenhiking member climbingpartyhadalready Escupidera at 3p.m. Two ofthenine- caught inthecoming storm. back inasingleday to avoid getting mostly Spanish—decidedto goupand group of40-somethingprofessionals, versity, andhiscompanions—a veteran f nal ascent thenext day. Inthemorn- The remaining climbersinched During theascent, theweather Traditionally, mountaineersallow There were timesgoingup“whenI The perilousslopeisaptlynamed They reached thebottom ofLa rm grip. ­ getting bad, ” recounts Yuste. O lympic luge

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­slithering t ­r there, grippingitwithbothhands.” says. “Finallytheaxe held. Hejust lay but hecouldn’t stop himself,” Yuste soft snow. “Hewasn’t goingvery fast, repeatedly stabbing hisaxe into the slowly slidtoward theedgeofcliff, fell. The otherswatched anxiouslyashe down thechute-like Spittoon. brief rest, they headedcarefully back view ofthecentral Pyrenees. After a rewarded by aspectacular100-mile they reached thecold, windysummit, every 10steps.” says. “We hadto stop andrest after step andrepeat theprocess,” Yuste to keep usfrom sliding,thentake a we hadto plantthembothinthesnow hand andalongpoleintheother, and edge as of the couraged by thedif of thesummitandwithoutbeing dis- small careful steps, withoutlosingtrack apparently unattainable goal,andtake As inscience, you setyourself ahigh, other challengesinlife seemattainable. thing really important.Having doneit, We feel we have accomplished some- Yuste. “To reach thepeakisbeautiful. to dothesecrazy things,” confesses but tremendously happy. hut, “completely destroyed” by fatigue, adventurers returned to themountain the to the otherclimber, andbothrejoined came to astop, slowly made hisway with hisaxe invain. Fortunately, he get there.” —Richard Saltus escue, he, too, slippedandfell, When theirleaderwent to the As they descended, oneoftheparty This went onfor aboutanhouruntil “Each ofushadanice axe inone “It’s hard to explain why we continue Twelve hoursafter settingout,the

Perdido climb, visit WEB EXTRA: party.

Spittoon asfar from thecliff

possible. oward thecliff, chopping To seephotos from Yuste’s Monte www.hhmi.org/bulletin/feb2011. f culties, untilyou

Ping Zhu upfront

08 When Worlds Collide The right time and place led to a new RNAi-like pathway in bacteria.

0S1 kin Sense An early question about aging skin has revealed how cells code for their location.

web only content

Right Be fore Your Eyes Revisiting an old technique provides researchers the breakthrough they need to couple protein sequence to function, thousands of variants at a time. Read the story at www.hhmi.org/bulletin/feb2011.

Our lives are driven by technology. It takes just a few keystrokes or a Skype account to reach out to scientific collaborators across the globe. Effortless long-distance communication makes it easy to forget about the resources down the hallway or across campus. Two teams of researchers, however, were able to dig deeper into their research questions by partnering with an investigator from another field, who happened to be in the same zip code. Find out what’s going on across the quad. Invite somebody for a cup of coffee—face to face. Good for the soul and maybe even the research.

February 2o11 | hhmi bulletin 7 upfront

When Worlds Collide The right time and place led to a new RNAi-like pathway in bacteria.

Though their labs at University of California, Berkeley, are

only a few buildings apart, biochemist Jennifer Doudna and geobiolo- gist Jill Banfield were strangers. But when Banfield needed expertise Soon after Wiedenheft joined the outside her scope, their worlds converged. ¶ Banfield studies microbes Doudna lab, graduate student Rachel that grow in extreme environments. She needed a partner who knew Haurwitz arrived and became fascinated about the gene-silencing process known as RNA interference (RNAi). with Wiedenheft’s project. “CRISPR in general is a pretty new field,” says Haurwitz. Doudna, an HHMI investigator who members led to Doudna’s team capturing “When I started my project, there had been studies RNAi in eukaryotic cells, had solved the first snapshot of a CRISPR enzyme in a lot of computational groundwork done the crystal structure of Dicer, a key enzyme action. They reported in September 2010 and it was really on the biologists to test in that process. that the CRISPR-associated enzyme Csy4 the hypotheses.” Realizing her luck at having a resource has the unusual property of recognizing, In 2007, the first report surfaced on so close by, Banfield called Doudna to dis- binding to, and cleaving RNA in a sequence- CRISPR-mediated acquired immunity. The cuss what appeared to be a microbial gene- and structure-specific way. Danish food production company Danisco silencing strategy analogous to RNAi that “As often happens in science, there needed a way to protect its yogurt-producing was accomplished by highly repetitive DNA is a lot of serendipity involved,” Doudna Streptococcus thermophilus cultures from sequence elements known as CRISPRs—an acknowledges. bacteriophages, viruses that attack bacteria. acronym for clustered regularly interspaced Its scientists established the relationship short palindromic repeats. The Timing was Right between CRISPR and phage resistance. Banfield and others suspected that Just as Doudna was becoming keen on The immunity depended on the bacteria microbes were using CRISPRs to fend off the idea of CRISPRs, Blake Wiedenheft acquiring new DNA in the CRISPR region invaders. But nobody knew how CRISPRs appeared. While earning his Ph.D. in of their genome upon phage infection. The could function as an immune system, and Montana, he had become intrigued by the DNA sequences were identical to sequences scientists were intrigued by what else the odd repetitive snippets of DNA he found in the infecting phages, and subsequently tiny bits of RNA derived from CRISPRs in the microbes of Yellowstone National the bacteria were immune to infection with might be doing. Park’s boiling acid pools. Wiedenheft was the same phages. The two researchers met for coffee a convinced that there might be a system in Armed with that new information, few times in 2006 and explored the overlap play in these organisms similar to RNAi in ­Haurwitz began her thesis project, ask- between their worlds. Those conversations eukaryotes. He wanted to pursue the ques- ing: What enzyme in the CRISPR system and the well-timed arrival of two new lab tion in Doudna’s lab. is responsible for making the small bits of

8 hhmi bulletin | February 2o11 Nick Tassone responsible for cuttingup the RNAtran- Haurwitz identified Csy4 as the protein A DiscriminatingEnzyme the lungsofcysticfibrosispatients. the persistentPseudomonas for controlling could beapotentialtarget ment inbiofilmformationsuggestedthatit Streptococcus. HintsofCRISPRinvolve- already known fromEscherichia coliand then comparethefindings withwhat was to studyitsenzymesandmechanisms and infection. Assuch,itofferedanopportunity cated directly in defending against phage with aCRISPRthathadnotbeenimpli- aeruginosa, a human bacterial pathogen and how doesitfunction? aphage, RNA thatarelaterusedtotarget The teamworkedwithPseudomonas infections in of the RNA atthe base of the stem(the ture oftheRNAmoleculeand sequence nized both the stem-loop, or hairpin, struc- by x-raycrystallography. RNA/enzyme complex,sothatitsthree- method tocreateindividualofthe crystals in action.HaurwitzandJinekdeviseda the RNA, thus immobilizing the enzyme enzyme tobindbutpreventedcleavageof of Csy4’sthatallowed the RNAtarget out tolearnhow Csy4works. biologist and postdoc in Doudna’s lab, set Haurwitz andMartinJinek,astructural segment specific toPseudomonas.Then, scribed fromaCRISPRsequence intoa ­double-stranded d imensional structurecouldbedetermined The teamdiscovered thatCsy4recog- Haurwitz designed a mutated version portion of the hairpin). ­ destroy RNA. Csy4’s and abilitytospecifically target nostic toolsandtherapeutics that relyon RNAi machinery, anddevelopingdiag cells withoutinterferingwith thecells’ ­e can envisioncontrollingmicrobial gene universe, she says,areconsiderable.She The rewardsofventuringintothisparallel different set of enzymes,” says Doudna. to RNAinterferencebutwithadistinctly bacteria might beusingapathwaysimilar September 10,2010,issueofScience. Jinek. Thegrouppublisheditsresultsinthe from all the other cellular RNAs,” says Csy4 protein todiscriminate RNA itstarget and shape-specific recognition allows the “This exquisite combinationof sequence- xpression, gene silencing in eukaryotic “It hasbeenquite asurprisetofindthat W February 2o11 –m i tz i bak

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9 upfront Skin Sense An early question about aging skin led to answers on how cells code for their location.

Howard Chang found that one long intervening noncoding RNA, called HOTAIR, is important

in breast cancer. Too much of it encourages a primary breast tumor to spread. Ramin Rahimian

10 hhmi bulletin | February 2o11 Early in his research career, Howard Chang asked a simple question: what happens to skin cells as an organism ages? Using genetic tech- nologies just emerging in 2000, Chang explored his question and ­parallel analysis of RNA structure, or PARS, revealed another complexity of skin—one that he’s still puzzling to ­puzzle out structures of the full 3,000 over. ¶ Chang’s curiosity also led him into a new realm of study: long RNAs in yeast cells. Their results appeared noncoding RNAs. In the past year, the HHMI early career scientist at in Nature on September 2, 2010. In the spirit of data sharing, they’ve cre- Stanford University debuted a technique for began to focus on one called HOTAIR. ated an iPhone application to allow others determining RNA structures, and now he’s The researchers hypothesized that blocking to access the structures (see Web Extra). making novel links between a specific type cells from making HOTAIR would affect Their own lab, of course, will use the data of RNA and human health. the neighboring Hox gene. But instead, the to find connections between the structures Chang is a dermatologist with M.D. expression of a Hox gene on a completely and functions of lincRNAs. and Ph.D. degrees. During his clinical different chromosome changed. While this research sounds far removed residency in dermatology, he worked in the “This raised the idea that these RNAs from skin, Chang still practices dermatol- Stanford research lab of HHMI investigator can have very profound effects all over the ogy, seeing patients once a week. It reminds Patrick O. Brown, where he learned about genome,” says Chang. His lab is beginning him why HOTAIR and positional identity microarrays. Chang saw the technology as to understand these far-reaching effects. in skin cells are so important: they relate an opportunity to determine the genetic dif- Chang compares HOTAIR—which is back to human disease. ferences between young and old skin cells. a large intervening noncoding RNA, or “One of the biggest clues to a skin dis- He collected skin samples from banks lincRNA—to a train. It’s a long, stringy ease is where it occurs,” he says. If a rash is of foreskin tissue taken from newborn boys. molecule that carries various enzymes to on your hands and feet, that means some- From adults, he gathered biopsies of arm, Hox genes to regulate their expression. Like thing completely different than a rash that scalp, and back skin. It was widely assumed train cars, HOTAIR sections are modular, is only on your belly button.” Understand- that skin was skin—identical all over the specific to their cargo. If Chang can fig- ing how cells code for their location using body. Chang’s research revealed, on the ure out which RNA structures carry which lincRNAs could explain why certain skin contrary, that differences in gene activity among the tissues stemmed not only from “I realized these cells have functional age but also location. differences based on where they are. It’s like “I realized these cells have functional differences based on where they are,” says a built-in address code.

Chang. “It’s like a built-in address code.” Ho wARD C hang Chang started frequenting the morgue, ” collecting skin samples from different enzymes, he may be able to predict the diseases affect only one area and maybe body parts of cadavers. Using microarrays, functions of lincRNAs other than HOTAIR. how to stop those diseases. he discovered that the differences in gene But the challenge, he says, is the struc- Recently, Chang’s team found that activity among skin cells could be traced to tures. The classic way to determine RNA HOTAIR is important in breast cancer. Hox genes, a large family of genes already structures, called reverse transcriptase PCR, When breast cancer cells make too much known to control positioning of body parts is “tedious, a lot of work, and only successful HOTAIR, their address code—which should during development. on short pieces of RNA,” he says. So his lab point to the breast—becomes jumbled, In 2004, Chang started his own lab. His developed a way to separate lincRNAs into allowing the cancer to spread. The levels of team devised a method to look at expres- manageable pieces. HOTAIR in a primary breast tumor predict sion of the 39 Hox genes—whether each is “If you have a chocolate bar with grooves whether it will metastasize, the research- turned on or off—and also at expression of along it, and you throw it on the ground, ers concluded in an April 15, 2010, Nature the DNA flanking each gene. the pattern it breaks in will likely follow ­article. Not something Chang expected to In humans, more than 200 of these sur- the grooves,” says Chang. He uses chemi- find when he asked a decade ago how skin rounding regions were actively expressed. cals to break the RNA at its thinnest and cells age, he says, but no doubt a worth- The researchers found this puzzling, since most exposed sections, like the grooves in while finding. W –Sarah C.P. Williams these regions of DNA are transcribed into the chocolate. Then his team sequences RNA but never go on to produce proteins. the fragments and pieces them together web extra: For more about Chang’s iPhone

They’re called noncoding RNAs. His lab again. His lab used the technique, called application, visit www.hhmi.org/bulletin/feb2011.

February 2o11 | hhmi bulletin 11

Experienced researchers have figured out how to find and train th e most promising postdocs.

BY Kendall Powell · ILLUSTRATION BY micah lidberg

February 2o11 | hhmi bulletin 13 Journeying along an uncharted river has parallels to exploring science, says Jim Bardwell, an HHMI investiga- tor and avid outdoorsman. The postdoctoral fellowship, for example, is like shooting a series of churning rapids with only a paddle and a helmet for protection. It’s a high-pressure series of challenges to join the best lab after graduate school, execute and publish stellar science, and then secure a full-time position afterward. Postdocs are a lab’s engines of creativity but also laboring apprentices. They work long hours for l­ imited pay to gain the experience and publications they need to earn their first independent job—be it lab head, industry researcher, or government scientist.

