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BULLETIN A u g . ’11 VOL.24 • NO.03

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Special Delivery What if a cancer patient’s own immune cells could be loaded with tumor-fighting drugs? Engineer and materials scientist Darrell Irvine has found a way. Irvine’s lab group has devised tiny drug-loaded

nanoparticles and strapped hundreds of them to the surface of T-cell •

lymphocytes. When tested in mice with metastatic melanoma, the www.hhmi.org enhanced T cells rapidly reproduced, moved through the body, and zeroed in on the spreading tumors. The tumors shrank and the mice lived longer than untreated mice. The team has also used the technique to send drug-studded blood stem cells to restore depleted bone marrow in mice. Fascinated by the complexity of the immune system, Irvine is working to remodel the surface of cells with synthetic materials to treat disease and reduce treatment side effects, with more applications in sight (see “T-Cell Booster Kits,” page 10). v ol. 24 / no. 03 Matthias Stephan / Irvine lab Read morein“LastingMemories” atwww.hhmi.org/bulletin/aug2011. Ryohei imageslivingspines assignalingoccurs,seeninthis seriesofphotos. what’sunderstand happening inthoseextendedmoments,biophysicistYasuda minutes orlongerare thought toencodelong-termmemories.To better as spines. Signalingstrength canfluctuaterapidly, butsomechangeslasting When neuronsfireinthebrain,theyexchangesignalsthrough tiny budsknown

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Yasuda lab

Jing Wei exclusive!). The motivation to doresearch hasto bemuch stronger A’s orearning aVarsity letter (thoughby nomeansare thesemutually rewarding thanotherhighschoolactivities,suchasgettingstraight Being ableto contribute to thepoolofhuman knowledge ismore common? Apleasure indiscovering somethingfor themselves. what they learnintheclassroom. What do thesestudents have in ­r Some students may notbecontent with just memorizingand progressively more sophisticated. conducting scientific experiments—and theirprojects are becoming researchers are younger—more secondary students thanever are ful female andmalescientists range from 10to 90years old.Today’s the stereotypical moldof“old, beaker-carrying men.” Infact, success- how-to. Earlyon,they reassure readers that scientists nolongerfit experiences ascompetitors. Theirbookishalfencouragement andhalf school science fairs—decided to give backandshare theiradvice and A motivated group ofHarvard undergrads—all winnersofelite high A G egurgitating scientific facts. Othersmay never blindlyagree with Observati uidi n g o ns L ig h t

by permission ofResearch Corporation for Science Advancement. Kominers, Dayan Li,Carol Y. Suh.©2011 Research Corporation. Used Research, by withMariaElenaDeObaldia,Scott ShivGaglani Duke From Success withScience: TheWinners’ Guideto HighSchool applications, networking andmakingprofessional boards and posters. tant life skillssuchasgivingpresentations, writingresearch papersand not just provide bookknowledge. Italsoenablesoneto develop impor- would inthree monthsofschoolwork. Unlike homework, research does one monthofresearch astudent canoften learnasmuchheorshe relationship between research andclass work iscloseto 1:3.That is,in most fulfillingactivityof your highschoolcareer. The stoichiometric and quite frustrating at times.At thesametime, though,itcanbethe By nomeansisresearch easy: itcanbeasubstantial timecommitment high schoolstudents whodoresearch eachyear. than that, however, ifwe are to account for thetens ofthousands august ’11 vol. 24 · no. o3

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Web Only Content Drink in the sights and sounds of Baltimore’s crowd-rowdy Kinetic Sculpture Race.

Travel through a 30-year timeline of discovery in the field of gene therapy.

Learn how the Summer Institute inspired radical change in one science educator’s approach.

Immerse yourself in heavenly wonders through the lens of Fred Eiserling’s telescopic camera.

Join us at www.hhmi.org/bulletin/aug2011.

24 30 Features Departments cover story PRESIDENT’S LETTER Institute News Evolution of the Textbook 03 Journal: Scientists at the Heart 40 Rosenfeld To Lead HHMI 1 2 Publishers are beginning to go digital CENTRIFUGE Documentary Initiative with textbooks, pushing boundaries 40 HHMI Teams Up for Open 04 Sink or Swim to give students a personalized, Access Journal 05 The Night Sky interactive experience. 41 Plant Science Gets a Boost 06 The Tao of Science Fairs Seeing Is Believing Lab Book UPFRONT 1 8 Scientists are cautiously bringing gene 42 The Buzz on Bee Viruses 08 The Goldilocks of Cells therapy out of the dark. 43 Memory Cells at the Ready 1 0 T-Cell Booster Kits Time to Teach 44 Leading a Double Life PERSPECTIVES AND OPINIONS 24 Is there room for teaching and A sk a Scientist 34 In Support of Undirected Research research in a postdoc experience? 45 Can stimulants exercise your heart 36 Q&A—What can you measure Let’s Get Small today that you never dreamed of and make it stronger, just like lifting 30 Janelia researchers are working their being able to quantify when you weights will make your body stronger? way up from simple to more complex became a scientist? Nota Bene organisms to measure brain activity. 46 CHRONICLE News of recent awards and other Science Education notable achievements

38 Going Viral OBSERVATIONS 39 2011 Holiday Lectures on Science A Guiding Light

VISIT THE B U L L E T I N ONLINE FOR ADDITIONAL CONTENT AND ADDED FEATURES: www.hhmi.org/bulletin COVER IMAGE: Keenan cummings contributors

A native of São Paulo, Brazil, graphic designer and illustrator Rubens LP (“Seeing is Believing,” page 18) has worked with companies worldwide, including Microsoft, Nike, Absolut Vodka, Sony Ericsson, Coca-Cola, MTV, Folha, Editora Globo, and Ride Snowboards. When not at (1) his desk, he enjoys nature, art history, movies and books, video games, beauty, friendship, and—most of all—life. (1)

Laura Putre (“Evolution of the Textbook,” page 12) is a freelance journalist from Cleveland whose articles have appeared in Miller-McCune, O Magazine, The Root, and the Chicago Reader. She loves walking on the beach, spending time with friends, and narrative journalism and wishes she’d had an interactive science textbook when she was in college. (2) (3) (2) Freelance writer Virginia Hughes (“Seeing is Believing,” page 18) lives in Brooklyn, New York, where she partakes in Brooklyn-y things like book readings, coffee cuppings, and dog sitting. She likes to write about brains, drugs, and genes, sometimes all at once. Her articles appear in Nature, Popular Science, Scientific American, and a quirky science blog called The Last Word on Nothing. (3)

California-born, Brooklyn-based designer and illustrator Keenan Cummings (cover and “Evolution of the Textbook,” page 12) enjoys working for a roster of clients from large organiza- (4) tions and brands to small publishing houses. In his personal projects, he explores themes and ideas he cares about: education, health, science, and the creative process. (4)

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 . Nitin Kotak / V.P. for Finance & Chief Financial Offcer Regental Professor & Chairman, Department of Molecular Genetics Avice A. Meehan / V.P. for Communications & Public Affairs University of Texas Southwestern Medical Center at Dallas Cheryl A. Moore / Executive V.P. & Chief Operating Offcer Hanna H. Gray, Ph.D. Gerald M. Rubin, Ph.D . / V.P. & Executive Director, President Emeritus & Harry Pratt Judson Janelia Farm Research Campus Distinguished Service Professor of History Landis Zimmerman / V.P. & Chief Investment Officer The University of Chicago Garnett L. Keith HHMI BULLETIN STAFF Chairman / SeaBridge Investment Advisors, LLC Mary Beth Gardiner / Editor Former Vice Chairman & Chief Investment Officer Cori Vanchieri / Story Editor The Prudential Insurance Company of America Jim Keeley / Science Editor Fred R. Lummis Andrea Widener / Science Education Editor Chairman & CEO Maya Pines Platform Partners LLC / Contributing Editor

Paul Nurse, F.R.S. Additional Co ntrIButors President / The Royal Society of London Cay Butler, Michelle Cissell, Dame Alison Richard Nicole Kresge, Heather McDonald, Professor / The University of Cambridge Sarah C.P. Williams Clayton S. Rose, Ph.D . VSA Partners, NYC / Concept & Design Professor of Management Practice, Harvard University Finlay Printing / Printing & Binding 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. Rubens LP, Laura Putre, Virginia Hughes, Keenan Cummings Hughes, Keenan Laura Putre, Virginia Rubens LP,

2 hhmi bulletin | August 2o11 James Kegley disciplines for aconversation.Keythemesemerged:beliefthat together journaleditors andagroupofscientists fromarangeof at HHMI’s JaneliaFarm ResearchCampuswhen webrought world ofpublishing. scientists asthey navigatebetweentheworldofresearchand in and of themselves, address the frustrations of many practicing dissemination ofresearchresults.Butinstitutional policies cannot, ing open accesspublisher, and adopted policies to ensure rapid provided earlysupportforthePublicLibraryofScience, apioneer- tific publishingandtheadoptionofopenaccesspolicies. HHMI changein scienPlanck Society- have longsupported fundamental ing andbelievewecandomore.TheWellcome Trust andtheMax and resources to encouraging creative thinking in scientific publish- to completion. prepared toplay a positive, active role in bringing the work the world’s leading scientists andtheir collaborators,weare publication. Asfunderswhosupporttheresearchofsome of science isn’t complete until the results are shared through making processaboutwhatgetspublished.Afterall,thework distinctive modelthatputsscientists attheheartofdecision- The worlddoesneedanotherscientific journal,albeit onewith a Max PlanckSociety believetheanswertothatquestion isyes. journal? TheleadershipofHHMI,theWellcome Trust, andthe ­rhetorical q postdocs wanttopublishtheir bestwork? me: Is this journalTHE place wherethe best graduate students and are cited. I can offer one practical indicator that makes sense to score assignedtojournalsbasedonthenumber oftimesitsarticles scientific community—rather thanbyimpactfactor,the numerical We willdefinesuccessbytheinfluencejournalhaswithin they willremainfreetopublishinthejournalsoftheir choosing. be opentothescientists supportedbyourthree organizations, but nal willseeksubmissions fromscientists aroundtheworld;itwill a rapid,efficient, andtransparenteditorial process.Thenewjour- overtime,butourfirstpriorityistodevelop become self-sustaining the fullspectrumoflifesciences. We expectthejournalto as anindependentscholarlypublication. practicing scientists and for bringing this exciting new venture to life be responsibleforrecruitinganeditorial teamcomposedofactive, serve aseditor inchief.Overthecoming months,Schekmanwill ­Schekman, ad issue to publish a year from now under the leadership of Randy forces tolaunch a top-tier scientific journal. We expect the first London to make a significant announcement: our decision to join Planck Society, andtheHoward HughesMedical Institutemetin Earli Scientists attheHeart Journal: We heardplentyataworkshopheldlastDecember certainly Our organizations havealreadyinvestedconsiderablethought As onemight expect, a fewobservershaveposedan obvious Our planisbold:topublishthehighest-quality researchacross e r thissumm uestion: doestheworldneedyetanotherscientific istinguished HHMIinvestigatorwhohasagreedto

e r, l e ad e rs ofth e W e llcom e

T rust, M ax

sacrificing originality, novelty, orrigor. Society, seektoachieveinanefficient andtimelymannerwithout what HHMIanditspartners,theWellcome Trust andMaxPlanck fordirectingstage futureinquiryThat is andexperimentation. however, describeacompellingstoryofdiscovery thatsetsthe continuum, that you can never have a complete story. You can, that is,publishableunits—reflect thefactthatscience itselfis a drawn? Whatisreasonable?Iforonewouldliketoseearticles— ments to satisfy reviewer comments? Where should the line be he or shethen be required to conduct numerous additional experi- spends sixyearsrigorouslydocumentinganewdiscovery, should many labs,including myown. Ifapostdocorgraduatestudent questionrepresent? This is a real and important that confronts lishable unit. Just how manyyearsofworkshouldasinglepaper significant goalofthenewjournal:redefining thesizeofpub- But I would like to focus on another aspect that exemplifies a sharing ofinformation. commitment toafullyonline,open-accessmodelthatenableswide tion thatscience iswellservedbydiverse publishingoptions;anda aconvic - data; work butresultinarticlesladenwithsupplemental too manyadditional experiments thatdonotnecessarilyadvancethe repeated cycles of review that delay publication and often generate be appropriatelycompensatedfortheir work;adesiretoaddress the publishingprocess,andthatbotheditors andreviewersshould selectively engagingactive,practicing scientists canaddvalueto “ Our plan is bold: plan is Our publish to the the sciences. life ofacross spectrum the full research highest-quality Robe Our plan for the new journal reflects these important themes. Our planforthenewjournalreflectstheseimportant r t T jian ” president August 2o11