Bardwell understands the importance of having the right team—in the lab and on adventures. With just a fold-up canoe in his backpack, he and a friend hiked through the wilderness of Papua New Guinea scouting rivers in 1994. They chose the seemingly easier Ramu River over the imposing Jimi but mid- course had to escape before the Ramu spit them into a desolate part of the Pacific Ocean. “Quite frequently, you have to redirect to find the path through the jungle, and science is often redirected quickly or dramatically, as well,” says Bardwell, at University of Michigan. In both cases, the expedition team has to be knowledgeable, hard working, flexible, and fearless. “You can run into indica- tions that your hypothesis is completely wrong. You don’t want people to wimp out on you, curl up in a ball, and start whimper- ing. And believe me, it can happen both on expeditions and in the lab.” Choosing the right people can make or break a lab group. And although there’s not one right way of going about it, experienced investigators are quick to say it’s not rocket science. With further prodding, however, they begin to describe well-honed techniques for recruiting, selecting, and managing postdoctoral fellows. The stakes for both postdocs and mentors are high. Today more than ever, postdocs need to find a lab with a strong pedigree. And

part 1 of 2 In the next issue, our series continues with the view from the postdocs themselves. Where do things stand for them today? What came of the bustle of activity to improve the lives of postdocs in the early 2000s? Does their future look bright?

14 hhmi bulletin | February 2o11 Peter Baker CV,” saysHHMIscientific officerEdMcCleskey. thananyotherpageontheirout oftheir labaremoreimportant scientist whoiscompatiblewiththerestoflab’stal employees. the investigatorswhohirethemmust identifyagiftedexperimen- wants toworkwithyou,andthendig deeper,” saysLuger. sonality. “You reallyhavetogetovertheexcitement thatsomeone outset, carefullyselectingpeoplewhofitthelab’s goalsandper- phy—is invaluable. - they areguaranteed“goodhands”atcellcultureorcrystallogra weight. Knowing firsthand a candidate’s true training level—that who knows thelab’s researchandmanagementstyleholdsalotof toapplyherlab. extends aninvitation If shefindstheright mix ofinnatecuriosityandenthusiasm,she University inFt.Collins. an HHMIinvestigatoratColoradoState too much;toalotofyoungerpeople,” Italk saysKarolinLuger, universities. summer training courses, and when giving seminars at other atscientific meetings,Seasoned investigatorsscoutfortalent Digging for own vision?” fight fortheir ideas?Dotheyhavetheir people going togooutonalimband who will speak their minds. “Are these interesting techniques tohergroupand than quantity. ity publicationsoncreativestudies rather succeed asapostdoc.” He looks forqual- lishing, that’s agoodindication theywill “If anapplicant has succeeded in pub- inception toitsconclusion,apublication?” “Can theyspearheadtheprojectfromits sachusetts Medical SchoolinWorcester. HHMI investigator at University of Mas- publications,” says Michael Green, an most important. many, publicationsandproductivity are tors rank different key elements first. For “Any researcherover50willsaythatthetraineeswhocome Above all,though,theseinvestigatorsarechoosyfromthe too.Areferralfromacolleague Matchmaking isimportant “When I go to a meeting I try not to hang out with my buddies Luger looksforpeoplewhowillbring Bardwell alsoemphasizespublications. “The number onethingIlookat istheir When screening applicants,investiga- G ol d who willfithisla Jim Bardw e ll loo k s f b it sealedhisdecision tojoin Bardwell’s group.Collet,thenat people inspireeachothertohigherheights.” their enthusiasmandpersonality. “Ilikealabthatisfun,where assessment. Bardwellalsolikestocallcandidates toquickly gauge He preferstoe-mailreferenceswithspecific questions. ambiguous,’” saysGreen. tosaytheyare‘interpretatively I like dation are very tricky because there is never a negative letter. little stockinlettersofrecommendation.“Lettersrecommen- Health inDenver. hired herandsherecentlylandedafacultyslotatNationalJewish “Wow, she’ssometimehere,” reallytaken herecallsthinking.He might beheadedandpositionedherskillswithinthelabteam. projects in Alt’spage cover letter projected where certain lab Boston, remembersbeing impressedbyanapplicantwhoseone- tive wouldbringfreshideas. and theenergeticsthatgovernitsassembly. Sheknewhisperspec- key assayandchangedthewayhergroupthinksaboutchromatin like hers. His influence on the lab resulted in development of a thermodynamics laboratory,” lab asopposedtoacrystallography ’ s groupd or postdocs withqualit Jean-François Colletvividlyremembersthatcallandhow Bardwell andLugercallreferencestogetafaster,candid When probingapplicantreferences,veteraninvestigatorsput Frederick Alt,anHHMIinvestigatoratChildren’s Hospital She recentlyhiredapostdocwhocamefrom“hard-core y namic. y pu b lications February 2o11

| hhmi bulletin 15 16 hhmi He says playing hard to get pays off. In 13 years, he’s trained find anotherlabbetweenthefirstandsecondconversation. candidate reallywantstobein hislab.Severaldropoutand without two interviews, mostly as a way to gauge how much the Research Campus,isveryselective.Heneverhiresapostdoc tor atHarvardMedical School. as afunctionalunit,” saysStephenElledge,anHHMIinvestiga- “The cohesivenessofyourgroupiscriticaltohavingithumalong have the candidate meet current lab members to check the fit. you willbetheluckyone.” rather thanabiglabthatislikelottery, whereyoudon’tknow if itwasbettertogoasmallerlabthatpublisheslot, “I thought lab. Bardwellstoodoutwithahigherratioofpaperstopeople. the lab’s recentpublicationsbythenumber ofpeopleinthe each oftheprotein folding labshewantedtojoin, Colletdivided make memoreproductive,” recallsCollet. inpartbecauseheknewthatwould would behappyintheStates, job tomove.Hecaredaboutthatandwantedmakesurethey young researcherthatBardwellwasaworld-classcommunicator. conversation inCollet’s nativeFrench, whichimpressedupon the cation andtwohourslaterthephonerang.Bardwellopened ­Catholic Un is pr A bulletin

key Karel Svoboda,agroupleaderatHHMI’s JaneliaFarm Everybody’s gotanindividual interviewingstyle.Buttheyall He thendid aunique calculationtoconfirmthematch. For “I hadayoungdaughterandmywifewouldhavetoquit her e part oftraining postdocs, according to paring th

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February 2o11 iversity ofLouvaininBelgium,sentane-mailappli- e m to e v e ntuall y run th e ir own la F r e b d s. A lt,

Columbia University doesn’t waste his timesitting through appli- tofillthevoid.”and talk talk,” as a new PI to she talk advises. “I made the rookie mistake would you deal with a messy bench mate?” she says. “Let them the biggestchallengeyouhadtoovercomeinyourPh.D.?How skills andhow wellthelabfitshisorherlong-termplans. gives herabettersenseofcandidate’s social andcommunication ing thescience forthenextmorning. Themorerelaxeddiscussion track positions. roughly twodozenpostdocs,18ofwhomarenow intenure- Nobel laureateandHHMIinvestigatorRichardAxelat She alsoprobespersonalitieswithquestions like,“What’s Luger dines withcandidatestalk, sav- thefirst night forsmall scientific imagination and scientific approach] forcesthemtodevelop their ideas, speculate,andhypothesize. “[This discuss through science, lettingthemtalk several hoursaweekforeach fellow to He keepshisdooropenandreserves firepower forthegroup.experimental laboratory, providing theintellectualand Axel callspostdocsthe“pillar”ofhis A nus Richard Scheller. Dulac, LeslieVosshall, andHHMI alum- David Anderson,LindaBuck,Catherine science, including HHMIinvestigators postdocs havebecomeiconsinneuro- rapport,” saysAxel.Severalofhisformer with whomyouhaveagoodpersonal postdocs whoaresmarterthanyouand “The trickistosurroundyourselfwith science andwhetherthetwowillclick. tion toprobethecandidate’s graspof right toalengthyone-on-oneconversa- orthesisseminars. Hegets cant jobtalks Subtle G ui d e

Jeff Barnett-Winsby Svoboda: Andrew Cutraro Luger: Matt Slaby record also becomes invaluable if it does come to letting someone record alsobecomesinvaluable ifitdoescometolettingsomeone really handytoremind someoneofwhatwe discussed.” Awritten learned to keep goodnotes on myconversations. It becomes the energy,” she notes. “You cannotmakesomeoneworkharderbyforce.It’s notworth tothepostdoc aboutwhatmight workbetter.problem, talking demic settings). Instead,shetriestoidentifythesourceof not liketofirepostdocs(noristhataneasyoptioninmanyaca - agement isn’tusuallypartofascientist’s upbringing. Shedoes can be“thetoughestthingwedo,” Choryadds.Conflictman- Addressing a lack of motivation or someone’s spinning wheels postdocs workbasedontheir own motivations.” manager. “I came fromthatbackgroundandIlikeitwhenmy let them.” Choryisa“sinkorswim” Aftertheinitial start-up, in LaJolla.“Theymight wreckthelab,butyoujusthaveto HHMI investigatorattheSalkInstituteforBiologicalSciences postdocs areheretocomeinanddoaproject,” saysChory, an says, soalight-handed,subtleapproachtomentoringworks. out forseminars andinterviewingforjobs.” front ofa regular crowd,” he says. “Itreallyhelpspostdocs going onyourfeet,in andprogress.“Itgetsyouusedtotalking data every week where all of his 15 or so lab members present their in DavidBaltimore’s lab,then atMIT. Heholdsalabmeeting more experiencethantheydo—I’manold man!” be ofhelptothem.They’re smarter thanme,butIhavemuch friend. Iliketopetit,touchandembraceit.That’s whereIcan data—it’s my but not overbearing in my influence. I like data approach,” hesays.“Itendtobeintimatelyfamiliar withtheir o Kar a f th nd a nd Luger tries to root out problems sooner rather than later. “I’ve But whatifapostdocisn’tperforming toexpectations? Joanne Choryagrees.“Ijokewithmylabmanagerthat Most postdocs are ready to test their own scientific wings, Alt Alt follows alessonhelearnedfromhisown postdoctoraldays e l e b i S i r int lit v o b y o to d to e da puts candidatda puts r e s e t in his la his t in a l with conflict as th as conflict l with b . K e arolin arolin s t hrough two int two hrough L u g e e i r sci r t ri e e n s t tific tific e r o l vi

e e e a w x rn as much a much as rn p s to g s to 10 percentmoreandthepayoffisalotovertime.” investment oftimeandeffort.It’s likecompoundinterest—putin kindof management. “Successasapostdocdemandscertain for themselveshow hardtowork.But,he’s alsofrankabouttime project tomatchthenewfocus. career goalsmidstream, soitmayjustbeamatterofrealigning a or go” decision, either.“stay Postdocs have been known to shift Be proactiveandgetadialogueearly.” started It’s notalwaysa go. “Don’tbetoosqueamish ifyouseethere’s aconflictcoming. more isolatedfromthebroader scientific community. sincehe’sleague inSaudiin contact likelytobe Arabiatostay same aspirationsIhave,” hesays.Heplanstoencouragethe col- professorinSauditant Arabia. large groupsof30scientists aswellonewhobecameanassis- He’s hadformerpostdocswhotookjobsinindustryoverseeing 37 percent actuallydid. respondents expectedtolandatenure-track position,butonly vey ofabout3,500formerandcurrentpostdocs,61percent of album atwww.hhmi.org/bulletin/feb2011). postdocs arenow tenured faculty members(seeAltlabalumni graduate studentsandestimatesthatmorethanhalfofhisformer success—he hastrainedmorethan100postdoctoralfellows and self-reinforcing system.” Clearly, he’sintoaformula tapped for my lab,” saysAlt.“Thosetwothingsgotogetherandmakeita part ofthetraining, asistryingtoenhancetheir successin “Getting postdocswell-preparedtoruntheir own labisamajor Venturing outontheirown e r Ultimately, saysSvoboda,postdocs areadultswhomust decide “I trytowalkintheir shoesratherthanpretend theyhavethe Bardwell sees more postdocs choosing nontraditional posts. That’s sur- agoodtrackrecord.In2010ScienceCareers tis e e t ac . l e b a o r s ut th ut e n s e e i r p

e r sonalit February 2o11 (continued onpage48) y

| hhmi bulletin 17 by sarah c.p. williams · photography by jeff barnett-winsby

18 hhmi bulletin | February 2o11 February 2o11 | hhmi bulletin 19 The toddler’s eyes were frozen in an uncontrollable been as complex and circuitous as that of the developing neurons she studies. Now, she’s closer than ever to her final destination: stare at the floor complete understanding of the disorders.