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race of human-powered art projects, such as fear, absent-mindedness, and sponsored by Baltimore’s American ­addiction. Postdoctoral researcher Visionary Art Museum. Captivated by (and race-day DJ) Andy Seeds was the participants’ creativity (a 15-foot- ­stationed inside the brain to run a tall pink poodle dominated the day) music and light show. and the spirit of the event (offcial rules At the starting bell, costumed teams include a “mandatory fun regulation”), dashed to their vehicles, among them a he came to work the next Monday with monocled blue caterpillar, a beehive, a a mission: to recruit a team and enter Viking ship, and the Janelia team’s brain. the following year. Some vehicles broke down immediately, The Kinetic Sculpture Race is some- creating a traffc jam that “probably thing of an anti-race. Teams must cross didn’t matter because our vehicle was 15 miles of highway, water, mud, and rather slow,” confesses mechanical sand on human-powered vehicles in engineer Brian Coop. With fve riders Sink or Swim and around Baltimore’s inner harbor. pedaling at full capacity, the brain’s max The grand prize goes to the team that speed was two miles per hour. Then At dusk on May 5, 2011, a dozen fnishes in the middle, and rule-breakers came the hill … and a broken chain. Janelia Farm scientists and staff escape penalty with bribes. “Then we were the traffc jam,” gathered at a remote corner of the Beyond that playfulness is a serious admits Coop. 689-acre campus to set their hand- mission—to honor collaboration, creativ- By the time they reached the water crafted amphibious vehicle on its ity, and community. Osborne submitted challenge, the Lobe Trotters were in last maiden voyage. They needed to know a proposal and recruited a core team of place. But once they rolled down the if it was ready for the annual Kinetic more than two dozen people. ramp and into Baltimore’s inner harbor, Sculpture Race in Baltimor­ e, Maryland. They solicited ideas (“Should it be their secret weapon—125 empty illy The vehicle—a hulking aluminum a fy? Should it be a rat? Should it coffee cans hidden inside the chassis chassis with 32-inch all-terrain tires, be a fy chasing a rat?” recalls neuro­ for fotation—prevailed. Having seen a powered by fve recumbent pedaling scientist Roian Egnor) and then settled number of vehicles falter, sink, or simply stations at the front and rear—did not on the closest thing to a common drift away, the massive crowd roared. look like something that would foat. denominator at Janelia Farm: the In the end, the Lobe Trotters took But its riders proved otherwise, pedal- brain. By January they had a design, home the Worst Honorable Mention ing confdently downhill and into the and by March, a shell. Ultimately, more award, in recognition of a tortoise-like murky water. The spectators, most than 100 scientists, students, and pace on land but a fawless fnish in the of whom had a hand in the vehicle’s administrative and operational staff water. With new ideas already bubbling design and construction, cheered. contributed ideas and labor. They to the surface, they might not be able “It felt like sliding on glass,” recalls called themselves the Lobe Trotters. to resist doing it again. —Sarah Goforth Jason Osborne, an instrument design On race day, bystanders peered into specialist at Janelia Farm for whom the the brain’s cubbyhole-like “portals” WEB EXTRA: For a glimpse at race day test was especially rewarding. A year each containing artwork and found mayhem, see our slideshow at www.hhmi.org/ bulletin/aug2011.

earlier, he had attended the annual objects depicting a state of mind Ping Zhu

4 hhmi bulletin | August 2o11 of Baja California in Mexico. There Eiserling and his brother built a small observatory, like a storage shed with a roll-off roof, to house their fve-foot- long telescope. Eiserling fell for the stars when he was 12 during a class trip to the local Griffth Observatory. Soon after, he joined fellow sky enthusiasts in the observatory’s basement, where he hand-ground the mirror for his frst homemade telescope. “It wasn’t the greatest,” he recalls, “but it was mine.” When Eiserling was a student at The Night Sky UCLA in the 1950s, advisors told him there were no jobs in astronomy—the For decades, Fred Eiserling squinted Nebula, in the fox-shaped constellation university didn’t even have a Ph.D. through electron microscopes to study Vulpecula, which looks like exercise program in the subject. So he turned bacteriophages—viruses that infect equipment for the gods. to bacteriology. bacteria—on the scale of millionths Eiserling is aiming toward the so- He indulged in one astronomy of millimeters. called Needle Galaxy. It’s not actually course, and in 1957, he and fellow In his free time, however, he photo- skinny, but it looks that way to Earth- students plotted the course of a little graphed faraway galaxies and nebulae lings because it appears edge-on in Russian orbiter known as Sputnik. measuring light-years across—a hobby our skies. That point of view makes Within a few years, the space race he continues to pursue today. it hard to discern much about the was on and, as Eiserling recalls, “They “It allows me to really put the galaxy’s three-dimensional layout. couldn’t fnd enough astronomers!” universe in perspective after having Eiserling wants to fnd out how far he He has no regrets, however, about stared at viruses for a few years,” says can push his equipment—a camera pursuing nanoscale biology. “I discov- ­Eiserling, an HHMI undergraduate pro- bolted to the telescope, mount, and ered that there were these incredible gram director and associate dean of guider to follow objects that move with tools … that allowed you to see things at life sciences at University of California, the Earth’s rotation, all tethered to a the level of molecules,” he says. “I found Los Angeles (UCLA). computer—to get the maximum detail. that to be tremendously exciting.” Among the most gorgeous objects Astrophotography is no point-and- Back at UCLA, Eiserling focuses in the sky, according to Eiserling, are shoot pursuit; plenty of things can go on what he calls his “experiments” in nebulae—billowing clouds of mostly wrong in the process. “It’s getting more ­education for about 200 undergrads: hydrogen gas that represent the births technical as I try to get better and bet- most recently, turning dull “cookbook” and deaths of stars. With a telescope, ter pictures,” Eiserling says. He has to labs into real experiments in which he can even capture the colors of dif- fnd the stellar object he’s after, focus students discover new viruses or pur- ferent stars. Hot ones glow blue; cold properly, track it across the sky, and col- sue other novel data. Some students ones appear red. The resulting photo- lect several pictures. Later, at his home get to take home electron microscope graphs look like wads of brightly hued, computer, he fts the individual pictures portraits of bacterial viruses they’ve otherworldly cotton candy. together into one stunning photograph. discovered in class. Like children gazing at clouds, Because so much artifcial light And on a dark evening, you can still astronomers and astrophotographers spills into the skies around Los ­Angeles, fnd him staring up at the sky. name these hydrogen clouds for their Eiserling can’t practice his hobby at —Amber Dance silhouettes. Eiserling has photographed home. So once a month, when the the Horsehead Nebula, which dangles moon is new, he and his wife, physician WEB EXTRA: To see a slideshow of Eiserling’s off the belt of the constellation named Phyllis Guze, make the seven-hour drive astrophotography, visit www.hhmi.org/bulletin/ aug2011.

Darcy Hemley for the hunter Orion. And the Dumbbell to much darker territory, the shore

August 2o11 | hhmi bulletin 5 6 hhmi had more guidance alongtheway. So occasionally wishedthey could have cess were wildlydifferent, butboth ciples ofmedicineanddisease. doctoral students getexposure to prin- of theHHMIMedinto Grad Program, of she isagraduate student at ­beha f dents develop innovative projects in elite science competitions, where stu- also aHarvard grad, went onto win with hisx-ray machine. De their dentist into irradiating fruit one experiment, thegirlseven talked science projects withhersisters. For delighted inworking onkitchen table Jersey, MariaElena(Ellen)De this summer. science accolades at aprestigious international back, buthenever envisioned winning watch theoilooze from itsblistered the oc did experimental fruitfarm where hisdad played inthecitrusgroves ofthe As akidinBrazil, Dayan (Jack) Li Science Fairs The Tao of He graduated from Harvard magnet, hewas hooked …andwinning. HHMI-funded science andtechnology Eleanor Roosevelt HighSchool,the seventh grader. By thetimeheentered land, andparticipated inoneasa was untilhemoved to Laurel, Mary- elds asdiverse asencryption,human centrifuge ­ P Li’s andDe Growing upinMoorestown, New Li didn’tknow what ascience fair f ennsylvania (Penn), where, aspart

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August 2o11 baldia’s paths to suc- O U U baldia, niversity niversity O poking ­ baldia f ies and they divvied up24 chapters, winners amongHarvard undergrads, recruitedGaglani fellow science fair peting inhigh-caliberscience fairs. mentor, initiating aproject, andcom- to demystify theprocess of 2010 Harvard graduate, thebookaims ing best practices andresearch.” scientists andtheimportance ofshar- “The bookshows thegoodnature of organizer ofelite science competitions. Science thelong-time andthePublic, science education at theSocietyfor says MicheleC.Glidden,director for recently experienced thesamething,” ing theadvice from peerswhohave so O Research—published inJanuary. (See The Winners’ Guideto HighSchool to write abook—Success withScience: work withthree otherHarvard students they jumpedat thechance in2008to on personaldevelopment, scienti ence fair winners.De ­culling thewisdomofabout50sci personalized it.“Iusedphotographs she hadwithherlogbookand how she did!” shelaughs,remembering thefun about documentingyour work, butI method, andkeeping alogbook. bservations, insidebackcover.) The brainchild a ofShivGaglani, “There isincredible value inhear- “No onewanted to write thechapter O baldia focused f nding a f c - that in process buildssomuchcon Penn. is aPh.D. candidate inimmunologyat Science Training Program. De M.D./Ph.D. intheHarvard/MIT Medical their career paths. Li will be pursuing an and De those following intheirfootsteps, Li of Health. David Roberts at theNational Institutes a summerintern intheresearch labof mentors. LididhisIntel project work as support asahelpfor the value ofinternships with and normsofbehavior.” Healsotouts to the environment andtherhythms prised that ittakes timeto getused country, noting,“some peopleare sur- dents to approach thelabasaforeign tubes andwhat materials Ibought.” to document thingslike how Isetup —Lisa Chiu accomplished,” De be creative andthenshow what Ihad fessor withherown research lab. Having smoothedthejourney for In hischapters, Liencourages stu- “Science fairs gave methechance to www.hhmi.org/bulletin/aug2011. achieved by eachofthebook’s coauthors, goto WEB EXTRA: U f ltimately, shewants to beapro- uences everything elseIdo.” O baldia are moving forward on To marvel at thescience honors O baldia says. “The f nding research f f dence and O nancial baldia

Ping Zhu upfront

08T he Goldilocks of Cells T oo much or too little cell death can lead to disease. Scientists are learning how to find the range that’s just right.