and his eyelids The Brain’s Intricacies Science wasn’t always forefront in Engle’s mind. She grew up in drooped over the Columbus, Ohio, devoting her spare time to playing the cello. Then, in junior high school, she met a teacher who took students on annual treks to the Bahamas to study marine biology. whites of his eyes. “My parents are both academics, and I learned early on that To look up at neurology resident Elizabeth Engle, he had to tilt they would support my interests if they viewed them as educa- his head way back. A conversation with the boy’s mother revealed tional,” says Engle, “and I thought this was the perfect way to that this defect ran in the family, but they knew nothing about go on a cool trip.” She got more than just a tan, it turned out. what caused it—or even if it had a name. She got hooked on marine biology and returned to the Bahamas Engle didn’t know either, so she referred the boy for a battery throughout high school. “I could spend hours snorkeling over the of neurology and ophthalmology tests. A short note back from Andros Barrier Reef watching fish dart among coral, or floating the consulting ophthalmologist stung: “Why are you putting the in a mangrove ecosystem watching crabs move about,” she says. child through all these tests? He has a well-described syndrome But Engle’s interests evolved as a freshman at Vermont’s that’s been in the ophthalmological literature since the 1800s. ­Middlebury College when she enrolled in a genetics course Congenital fibrosis syndrome.” because she couldn’t get into her desired geology class. She Embarrassed that she hadn’t recognized the syndrome, found herself addicted to the testable hypotheses that genetics Engle—now an HHMI patient-oriented researcher—went presented. “I loved to ask questions when I knew there was a real straight to the literature. True, the disease was well described, foundation for an answer and an organized way of getting there,” but it wasn’t well understood. She was determined to look at it she says. As her interests in the cello and marine biology faded, with fresh eyes. Engle was introduced to genetic research by a mentor at Middle- Engle saw the case as a chance to put fledgling genetic tech- bury and then debated her next step. She was interested in both nologies to the test and track down the gene that caused the research and patient care. She chose to go to medical school, disorder. She didn’t consider it a problem that she had no idea figuring that would leave both doors open. how to do the required experiments, or that she knew nothing At the Johns Hopkins University School of Medicine, Engle’s about the eye disorder; she viewed it as a learning opportunity. first anatomy class sparked another new interest: the brain. That mindset has characterized Engle’s career. “I hadn’t thought much about how the brain was put together “Elizabeth had a fire in her belly to really do research,” says prior to med school,” she says. “To suddenly look at this puzzle Alan Beggs, an early mentor of Engle’s. that is the brain, with its precise tracts and complicated anatomy, That 1992 encounter with the young boy at Children’s Hos- was so fascinating.” pital Boston led pediatrician and neurologist Engle to become With her overflowing interests, Engle chose to do two residen- a scientist who follows the trail of her research wherever it takes cies—one in pediatrics at Hopkins and a second in neurology her: genetics, developmental biology, neuroscience, cell signal- at Children’s Hospital Boston. She spent a gap year between ing. She’s discovered how a class of rare eye disorders, including them in a fellowship in neuropathology—that is, autopsies of the the one affecting the boy, are caused by mishaps in the devel- brain—at Boston’s Massachusetts General Hospital. opment of the nervous system, and she’s linked specific gene “I had this need to know what a diseased organ looks like, mutations to seven of the disorders. feels like, smells like,” Engle says. “To really get to know what a At each fork in the road, she chooses the gutsiest way forward, disease is, I felt it was necessary to look at it grossly and microscop- the path she hasn’t traveled before. The course of her career has ically, and to put my hands on it.” Though she’s no longer elbow

20 hhmi bulletin | February 2o11 deep in body parts, Engle has an innate need to understand what the ins and outs of running a genetics study—everything from makes the body tick. enrolling patients to using the novel technologies of the 1990s to Under the tutelage of E.P. Richardson, whom Engle calls zero in on the genetic mistake causing a disorder. “one of the great fathers of neuropathology,” she learned her way “The time that we worked together was marked by a very steep around a pathology lab. She spent her days looking at brains, cut- learning curve for Elizabeth,” says Beggs. “And she learned things ting them up, preparing samples, and looking at them under a much faster than anyone I’ve ever worked with.” two-headed microscope with Richardson. She grew to know, and Only a few years later, in 1994, Engle’s search for the gene love, the intricacies of the brain. It’s an experience that few neu- causing CFEOM type 1 led her to the center of chromosome rologists get now, Engle says, since MRI technology has become 12—one of the 23 chromosome pairs in which every human cell the go-to way to understand neuroanat- omy and diagnose neurological diseases.

Family Studies Three years later, in the last year of her neurology residency, Engle was forging ahead with her plan to learn genetics by studying the toddler’s disorder, specifically called congenital fibrosis of the extraocu- lar muscles (CFEOM) type 1. For help, she approached Beggs—a colleague at Children’s Hospital studying muscular dystrophy with former HHMI investigator Louis Kunkel. “She literally walked up to me in the quad one day with this proposal,” says Beggs. “I was quite taken aback.” In muscular dystrophy, the eye muscles are spared from the progressive muscle weakening that affects the rest of the body. So Engle presented her idea to study CFEOM type 1 to Beggs and Kunkel as a project that could answer some of their questions about the uniqueness of the eye muscles. They agreed to take her on. Engle and Beggs drove to the toddler’s home in New Hampshire and spent an afternoon sitting in the family’s kitchen meeting relatives affected by the disorder. Engle collected blood samples, Beggs labeled the tubes, and they both observed the signs of CFEOM. They would do elizabeth engle waited in study participants’ driveways until midnight this many more times over the next three to enroll them in her genetics studies of eye disorders. she didn’t years. As she’d hoped to do, Engle learned want to miss any opportunity to get closer to a culprit gene.

February 2o11 | hhmi bulletin 21 “We did what I felt would be most exciting and meaningful in the long haul. Just follow the trail wherever it leads us.” elizabeth engle

packages its genetic information. Frustratingly, at that time the just the right time and was a key player in the lab’s evolution over centers of chromosomes were notoriously hard to decode, packed the next seven years, bringing his own expertise in developmental with repetitive strings of DNA. But the Human Genome Project neuroscience to the then largely genetically oriented lab. He led was under way, and Engle knew it wouldn’t be long until other the effort to study the latest set of gene mutations that the Engle scientists published a complete genetic map of chromosome 12. lab had discovered—work that drew the lab into studying the role So she made a calculated move: she stepped back to wait for the of microtubules in nervous system development. map of the chromosome before finishing her gene hunt. Tischfield, now a postdoctoral fellow in the lab of HHMI Her lab spent the next several years building up what Engle investigator Jeremy Nathans at Hopkins, says, “I’m very proud of calls their “treasure chest” of rare eye disorders—finding fami- where Elizabeth’s lab is today. When I joined, the lab was very lies, defining their disorder, and then determining which ones much clinicians, trying to classify these diseases. Now, there are fell into groups. “I admit I am a tenacious individual,” says Engle. experimental neuroscientists, cell biologists, geneticists. That was “I would travel all over the country finding families. I would wait the natural transition that the lab was headed for, and I’m very in someone’s driveway until midnight when they got home so glad I got to be there for that.” I could enroll them in our study, because maybe they’d be the person that would get us that much closer to a gene.” Correcting Genetic Mistakes By 2003, Engle had pinpointed the mutations that cause Neurons are born amidst a concoction of chemical signals in a CFEOM type 1, as well as CFEOM type 2, which she’d discov- developing embryo’s brain. Each cell’s location in the brain is ered in families in the Middle East. Both mutated genes suggested genetically programmed. Moreover, each neuron must stretch that the root cause of CFEOM disorders was in the development its long axon out to a specific location in the body—be it a big of neurons, not in the stiffening of the eye muscles (as was previ- toe, a liver, or an eye muscle. To get there, each neuron follows ously thought and suggested by the “fibrosis” in CFEOM). Engle chemical road signs, which interact with unique sets of surface was intrigued by exactly how the genetic mutations caused the proteins on each axon’s tip. For the axon to lengthen, stiff struc- developmental problems. But she knew little about this area tural filaments—called microtubules—arrange themselves in the of biology. right direction inside the neuron. Microtubules also become the Her lab had the choice of continuing to identify genetic highways that carry materials and messages between the axon and causes of eye disorders, and then pass the genes along to other the neuron’s control center, back in the brain. groups to study, or delving into the molecular details of the dis- Engle’s lab has discovered that when it comes to the neurons orders themselves. She chose the harder path, heading straight to that lead to the eye muscles, mistakes at any step of this process developmental biology textbooks. “We did what I felt would be can lead to disorders. Some disorders are caused by a mutation most exciting and meaningful in the long haul,” Engle says, “just in genes that give these neurons their identities. Others develop follow the trail wherever it leads us.” from mistakes in the proteins on the tips of axons. In these cases, That same year a graduate student in neurobiology approached the axons may veer off in the wrong direction and never reach the Engle, interested in working in her lab. Max Tischfield arrived at eye. Microtubules that don’t form properly cause another set of

22 hhmi bulletin | February 2o11 disorders, and malfunctioning molecular motors that carry cargo “A lot of people didn’t think it was a good idea for her to study along the microtubules cause yet another, thwarting the relay of such rare disorders,” Hunter says about Engle. “It’s just a testa- messages from the brain (see Web extra). Engle’s team has linked ment to her persistence that it didn’t matter to her what people mutations to seven complex eye movement disorders, including said. It wasn’t about trying to make a big discovery, it was about CFEOM types 1, 2, and 3; horizontal gaze palsy; and Duane’s trying to help these patients.” retraction syndrome. But bringing the science back to the patients is especially “Wiring the brain to the periphery requires remarkable and tricky in the case of CFEOM, Engle is the first to admit. “Trans- complex genetic programs,” Engle says, “and as you might imag- lating genetic research back to the patient is often challenging,” ine, these developmental programs can go wrong.” Humans she says, “but for these complex eye movement disorders it is likely have variability in the exact projections of their axons to particularly so. These neurons are born and extend their axons muscles, she hypothesizes, but in most cases, these errors prob- at around 4 to 6 weeks of human gestation; the developmental ably go undetected. “A crooked smile is viewed as charming. errors occur before a woman may know she’s pregnant.” A small error in wiring to the huge quadriceps muscle may make Engle and Hunter’s clinic offers diagnostics and genetic coun- you less of an athlete, but wouldn’t be very noticeable.” seling for those more severely affected who want to prevent the But eye movements must be precisely controlled. Your left and disorder in their children. But scientists aren’t yet at the point right eye must point in the same direction, focus on the same where they can interfere with early developmental processes in object, and move at the same time for ideal vision. We use our the brain once the disorder is inherited. eyes to communicate, express feelings, and explore our world. There are still plenty of questions about CFEOM and other Complex eye movement disorders turn out to be sensitive indica- complex eye movement disorders that Engle hopes to answer. tors of wiring gone wrong. She is using her findings thus far as a springboard to jump off in new directions, enabled in part by HHMI funding which began Back to the Patients in 2008. Many of the genes that are mutated in these disorders Since 2008, Engle’s been running a monthly clinic with David are in every neuron in the brain, and in some cases, other organs Hunter, chief of ophthalmology at Children’s Hospital and vice as well. So why aren’t other parts of the brain and body affected? chair of ophthalmology at Harvard. Hunter is a specialist in What makes these neurons vulnerable to some disorders and ­surgeries that, in some cases, can correct complex eye movement spared in others? And though Engle has identified the gist of how disorders. Patients come from around the world, and the two some of the mutated genes cause a disorder, there are still molec- ­doctors pair up to consult with them—taking on only a couple ular caveats to work out. With a powerful new microscope that of patients in an afternoon so they have ample time to explore can zoom down to single molecules, for example, she’s hoping every aspect of each case. Using the genetic information that to understand the effect that microtubule mutations have in the Engle has uncovered gives Hunter a better idea of what symp- neurons leading to the eye. Is the microtubule too stiff or not stiff toms to ask the patients about and what to expect when he goes enough? Does cargo fall off the microtubules as it tries to move into surgery. along? Does it stall in place? Where these questions will lead her Cases of the disorders vary greatly in severity. Some disorders next is anyone’s guess. affect both eyes and are often accompanied by other develop- Engle is incredibly devoted to her work and very intense—in mental disabilities; others rarely affect anything more than one a good way—says Beggs, and if anyone can answer these ques- eye. Some cause drastic paralysis of particular eye muscles, while tions, she can. ­others can be corrected with glasses or patches. “If reviewers of one of her papers come back and request some “We’re at the stage now where we see these patients knowing additional work that will take six months, a lot of authors might what the mutation is, and so when I do surgery I at least know just try submitting it to another journal,” says Beggs. “But she’ll that going in,” says Hunter. He can often tweak the placement of start whole new collaborations and learn new methods to address an eye muscle so that the eye’s default position is forward, rather one of these questions. She’s so precise in doing the best science than a fixed gaze downward or to the side. that she can.” W

February 2o11 | hhmi bulletin 23

Stringing molecules on threads of DNA gives a new view of their interactions.

by Sarah C.P. Williams · illustration by Laura Carlin

February 2o11 | hhmi bulletin 25 ric Greene smashes involved ­essentially dumping proteins ful one. Now, his lab uses electron-beam molecules together. He precisely arranges into a vat of DNA and watching one at a lithography, a technology developed for proteins on strands of DNA and sends one time—became frustrating. manufacturing electronic circuits, to zipping toward another, headed for an “I’d spend hours doing tedious manipu- make precisely controlled barriers on the impact. Sometimes, a weaker molecule lations,” says Greene, “and at the end of glass that can be used to define the orga- falls off the DNA immediately. Other the day have only one or two data points. nization of thousands of DNA molecules. times, in a feat of acrobatics, one protein This really limited what we could do. It hurdles another. Recently, Greene saw a often took weeks or months just to figure Crash Test Dummies protein push another one backward when out if an experiment was even working.” In principle, the technique behind DNA the two collided. Moreover, in many instances the proteins curtains can be used to study any kind of How proteins behave in such a crash test would stick to the microscope slide, and linear molecule. A scientist could tether gives scientists data about their structural this nonspecific sticking was a huge prob- RNA, or long filaments that act as cellular integrity, how they attach to DNA, and how lem in the field. Greene struggled to find a highways, to the lipids. But Greene’s pas- they behave in a cell—where molecular surface that worked for all his experiments. sion is understanding how proteins interact fender-benders are likely a commonplace By the time he started his own lab at with DNA. “These relatively simple interac- occurrence in the jam-packed nucleus. Columbia, Greene had a plan. He realized tions can drive what an organism looks like, Greene, an HHMI early career scien- that one surface was natural to all proteins: what an organism does, or how it evolves,” tist at Columbia University, is doing these the lipid bilayer, which surrounds every says Greene. “It’s always fascinated me.” kinds of experiments on an entirely new living cell. Greene figured that a bilayer Some of the most important protein scale. Rather than looking at the behavior would provide an inert environment to pre- complexes on DNA are the nucleosomes, of just one molecule at a time, he lines vent proteins from sticking to a glass slide the packaging units that consist of DNA up hundreds of DNA strands and watches and also a way to tether DNA in place. wrapped tightly around a protein core. hundreds or thousands of proteins as they The crux of his method lies in the Once Greene established that his cur- interact with the DNA. The aligned mol- ability to corral lipids into separate areas tains worked, he wanted to know whether ecules of DNA with bright dots of fluores- of a glass slide. He scratches miniscule they would still work for DNA wrapped cent protein look like glittering, beaded lines into the glass, which keep lipids in around nucleosomes. curtains—leading Greene to dub them separate areas—they can’t move across the Greene and his team added nucleo- “DNA curtains.” But these flashing cur- blemishes. He then encloses special lipids, somes to DNA before lining up the tains provide more than stunning images. tagged with a molecule called ­biotin, in strands. When the strands were aligned, They give researchers powerful insights one linear area. Unmarked lipids cover the scientists saw that nucleosomes are into how DNA-bound proteins interact the rest of the glass slide. Specially engi- static once they’ve attached to DNA. with the DNA and with each other. neered strings of DNA attach only to Moreover, by recording the positions of the biotin-marked lipids, so the ends of thousands of nucleosomes at one time, Corralling Lipids the DNA are arranged in a line. Finally, Greene’s lab had a powerful case for As a postdoc at the National Institutes of Greene turns on a flow of liquid across understanding where on DNA nucleo- Health in the late 1990s, Greene learned the surface, sweeping all the strands in somes attach. The results appeared in the how to watch the dynamics of DNA- the same direction, forming a curtain of October 2009 issue of Nature Structural bound proteins under the microscope. aligned DNA. & Molecular Biology. The experiment was The ability to see the physical wrangling The first time Greene tried this tech- the first proof of concept that the tech- at such a small scale fascinated him. But nique, he used a razor blade to scratch the nique worked on DNA associated with limitations of the technique—which glass—a rudimentary trial, but a success- nucleosomes, says Greene.