10 T-Cell Booster Kits A bioengineer remodels cell surfaces to prod the immune system.

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l asting Memories Measuring molecules at a single synapse gives clues to how memories become long term. Read the story at www.hhmi.org/bulletin/aug2011.

Scientists are an inherently curious bunch. If they need a new tool to find answers, they often figure out a way to build it. Like a microscope to observe the what, where, and how of protein interaction at a synapse. Or small molecules to explore the tight regulation of cell death in cancer and wound healing. Even designing nanoparticles to learn how to make immune cells better pathogen fighters isn’t too far a stretch. Who says science isn’t a creative pursuit?

August 2o11 | hhmi bulletin 7 upfront

The Goldilocks of Cells Too much or too little cell death can lead to disease. Scientists are learning how to find the range that’s just right.

Every day, billions of cells in the human body undergo a quick and painless suicide called apoptosis. Self-destruction of so he blocked expression of the protein in the right cells—those that are old and slow, have mutations, or are mice. A third of the mice developed leuke- damaged by a virus, for example—keeps the rest of the organism mia or lymphoma within 15 months, his lab alive. But when too many healthy cells die, the body suffers. group reported in Genes & Development in October 2010. Without the cellular sui- “Apoptosis is one of the most tightly cell death. In humans, there are eight IAPs, cide pathway kicking in, their low apoptosis regulated pathways in cells,” says HHMI with different effects throughout the body threshold allowed cancer cells to thrive. But investigator Hermann Steller, “because so that long-living cells, like neurons, don’t when the researchers also blocked expres- if you make a mistake, you can’t undo it. die as easily as those with a short lifecycle, sion of a key IAP protein, the effect was Dead cells can’t come back to life.” like skin cells. Other proteins, in turn, regu- reversed—apoptosis could proceed, killing Steller, at the Rockefeller University, late the IAPs: in humans, Smac and ARTS off cancer cells. has spent the past three decades trying to do the job; in fruit flies, it’s the aptly named “The ideal cancer drug would block the understand these strict levels of regulation. reaper, hid, and grim, discovered in part IAPs, as ARTS normally does, or restore Now, he’s translating those findings into by Steller’s lab group in the 1990s. ARTS, ARTS expression,” says Steller. With his developing small molecule drugs for two reaper, hid, and grim all encourage cell sights set on such a drug, he’s collabo- diametrically opposed purposes: healing death by blocking IAPs. rated with clinical scientists to find out wounds and treating cancer. Abrasions and “These are the brakes and the accelera- how ARTS is silenced in leukemia and to burns heal faster, he’s found, when cellu- tors of cell death,” Steller says. “They hold develop molecules to block IAPs. In work lar suicide is turned down. By turning up the keys to controlling the whole pathway.” published September 2010 in the Journal of apoptosis, however, he can treat cancers by Scientists studying acute lymphoblastic Cell Biology, Steller and his colleagues con- killing off the cells that drive their growth. leukemia had found that in many instances cluded that reaper and hid—the functional At the crux of Steller’s research is a fam- of the disease, ARTS expression was dimin- equivalents of ARTS in the fly—work by ily of proteins called IAPs (inhibitors of ished. Steller wanted to know whether a clustering on the mitochondria, a cellular apoptosis proteins) that put the brakes on lack of ARTS was sufficient to cause cancer, organelle critical to apoptosis. Now they’re

8 hhmi bulletin | August 2o11 Emily Robertson heal slower. that whencelldeathisincreased, wounds cuts andburns.Likewise,Steller hasshown wounds healfaster—goodforhealing nasty wound healing.Withimpaired apoptosis, their cancer-free counterparts: speedy ­an expression in mice, the tumor-ridden drawback. WhenStellerblockedARTS studies thecellularsuicide pathway. sachusetts InstituteofTechnology whoalso Horvitz, anHHMIinvestigatorattheMas- strong andthepromise great,” saysH. sion totreatcancerisinearlyanimal trials. sends themoleculetomitochondria. Aver- they’re onaprotein sequence tacking that conserved regionofreaperandgrim, developing asmallmoleculebasedon imals had one health advantage over imals hadonehealthadvantage Turning upapoptosis,however, hasa “The rationaleforthesedrugsseems ­ Robert

(which killscancerthroughinducing wide- including cancerousones—tomultiply. increase thesignalsthattellnearby cells— duces aproblem:moreapoptosis may process ofhealing.Butincancer,itintro- some levelofapoptosisactuallyhelpsthe he explains.For woundhealing,thismeans I’m going todie, youneedtoreplaceme,’” Steller hasfound.“Thecellissaying‘look, nearby cellsencouragingthemtodivide, goes apoptosis,italsosendsoutsignalsto clear-cut, he’s found.Whenacellunder- and regeneration.” pathways. It’s thissliderbetween cancer patient youwanttodiminish thosesame them faster,” saysSteller. “Butinacancer wound, youcanstimulate pathways toheal This maymeanthatradiation therapy But the dividing line may not be so “This meansifpeoplehaveamajor to liveordie. cell’s decisions: whether mostfundamental howing scientists tocontrola understand rapidly totherapeutics,hisresearch ishelp- text ofpossiblenoveltherapeutics.” andintriguing inthecon- novel, important, of mitogens. goal wouldbelessapoptosisandasurplus tosis withnomitogens. For healing,the cancer, theidealmix wouldbemoreapop- pick andchosewhichonestoturnon.For of theapoptoticpathway, they’d beable to signals—called mitogens—from therest Steller canteaseapartthesegrowth-causing ing aprimarytumor. Ifresearcherslike cancer tospreadatthesametimeit’s kill- small molecule compounds could force a spread apoptosis)oroneofSteller’s new Andwhetherornothisfindings lead “Steller’s recentwork,” saysHorvitz,“is W

– August 2o11 S arah C .P. W

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hhmi illi

ams bulletin 9 upfront

T-Cell Booster Kits A bioengineer remodels cell surfaces to prod the immune system.

Darrell Irvine is focusing his engineer’s mind to boost the body’s defenses against cancer.

He’s also working on ways to deliver drugs directly—and only—to the cells that need them. Matt Kalinowski

10 hhmi bulletin | August 2o11 T cells from the immune system can be removed from a cancer patient, trained in a laboratory dish to recognize and attack tumor cells, and then returned to the patient ready for battle. In some of hours to days, particles placed on the plasma membrane would rapidly be swept clinical trials, up to 70 percent of patients with advanced melanoma into the cell’s recycling bins and inacti- have seen their tumors shrink with this experimental immunotherapy. vated. After some trial and error, Irvine found he could shackle the booster kits to These tumor-hunting T cells don’t and accurately zeroed in on the metastatic small reactive sulfur groups, called thiols, remain active for long, however, unless tumors, according to the researchers’ report which remain stable on the cell surface, the patient receives sustained doses of in the September 2010 Nature Medicine. allowing the nanoparticles to survive for at stimulatory interleukins such as IL-2. These Importantly, the enhanced cells remained least a week. “I think this linkage is some- powerful immune stimulants can cause low viable longer than untreated T cells and how stabilizing the material on the surface,” blood pressure, flu-like symptoms, nausea, increased the survival rates for the cancer- Irvine says. diarrhea, and dizziness. For some patients, ridden mice receiving them. The bioengineer envisions an array of this adjuvant drug treatment makes T-cell Remodeling the surface of cells with additional applications. In a related experi- therapy too dangerous. synthetic materials for therapeutic ends ment described in the Nature Medicine But what if the T cells could carry reflects Irvine’s merger of materials science paper, Irvine attached drug-filled nanoparti- their own tiny supplies of interleukins, just and immunology. He studied engineering cles to blood stem cells. When transplanted enough for their own needs? in college and materials science in graduate into mice lacking blood-forming cells, the HHMI investigator Darrell Irvine has school. “I became attracted to life science enhanced stem cells restored the bone mar- found a way. In his laboratory at the Massa­ and problems in medicine, and how some- row more quickly than stem cells without chusetts Institute of Technology, he and his one with an engineering background could the drug boost. He’d also like to try trans- colleagues make nanoparticles filled with have a role in those fields,” he says. In porting small molecule drugs such as interleukins and attach these immune particular, he became fascinated with the vaccines or contrast agents into patients. “booster kits” to the surface of T cells. immune system and its complex regulatory Another possibility is using T cells to carry They’re so minuscule that 100 booster kits actions that control the body’s defenses. antiretroviral drugs into the deepest recesses can fit on just 3 percent of the cell’s surface of HIV/AIDS patients’ immune systems. area, where they slowly release their con- Improving Cell Therapy Transferring cells in and out of the body tents to the cell. Irvine found success when he turned a along with the necessary lab work makes By “getting the drug just to the cells that standard approach on its head. For several T-cell therapy costly and time-consuming. need it,” says Irvine, “we’re looking for the decades, researchers have explored the pos- Ever the engineer, Irvine is brainstorming extra nudge that could take immune-cell sibilities of using cells directly as therapy possible shortcuts, aiming for “strategies therapy from working [only] in a subset of (stem cell transplants, for example) or as where you could deliver drug agents, like people to working in nearly all patients.” transporters. One research group was devel- interleukins, directly to specific cells within Irvine and postdoctoral research associ- oping T cells as vehicles to infect tumors the patient,” he says. ate Matthias Stephan mounted booster kits with cancer-killing viruses. “Instead of using Meanwhile, his group continues to containing IL-15 and IL-22 onto T cells the T cell as a ferry for a virus,” Irvine says, develop the booster kit method, filling the extracted from metastatic melanoma tumors “we started thinking about putting synthetic particles with IL-2 and testing them in implanted under the skin of mice. The drug particles onto T cells to make them more clinically relevant melanoma mouse T cells were “educated” in laboratory dishes function better.” models. The researchers look forward to a to recognize and destroy the melanoma First Irvine’s group had to overcome a day when patients undergoing T-cell ther- cells. When infused back into the rodents, difficult challenge: because components of apy may be spared any toxic side effects. the enhanced T cells rapidly proliferated the T-cell surface are recycled over periods W –Richard saltus

August 2o11 | hhmi bulletin 11

first time myself, I found the textbook approach very dry,” she says. “It really did not give a sense at all of science being a living, breathing, growing, changing kind of field.” In the first edition of Molecular Biology, Doudna and her coauthors Michael M. Cox and Michael O’Donnell had set out to humanize their subject matter almost entirely within the confines of the printed page. For instance, they opened each chapter with a first-person vignette from a scientist talking about a moment of discovery. But Steinberg’s tablet computer demonstration got them dreaming about adding video versions of the vignettes that stu- dents could tap into as they read. They imagined 3-D animations and virtual experiments where students could choose their data sets and follow them through to the outcome. “We have ideas and the ground is definitely shifting quickly,” on the first edition of Molecular Biology: Principles and ­Practice says O’Donnell, an HHMI investigator at Rockefeller University. when its scientist authors began dreaming up ideas for the second. “We’re all thinking about it and we’re all very excited.” They would go way beyond words on the page to give students a So what will college science textbooks look like in five years? front row seat to science in action. A decade? The boundaries have already stretched beyond the It was the summer of 2010, and the collaborators had just met physical page to incorporate animations of molecular processes, with Adam Steinberg, the book’s artist. On his newly minted iPad, videos of scientists talking about discoveries, and social net- Steinberg showed them a splashy periodic table application called working between researchers and students around the world. The Elements: A Visual Exploration that rocked their world. Publishers are offering content that teachers can customize as The app included cleverly worded facts and scintillating they see fit. However, a flock of unknowns is circling—Will the periodic table trivia. But its real impact was visual. Its creator, iPad prevail? Will the cost for developing spectacular apps be scientist Theodore Gray, had gathered a mini-museum’s worth more than students are willing to pay? of fascinating objects to represent each element—from an Jonathan Crowe, an editor in chief at Oxford University Press iridescent hunk of bismuth to a dimestore dragon figurine who works with science authors, predicts the textbook industry made of copper. App users could see the objects in 3-D and will change more in the next few years than it has in the past 50 rotate them, front to back and front again, with the swipe or 100. And plenty of new and traditional publishers are moving of a finger. fast to stake a claim to that future. It wasn’t quite holding an object and turning it over in your hand, but it was pretty close. Still a Small Market Jennifer Doudna, an HHMI investigator at University of Cali- College textbooks are big business. Higher education textbooks fornia, Berkeley, and coauthor of the textbook, marveled at how sales were $4.58 billion for 2010, an increase of 7.8 percent since the app transcended the traditional boundaries of a textbook. 2009, according to U.S. publishers’ net sales revenue released by “When I was in college and learning [molecular biology] for the the Association of American Publishers in February.

14 hhmi bulletin | August 2o11 “When I was in college and learning [molecular biology] for the first time myself, I found the textbook approach very dry. It really did not give a sense at all of science being a living, breathing, growing, changing kind of field.” —Jennifer Doudna

Digital textbooks, however, make up roughly 5 percent of Users can access a growing library of original content as well as the textbook market, says Vikram Savkar, publishing director at previously published material from Nature, mostly in genetics, Nature Publishing Group (NPG), which will soon launch its sec- cell biology, and ecology. ond college-level digital initiative. Other numbers bear this out: “Eventually it will have coverage across all of biology,” he for John Wiley and Sons, a major publisher of science textbooks adds. Instructors can assign readings, asking students to explore for the higher education market, $10 million of its $290 million them at their leisure, plus students can log on and ask questions in higher-education revenue last year came from digital-only sales of scientists, communicate with students in other parts of the (titles not packaged with a print textbook)—that’s 3.5 percent of world, and read student-written blogs on topics like global warm- the company’s higher-education revenue. ing and neuroscience. “Everybody in the market says it’s time to go digital, yet year The second NPG project is a $49 interactive digital Principles after year people still spend most of their money on print text- of Biology textbook that will debut in September 2011 at three books,” says Savkar. “I personally believe that’s because there California state university campuses. Principles of Biology sets out haven’t been digital projects that have come out yet that are to combine the scientist-produced content and high-quality illus- really exciting to the market and that are designed to be effective trations of a print textbook with primary literature from Nature, as replacements for textbooks.” well as animations, assessment tests integrated into the lessons, and interactive simulations of concepts that students can manipulate. A New Entity “Wherever possible, we try to get the student actively engaged,” Matt MacInnis, CEO of an interactive publishing company Savkar says. A “Build a Fly” module, for example, allows students called Inkling, says “textbook” is too narrow a term for the new to choose different types of genetic material for a fly and then see kind of learning content his company is developing. An alumnus how the phenotype changes with their choices. of Apple’s international education division, MacInnis envisions Students can access the material on a desktop, laptop, smart- traditional print textbooks being replaced by a new generation of phone, or tablet. They can also print one color copy of the media-rich learning platforms. textbook for free. If teachers want to customize the content—as Inkling, which was born in 2009, takes existing textbooks 25 to 35 percent of instructors have indicated to NPG—the digi- (and their supplemental online content like animations and tal textbook will automatically rearrange itself as requested. self-assessment­ quizzes), “gently disassembles” them, and then Free updates will come continually, after review by an edito- reassembles them for multitouch tablet devices like the iPad. rial board. “We’re looking at this as a living edition,” says Savkar. For example, Inkling’s version of Hole’s Human Anatomy and ­Physiology features 400 interactive “exhibits” embedded in the An Investment text, including 3-D animations, anatomical diagrams where Issues of price, always a hot topic among cash-strapped college ­students can make the labels disappear and test themselves, students, are complicated. E-textbooks cost about half the price of and interactive quizzes that give instant feedback. Students can print. Inkling’s titles generally cost 15 percent more than e-books, highlight passages with a finger swipe, swap ideas onscreen with but students can pay as they go for the content at $2.99 per chap- friends on blue “sticky notes,” and read handy annotations, in ter. Teachers can pick and choose chapters for a course, so if they purple, from their teachers. need only 15 chapters, students pay $45 instead of $180 for the Brown University School of Medicine recently bought into full 60-chapter book. the Inkling concept. Its incoming first-year students, 108 of them, Still, students will need to shell out the $500 or more for the will be required to purchase an iPad and will use six Inkling titles tablet device. And interactive publishers who develop iPad con- as their textbooks for core preclinical classes. tent may save on printing and paper, but they will have higher NPG, publisher of the journal Nature, is finding ways to make development costs for the multimedia features, says Alison Pend- scientific instructional content more accessible to students. In ergast, senior vice president and chief marketing officer at Jones January 2009, NPG unveiled a free collaborative learning site and Bartlett Learning, a large U.S. college textbook publisher. called Scitable, “as a personal research space for undergrads and “I don’t necessarily think technology is going to drive down high school students with a deep love of science,” Savkar says. the cost of textbooks,” says Pendergast. “If anything, it’s going to

August 2o11 | hhmi bulletin 15 keep them priced where they are. All of those additional compo- The landscape of textbooks is changing rapidly, says Lue, but nents—animations, simulations, and interactivity—are expensive he’s less interested in whether it brings the latest whizbang inter- to develop. active features to a nearby screen than in how it’s changing to “We’re continuing to try to find business models that keep the meet teachers’ increasingly well-defined and precisely planned resources affordable for students but at the same time are cutting pedagogical goals. Textbook authors used to focus just on clearly edge. It’s hard to do this stuff cheaply—and in order to do it well, explaining concepts, but “authors now have to spend a lot of time there has to be investment.” thinking not just about how to present something but about how The nonprofit E.O. Wilson Biodiversity Foundation estimates to teach it,” says Lue. it will need $10 million to develop a 59-chapter digital biology “In the past, textbooks were simply laying out the information textbook called Life on Earth. But the foundation plans on paying in the written word with still diagrams that were clear. But there for it with money from private and public donors and making the is so much we have learned about how best to teach material, textbook available to the public for free. how best to use interactivity and activity-based learning methods,” HHMI investigator Matthew Scott, a professor at Stanford he says. For example, students in biology, computer science, and University and coauthor of Molecular Cell Biology, is a fan of visual art courses can work together to develop their own scien- another nonprofit site with free content, Khan Academy. Devel- tific animation. oped by an MIT graduate named Salman Khan, the site offers “It’s not just the material between two covers,” Lue says. “It’s upward of 2,000 video tutorials that consist of scrawled notes and also a whole program in terms of how to teach more effectively.” colored doodles on an electronic blackboard, with Khan’s voice “The textbook is always there as a framework,” says ­Dennis explaining it all. The content leans heavily toward precollege Liu, who heads HHMI’s education resources group, which pro- math and physics but also includes dozens of higher-level biology duces materials to supplement textbook content for HHMI’s and organic chemistry videos. Teachers can have their students ­BioInteractive website (www.hhmi.org/biointeractive). “We have log on as a class, then direct them to particular videos and assess- to be mindful of what teachers are teaching now while also expos- ment exercises and track their process. ing them to new content and ideas and helping them to inject “It’s enormously well done,” says Scott. “I use it, my kids use cutting edge research into their curricula.” Liu hopes to see it, and friends who are Stanford faculty use it.” BioInteractive animations, some of which are being adapted for smart phones and the iPad, become incorporated as digital assets Effective Teaching in new textbook-like products. “I can imagine future partnerships At Harvard University, students may be fused to their iPads in with authors and publishers to custom design some of our media their off hours, but they’re not using them in their undergraduate to match new digital textbook content,” says Liu. biology classes yet. Instead, teachers rely on the latest in interac- tive technology such as animated movies that illustrate cellular Nonstop Updates processes and handheld clickers to gauge the class’s understand- One dilemma in the life sciences is how to distill into a single ing of a particular concept and drive discussion. course the “enormous explosion” of information that has come “After watching an animation of, say, the transport of proteins with breakthrough discoveries in the past 20 to 30 years. “It’s both across a nuclear envelope, we’ll have a discussion of the core pro- a very rapidly expanding area and one where there are still a lot cess that’s being shown,” says Robert Lue, a professor of molecular of things that haven’t been settled yet,” says Lue. “That means the and cellular biology and director of Life Sciences Education at life sciences courses and textbooks are constantly responding to Harvard University as well as an HHMI undergraduate program revisions of fundamental paradigms.” director. “But then we’ll have a discussion in the context of a liv- With two or three competing models for a particular idea, ing cell—what are some of the things we didn’t show and how are Lue says the current challenge for textbook authors is to assess they going to affect the process we’re talking about? the entire spectrum of materials and choose which examples “It becomes a real teaching tool, not like a passive look at best illustrate fundamental principles. “We have to help instruc- something,” says Lue, who runs Harvard’s Biovisions program tors use the material most effectively, rather than just handing for digital animations. it over,” says Lue.

“It’s both a very rapidly expanding area and one where there are still a lot of things that haven’t been settled yet,” says Lue. “That means the life sciences courses and textbooks are con- stantly responding to revisions of fundamental paradigms.”