26 hhmi bulletin | February 2o11 For Greene, the next natural question By following the proteins along thou- exceedingly difficult if the experiments was what happens when proteins moving sands of DNA strands, Greene and his had to be done by looking at one mol- along the DNA run into nucleosomes. To colleagues found that the two behave ecule at a time, says Greene. You would study proteins that move randomly along differently when they encounter nucleo- never know if what you were seeing on any DNA, Greene adjusted his DNA curtains somes. One hops off the DNA and given strand was the norm. to avoid having a constant flow. Instead, reattaches on the other side of the nucleo- Greene got back to collisions in his he attached not one but both ends of the some; the other protein stops, unable to most recent work, published online DNA to the glass slide. He added nucleo- continue. Inside a living cell, Greene’s November 24, 2010, in Nature. He sent somes first, and then two types of DNA team hypothesizes, another protein cou- a fast-moving molecular motor protein repair factors—which constantly peruse ples with the stalled protein to help it cross toward other stationary proteins bound DNA strands for mistakes. He tagged each the barrier. The work, published in the to the DNA. “This paper embodies all of type of protein complex with a different August 2010 issue of Nature Structural & the excitement I felt when I was a gradu- fluorescent color. Molecular Biology, would have been ate student first thinking about these problems,” says Greene. “In essence, this boils down to a very simple question: what happens when one protein rams into another? These types of collisions happen all of the time in our cells, but we have a very limited understanding of how they are resolved.” His lab chose a protein called RecBCD, which processes the ends of broken DNA strands in bacteria and can travel at 1,500 base pairs per second. The lab then picked four different proteins as potential roadblocks. When RecBCD encountered the first of the four—one of the tightest known DNA binding proteins—RecBCD rammed into the ­stationary protein and pushed it thousands of base pairs before finally kicking it off the DNA altogether. “It’s like running a car into a flower,” says Greene. “The car feels nothing and keeps going, while the flower takes the brunt of the punishment.” After this remarkable show of strength, it wasn’t sur- prising that RecBCD did similar damage to the other three proteins that Greene’s lab put in its way.

Power in Numbers Greene is not the only one who sees the power of his new technique. HHMI investigator Michael O’Donnell at the Rockefeller University studies DNA rep- einberg W Eric Greene found a way to ask what happens when one protein rams into another. lication—the process by which proteins “These types of collisions happen all the time in our cells,” he says. “But we have a copy DNA strands. He wanted to know

Elizabeth very limited understanding of how they are resolved.” (continued on page 48)

February 2o11 | hhmi bulletin 27 by Brian Vastag illustration by The Heads of State HOPE FLO ATS With a new arsenal of robust models of ALS, drug development may move to the fast track.

28 hhmi bulletin | February 2o11

HHMI investigator Nancy Bonini’s sprawling laboratory at the University of Pennsylvania is filled with fruit flies. But they’re not swarming. They’re sequestered in glass tubes tion, while both Horwich and HHMI investigator Hugo Bellen at ­stoppered with cotton. Endless boxes of the white-tufted tubes Baylor College of Medicine have bred colonies of mutant mice crowd the benches and stack high on the shelves, overflowing that reliably develop ALS. Meanwhile, at the Harvard Stem Cell onto the floor. Institute, HHMI early career scientist Kevin Eggan is incubat- Postdoctoral fellow Hyung-Jun Kim taps the bottoms of two ing dishes of human motor neurons grown from the skin cells tubes on a lab counter, agitating the roughly two dozen flies of patients with the disease. Never before have researchers had in each. In one tube, flies zip around and scale the glass, some access to human motor neurons in the laboratory, let alone nerve nearly reaching the top. In the other, the flies are sluggish. Most cells harboring the disease. crawl on the bottom; a few make feeble attempts to climb but During the past 5 to 10 years, there has “almost been a renais- don’t get far. “They don’t look as happy,” remarks Bonini. sance in model organism genetics, applying them to human The source of the stark contrast in energy and climbing ability brain diseases,” says Bonini. “It’s been really exciting.” is surprising: a human gene that is involved in amyotrophic lat- eral sclerosis (ALS), known as Lou Gehrig’s disease. The sluggish Sorely Needed Methods flies carry the gene and an abundance of the protein it produces, Collectively, these new weapons in the fight against ALS while the sprightly flies do not. provide a huge leap in scientists’ ability to divine the genetic Fruit flies have been a favorite of developmental biologists and ­molecular origins of the disease, says Amelie Gubitz, pro- since the 1970s, with their rapid reproduction and easily manipu- gram director for neurodegeneration at the National Institute of lated genome. In 1998, however, Bonini authored an idea that ­Neurological Disorders and Stroke (NINDS). The menagerie radically extended the scientific reach of the humble insect. She of ALS animal models should also speed the development of mused that inserting genes related to human brain diseases might drugs, she says. yield critical insights into poorly understood neurodegenerative In the past 15 years or so, patients and their families have conditions, including Huntington’s disease, Parkinson’s disease, experienced disappointment after disappointment as two dozen and ALS. “I saw it as, ‘Hey, there are all these terrible diseases and initially promising ALS drugs ultimately failed to help patients. nobody is really studying them in model organisms,’” Bonini says. Most recently, in 2009, a NINDS safety board halted a large trial “I knew it was a high-risk thing.” of the brain drug lithium after determining it provided no benefit That risk is paying off. In August, Bonini and colleagues to patients. Though there could be many reasons why the trials announced in Nature a genetic factor that contributes to ALS failed, says Gubitz, one possibility is that the drugs were tested in some patients. Bonini collaborated with Aaron Gitler, a Penn in animal models that did not faithfully reproduce the disease. ­colleague who studies ALS genetics in yeast. Both are keen to That’s why there is now “a big push to integrate the new animal define additional genes involved in ALS. Says Gitler: “My hope models into the drug discovery pipeline.” is that in the next three to five years we find all of the genetic Gubitz is also pushing ALS researchers to collaborate more contributors to ALS.” closely and to identify the strengths and weaknesses of each ani- Bonini and Gitler’s powerful fly and yeast tools are proving mal model. To that end, at the Society for Neuroscience meeting themselves just as other advanced animal models to study the in November, Gubitz and Lucie Bruijn, of the ALS Association, disease are coming online. At Yale Medical School, HHMI inves- gathered 125 scientists working with ALS animal models for an tigator Arthur Horwich has developed Caenorhabditis elegans idea exchange. “We’re trying to figure out which models should roundworms as a model organism for studying nerve degenera- be made more broadly available,” she says.

30 hhmi bulletin | February 2o11 Bonini: Nick Antony Horowich: Chris Jones Bellen: Misty Keasler Eggan: New York Stem Cell Foundation shutting down thelungs.In othercases,thefaceisaffectedfirst. legs goes first, and then paralysis marches upward, eventually the disease andcansurvivefordecades.)Often,controlofthe cosmologist StephenHawking, haveaslowly progressingform of more thanfiveyears.(About 10 percentofpatients,including diagnosed betweentheagesof40and70,theyrarelysurvive control movement, degenerate and die. Patients are typically disease inchildren—hasbeenmaddeningly slow. as spinalmuscular atrophy, which,initsseverestform,isafatal of ALSand related motorneurondiseases—such ing the causes the from muscle to shriveled nerve spasticity fibers in and wastage the mid-19th century, whenFrench physicians linkeddeaths remains afrustrating,deadly mystery. It was first describedin On agrosslevel,motorneurons,thelongnervecellsthat New methodstostudyALSaresorelyneeded,asthedisease ­ s pinal column. In the time since, progress on understand - for studying A studying for models new are contributing scientists HHMI Eggan. These and Kevin Hugo Bellen, Horwich, Bonini, Nancy Arthur left: top from Clockwise called in families. By 1993,theteam and others,including HHMI,identifiedaformofALSthatruns approach launchedthisyearin twophase1trials,researchers abandoned afterfailinginlarge studies. Inonenewtreatment A handfulofotherdrugsarein clinical trials, butmanymorelie is approvedtotreatALS,andit extends lifebyonlyafewmonths. Just onedrug,riluzole(marketedunderthebrandnameRilutek), scratching their headsastothecauseofvastmajoritycases. to becausedbytheinheritedSO only a small proportion of ALS cases—perhaps 2 percent—appear it affects about2in100,000peopleworldwide. their bodies wither. “It’sdisease,” a devastating saysBonini, and The diseaseas leavestheintellect andemotionsofpatientsintact The searchfortreatmentshasbeennearlyfruitless,aswell. In 1991,aninternationalteamfunded SO D L as responsible for some of these inherited cases. But 1 asresponsibleforsomeoftheseinheritedcases.But S a nd testing new treatments. new testing nd had pinpointed mutationsinagene D mutations, leaving researchers 1 mutations,leavingresearchers February 2o11 by theALSAssociation

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bulletin 31 implant nerve or bone marrow stem cells into the spinal columns hit—the yeast homologue of a gene previously implicated in sev- of ALS patients. The hope is that the stem cells will pump out eral human neurodegenerative conditions, ataxin-2. protective growth factors that rescue or rebuild dying motor neu- When Bonini added ataxin-2 to her TDP-43 flies, they rons, says the leader of one of the trials, Clive Svendsen, director became even sicker; the gene clearly enhanced the toxic effects of the Regenerative Medicine Institute at Cedars-Sinai Medical of TDP-43. “That was a ‘Whoa’ moment,” says Bonini. “So we Center in Los Angeles. But it will be years before researchers just went after ataxin-2.” know whether stem cell therapy helps ALS patients. The pair enlisted the help of clinicians who treat ALS, test- ing samples from 900 patients and 900 controls for variations in Fingering Protein Clumps ataxin-2. What they found was remarkable: Some 5 percent of “Oh, that’s disturbing,” Bonini proclaims. She’s watching a big- patients carried an altered version, whereas just 1.4 percent screen monitor that displays microscope images of motor neurons of controls did, as they reported in Nature. “It’s a risk factor for autopsied from an ALS patient. Gitler, operating the microscope, ALS,” says Bonini. points to the ugly brown smear that caused Bonini’s reaction. It’s The discovery also hints at a common mechanism of neuro- a large clump of protein and it’s not where it belongs. nal damage caused by interactions between ataxin-2 and TDP-43 In healthy motor neurons, this protein, TDP-43, accumulates proteins. Previously, a long form of ataxin-2 had been implicated only in the nucleus, where it’s required for normal processing of in a nerve disease called spinocerebellar ataxia type 2 (SCA-2). RNA. But in the motor neurons of ALS patients, TDP-43 some- That disease, like ALS, also features clumps of TDP-43 protein how escapes the nucleus and clumps in the cell body. “It’s like in certain neurons. The 5 percent of ALS patients with abnormal a skein of yarn coming out of the nucleus,” Gitler says. “It’s just ataxin-2, in contrast, carry a medium-long version of the gene. really striking. It’s a dense aggregate.” “It may be that interactions between these proteins are under­ In 2006, Penn Medicine neuroscientist Virginia Lee and lying different presentations of neurodegenerative disease, but colleagues reported finding clumps of TDP-43 in the motor the same pathway is involved,” says Bonini. “There might be a neurons of ALS patients and in other nerve cells in patients continuum of damage caused by different versions of ataxin-2.” with frontotemporal dementia, a condition that can cause sud- In a relatively short time, the pair has inched closer to den and baffling deviant behavior. The telltale clumps have also understanding the causes of ALS. And even if they never been found in athletes—including former professional football fully understand what triggers the disease—a fear that Bonini players—who later in life developed ALS-like disease and died. expressed—their yeast and fly systems can help identify poten- Subsequently, various research groups reported mutations in the tial treatments. Already, they have identified several genes TDP-43 gene (also called TARDBP) in families in which mul- that appear to slow the toxic effects of TDP-43 and ataxin-2. tiple members had ALS. If ­confirmed,these protective genes could inspire drug develop- The discovery attracted Bonini’s attention. “TDP-43 is proba- ment, Bonini says. bly a big player in different types of neurodegeneration,” she says. In the laboratory of Arthur Horwich, mice engineered to carry “Everyone is trying to figure out how it hurts neurons.” the human SOD1 gene linked to hereditary ALS serve as sub- Around the same time as the TDP-43 discovery, Gitler arrived jects for drug testing. To generate ALS-like symptoms quickly at Penn and set up a system to rapidly screen the effects of thou- in the animals, Horwich revved up expression of the SOD1 sands of genes on yeast growth. When he spliced human TDP-43 protein. “In mice you might need 50 to 100 times the concentra- into yeast, sure enough, clumps formed and the cells died early. tion of [SOD1],” he says. “Then you get roughly the same level Likewise, Bonini added human TDP-43 to her fruit flies, and the of toxicity you see accreted in humans over many decades.” He insects weakened, unable to move and climb normally. Those adds, “Of all the neurological diseases, ALS is really the most findings proved that yeast and fruit flies could serve as models accurately recapitulated in mice. We’re beginning to see what of the deleterious effects of TDP-43 aggregation, an important the toxic effects are at the level of the neuron. We’re trying to confirmation. Bonini and Gitler hoped they could use the com- connect the dots.” bined input of yeast and flies to address genes important for One connection has become clear: in all types of ALS, whether TDP-43 toxicity. linked to SOD1 or TDP-43, clumps of protein aggregate where Gitler amped up a high-throughput genetic screening system, they shouldn’t in motor neurons. In 2009, Horwich published testing in TDP-43 yeast thousands of genes to see which, if any, two papers showing that worms or mice carrying mutant human accelerated or slowed cell death. They soon got an intriguing SOD1 produce aggregates in neurons similar to what ALS patients

32 hhmi bulletin | February 2o11 “The field is making progress,” Hugo Bellen says. “Every year we make strides toward better understanding. But it’s been a very tough nut to crack.” produce. Intriguingly, SOD1 mice show that motor neurons can, motor neurons early in his career, as they’re fundamentally differ- for a time, successfully clear the aggregates. But eventually, the ent from the 10,000 other types of neurons. Motor neurons send cells’ ability to disperse the clusters wears down and the nerves long axons—up to three feet long—outside the spinal sheathing become dysfunctional. Horwich hopes some of the wide range of to every muscle in the body. “They’re the sole means of communi- drugs he’s testing on mice and worms rev up the cells’ ability to cation between the central nervous system and the body,” he says. clear the clumps. “If we can do that, the downstream toxicity is “So in this feature they are distinct from all other CNS neurons.” prevented and the animals walk away free,” he says. Working with chicken and mouse embryos, Jessell figured out Bellen at Baylor College of Medicine is also trying to connect the sequence of genetic switches that turn on and off in embry- the molecular dots in mice bred with ALS-causing SOD1 muta- onic nerve tissue to produce motor neurons. Building on that tions. Over the past decade, he’s focused on the junction between work, a postdoctoral fellow in Jessell’s lab, Hynek Wichterle, motor neurons and muscle cells, studying a protein that may one discovered in 2002 that adding two small molecules to embry- day serve as an early warning sign of ALS. The protein, called onic stem cells coaxes them to generate motor neurons with high VAPB, directs proper development of the neuromuscular junc- ­efficiency. Wichterle and Jessell told Eggan about the advance tion, and it appears to be depleted in ALS patients and SOD1 over coffee, and the young Eggan—who was then deliberating mice, several other research groups have found. A critical seg- a career path—decided to work on motor neurons and ALS. ment of this protein also circulates in the blood and functions “Hynek’s work distilled 20 years of developmental biology into as a hormone, which makes it an ideal candidate for an early a simple and reproducible molecular recipe for making a motor ­detection blood test. Bellen is now supplying his ALS mice with neuron,” Eggan says. “These cells were not like motor neurons, extra VAPB to see if the protein slows or reverses symptoms—a they really were motor neurons. They were electrophysiologically small, early step toward developing the protein as a drug. active; they made synapses with other cells.” Though progress identifying the causes of ALS has been slow After Eggan landed a faculty position at Harvard, he and his and piecemeal, researchers are inching closer to a unified theory colleagues had some early successes in making human motor of the molecular mechanisms of the disease. “The field is making neurons, but the difficulty in obtaining a sufficient supply of progress,” Bellen says. “Every year we make strides toward better human embryos slowed the work. Then in 2006, while attend- understanding. But it’s been a very tough nut to crack.” ing a stem cell conference in Whistler, British Columbia, Eggan heard about a second advance that would prove crucial to push- Making Motor Neurons ing the work forward. Shinya Yamanaka of Kyoto University told Perhaps the newest means to study ALS will finally provide the attendees that he had reprogrammed ordinary skin cells to act like scientific nutcracker researchers have long been searching for: embryonic stem cells. Yamanaka called the new cells induced dishes of human motor neurons grown from ALS patients. Until pluripotent stem (iPS) cells. “I was sitting in the back row and now, “never have we ever, ever been able to isolate a single motor this wave of realization washed over me,” Eggan says. He visual- neuron from a [nonfetal] source that could survive,” says Kevin ized a path to an unlimited supply of motor neurons carrying all Eggan. He has perfected the molecular recipe for making the the genetic mutations found in ALS patients. Step 1: Obtain skin cells, a recipe that promises a nearly unlimited supply of motor cells from patients. Step 2: Reprogram those cells into iPS cells. neurons that can be used for basic physiological studies of the Step 3: Apply Wichterle’s recipe to grow those embryonic-like cells and for screens of potential new drugs. cells into motor neurons. The recipe builds on two decades of work centered in the lab- Now, after collecting skin cells from several dozen ALS oratory of developmental biologist and HHMI investigator Tom patients and transforming them, Eggan is confident that the Jessell of Columbia University. Jessell became fascinated with (continued on page 48)

February 2o11 | hhmi bulletin 33 perspectives & o pinions

Evan Eichler Crucibles of Dynamism Scott Areman

34 hhmi bulletin | February 2o11 Puzzling pockets of redundancy account for about 5 percent of the human genome. HHMI investigator Evan Eichler found a way to interpret what is happening in these areas of genetic repetition. The University of Washington researcher’s discovery holds promise for our understanding of evolution and neurocognitive disease.

We’re accustomed to thinking of evolution moving forward one heart of most regions of dynamic genetic change. From their base pair at a time: A single nucleotide is replaced in the ribbon new roost, the duplicons gathered additional flanking regions, of our DNA and a gene is gradually transformed from one func- and again continued their march along the chromosome, tion to another, or a disease emerges as the gene’s function is ­creating complex regions of duplications within duplications perturbed by these small stepwise changes. But there is another, at many new locations. parallel story unfolding within our genes, which, until recently, This architecture can create problems. Any time you have no one was able to easily read. To all appearances, it’s a more identical sequences, it’s easier to trick DNA’s recombination dramatic tale, with big events and rapid cataclysmic change. machinery. These repeating segments and the regions that If the single-nucleotide substitution view of genetic advances flank them are susceptible to unequal crossing-over events. relates a drawing room drama of our evolution, the story my lab That is, chromosome pairs, no longer perfectly aligned, is uncovering is more like an action-adventure movie with mul- swap genetic material unequally during meiosis, leading to tiple car crashes. We think it is in this part of the story where big changes when sperm and egg form. Some of the most profound changes took place in our evolution. The regions we common genetic causes of epilepsy and autism are due to examine also appear to be a source of vulnerability to cogni- rearrangements in these duplicated genes. tive disease, where big genetic errors can lead to intellectual When we looked more closely into these regions, we saw disability, autism, and schizophrenia, among other disorders. an incredible amount of variation between individuals and Although it was long apparent that duplication reigned some intriguing genes that have expanded in primate evo- in parts of our genome, there was no way to accurately ana- lution. Although we have been studying these regions for lyze these repeating elements. Our assays were based on 15 years, the extent of genetic variation still surprises me. hybridization, which relied on nucleotide probes to suss out Of course, the big challenge now is to sort out just what complementary sequences, and such probes could not dis- this means, to link this more complex variability to pheno- tinguish among identical regions. We could not count the type—that is, any observable traits. Early data suggest that the multiple copies of genes accurately, and we could not relate genes within the core duplicons are expressed preferentially genetic changes to function. in neurons, particularly at sites of new nerve growth. We Using next-generation genetic sequencing and a new com- know that the large-scale copy number variation can explain putational algorithm, my lab can now read about 70 percent about 17 percent of the cognitive disability among children of the chaotic chromosomal regions. The emerging picture we study from University of Washington Autism Center and is of regions that are crucibles of dynamism, where lots of other clinics around the world. change happens quickly, both adaptive and deleterious. One has to wonder why this kind of structural vulnerability It appears that in the early common ancestor of humans hasn’t been selected against over the generations. The persis- and the great apes, certain genetic segments began ­hopping tence of this genomic architecture suggests that these regions around the genome, inserting a duplicated version of them- also confer important evolutionary benefit. I believe there’s a selves at new locations. This pattern is rarely seen in other balancing act at play, especially considering the point in our mammals. While mice, cows, and dog genomes carry evolutionary history when the burst of duplications occurred. repeated genes, the repeats tend to follow one after the other. The circumstantial data argue for something fundamen- But our analysis of duplication in the genomes of macaque, tal that we’re missing about evolution and disease—that this orangutan, chimp, and human, published in Nature in 2005 structural variability contributes to what distinguishes us from and 2009, showed that in the early common ancestor, repeats other primates. Is that the whole story of how we evolved? may be more than a million bases apart. Absolutely not. But it is an important part that I think has When these hopscotching genes relocated—and we don’t been overlooked. Over the next couple of years, we’ll either actually know how or why—they picked up whatever genetic prove or disprove that hypothesis. code sat beside them, and then duplicated it and themselves somewhere else along the genome. We call these hopscotch- Interview by Jenni Laidman. Evan Eichler is a professor of ing genes “core duplicons” because they seem to be at the genome sciences at the University of Washington.

February 2o11 | hhmi bulletin 35 Q & A Tell us something a postdoc said or did during an interview that made you sure he/she wasn’t right for your lab. One of this issue’s feature articles explores the secrets of hiring good postdoctoral fellows, calling them “the backbone of a lab.” But not every postdoc who applies for a spot is a good fit, and the interview process is key to finding the best match for a given lab. Here, four scientists share moments when they knew a potential postdoc wouldn’t work out.

— EDITED BY Sarah C.P. Williams

Leslie B. Vosshall Leonard I. Zon Bradley Cairns Lily Jan HHMI Investigator HHMI Investigator HHMI Investigator HHMI Investigator The Rockefeller University Children’s Hospital Boston University of Utah University of California, School of Medicine San Francisco “I prescreen my postdoc “I interviewed a postdoc applicants with a written­ candidate from France. “My lab utilizes genomics “One potential postdoc questionnaire before He seemed pretty well to study transcription and appeared to pay more they set foot here for an qualified and was nice. chromatin, and statisticians attention to whether interview. I ask potential At the end of the interview, are becoming very valuable studies—both his and postdocs what kind of proj- the postdoc said he had one for the analysis of genom- ours—were published ect they would like to work other request: “In France, ics data. One postdoc we in high-profile journals on, among other questions. we go on vacation in the interviewed last year had than to the content of the If the answer shows a fairly summer. I must request been working on statistics studies themselves. This standard approach to prob- 5 weeks of vacation per involved in air pollution left us unsure that this lems and lacks creativity year, and that all of those and traffic patterns and had very accomplished young or a sense of excitement, weeks are to be taken in done very good statistical scientist was right for our I pass on the candidate. If August–September.” I must work. When he arrived for lab—though it’s always the person comes up with say that I was taken aback his interview, however, he difficult to gauge based on projects that are in progress and couldn’t hire him.” assumed we had read all of brief interactions. On the in the lab (but not generally his and his mentor’s papers, other hand, our experience publicized, meaning they yet he had not read a single has been very good with have guessed what we are paper of ours. When chal- postdocs who came without doing), or comes up with lenged on this, he said he flashy publications and new interesting ideas, I will was confident he could interviewed well.” eonard Zon Cairns: Paul Fetters Jan: Fred Mertz Fred Jan: Fetters eonard Zon Cairns: Paul

definitely consider inviting master all the literature L them for an interview.” on vertebrate development, epigenetics, and transcrip- tion in a month, two at the most. To justify, he said that statisticians (himself in par- ticular) were much smarter , ©HHMI Zon: Courtesy of than molecular biologists. We are still laughing about that interview.” osshall: Allan Zepeda / AP V

36 hhmi bulletin | February 2o11 chronicle

38 scieNCE EDUCATION Road Warrior

40I NSTITUTE N EWS 2010 Holiday Lectures on Science—Viral Outbreak: The Science of Emerging Disease / SEA Reaches New Shores / HHMI Launches International Competition for Early Career Scientists

42 laB B OOK Forgetting Fear / Releasing the Brakes on Cell Fate / Warming Malaria

45 ask A SCIENTIST How do internal stresses cause the external appearance of humans to change with things such as wrinkles? Can appearance predict general health?