16 hhmi bulletin | August 2o11 Doudna: Michael Marsland / Yale University O’Donnell: Rockefeller University Scott: Matthew Scott Lue: Harvard University gast. “It’s stillaprettyfunctionaltool.” will probablynotgoaway asfastpeopleanticipate, saysPender- a yellow markerisjustsimpler thanhighlightingelectronically? book because sitting in the grass and highlighting a page with and illuminated manuscripts? Orwillstudents clingtothetext- morass, willthepapertextbooksoongowayofcavedrawings So while authors and educators wend their way through the digital T thanfiguringouthowtouseinteractivityteachmoreeffectively.Lue notesthatcoolinteractivefeaturesarelessimportant a textbookauthor, isalreadyafanofoneteachingwebsitepackedwith2,000video tutorials onmathandsciencetopics.Robert experimentsandconversationswithpracticingscientiststohelpmakesciencecomealiveforstudents.MatthewScott,also virtual (l-r) Thesecondeditionofthemolecularbiologytextbookco-authoredbyJenniferDoudnaandMichaelO’Donnellwilllikelyinclude into the narrative.” this journalforparticularadvance.” Andthenwhenthenew that feed will see it has happened and then go have a look at with thebookifadiscovery comesin.Anybodywho’s following come in,” saysCrowe. “You couldhaveaTwitter feedassociated topical matters,“that’s wherethings likesocial networkingcould ones,andthenneweditionsconstant everythreeyears.For more month, anditcouldneverstop.” without mebreathingdown their necks.Icouldbeonthemevery lar biologyteamIworkwith,atleastthey’vegotacoupleofyears with thelatestdiscoveries, orstick totheoldwayofcurating. updatingthingstokeeppace whether authorswillbeconstantly to changedigitalcontentatwill,itwillbe“fascinating” tosee you’re doing abalancing act.” moment,” hesays.“Yet you want thebooktoseemupdate,so thanare perhapsthey may wrong seem orat lessthe important are ofenduringvaluefromthosethatmerelyinvogue. ling partoftextbookauthorshipisdistinguishing discoveries that ­version ofthetextbookcomesalong,“theauthorscanbuild it he The bestprinttextbooks,especially forupper-level courses, He suspects there will be incremental updatesratherthan He suspectstherewillbeincremental “In theory, could never end,” their task he says. “The molecu- Oxford University Press’s JonathanCrowe sayswiththeability “You don’twanttoputintoomanyofthelatesthotthingsthat For HHMIinvestigatorMatthewScott,aparticularlycompel- B e s t of B oth

Movement, theycouldgoonawebsiteandseevideoof ing of thematerial. at their own- paceandusevisualstoenhancetheir understand izes thelearning experience,sostudentscanprocessinformation you’re tryingtolearn.” theconcepts to providetheexplanationyouneedunderstand life vest.It’s insurance—yougrab ontoitandhopethatit’s going and thisstuffisreallyhard,Ithinkpeopleusethetextbookasa said, ‘Don’t relax. In afew months I’m going to be calling you.’” our booksigning party [for the first edition], and our publisher the experiment.” andwalkingthemthroughhow onedoesshowing themdata to datewithinterviewsasnewdiscoveries aremade. We could have discussions with practicing scientists kept very up allow studentstogetreal-timeinformationaboutthatconcept. topic inmolecularbiologyandhaveanapplicationthatwould allow ustogivepeoplemoreoptions.We couldpickanysortof quite ahighlevelofdiscussion findings. aboutexperimental there willbelesstext,frankly, because we’vefoundthatfacultywant Practice, Doudnahopestofusethebestofprintanddigital.“Idoubt a lifevest.Inthesecondedition of MolecularBiology:Principlesand 1.35 pounds,makingthetextbookseemmorelikeamillstone than MLK andJFKgetamuch more visualexperienceovertime.” Luther King,” she says. “They could see and read original text from “Instead ofreading 20pageson theCivilWar orCivilRights ofdigitalcontent,shesays,isthatitpersonal- The advantage “When you’re trying to learn math orchemistry or physics, Doudna hopestohaveallthatoutinthreeyears.“We just had “Or itcouldbeahands-ondemonstrationofthediscovery, “But expanding intootherkindsofmedia liketheiPad will The iPad isaphysicalobject,too—and onethatweighs amere

we visit b www.hhmi.org/bulletin/aug2011. e xtra: To learnmoreaboutdigital supplementstotextbooks, August 2o11

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17 S ciENTISTS are cautiously bringing gene therapy out of the dark.

by VIRGINIA HUGHES illustration BY RUBENS LP

At age 8, Corey Haas stood at SQUARE ONE of a floor maze at the Children’s Hospital of Philadelphia.

Black and white squares covered the ground, with an arrow they used it on people, they came up against two major obstacles: on each to show him the correct path. He took a few steps and the new gene would be expressed only for a short time or the then paused. “This is being really hard,” he told the adults in the immune system would reject the therapy outright. room. After about a minute, they nudged him in the right direc- Today, researchers are tackling both problems by finding tion. After a couple more timid steps, he stopped again, frustrated. clever ways to deliver long-lasting, healthy genes without trigger- “I can’t even see anything.” ing a serious immune response. One promising approach is to Corey has Leber’s congenital amaurosis (LCA), a rare inher- repair a gene in the patient’s cells outside the body and then put ited disease in which a genetic glitch damages cells in the retina, the cells back after the gene has fully integrated into the genome. causing blindness. On that fall day in 2008, he was tackling the Another tactic is to tweak the vehicles that deliver the gene so that maze as the youngest of 12 patients who had received an experi- they aren’t as easily seen by the immune system. mental therapy for LCA. Ninety days before, a surgeon had Then there’s the strategy behind the LCA trial: targeting injected a healthy version of a gene called RPE65 into the back parts of the body—such as the eye or brain—that are some- of Corey’s left eye. His eye cells began pumping out the protein what isolated from the immune soldiers in the blood. A leader that he was born without, allowing him to see. of this study is Katherine High, a gene therapy pioneer and In that first, frustrating maze, Corey was relying on his HHMI investigator at Children’s Hospital. High has her hands untreated eye, wearing a patch over the newly treated left eye. in many lines of gene therapy research, but so far the LCA trial About an hour later, he did the maze again, this time using his has produced the most dramatic outcomes. At a conference in left eye to guide him. He cruised through it in about 20 seconds. May 2011, her team announced the latest results: 3 of the origi- The spectators burst into applause. nal 12 patients have received the therapy in their second eye, The trial’s participants ranged from 8 to 44 years old, and and their vision has improved further. The researchers plan to the therapy worked, to varying degrees, for all of them. When launch a phase 3 trial—the last step on the long road to regulatory the results were published, in November 2009, it was a boon approval—this fall. to the gene therapy field, which has had highly publicized ups After two decades in this controversial field, High has diffi- and downs since its debut in the late 1980s (see Web Extra gene culty wrapping her head around this medical miracle. “It’s almost therapy timeline). The general pattern: scientists would see fan- Biblical,” she says. “I still can’t quite believe that something like tastic results when testing gene therapy on animals. But when this could actually happen.”

20 hhmi bulletin | August 2o11 Beyond dogs pharmaceutical companies in pursuing gene therapy and height- High has been fascinated with the idea of gene therapy since she ened the perception that it was somehow dangerous.” launched her first laboratory, at the University of North Carolina, In the summer of 2001, High and Kay began a trial in which in 1985. She had spent years pinpointing the genetic glitches they injected factor IX into the liver of volunteers with hemo- responsible for bleeding disorders called hemophilias. Most of philia B. One participant, a 31-year-old man, had a baffling these mutations damaged clotting factors, enzymes that help the reaction. At first, the therapy worked exactly as it had in dogs: lev- blood clot. “From there, it’s not a very far leap to ask if there’s a els of clotting­ protein in his blood rose dramatically. But after four way we can use the gene to go into a person with hemophilia and weeks, his factor IX levels dropped, while liver enzymes—a sign of correct their disease,” she says. liver injury—began to rise. By 12 weeks, his enzyme levels were Those were the glory days of gene therapy, when researchers back to normal, and he had no detectable factor IX in his blood. were seeing their first successes in animal models and declaring The liver enzymes were a sign that the man’s immune system that the treatment could one day cure thousands of genetic dis- was killing all the cells that had received the new gene. As High eases. The first human clinical trial, launched in 1990, treated a and Kay later figured out, the patient’s immune system was react- rare immune deficiency, dubbed SCID, in a 4-year-old girl. ing not to the new gene itself but to proteins, called capsids, that Researchers removed some of the girl’s blood, used a retro­ make up the shell of the AAV vehicle (known as a vector). virus to insert a healthy version of the broken gene into her “This was totally unexpected,” says Kay, now professor of pedi- white blood cells, and then infused the altered cells back into atrics and genetics at Stanford. “There had been tests in dogs, her body. The therapy seemed to work: four years later, the girl monkeys, rabbits, rodents—nobody had seen this response in carried the healthy gene in half of her white blood cells. From animals.” After hearing the news, Avigen, the California biotech 1989 to 1998, some 275 other gene transfer protocols were listed company that was providing High with AAV vector, pulled out of in U.S. regulatory registries, according to the NIH Office of the research. In short order, High convinced her hospital’s lead- Biotechnology Activities. ership to build its own multimillion dollar, industry-grade vector By the late 1990s, High’s team and a group at Stanford Uni- manufacturing facility. It was up and running by the summer of versity, led by Mark Kay, had independently cured hemophilia B 2005, and two years later the National Institutes of Health chose in dogs. Both groups used a new delivery method: they used part the facility to be the sole provider of all the AAV clinical trials of a virus, called adeno-associated virus (AAV), and its outer shell it funded. to carry the factor IX gene, which codes for a clotting factor, With an ample supply of AAV, High extended her work to into the dogs’ cells. AAVs were thought to be safer than retro- other diseases. For years, she had wanted to collaborate with one viruses, which integrate themselves into the host’s genome and of her Penn colleagues, ophthalmologist Jean Bennett, who she could potentially turn on cancer genes. In contrast, these modi- had gotten to know because their daughters ran on the same track fied AAVs almost always unload their genetic packages outside team. Bennett had used AAV gene therapy on dogs with LCA, the host’s genome. and all of them showed improved vision. High had tried to con- High and Kay collaborated to bring this therapy to human vince Avigen to begin an LCA clinical trial, but the company did clinical trials. But eight months after they published their dog not want to invest in such a rare disease. data, the field took a major hit. In 1999, a gene therapy trial for With the new AAV manufacturing facility, High and Bennett a rare metabolic disease at the University of Pennsylvania caused could do it themselves. “Jean had done 35 dogs—it was clear that the death of an 18-year-old named Jesse Gelsinger. it worked,” High says. It was time to test it on people. Gelsinger’s death unleashed a mountain of scrutiny from the press and regulatory agencies. The Food and Drug Admin- Seeing success istration temporarily suspended two other studies using the same LCA is an untreatable group of diseases that crop up in about 1 in viral vehicle—adenovirus—that was used to deliver Gelsinger’s 80,000 people. The condition is caused by mutations in any of 13 therapy. (Despite the similar name, adenovirus is very different known genes, including RPE65, which leads to the breakdown of from AAV.) Within months, the agency issued more stringent regulations on gene therapy clinical trials and the University of Pennsylvania (Penn) stopped all clinical trials at its Institute for “It’s almost Biblical,” she Human Gene Therapy. High’s hemophilia trial at Children’s Hospital, just down the says. “I still can’t quite road, used the AAV vector and was not delayed or shut down. believe that something like Still, she says her work was affected in a broader sense. “It raised this could actually happen.” questions about the safety of gene therapy, and that had broad Katherine High ramifications for the field,” she says. “It reduced the interest of