46 NOTA B ENE National Medal of Science Goes to Lindquist and Benkovic / Six HHMI Researchers Elected to Institute of Medicine

Jay Groves turned his physical chemistry expertise on a biological question: does organization in a cell affect function? To find the answer, he creates gridded membranes, introduces proteins, and watches them behave as he adds blocks and hurdles. The results he’s getting from his experiments— an example is depicted in these images—suggest just how important spatial organization of molecules inside cells is to human health, with ­implications for the immune system and cancers. Read about his work in the online article “Enforcing Order,” at www.hhmi.org/bulletin/feb2011. roves lab G

February 2o11 | hhmi bulletin 37 38 hhmi electric currenttoseparateDNA strandsinagelslabforanalysis. to doDNAelectrophoresis,asophisticated technique thatusesan Ohio. Hismission: teacharoomfullofhalf-interested teenshow Cuyahoga Valley CareerCenter, avocationalschoolinBrecksville, classes, andeverythinginbetween. InNovember,hevisitedthe students from special education groups, advanced placement day. Eachyear,heshareshisloveofscience withabout2,000 Darwin whenhebecameaU.S. citizen days beforehis40thbirth- borrow expensiveequipment. Ithaca, andrunsalending librarywherecash-strappedteacherscan conducts workshopsforscience teachersinCornell’s hometown of by anHHMIgrant,CIBTbringscollege-levellabstohighschools, of theCornellInstituteforBiologyTeachers (CIBT).Supported NewYorkto schoolsinupstate andbeyondasthemobiledivision moniker: roadwarrior. Hisappearancealsofitswithhisinformal looks likearockstar. T S Road Warrior a preading science education ll A primatologistfromSwitzerland,Yerky tookthemiddle name Yerky travelsin a minivan—packed with pipettes and gel rigs— , bulletin lon g-ha

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in Sheri Zakarowsky, ascience teacheratthecareercenterwho “If you’re betweensixandsevenmilliliters afteradding the “Yes, yes,youcan,” saysYerky, herthroughstepbystep. talking “I don’tthinkIcandothis,” saysagirlnamedDanielle, asshe M ike Y re ingoodshape,” heannounced atonepoint. “If erky ’ s DNA

VSA Partners Teachers in Ithaca Each year, Wilcyznski attends follow-up workshops in Ithaca to Zakarowsky met Yerky when she attended CIBT’s two-week work- stay sharp. In the classroom, “I like talking with the kids, but the shop last summer. Every year, 40 to 50 new teachers go through the interaction with my peers is on a different level.” program. Shorter workshops during the school year attract another Wilczynski teaches about 60 at-risk students. “They might not 50 or so. “It was grueling,” Zakarowsky says. In one lab, she and otherwise meet a scientist in their lives,” she says.” Having someone other teachers performed DNA analysis on insects to determine the like Yerky come in is really exciting for them. When they figure prevalence of parasitic bacteria. “But I learned a lot.” out the results of their lab—oh, my gosh, the joy! They’re running Yerky enjoys seeing the teachers come into their own during to tell the secretary what they’ve done. I’ve taught the accelerated their time away from the classroom. kids, but they’re more reserved. They’ve done a lot of involved “We usually get people who are not that secure in how they experiments already.” teach science, and they soak up stuff like sponges. They exchange Back in Zakarowsky’s class, the students finish running their gels. information and experiences. So you see them progress in their con- Yerky instructs them to come to the front of the room, one group at fidence level. ‘Oh, yeah, I can do that now!’” a time, to review their findings. “But first you have to disconnect and After a workshop, teachers can borrow from the CIBT lending unplug everything,” he instructs, with a wink. “We don’t want you to library—a real boon, considering equipment for the DNA lab, for leave with a free perm. Right?” example, can run about $10,000. Another popular high school lab is An all-female group of budding forensic scientists goes first. a protein gel kit for analyzing and comparing protein bands according They’ve made a few technical mistakes and the output is a “little to their molecular weights, then establishing evolutionary relatedness weak,” says Yerky, but strong enough to see some results. among different groups. There are kits designed specifically for elemen- One girl, Barbara, looks crestfallen. “I was disappointed about my tary teachers, too, like a “Bat Trunk” for learning nocturnal animals’ DNA—I got some, just not enough,” she says. “But I really liked the habits and habitats, with interactive learning games, videos, and plenty of cool stuff to pass around: desiccated bat wings and skin, and “We usually get people who are not that bat masks and puppets. Teachers can also secure in how they teach science, and they borrow microscopes and anatomic models. soak up stuff like sponges. They exchange Tips and Tricks information and experiences. So you see them School visits give Yerky follow-up time with progress in their confidence level. ‘Oh, yeah, teachers after they return to the classroom. “They can see me present the lab again and I can do that now!’ take notes on what I do, jot down little tips mike yerky and tricks that I point out that might not be ” in the written lab.” Carolyn Wilczynski, a science teacher at Binghamton High experiment. I understood everything. And I thought it was all interest- School’s Regents Academy for at-risk kids in New York, attended ing.” She wonders aloud whether she and her fellow group members her first CIBT summer workshop in 2000, as a rookie teacher. can divide up their gel and take a piece home as a memento. But her “It gave me a community of teachers that I could interact with all chemistry teacher, Brad Lambert, proudly says he first wants to show over the state,” she says. “And a support system at Cornell. I could it to the principal, “so he can see what we’re doing.” borrow equipment that wasn’t available at the high school and ask As Barbara leaves, she says goodbye. “Thank you for everything. questions.” She also learned more about cellular molecular biology. Wonderful lab.” “I had never used a pipettor before,” she says. “I had never run DNA “You’re welcome,” Yerky replies. “Maybe I’ll see you at Cornell gel electrophoresis in any of my college courses.” a couple years from now.” W –laura putre

February 2o11 | hhmi bulletin 39 40 hhmi using microarray data from JoeDeRisi’s lab. Bottom right:Students helpeachother identifymystery viruses insects. Bottom left: Eva Harristalks about herwork inNicaragua. shows aNodamura virus,acommon virusthat infects mammalsand Top left:Students learnaboutvirusthreats. Top JoeDeRisi right: detection andtreatment.Harrisshowed amusic videoproducedby scientists and clinicians inNicaragua andtheir effortstoimprove ley, toldstudentsaboutherexperiencestudyingdenguefeverwith Emerging Disease. webcast ofthelectureseries,ViralOutbreak:TheScience of Lectures onScience. Atleast3,000otherswatchedthelive and otherdeadlyvirusesonDecember 2–3atthe 2010 firsthand how scientists study the emergence and spread of these school studentsfromacross theWashington, D.C.,arealearned  that fellparrotsanddestroycolonies ofbees.Almost200high Vi Viral Outbreak:TheScienceofEmergingDisease 2010 Ho rus institute news Eva Harris,aprofessorattheUniversity ofCalifornia, Berke-

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­dengue feverandW storming tocreaterelatedlessonsasaresource forotherteachers. and Canadaattendedthelectures andspentthenextfewdaysbrain- spread ofmosquito-borne diseases suchas intheUnited States, withpublichealth experts whoworktocontrolthe lab, ortalk fromDeRisi’sfication, workinginsmallteamstoanalyzevirusdata sized virusmodelcreatedonathree-dimensional printerinhislab. types ofvirusesandgaveeachstudentabrightlycolored,racquetball- nology hedevelopedcalledVirochip.Healsodescribedthedifferent distinguishes newthreatsfromoldervirusesbyusingamicrochip tech- University of California, SanFrancisco. DeRisishowed themhow he unknown viruses from HHMI investigator Joseph L. DeRisi, of the mosquitoes, whichcarrythevirus. local musicians thathelpededucatethepubliconhow tocontrol In addition tothestudents,14teachersfromUnited States After thelectures,studentsgottotrytheir handsatvirusidenti- The students also learned how scientists identify previously est Nilevirus. W

Paul Fetters SEA Reaches New Shores HHMI’s Science Education Alliance announces new members.

HHMI has selected a diverse group of two parts. In the first part, students isolate 2011ience Sc Education Alliance members 12 colleges and universities to become part bacterial viruses, called phage, from local Brown University Providence, RI of its Science Education Alliance (SEA). soil samples, purify them, and extract their Carthage College Kenosha, WI The institutions will join 36 other schools DNA. In the second part, the students use College of St. Scholastica Duluth, MN Georgia Gwinnett College Lawrenceville, GA in offering a year-long course that gives bioinformatics techniques to analyze the Johns Hopkins University Baltimore, MD Montclair State University Montclair, NJ first-year students the opportunity to do phage’s genome. So far, almost 1,700 stu- Ohio State University Columbus, OH sophisticated, hands-on research. dents have participated in the NGRI course Ouachita Baptist University Arkadelphia, AR Southern Connecticut State University The 12 new alliance members include at 39 schools. During the first two years, New Haven, CT large research universities and small col- the students sequenced and annotated 37 University of Florida Gainesville, FL Washington State University Pullman, WA leges from urban centers and rural towns. phage and then deposited the data in the Xavier University of Louisiana Another 14 schools—including a consor- national GenBank database. Another 50 New Orleans, LA tium of four Maine colleges—will join are expected to be completed this year, ASSOCIATE MEMBERS SEA as associate members. Faculty from Jordan says. Del Mar College Corpus Christi, TX associate member schools, like those at “This experience makes excellent stu- Gettysburg College Gettysburg, PA full-member institutions, will attend train- dents that much more excited, and it makes Hampden-Sydney College Hampden-Sydney, WV Illinois Wesleyan University Bloomington, IL ing sessions to implement the phage course students who weren’t sure about their level Miami University Oxford, OH Morehouse College Atlanta, GA but have the option of offering students an of interest in the life sciences a lot more Oklahoma State University Stillwater, OK abbreviated version. Director Tuajuanda engaged,” says Sean B. Carroll, HHMI’s Providence College Providence, RI Smith College Northampton, MA Jordan is excited that the initiative will now vice president for science education. Southern Maine Community College reach students in 29 states and Puerto Rico. The new group will go through training South Portland, ME Trinity College Hartford, CT “The SEA tide continues to roll.” in the coming months and will offer the University of Maine Honors College The course, called the National Genom- NGRI course in classrooms beginning in Orono, ME University of Maine at Fort Kent, ME ics Research Initiative (NGRI), is taught in the fall of 2011. W University of Maine at Machias, ME

HHMI Launches International Competition for Early Career Scientists

HHMI opened an international competition in December successful, it could form the basis for a larger international endeavor. aimed at helping up to 35 early career scientists establish indepen- “HHMI’s investigators are deeply involved in the international dent research programs. Scientists trained in the United States who research community, and we want to make sure that community are now running a lab in any eligible country may apply. is as robust as possible,” says HHMI vice president and chief scien- “Science is an international endeavor,” says HHMI President tific officer Jack E. Dixon. Since 1991, HHMI has spent more than Robert Tjian, “and HHMI wants to help develop the next genera- $145 million to fund international scientists working in specific tion of scientific talent worldwide.” geographic areas, including Canada, Latin America, and Eastern HHMI has committed $24 million for the International Early Europe, or in a specific field of research, such as parasitology or Career Scientist Program. Each selected scientist will receive infectious disease. $650,000 over five years, with eligibility for a five-year extension of In a June survey of HHMI investigators and early career sci- the grant. The competition is open to scientists who have trained entists, 73 percent of those who responded reported international in the United States at the graduate, medical, or postdoctoral level; collaborations and 62 percent said they have international postdoc- have run their own labs for fewer than seven years; and work on bio- toral students in their laboratories. medical research in a university or nonprofit research institution in The competition is open until February 23, 2011. Interested one of 18 eligible countries: Argentina, Brazil, Chile, China, Czech scientists can submit their applications on HHMI’s website, Republic, Egypt, Hungary, India, Italy, Mexico, Poland, Portugal, www.hhmi.org/research/application/iecs2011. Panels of distin- Russia, South Africa, South Korea, Spain, Taiwan, and Turkey. guished biomedical researchers will evaluate the applications; The program will complement HHMI’s 2008 initiative sup- finalists will be invited to give a presentation on their work at porting 50 early career scientists in the United States. Early career HHMI’s Janelia Farm Research Campus in November 2011. W support can be even more important internationally, because many scientists working outside the United States do not receive the large FOR MORE INFORMATION: To learn more about the International Early Career startup packages available at many U.S. universities. If the program is Scientist Program, visit www.hhmi.org/research/competitions.

February 2o11 | hhmi bulletin 41 lab book Forgetting Fear A compound given at just the right time may make mice forget to be afraid.

The ultimate memory eraser—a way to avoid posttraumatic stress The team discovered that as CP-AMPARs the receptors are disorder—is now a reality for mice. HHMI investigator Richard ­especially unstable and can be selectively removed from synapses by Huganir has discovered a protein critical for erasing memory of a activation of another brain receptor, mGluR1. They hypothesized traumatic event. that removing CP-AMPARs at just the right time could prevent the When the brain learns something—a new skill or a fear response, memory linking the tone and the shock. The receptors’ rarity meant for example—neurons gain surface receptors at synaptic connec- that other parts of the brain wouldn’t be affected. tions that strengthen signals from neighboring neurons. When fear Their hypothesis was right; a behavioral therapy known to activate is learned, this strengthening happens in an area of the brain known the mGluR1 pathway removed these rare receptors and erased the fear as the lateral amygdala. memory. Now, the researchers are working to develop drugs that could To find a way to block this memory formation, Huganir and activate mGluR1 to erase the memory in place of behavioral therapy. collaborators at the Johns Hopkins University School of Medicine The only caveat: the compound imparted fear in mice by giving them a mild shock while playing would have to be administered in a a specific tone. When the mice heard the tone again—for weeks brief window of time after the event, afterward—they froze. when CP-AMPARs are present. The researchers examined the animals’ brains at various times Huganir thinks the results, postshock. After a few hours, the number of glutamate receptors— published in Science on Novem- common in neuron signaling—had increased at synapses in the ber 18, 2010, will likely translate lateral amygdala. Twenty-four hours later though, most of these to humans. If so, there might be receptors had lost a subunit, turning them into more rare calcium-­ a period of time after a traumatic

penetrable AMPA receptors (CP-AMPARs). This finding was a The amygdala, shown here event when the brain can be surprise, especially since, a few days later, the receptors regained in red, is the area of the brain coaxed to forget. W that learns fear. the subunit, returning to the more common form. –Sarah C.P. Williams