August 2o11 | hhmi bulletin 21 cells in the retina, the light-sensing film that lines the back of the “After she had this procedure, she was sitting in the stands eye. (See Web Extra sidebar, “RPE65: A Blinding Gene.”) one day. She couldn’t see the outlines of her daughter’s face, but “These kinds of inherited retinal degenerations are just she saw the person on third base steal home. And that was her devastating—patients end up blind at a very young age,” notes daughter,” High says, tearing up. “It’s very, very hard to fully com- Joan Miller, chair of the ophthalmology department at Harvard prehend that kind of thing happening.” ­Medical School. Although some patients benefit from implanta- Tami’s improvement is impressive, but the younger partici- tion of artificial retinas, “it would just be wonderful to restore a pants showed even better results. Corey, for instance, now age more natural vision to these patients,” she says. 10, can read the blackboard at school if he sits in the front row. After the disappointing hemophilia trials, High began to brain- He plays outfield on a Little League baseball team and rides storm ways to avoid the body’s immune response to gene therapy. his bike independently. “There are a lot of differences in col- The eye, she thought, might be an ideal spot: it’s a small and con- ors now,” Corey says. “When I go outside, my pupils will shrink tained area—it would need only a small amount of AAV—and it right down.” is relatively easy for surgeons to access. The eye is also somewhat At the same time as the Penn trials, research groups in London isolated from the peripheral immune system. and Florida were doing similar AAV therapy for LCA. Patients Between October 2007 and June 2009, the five children in all three groups saw gains in vision after the treatment. And, and seven adults in High and Bennett’s eye study underwent perhaps best of all, none had an immune reaction to the therapy. a 90-minute surgery to receive the gene therapy. The surgeon, “The ophthalmology field was very excited because this Albert Maguire (Bennett’s husband), had done all the canine eye was such a huge advance,” says Harvard’s Miller. The findings, surgeries in Bennett’s earlier work. which received a lot of media attention, also helped gene thera- Maguire injected a tiny amount of liquid holding the AAV py’s reputation. “Gene therapy had taken a major hit before this,” package into a pocket of space under the retina. The vector Miller says. “So this [research] was a huge push for gene therapy would migrate into retinal cells and release its DNA contents: the of any kind.” healthy RPE65 gene. The DNA would then invade the nucleus and be expressed just like a normal gene. Evading the alarm system For three months after the surgery, the 12 patients returned to There are dozens of viable approaches to gene therapy, and High the hospital several times for various vision tests, from eye charts has, at some point, worked on most of them. For example, the to measuring the range of peripheral vision to navigating floor vector manufacturing facility at Children’s Hospital produces not mazes. All the participants showed improvement in at least one only AAV viral vectors but also lentiviral vectors. Lentiviruses— of the tests. Their pupils showed a 100-fold or greater response to retroviruses of which the most famous is HIV—work by quietly light. Four patients are no longer classified as legally blind. slipping their contents into the host’s genome, so that every time High is professorial and intense when she discusses the molec- the host cell replicates, so does the virus. This is one reason ular tricks of gene therapy. But she gets emotional when talking why HIV is so destructive—and why lentiviral gene therapy has about LCA patients. Her favorite anecdote concerns the oldest much promise. participant, 44-year-old Tami Morehouse, whose daughter is a Retroviruses were used in the first gene therapy trial and now, star softball player. Before the treatment, Tami would sit in the 20 years later, several groups are making headlines for treating bleachers at her daughter’s games, in near darkness, hanging on blood diseases with the same approach. Researchers first harvest every word of a play-by-play from her husband. blood stem cells—which can give rise to any type of blood cell— from the patient’s bone marrow. In the lab, they mix the stem cells with a lentivirus that delivers a healthy version of the broken gene. Finally, patients receive an infusion of their own repaired He knew the surgery was the stem cells. If all goes well, their daughter cells will carry working right decision four days after copies of the gene. Corey left the hospital, when With this so-called ex vivo approach, “immunity is not a big the family took a trip to the zoo issue,” notes Luigi Naldini, director of the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, who has worked on and Corey said that the sun lentiviral vectors for 15 years. The lentivirus delivering the new was hurting his eyes. “That had gene is cleared away before the cells are infused back into the never happened before. It was body, so the immune system has nothing to pounce on. “You pre- a pretty big deal.” vent the alarm system from going off,” he says. Ethan Haas Starting in 2006, French researchers performed ex vivo lentiviral gene therapy on two boys with X-linked adrenoleu-

22 hhmi bulletin | August 2o11 Researchers Katherine High (left) and Jean Bennett collaborated to move gene therapy for a blinding eye disorder from animal studies to human clinical trials, with promising results. This fall the researchers plan to launch a phase 3 trial, the last step to regulatory approval.

kodystrophy, a fatal brain disease caused by loss of the ABCD1 the field is well aware of and that we need to improve upon,” gene. This gene plays an important role making myelin, the fatty Leboulch says. sheath that insulates neurons. Without ABCD1, the brain can’t Cancer is less of a concern with the AAV vector used in the send electrical messages properly. eye trials because most of it stays outside the genome. Because it The boys received a transfusion of their own modified blood doesn’t integrate into the DNA, however, it’s not useful in cells stem cells. Two years after the therapy, about 15 percent of their that constantly divide, such as those in the blood, skin, and intes- blood stem cells carried the fixed version of ABCD1. Their brain tine. And, of course, AAV’s capsid envelope brings about that cells had started making insulated neurons and the damage unwanted immune reaction. ceased. Although the boys still have some cognitive difficulties, Several groups are at work fine-tuning the AAV vector so that the therapy saved their lives. it’s more efficient, delivering more of the target gene with less In 2007, some of the same researchers used the approach on exposure to the viral capsids. High’s group, for example, is col- an 18-year-old man with ß-thalassemia, a genetic disease that pre- laborating with researchers from St. Jude Children’s Research vented him from making healthy red blood cells, which carry Hospital, Stanford University, and University College London to oxygen throughout the body. The man had received a blood test a modified AAV vector that may reduce the immune response transfusion every month since he was 3 years old. in people with hemophilia. After receiving the gene therapy, he started making his own She’s also working on a different approach in which, rather healthy blood. “He has not received one drop of blood for three than adding a healthy gene, a molecular knife—called a zinc years,” says Philippe Leboulch, professor of medicine and cell finger nuclease—corrects the broken gene. These fingers have biology at the University of Paris and visiting professor at Harvard received much attention in the past couple of years, since High’s Medical School, an investigator in both studies. “He has a full- colleagues at Penn began using them to alter an immune sys- time job as a cook in a Paris restaurant, he has a girlfriend, he tem gene ex vivo in blood cells of patients with HIV. In a study feels good.” Leboulch plans to transplant a second ß-thalassemia of mice with hemophilia, published June 26, 2011, in Nature, patient this fall. High’s group reported the first demonstration that zinc fingers can also work their magic inside a living animal. The right vector for the job “Zinc fingers have several advantages over AAVs,” High says. Every gene therapy strategy has pros and cons. So far, ex vivo Perhaps most notably, they correct genes inside the stretch of the approaches haven’t run into a major immune response. But genome where they belong, meaning that normal cellular cues because their vectors are permanently inserted in the host’s will be able to turn them on and off when necessary. genome, they could inadvertently turn on cancer genes. Still, High says that in the short term, hemophilia patients are In the ß-thalassemia trial, for example, the lentivirus turned more likely to benefit from AAV approaches. “I know how long on expression of a protein called HMGA2, which has been it is from a mouse study to a clinical trial that works,” she says.

High: Universitat Autònoma de Barcelona Bennett: Daniel Burke Photography linked to benign and malignant cancers. “It’s something that (continued on page 48)

August 2o11 | hhmi bulletin 23

s she faced the end of grad time away from the lab will mean fewer publications—and more school, Karmella Haynes difficulty getting a job. wasn’t sure what direction Haynes’s mentor was Sarah Elgin, an HHMI professor who to take. “I couldn’t think of a created the Genomics Education Partnership and is intensely research project that got me involved in developing better ways to teach genomics. Haynes really excited,” says the gradu- recalls Elgin strongly encouraging her to take a traditional ate of Washington University research postdoc at first. But Haynes was persistent, so Elgin in St. Louis. pointed her toward a teaching postdoc position at Davidson Col- Haynes thought she might want to teach. But, like many lege in North Carolina. modern grad students and postdocs, she didn’t have enough Haynes thought it might be a chance to find out about life at experience teaching to know if she liked it—or if she could a liberal arts college while exploring whether she liked teaching. get a job doing it. She chose Davidson’s postdoc over other teaching opportunities Science educators say teaching experience is vital for post- because it provided a mix of education and research—just in case docs, many of whom are going to be teaching as part of their she changed her mind. faculty duties someday. But a lot of schools are struggling with “I was very aware of the fact that I was taking an alternative how to prepare graduate students and postdocs to teach, and there path,” Haynes says. “A bad move would have been to jump into is no consensus on the best approach. the first teaching position I saw. I was really careful to make sure “For someone truly interested in becoming an academic scien- the course of the fellowship left me with my options open.” tist, traditional training usually won’t offer lessons in pedagogy or how to teach,” says David J. Asai, director of HHMI’s precollege Teaching and Research Mix and undergraduate education programs. “I think teaching expe- A focus on research appears to be the hallmark of many of the riences for postdocs are a great idea if someone can be patient, successful teaching postdocs at liberal arts colleges and research get their research solid, and do a postdoc where they can learn universities. Many also include formal education mentoring by to teach and mentor undergraduates in their own research lab.” current faculty members or seminars on how to best teach so Few postdocs are getting teaching experience now. Greater students learn. The duration of teaching postdocs is traditionally than 60 percent have 21 or fewer hours of teaching experience, shorter than a typical biology research postdoc (two or three years, and almost a third have no experience at all, according to an rather than five or more). ongoing longitudinal study of science graduate students from At Davidson, Haynes spent the first year of her two-year post- Arizona State University, the University of Washington, and the doc doing research in a new field, synthetic biology, with mentor University of Wisconsin–Madison. Malcolm Campbell. Working at a college research lab was com- Postdocs who want some teacher training will find a handful pletely different from her grad school experience. “It was very of training opportunities, and the numbers are increasing. They small, in a wash-your-own-glassware, stuff-your-own-pipette-box range from formal teaching postdocs to programs that expose post- way,” she says. docs to teaching while they work in a traditional research position. Campbell taught her how to design projects that were easy for To land a job when the training is over, however, a student undergrads to jump into. “His approach was setting up student- must strike a fine balance between research and teaching, accessible science, rather than bringing the students up to the and few positions offer that balance. Teaching experience isn’t science,” Haynes explains. The lab focused on bacteria, which always seen as a plus by hiring institutions, especially research are easy for students to work with themselves, instead of using universities. Many faculty discourage graduate students or post- animals or complicated equipment. “They were pretty big impact docs from going after teaching experiences because they fear that projects but there wasn’t this big hurdle of technical difficulty.”

26 hhmi bulletin | August 2o11 “ I was very aware of the fact that I was taking

an alternative path.” —karmella haynes

The group published a research paper in the Journal of Biologi- Haynes says. “So I wanted to make sure I was competitive for a cal Engineering describing how they engineered the bacterium small liberal arts college job or a research university job.” Escherichia coli to solve a mathematical problem. The publica- tion landed Haynes on National Public Radio’s Science Friday. The College Myth “It was just really cool how this paper with undergraduates—not Haynes made a wise choice. Schools at all levels—liberal arts coming from a big, powerful research university—got us a lot of colleges, regional public universities, and major research insti- attention,” she says. The research also allowed Haynes to attend an tutions—look first at research, says Jo Handelsman, an HHMI international synthetic biology conference—her first professional professor and national education leader who runs a science edu- trip overseas—and meet some prominent scientists in the field. cation training program for graduate students and postdocs at In her second year at Davidson, Haynes focused on teaching. Yale University. She redesigned a bioinformatics course to overcome its intimidat- “If people want to go into academic positions, a pure teaching ing reputation among students. They were no longer left on their postdoc can be fatal,” Handelsman explains. “There is a myth own to navigate databases and new software; instead, she walked out there that you don’t need a research postdoc if you are going students through the complex material in class—a method she to a predominantly undergraduate institution, but many of them affectionately calls “synchronized swimming exercises”—before expect a strong research program.” making them go solo. She also taught an introductory biology Chris Himes learned that lesson the hard way. course that had even nonmajors doing polymerase chain reaction As a graduate student at the University of Washington, Himes and biochemistry. sought out teaching opportunities and eventually won his uni- But the very experience she thought would cement her desire versity’s teaching award for co-developing a course that teaches to teach instead drew her back to research. She decided to fol- study skills to students from groups traditionally underrepresented low her two-year postdoc with a traditional research postdoc in in the sciences. When it came time to graduate, Himes had synthetic biology at Harvard University. an offer for a traditional research postdoc, but he decided to “When I immersed myself in teaching there were some things take a two-year teaching postdoc position at Williams College I missed, like being able to mentor grad students and postdocs,” in rural western Massachusetts instead. “I wanted to see how

Karmella Haynes and Chris Himes enjoyed formal teaching postdocs. Both, however, went on to a

Haynes: Jared Leeds Himes: Jen Judge Leeds Himes: Jen Haynes: Jared second postdoc to get the research experience they they’d need to get a good faculty position.

August 2o11 | hhmi bulletin 27 research is done at a college, see how teaching is done, and learn get better jobs, they think schools just use them to fill teaching what a liberal arts college is like.” slots. “All too often teaching postdocs are primarily … to teach The two-year postdoc was set up to include both research and a class or two to relieve a faculty member from his or her teach- hands-on teaching experience, but because of his interests—and ing duties,” says Chris Craney, an Occidental College chemistry the shock of being in such a different environment, with so few professor. “We didn’t want to do that.” colleagues at his level with similar scientific interests—he did Occidental has had a teaching postdoc in the sciences for more teaching than research. He taught in a whole range of set- almost 20 years. When the college redesigned the program in tings: labs, seminars, and large lecture courses. 2004, the focus was on a postdoc’s future. “We thought, what Himes had a great experience at Williams and learned a lot would this postdoc have to demonstrate to make them a top can- about teaching. He may even want to work at a liberal arts col- didate at a place like Oxy?” explains Craney, who led the program lege someday. But when he looked for a job after the first year of through the changes. his postdoc, he didn’t get a single offer. Williams had an open The school settled on a two-year postdoc for a single Ph.D. position in his area; he applied but didn’t even get an interview. graduate that focuses primarily on developing the capacity to “That was an eye opener for me,” Himes says. “Here I am doing combine teaching and research. Both a teaching mentor and the work at a liberal arts college that I would be expected to do a research mentor, or one person filling both roles, commit to later, but I wasn’t considered for the job.” guiding the postdoc in everything from balancing teaching and Wendy Raymond, who oversaw the postdoc program at research to college politics. ­Williams, says the school doesn’t emphasize teaching experience The trainee spends the first year working in the lab, choosing when hiring faculty. Any postdoc with only two years of experi- a research project and learning how to create a research program ence would be in the same boat as Himes, she says. “We wouldn’t that can work for undergraduates. In a twist from other teach- hire a teaching postdoc for a faculty position without a strong ing postdocs, no classes are directly assigned to Oxy’s postdocs. research record,” she says. Instead, they coteach courses with their teaching mentor during Himes doesn’t regret going to Williams, but he does wish he the second year, while continuing to do research. had had different priorities. “My advice: even if you are going Craney and Eileen Spain, who runs the program now, say this to do a teaching postdoc, focus on research and take the teach- model of teaching and research works, and the proof is in the jobs ing experience as a plus,” says Himes, who is now in a second that have come later. Their postdocs, eight in all, have landed ­teaching postdoc with a stronger emphasis on research. “At the the jobs they wanted, including tenure track positions at places end of the day, it is the publication record that will get you the like the College of Charleston, Mount Holyoke College, Loyola interview, then the job.” Marymount University, even Occidental itself. Many in the academic community have a negative view of For those seeking a job at a liberal arts college, “the game has teaching postdocs and other teaching positions for newly minted changed from 20 years ago,” Spain says. “The bar is higher, the Ph.D.s. Rather than helping postdocs become better teachers or expectations are higher. They need to come to the table with a robust plan for how they can do their research with undergraduates and a clear understanding of what it is like to be at a liberal arts college.” Like Occidental, schools that offer teaching postdocs need to keep those larger goals in mind. “It is a big responsibility,” Asai says. “It’s not, let’s hire a teaching postdoc so that my workload goes down. In fact, when done right it will likely increase your workload because you have the added responsibility of mentoring the teaching postdoc.” Teaching on the Side While not going as far as a formal teaching postdoc, some programs help traditional research postdocs at major colleges and universities get teaching experience.

Postdocs need to focus on research first, teaching second, The largest is the federally funded Insti- says Jo Handelsman (left). But they do need to learn how to tutional Research and Academic Career

teach, says Diane Ebert-May, and the earlier the better. Development Awards (IRACDA), which Baker Ebert-May: Peter Kegley Handelsman: James

28 hhmi bulletin | August 2o11 teaching with formal courses, mentored teaching opportunities, or both. “Some of the students say getting a break 10 hours a week actually makes them more excited to go back to their research,” “The mixed teaching and research says Pat Marsteller, who runs a program at Emory. “And they learn how to get the work done for both things—research and postdoc is the Ideal for the teaching—which they will have to do as faculty.” Diane Ebert-May from Michigan State University runs a pro- greatest depth of academic jobs… gram recently funded by the National Science Foundation called They are getting supervisory FIRST IV that is available to postdocs in biology from any uni- versity. The idea for the program grew out of Faculty Institutes experience, they are getting multi- for Reforming Science Teaching (FIRST), which showed that the longer faculty teach, the less likely they are to adopt student- tasking experience.” ­—JO HANDELSMAN centered teaching techniques. This prompted her to target future faculty for the FIRST IV program to help them learn how to teach from the get-go. support traditional postdocs at research-intensive un­ iversities The two-year program began in the summer of 2009 when who also teach at nearby predominantly minority institutions. the first 100 postdocs were selected for intensive training. The The awards currently fund around 180 three-year postdocs at postdocs then went back to their home institutions to use what 17 research universities across the country. In addition to their they learned to teach or coteach a course. The following summer, research positions, the postdocs teach classes with help from they came back together to share what they learned in the class- mentors and get formal instruction in the science of teaching room, review videos of their teaching, and revise their courses. and learning. “We confirmed that learning how to teach is better at the outset Clifton Poodry, director of the division of minority opportu- of a career,” says Ebert-May, whose second cohort of FIRST IV nities in research at the National Institute of General Medical postdocs began training this summer. Sciences, designed the program in 1997 when he saw a golden Around 25 percent of the first cohort have finished their opportunity: postdocs told him they wanted teaching experience postdoc and moved into jobs, and Ebert-May thinks their partici- and minority-serving institutions expressed the need for more pation in FIRST IV gave them a competitive edge. For the most research-active faculty to help update their courses. The trainees part, they have been able to land the types of jobs they want at the spend 75 percent of their time on research and 25 percent on types of institutions they are interested in. Those who have faculty career development, including teaching, Poodry explains. jobs now “are becoming change agents in their departments and “Initially there was real concern that this would be a burden are influencing their peers’ approaches to teaching.” on postdocs. How could they be competitive if they are teach- The biggest challenge for someone who wants to apply to ing a quarter of the time?” Poodry remembers. Assessment of FIRST IV and many other university teaching programs is get- the program showed that the postdocs (500 to date) do as well or ting their lab head’s permission, which is required. ­better than their peers and publish as much as or more than their But she is optimistic that scientists’ attitudes toward teaching peers. They have gotten jobs at research universities, liberal arts and learning are changing. Most applicants don’t have a problem colleges, minority-serving institutions, and industry, says Shiva getting their lab heads to sign off, and she thinks that it is impor- Singh, who currently directs IRACDA. “For people who believe tant for faculty mentors to support postdocs who want to develop data, the idea that teaching experiences are hurting these post- not only as researchers but also as teachers. docs should be dispelled,” Poodry says. When Himes finished his postdoc at Williams and didn’t get Advice for the Future a job, he started an IRACDA postdoc at the University of New Emory’s Marsteller hopes that awareness will lead to expanded Mexico in Albuquerque. He says the structured split of research teaching opportunities for postdocs. “I think it is unconscionable and teaching has been a good fit. He also values the formal for universities to not prepare people for the jobs that they want to teacher training seminars—his mentorship at Williams was more do,” Marstellar says. “We are way past the time where we should freeform—and his interactions with other postdocs who face the be thinking that we can just throw people into a classroom if they same challenges and concerns. can give a good lecture.” Even in his first year, “the goal of the program is clear,” Himes More fellowships that allow teaching or other professional says. “They want us to get this teacher training but they also rec- development as part of a postdoc would better train these students ognize that the primary goal of this postdoc is research.” to balance the mix of demands they will face as faculty members, Several other programs that offer teaching as a supplement says Handelsman at Yale. “We as a scientific community need to research postdocs have the same approach. The University of to be thinking about what the goals for postdocs are and what Wisconsin and Emory, Stony Brook, and Yale Universities have the opportunities should be, ” she says. “The mixed teaching programs that provide postdocs and grad students interested in (continued on page 48)

August 2o11 | hhmi bulletin 29 Janelia researchers are working their way up from simple to more complex organisms to measure brain activity. by Helen Fields | photo illustration by Fredrik Broden

flies, with tools that can measure electricity either directly, with an electrode, or indirectly, with proteins that light up when an electrical pulse goes by.