IN BRIEF

New Timeline for tumor to form after the frst cancer-related of Medicine, has discovered that losing Pancreatic Cancer mutation, metastasize to another location MeCP2 causes a shortage of a signaling Pancreatic cancer, once thought to be with new mutations, and kill the patient. molecule called GABA. Deleting MeCP2 among the fastest-growing cancers, has The researchers concluded, in the Octo- protein from GABA-expressing neurons, been revealed to have a long, slow pro- ber 28, 2010, issue of Nature, that it averaged which make up 15 to 20 percent of all neu- gression of more than 20 years. Scientists close to 12 years from the frst mutation rons, was enough to cause the symptoms pieced together the new timeline by track- to the formation of a mature pancreatic of Rett syndrome in mice. ing the accumulation of cancer-causing tumor. Then, on average, 7 years elapsed Looking closer at the neurons, the mutations. The fnding opens the possibil- before the lesion acquired the ability to researchers found that without MeCP2, lev- ity of detecting the cancer early. colonize other organs, and another 2.7 els of an enzyme that helps produce GABA HHMI investigator Bert Vogelstein, of years went by before the patient died. dropped by 30 percent. GABA is respon- the Johns Hopkins University School of “It gives us hope that we will eventually sible for preventing neural overactivity. Medicine, was a lead researcher on the be able to reduce morbidity and mortal- Without it, the neural network becomes too study. He says there were two theories on ity from pancreatic cancer through earlier active, the team found, leading to the symp- why pancreatic cancers—with fewer than detection,” says Vogelstein. toms of Rett syndrome. The results appear 5 percent of patients surviving 5 years in the November 11, 2010, issue of Nature. after diagnosis—are so lethal. First, that Rett Syndrome Linked to Zoghbi calls the results encouraging. they are a fast-growing, aggressive cancer. Signaling Molecule “It gives you a path forward,” she says. “If Second, that symptoms don’t appear until A set of neurons in the brain has been you can improve GABA signaling pharma- the disease is far along. newly implicated in Rett syndrome—a cologically, you might improve features of “We were surprised and pleased to disease of the nervous system that can Rett syndrome.” discover that this second theory is correct, cause autism-like symptoms, breathing at least for a major fraction of tumors,” problems, and a shortened lifespan. It was Lessons from a Model Flatworm says Vogelstein. already known that a mutation in a gene The fatworm Schistosoma, which infects He and his colleagues collected samples called MeCP2, located on the X chromo- 200 million people a year around the world from seven autopsied pancreatic tumors some, causes the syndrome, which appears with a chronic parasitic disease, is notori- as well as metastatic lesions from other primarily in girls. But scientists couldn’t ously hard to study in the lab. But planarians, organs. The team then sequenced each explain how the mutant MeCP2 protein considered a “cousin” of schistosomes, are sample’s DNA. Because mutations accu- leads to the symptoms. well established as a model organism. So mulate at a steady rate, the scientists could A team of scientists led by HHMI inves- when HHMI investigator ­Phillip Newmark iving Art Enterprises / Photo Researchers, Inc. iving Art Enterprises

track how long it had taken for a primary tigator Huda Zoghbi, of the Baylor College wanted to know how to block reproduction L

42 hhmi bulletin | February 2o11 Releasing the Brakes on Cell Fate Removing one transcription factor allows others to drive cellular destiny.

Converting one cell type directly into another is a kind of has never before been linked modern-day alchemy, an ultimate goal in biological research. But to the ability to reprogram unlike turning base metals into gold, changing a cell’s identity is a cell. Hobert’s team was feasible, new research shows. able to convert the germ While many scientists attempt to convert cell types by beginning cells to three different types with the clean slate of a stem cell, HHMI investigator Oliver Hobert of neurons by using dif- wanted to skip a step and change one cell to another without using ferent neuron factors. In In normal nematodes, there’s only stem cells. But in his study organism, the nematode Caenorhabditis each case, within 6 hours one ASE neuron (green dot), but elegans, the factors required to produce neurons from stem cells had of receiving the Lin-53 ­researchers have now coaxed other cells to turn into ASE neurons. no effect when expressed in other cell types. block and a ­neuron-specific Hobert and his colleagues at the Columbia University factor, the cell changed its gene expression and underwent mor- College of Physicians and Surgeons hypothesized that the problem phological changes. The results appeared online in Science on wasn’t the factors—it was that cells have a protective mechanism in December 9, 2010. place to prevent reprogramming. “This is a potential first step toward being able to generate To find the key that makes cells impervious to reprogramming, any cell type you want,” says Hobert. “By removing Lin-53, we Hobert’s lab group individually blocked expression of different have put a foot in the door to allow other transcription factors genes in thousands of C. elegans worms and then induced expres- to drive cell fate.” His team has also found ways to convert skin sion of a neuron factor. In one line, which could not make a protein cells into neurons by removing a separate factor, also called Lin-53, the germ cells—precursors to sperm and egg cells— involved in chromatin biology. Hobert thinks that each changed to neuron cells. tissue type has its own reprogramming deterrent in place. Lin-53 plays a role in controlling gene expression in a cell Releasing these brakes allows cell switching to speed ahead. W by altering its chromatin, or DNA packaging. But the protein –Sarah C.P. Williams

IN BRIEF

of schistosomes, he turned to planarians. fed similar hormones in Schistosoma, which 2010. In addition, Rafi and his collabora- His fndings could now lead back to ways to could lead to a new way to block the repro- tors found evidence that activation of the thwart schistosome infections. duction cycle of the infectious fatworm. endothelium is vital to tissue regeneration Some schistosomes and planarians have in the lungs and pancreas. complicated sex lives—they can switch Turning on Stem Cell A next question, Rafi says, will be to between sexual and asexual reproduction Multiplication determine the mechanisms by which acti- depending on the environment or life-cycle An overlooked layer of cells that line blood vated endothelial cells trigger stem cell stage. Newmark and his colleagues at the vessels and are found in bone marrow growth in each organ. “The challenge that University of Illinois at Urbana–Champaign and other tissue is key to coaxing adult lies ahead is to discover the organ-specifc suspected that this switch was triggered stem cells to multiply, a new study shows. growth factors produced by the endothe- by a signal from the brain, since planarians The endothelium, thought to be largely a lial cells,” he says. without heads (famous for their regeneration source of oxygen and nutrients to tissues, skills) reabsorb their reproductive organs. also releases growth factors. Clocking Temperatures The researchers knew that enzymes In March 2010, HHMI investigator Fluctuations in body temperature are intri- called convertases are required to pro- Shahin Rafi of the Weill Cornell Medical cately tied to the 24-hour circadian rhythm duce neuropeptides, the molecules they College published evidence showing that of gene expressions in mammals, new suspected played a role in signaling. So endothelial cells in bone marrow express research shows. While scientists knew that they deleted a convertase called pc2 from growth factors. Now, he and his collabora- the internal clocks of plants, bacteria, and planarians. Sure enough, the flatworms’ tors have found the pathway that controls cold-blooded animals could be controlled reproductive tissues reverted to a more expression of these growth factors. by temperature, the new study by HHMI primitive, asexual state, just like they’d seen When the researchers triggered activa- investigator Joseph Takahashi is the frst to in planarians without heads. tion of the biochemical pathway Akt in the conclude that temperature can be used as a Then the scientists searched the pla- endothelium, the number of stem cells in the universal internal timing signal in mammals. narian genome for genes encoding bone marrow increased 10-fold. When they The suprachiasmatic nucleus (SCN), neuropeptides. They found around 50 switched off activation, the number of stem a tiny structure deep in the ­mammalian genes, which helped them narrow their cells decreased. The results appear in the brain, is known as the body’s master focus to one that’s expressed only in sexu- November 2010 issue of Nature Cell Biology. clock. It receives light input from our eyes ally reproducing fatworms. Disrupting this In a second study, the team discov - and sends out signals to the rest of the ab

L gene had the same effects as deleting pc2, ered that endothelial cells in the liver also body to synchronize functions to a daily the team reports in the October 12, 2010, prompt stem cells to expand. That fnd- schedule. Over the past couple of years,

Hobert issue of PLoS Biology. They have also identi- ing appeared in Nature on November 11, Takahashi’s lab group at University of Texas

February 2o11 | hhmi bulletin 43 lab book Warming Malaria Climate change is expanding the disease-causing pathogen’s comfort zone.

As temperatures rise in the East African highlands, so does the number carry the pathogen develop faster and bite more often. Because of of malaria cases. This conclusion of a new study by HHMI scientists this link, the Kenyan highlands are considered a “fringe region” suggests that areas not historically affected by malaria epidemics are for malaria transmission—their cooler climate has historically kept at increasing risk of outbreaks due to rising global temperatures. malaria levels much lower than in nearby warmer lowlands. The retrospective study, led by HHMI investigator Mercedes Pascual wondered whether long-term shifts in temperature had Pascual of the University of Michigan, focused on a highland already changed the incidence of malaria in this fringe region. Her region of western Kenya. Here, a tea plantation made up of several team isolated the effect of temperature—as opposed to drug resis- estates, with a combined population of 50,000, kept detailed hos- tance and land-use changes, among other factors—and revealed that pital admissions data, including confirmed monthly malaria cases, warmer temperatures explain a significant fraction of the increase in ­spanning 1966–2002. malaria cases from the 1970s through the 1990s. The work appeared “There aren’t many data sets on malaria that span such a long online in Proceedings of the Royal Society B on November 10, 2010. time period and are of such good quality,” says Pascual. The wealth The researchers are now looking at fringe regions of eastern of data combined with local Africa and India—including deserts, where low rainfall has typically temperature records made the limited malaria—to study the changing prevalence of the disease new analysis possible. not just in the long term but also from year to year. Establishing a At a physiological level, the link between climate and malaria cases at these interannual time effect of temperature on the scales could help predict epidemics. malaria parasite has been well- “Climate’s effect on epidemic malaria does not mean that inter-

The mosquito Anopheles studied: the parasite reproduces ventions cannot be effective,” stresses Pascual. “It might just mean gambiae spreads the malaria more quickly at higher tempera- a bigger control problem.” And understanding climate’s effect, she parasite in Africa. tures, and the mosquitoes that says, might be key to this control. W –Sarah C.P. Williams

IN BRIEF

­Southwestern Medical Center at Dallas and Waldor. The fnding supports the idea that Aging Mitochondria Related others have shown that virtually every cell the cholera arrived on the island through to Diabetes Risk in the body contains a circadian clock. human activities, rather than washing up Weakened mitochondria are the reason a To study how the expression of cellular environmentally from Latin America. person’s risk for type 2 diabetes increases clocks waxed and waned over the course of To determine the origin of the cholera with age, according to research by HHMI a day in mice, Takahashi and his colleagues that has killed more than 2,500 people in investigator Gerald Shulman.­ attached a luminescent protein to Per2, Haiti as of mid-December 2010, Waldor and Mitochondria generate energy and an important clock gene. Then they stud- his colleagues at Harvard Medical School are particularly active in muscle cells. ied rhythms in Per2 expression in cultured obtained two samples of Vibrio cholerae, Schulman’s lab group at the Yale School lung and pituitary tissue from mice. When the bacterium that causes the intestinal of Medicine had already shown that they changed the temperature from 36°C disease, from two Haitian patients. In collab- elderly individuals have lower mitochon- to 38.5°C, within the normal range of body oration with Pacifc Biosciences, a company drial activity in their muscles, which is temperature for mice, the cycle of Per2 was that manufactures DNA sequencing associated with higher fat content and strongly reset to the temperature signal. In machines, the scientists quickly sequenced insulin resistance. contrast, the SCN clock was resistant to the genomes of the cholera bacteria. To test the hypothesis that oxidative the same temperature signals—explaining The DNA sequences revealed that the damage in mitochondria was responsible, why mammals are largely insensitive to two samples of V. cholerae were virtually the researchers overexpressed the human environmental temperature cycles at the identical. When compared with 26 other catalase gene, which encodes an enzyme organismal level. V. cholerae strains, the samples matched that protects against oxidative injury. Cell-cell communication in the SCN is strains currently circulating in South Asia, The latest work shows that, similar to responsible for temperature resistance, which have different genetic markers than humans, older mice have reduced mito- the researchers concluded on October 15, strains in South America. chondrial function, increased fat in their 2010, in Science. Thus, the SCN clock in “The most likely explanation for the muscles, and insulin resistance. In con- the brain can transform 24-hour light-dark sudden appearance of cholera in Haiti, trast, mice with higher levels of catalase cycle information into an internal body the authors conclude, is transmission of were protected from these age-associated temperature signal that syncs cellular the bacteria by an infected human, food, changes. clocks throughout the organism. or other contaminated items from a region The results, published in the Decem- outside of Latin America to Haiti. ber 1, 2010, issue of Cell Metabolism, offer Tracing the Roots of Haiti’s The analysis, which appeared online further evidence that altered mitochon- ondon School of Hygiene and Tropical Medicine of Hygiene and Tropical ondon School

Cholera Outbreak December 9, 2010, in the New England drial function plays a role in age-related L The strain of cholera that began sweeping Journal of Medicine also found that the insulin resistance and suggests that through Haiti in October 2010 originated strain, while potentially more virulent reducing oxidative damage in mitochon- in South Asia, according to a study co- than average, should respond to tetracy- dria may be a way to prevent age-related an Salaman /

authored by HHMI investigator Matthew cline antibiotics. type 2 diabetes. D

44 hhmi bulletin | February 2o11 ask a scientist

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How do internal In nature, external appearance abso- To understand how external stressors stresses cause lutely predicts general health and is one from the environment—like smoke and of the driving forces of survival of the fit- UV radiation—can alter the skin, let’s the external appear­- test. Within one species of multicolored examine the skin’s anatomy. The epi- ance of humans to parakeets, for example, females prefer to dermis, the top layer, contains sheets of change with things mate with the male that sports the bright- skin cells. Immediately below that is the such as wrinkles? Can est colored feathers. While it seems dermis, which contains blood vessels, purely aesthetic and random to fixate on nerves, and the proteins that give the appearance predict such features, the male with the brightest skin its structure and texture. One such general health? colored feathers is in fact the healthiest protein, called collagen, is continuously bird; his vibrant hues indicate he has created and broken down in the skin. Asked by Joe, the highest levels of important vitamins Both UV radiation and tobacco smoke from Pennsylvania in his body. Humans, as well, are pro- increase the rate of collagen destruction. grammed to gravitate toward healthier The body tries to repair this damage, but individuals when choosing a mate. the process is never 100 percent perfect. The largest organ in the human Over time, with repetitive exposures to body—the skin—is a remarkable con- UV radiation or cigarette smoke, the skin veyor of health. Physicians are trained to loses structural integrity—as it loses col- look to the skin for the external signs of lagen—and wrinkles form. diseases, which can sometimes be very UV radiation can cause even more subtle. For example, jaundice, a yellow- severe changes in appearance if it leads ing of the skin, results from a buildup to skin cancer. The radiation from the of a chemical called bilirubin, which sun’s rays can damage DNA inside skin is generated from the breakdown of cells, eventually damaging it enough so red blood cells. In a healthy body, it’s that the cells grow uncontrollably, form- excreted by the liver through the feces ing a cancer. and urine. When the liver is diseased, Each time the body replaces collagen however, bilirubin piles up in the blood in its natural turnover cycles, it produces and eventually deposits in the skin. slightly less. So even someone who never Another internal condition that smokes and who consistently wears sun- changes appearance is Addison’s disease, screen will eventually get some wrinkles which is an inability of the adrenal glands with age. Eventually, the dermis has less FURTHER READING Skin aging induced by ultraviolet exposure and tobacco to produce adequate amounts of certain collagen, as well as less elastin, a protein smoking: evidence from epidemiological and molecular hormones. In response, the brain ramps that helps keep the epidermis stretched studies. Yin L, Morita A, Tsuji T. Photodermatol Photoimmunol Photomed. 2001 Aug;17(4):178–83. up production of adrenal-stim­ ulating tightly over the body. hormones to try to turn on the adre- Pathophysiology of premature skin aging induced by ultraviolet light. Fisher GJ, Wang ZQ, Datta SC, nal gland. This adrenal-­stimulating Varani J, Kang S, Voorhees JJ. N Engl J Med. 1997 hormone is structurally similar to a pig- Nov 13;337(20):1419–28. menting hormone. As a result, people Answer Researched by Nefthi Sandeep, Matrix metalloproteinase-1 and skin ageing in smokers. a third-year resident in pediatrics at Lahmann C, Bergemann J, Harrison G, with Addison’s disease often experience Young AR. Lancet. 2001 Mar 24;357(9260):935–6. darkening of their skin. Columbia University Medical Center.

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?

February 2o11 | hhmi bulletin 45 46 University; The K-RITHboardmemberis M research scholars are Bloom Hospital Boston; Hospital Boston; Hospital Hospital; Hospital; Ji hhmi James Jea R tors are Advancement ofScience. Theinvestiga- fellows of the American Association for the K-RITH advisoryboardmemberwerenamed international researchscholars,anda of 9 HHMI investigators, 2 HHMIA total Y University ofToronto, and University of California, San Francisco; Memorial Award, from the International ter, wonthe2010RichardV. Smalley, MD at MemorialSloan-KetteringCancer Cen- of Pennsylvania SchoolofMedicine; setts InstituteofTechnology; and ­ ork o iller n nota bene s b , University ofCalifornia, SanDiego; Six HHMIResearchersElectedtoInstituteofMedicine nn U of Medicine. The investigators are Four HHMI investigators and an HHMI early career scientist were elected to the National Academy of Sciences’ Institute L at HHMI’s JaneliaFarm Research Campus,was namedaforeign associate oftheinstitute. Francisco. The early career scientist is p

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dna er K freshmen eachsummer. one-week bootcampinbiologyfor incoming associate professorofsoil science, teachesthe ment andSupportofEducation. Balser,an of Teaching andtheCouncil forAdvance- Carnegie Foundation fortheAdvancement named U.S. Professor of the Year by the University ofWisconsin–Madison, was supported “MadBioBootCamp”atthe the University ofOxford. ­Altemose willcontin at Duke.WiththeMarshallScholarship, Institute forGenomeSciences and Policy sor HuntingtonF. Willard,director ofthe award, AltemoseworkedwithHHMIprofes- Scholarship. WithsupportfromhisEXROP gram (EXROP)in2009,wonaMarshall Exceptional ResearchOpportunities Pro- undergraduate whoparticipated inHHMI’s T Nicolas immune systemandcancers. research focusesonthelinkbetween the society’s 2010annual meeting.Allison’s Society forBiologicalTherapyofCancerat C arl , S eresa resswell, Yale h D o kat eisseroth, Stanford , D C . Balser . A eisser ltemose U o niversity School of Medicine; th , wholeadstheHHMI- ue geneticresearchat , B , a Duke University renner U niversity. In addition, K e van M . S G vid D tion inOctober. Theyare European MolecularBiologyOrganiza- American scientists namedmembersofthe Three HHMIinvestigatorswereamong14 HHMI professor clotting disorders. chosen forhisresearchoninheritedblood cal school faculty member. Ginsburg was clinical orlaboratoryresearchbya medi- Colleges. Theannual award recognizes the Association ofAmericanMedical in the Biomedical Sciences Award from School, received aDistinguishedResearch tor attheUniversity ofMichiganMedical ogy. from theAmericanSociety for Microbiol- White ResearchandMentoring Award of Yale University, wonthe2011D.C. accomplishments. elected annually based on their scientific Columbia University. Newmembersare The RockefellerUniversity; cal School; and hokat, a ree R obert S ­ R y n ecipients are chosen annually for dney Brenner, a senior fellow , University ofMassachusettsMedi- U G niversity of California, San California, niversityof i B. n s D b arnell, The Rockefeller urg T homas , anHHMIinvestiga- Jo H E a lai n M M delsma . Jessell . n ichael e Fuchs e n R , , , .

Cresswell: Courtesy of Peter Cresswell Darnell: Courtesy of The Rockefeller University Doudna: Michael Marsland / Yale University Shokat: George Nikitin / AP, ©HHMI Deisseroth: L.A. Cicero / Stanford News Service Brenner: Paul Fetters Lindquist: Cheryl Senter / AP, ©HHMI Benkovic: Greg Grieco adolescent psychiatry. and memoryhashadinthefieldofchild for theimpactthathisresearchonlearning Adolescent Psychiatry. Kandelwaschosen from theAmericanAcademyofChild& AwardCatcher intheRyeHumanitarian cians and Surgeons, was awarded the 2010 the Columbia University College of Physi- in Miniaturisation Prize from the journal University,Stanford wonthe2010Pioneers Y HHMI investigator the classroom. to bringing creativityandexperimentation of Sc Biology, sponsoredbytheNational Institute onUndergraduateEducationin been aregularco-organizer oftheSummer dedication tomentoring. Handelsman has their scientific accomplishmentsandtheir HHMI investigator global governanceanddiplomacy. plans tostudyglobalhealthscience and studies attheUniversity ofOxford.Kang provides funding fortwoorthreeyearsof The scholarship,awarded to32Americans, program, wasnameda2010RhodesScholar. HHMI-funded “BeyondTraditional Borders” at RiceUniversity andparticipant inRice’s e- s j Su National MedalsofScienceGotoLindquist andBenkovic p i iences andHHMI.Shefocuseson n otli san

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HHMI President development. in anadultdiffer fromthoseformedinearly Schinder studies how nervecellsthatmature Latin AmericanandCaribbeanFellowship. Institute Foundation, wonaGuggenheim at the14thInternationalConferenceon Quake waspresentedtheannual award and assaystobeperformedatasmallscale. ing onmicrofluidics, allow biologicaltests of biologyandmedicine. Their systems,rely- biotechnology todeveloptoolsforthefields Quake’ L A ­ HHMI internationalresearchscholar Life Sciences inOctober2010. ­Min Léopold MayerfromtheF honored withthe2010GrandPrixCharles- terization oftheelements.Tjianalsowas a UCLAgraduateknown forhischarac- recipient of the Nobel Prize in Chemistry, chemistry and is named for the 1951 accomplishments in chemistry or bio- (UCLA). Theannual medal is given for the University ofCalifornia, Los the 2010 Glenn T. Seaborg Medal from to aresearcherforoutstandingworkin emy ofSciences, anaward giveneachyear ab onaChipandCorning Incorporated. le studies how enzymesdrive chemicalreactions insidecells. U receivedincluding also medals, neurodegenerativeof and prions of standingTen ¶ diseases. scientists other in can proteinsaggregatesof proteins and misfoldedhow and proteinfolding of studies recognizedher wasCongress.forby Lindquist 1959 in established wasgovernment, the bestowedby honor scientific highest nation’s the President fromScience of Technology,Medal of National Institute a presentedwas investigatorNovember,HHMI In iaturized SystemsforChemistry and j niversity, who is a member of HHMI’s scienti HHMI’s of member a is niversity,who a s labintegratesbiology, physics,and n dro F.dro f uence human health. Her research has led to an increased under- increased an to led has research Her health. human uence O bama in a ceremony at the White House. The National Medal, National The House. White the ceremonyat a in bama S rt R chi o b e n der T j , of the Leloir rench Acad- i a n received Angeles ­ S t of PennsylvaniaBenkovicStateJ.of ephen S usan ­

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47 continued from page 17 Patrick Kanold trained as a postdoc in the Harvard Medical (the next generation) School lab of Carla Shatz, now director of Bio-X at Stanford Univer- Good mentors find ways to train their postdocs to excel at men- sity in California and member of HHMI’s medical advisory board. toring when they launch their own labs. Luger pairs postdocs with He says her skilled but understated mentoring prepared him to eas- an undergraduate, rotation, or graduate student, and she checks in ily set up his own group at University of Maryland in College Park. with the student to see how the relationship is working. “She gave me room to develop my own thoughts and questions One Luger postdoc learned an invaluable lesson about adjust- with subtle little pushes. I was being directed, but at the time I didn’t ing mentoring approaches. Paired first with an undergraduate of notice,” he says. “By building my own experimental set-ups and similar personality, the postdoc delivered criticisms directly with no training grad students through guided mentoring, I was being given “gift-wrapping.” His next student, however, shriveled under what really important experiences that I carried with me.” she considered offensive feedback. Bardwell is often reminded of his experiences shooting unex- Luger warns her postdocs to allow for a “training period” for the plored rivers. His contacts tell him that Papua New Guinea’s Jimi students, who often cannot keep up intellectually with a postdoc at River awaits a first descent by humans. He’d love to give it a shot, the top of his or her game. She has a favorite exercise for reminding with the right team beside him. The same goes for his lab—a well- them that trainees are not mini-me’s: “Take a page from a paper, chosen team with the right training makes for a gratifying journey. W and replace every third noun and the occasional verb with the word ‘Yakutat.’ That’s pretty much an undergraduate’s experience when web extra: For more on how these lab leaders prepare their postdocs to run a lab, visit

they first talk to their new mentors.” www.hhmi.org/bulletin/feb2011.

continued from page 27 at one molecule and find out later that I was RecBCD and other motor proteins behave (BEHIND THE C URTAIN) observing something that is not general.” when they encounter not just one protein how fast proteins produce new ­copies. Bio- O’Donnell’s DNA curtains showed that in their path but a whole stretch of road- chemical experiments in his lab had hinted individual replisomes’ movement rates blocks. “If you think about what DNA looks that replisomes, the proteins involved in vary as much as 5-fold, his team reported like in the nucleus, it’s jam-packed with replication, move at different rates on dif- in ­Proceedings of the National Academy of proteins, so we would really like to mimic ferent DNA strands. The lab was stumped ­Sciences on August 11, 2009. Now they have that environment by putting lots and lots as to how to quantify this variation until a working average and a way to test what of proteins on the DNA.” On thousands of O’Donnell heard Greene talk about ­factors can shift that average. DNA strands, this will mean many thou- DNA curtains. As for Greene, he’s ready to add com- sands of collisions. It will be a fascinating “The one disadvantage of single mol- plexity to his curtains. “We’d like to make show to watch. W ecule work is that you’re looking at a single arrays where the DNA is crisscrossed or molecule,” says O’Donnell. “Greene’s supercoiled,” he says. True to his love of web extra: To see videos of DNA curtains in action,

method got around that. I didn’t want to look molecular crashes, he also plans to see how visit www.hhmi.org/bulletin/feb2011.

continued from page 33 already, researchers at Harvard and at Columbia University are (hope floats) using the cells to screen for potential new treatments. “We can now resulting cells “are real, functional motor neurons. We had to go to model ALS more accurately,” she says. “We hope that the drugs that great lengths to show that,” he says. The Harvard Stem Cell Institute emerge from the screens are contenders.” is preparing to provide the cells to qualified researchers. Of course, that’s the ultimate goal for ALS researchers—to Valerie Estess, director of research for Project ALS, which helps provide treatments for patients who now have few options. Yeast, fund Eggan’s work, calls the advance “ALS in a dish.” She says that, worms, flies, mice, and, now, human neurons in a dish all offer platforms to quickly test drug candidates against the range of defects that lead to ALS. “It’s great to have an arsenal of models to study disease,” says NINDS’s Gubitz. “Every model mirrors a specific aspect of disease, and they’re much more powerful when combined.” And so with this solid foundation for discovery, ALS researchers expect an avalanche of advances in the coming years. Says Bonini: “You can’t predict where the big breakthroughs are going to come This paper is certifed by SmartWood for FSC standards, which promote environmentally appropriate, socially benefcial, from, which is why it’s important to take many different approaches. and economically viable management of the world’s forests. It’s really important to cast a wide net.” Because, in the end, “the whole reason we’re doing this is to make an impact for patients.” W

48 hhmi bulletin | February 2o11