Start Simple One way to understand a behemoth like the Empire State Build- ing, Harris says, is to first figure out the workings of a one-room, mud-brick hut. In neuroscience, that’s the nematode Caenorhab- ditis elegans. The tiny, see-through worm has 302 neurons—much o Tim Harris, understanding the easier to study than a human brain. Rex Kerr, a fellow at Janelia brain is like understanding a build- Farm, is trying to understand how worms do what they do. And ing—a really big building—from the one of the tools he’s using to measure the worm’s brain was devel- vantage point of the sidewalk. “The oped at Janelia by group leader Loren Looger’s team: GCaMP3, a brain is the Empire State Building, and protein that lights up in the presence of calcium and is now used it’s opaque. You’re standing there look- in labs throughout the world. ing at the outside and wondering: is the Neurons make their electrical impulses by moving ions hot water faucet on the third sink of the 65th-floor restroom on around. One of the main ions is calcium. GCaMP3 is a kind the left or the right?” of protein known as a genetically encoded calcium indicator, This is the situation neuroscientists find themselves in, Harris or GECI. The cell is engineered to express GCaMP, so when a says. They can see your head, they can see you sensing your envi- blue light is shined on it, the GCaMP lights up—giving off green ronment and doing things, but they have only the murkiest sense light—when it detects calcium. These proteins let neuroscientists of your brain’s inner workings. Harris, a physicist at HHMI’s see electricity in the brain, with the help of a microscope. Janelia Farm Research Campus in Ashburn, Virginia, develops “The challenge here is that we have neurons in three-­ tools neuroscientists can use to measure the brain’s activity, to dimensional space,” Kerr says. A worm’s brain is tiny and clear, give them a quantitative view inside the elaborate structure of but it’s still 3-D, with cells stacked on top of each other and inter- the brain. twined. With instrument design experts at Janelia, Kerr developed Harris spent the early part of his career at Bell Labs, where he a microscope that can image the whole brain. A laser sweeps developed optical methods for studying semiconductors. Later, through the brain over and over, lighting it in sheets from the at Helicos Biosciences and elsewhere, he became interested in side. As the laser beam touches each level, it hits the GCaMP3 biological measurements that generate huge amounts of data. He proteins and they fluoresce, sending light to the waiting micro- sees neuroscience as one big measurement problem. All science scope to record which neurons are active. depends on good measurements. But the unbelievably complex Kerr can measure neuron activity in live worms while they are brain makes measuring particularly challenging. The human sensing the environment. An individual worm is placed under brain has more than 80 billion neurons, and each neuron can the microscope lens and herded into a wedge-shaped chute like have 10,000 connections to other neurons. There’s no way to a sheep waiting for a vaccination. A researcher uses a setup of measure the whole thing at once. syringes to squirt chemicals past it—and then watches to see how Taking it apart, however, isn’t the answer. The brain is a live, neurons that have been engineered to make GCaMP3 react to, working system; cut out a piece and you’re left with a blob of goo. for example, a scent that the nematode associates with food. Then there’s the problem of the unyielding skull. Cutting a hole For now, the worm has to be stuck in a chute to line up its in it opens a window to the electrical signals that carry informa- brain just so with the laser and microscope lens. But Kerr’s dream tion but offers only a limited view: “If I punch a hole in a wall is to be able to take a dish of free-swimming worms, “and tell the and look through the hole, I can see many things. I’m not sure scope, ‘Follow that worm! Tell me what it’s thinking wherever what fraction of them are engaged in my problem and what frac- it goes.’ Or tell me what that small subset of neurons is doing tion are not relevant to my problem,” Harris says. wherever it goes.” He’s working on a system to do this—it involves To study the brain, he adds, “the question is, where did the putting the dish on a platform that tracks the worm’s movement electricity go and when did it go? The essence of all neurosci- and moves the plate so the worm’s head stays centered under the ence is summed up in that one thing.” Since it’s impossible to lens. He already has a system that can track worms as they squirm work out the entire human brain at once, Harris and the other around under a microscope (see Web Extra, “Follow that Worm”). instrument experts at Janelia help neuroscientists figure out Kerr thinks it might be possible to learn how a worm does what they can measure and how to do it. They’re getting at the what it does in the next decade or so. And those lessons could be brain by studying simpler animals, like nematodes and fruit applied to understanding more complicated animals.

32 hhmi bulletin | August 2o11 Moving on Up to those patterns, trying to walk or fly toward a fixed line or fly It’s still just a worm, but Tim Harris says that’s a good start. “Learn- straight when it seems the world is moving to the left. ing how to build a one-story, mud building is a pretty good idea,” Crucially, the top of the fly’s head is open and bathed in saline he says. “Then people think, ‘ok, so, mud is never going to get under a microscope; a researcher removes a smidgen of the fly’s us to the Empire State Building. We’ve got to learn how to build cuticle, and nudges a probe into the working brain. Harris’s using bricks and do plumbing and all that jazz.’ So that’s now improved probes should help Jayaraman get better measure- another measurement problem that’s even harder.” ments from neurons and understand more about how the brain A fruit fly brain is a lot easier to study and less complex than a makes decisions. human brain, but more complicated than a worm brain. When dealing with a lot more neurons, you want more measurements. Illuminating Windows It’s possible to buy a probe from a supply company with many The next step on the way up to the Empire State Building, Harris tiny wires on the end. Ease it into the brain and the tip of each says, is the mouse. “The mouse brain is even bigger, with even wire records the electrical impulses around it. The probe can more neurons. So you have to study smaller parts of it to under- record data for many neurons at once, Harris says. “But, you’re stand what’s going on.” still poking a stick into a brain. You’ve probably caused some Karel Svoboda, a group leader at Janelia Farm, studies mouse damage. We’d rather have a magic microscope that could see brains. His team builds a tiny glass window into each animal’s through the brain and measure the electricity, but we don’t know head. This doesn’t seem to bother the mice, and the researchers how to make that.” can follow one mouse for months as its brain changes to accom- Instead, he’s making better probes. Along with fruit fly modate its new knowledge. researcher Vivek Jayaraman, Harris and Mladen Barbic in his He uses GCaMP3 and other tools to measure electrical activity group have developed smaller, skinnier probes for fly brains. in mouse brains. But he says the tools available to do neurosci- Because they’re 10 times narrower than commercial probes, they ence today still aren’t good enough. “In brain research, we make destroy less tissue on the way in, and the tips of the wires are tiny, up a lot of stories based on incomplete information,” ­Svoboda suited to flies’ small neurons. says. “We’re still looking at large populations of neurons, but we Like Kerr, Jayaraman wants to measure neuron activity in flies have only probed a small part of the brain. In many ways we’re living in a sort of virtual reality arena. An individual fruit fly is still very much limited by measurements.” glued by its head to a bracket and then allowed to fly or to walk on As part of the GECI project at Janelia, Svoboda, Jayaraman, a ball, like a treadmill. Meanwhile, the researchers display mov- and Kerr are working with protein engineer Looger to develop ing patterns on a U-shaped bank of light-emitting diodes designed improved versions of GCaMP3. The new proteins should be by Janelia group leader Michael Reiser. The fly sees and reacts better at binding calcium, so they will respond when there’s less calcium. They hope newer versions will also light up sooner after calcium rushes into the cell. And while the current ver- sion can impair cells when it builds up, the next proteins may do less damage. “The major discoveries of neuroscience in the modern era correlate directly with advances in measurement technology,” Svoboda says. Around the turn of the 20th century, Spanish physiologist Santiago Ramón y Cajal perfected a technique for looking at slices of brains and determined that brains were made of cells. Neuroscientists figured out some basics about how the visual cortex works because they invented a technique for record- ing electrical signals from cells. This work continues at Janelia Farm, as its neuroscientists keep working to understand the brain. Harris thinks neuro- scientists won’t understand the human brain for a thousand years, at least; but with new tools, they can keep chipping away at the problem—and make a little bit more sense of what goes Rex Kerr (left) can measure neuron activity in on inside our heads. W worms as they sense chemicals in their environment. Tim Harris says worms and fruit flies are a good start for eventually answering questions about web extra: To learn how scientists quantify worm behavior and study salamanders at dinner, visit www.hhmi.org/bulletin/aug2011.

Kerr: James Kegley Harris: Paul Fetters Harris: Paul Kegley James Kerr: the brains of larger animals.

August 2o11 | hhmi bulletin 33 perspectives & o pinions

Karl Deisseroth In Support of UNdirected Research a disease focus can color the scientific process. Ramin Rahimian

34 hhmi bulletin | August 2o11 Karl Deisseroth surprised his neuroscience colleagues at a February 2011 panel discussion by defending the legitimacy of doing science for its own sake rather than being motivated solely by the need for cures. In recalling that moment, the HHMI early career scientist at Stanford University—a practicing psychiatrist, neuroscientist, and bioengineer—urges public and private funders to diversify their portfolios when they invest in science and biomedicine.

At that AAAS symposium in Washington, D.C., panelists were Yet we now stand on their shoulders. Based on that his- invited to discuss neuroscience research. After we presented tory, I offer a challenge. Let’s make the explicit absence of a our work, the moderator, Story Landis, head of the National potential disease justification—a health relevance of zero— Institute of Neurological Disorders and Stroke, observed that a priority when evaluating scientific programs supported by every speaker had tried to link their work to a brain disease. funding agencies, even those with a disease mission. She asked, was this necessary? Disruptive, landscape-shifting ideas that enhance our That was a provocative question. Do we neuroscientists understanding of disease processes will likely come from always have to justify what we do in a disease context, or can research with little apparent disease connection. Talented we make a sufficiently compelling argument for the intrinsic young scientists will always choose problems that illuminate excitement of doing biology? the complexity of the biological world. How an organism As the only practicing physician on the panel, I was turns light into ion flow—now that is an interesting question! expected to advocate for tying research to disease, but I took But if in 1971 a funding agency had called for new ideas to the opposite viewpoint. I argued that we must support work study Parkinson’s disease or anxiety, the likelihood of sup- that is not related to disease models and value completely porting bacteriorhodopsin work would have been zero. It undirected research with no implications for health. took decades of poking around algae and bacteria for us to That answer may seem surprising, because I still practice understand how light-sensitive channels work, followed by psychiatry and have always had a translational motivation. the unlikely step of putting them into neurons. In the 1990s, I went through an M.D./Ph.D. program at Donors interested in funding high-impact science should ­Stanford and became fascinated by psychiatry. The patients know the optogenetics story. Its lesson is that we don’t know were suffering severely, and I felt a need to develop methods enough to guide research fully and should instead seek to to understand their diseases. My psychiatry colleagues were understand the complexity of the natural world. brilliant, thoughtful, and caring but lacked tools to probe Scientists constantly think about how to fund their the brain with precision, and our interventions often lacked research, and many funding agencies favor a clinical justi- specificity. So when I set up my lab in July 2004, I wanted to fication. Nobody wants to criticize those agencies, because create targeted approaches for understanding brain disease, funders have their own reasonable constraints. Making a which led to my development of optogenetics. disease-related justification has become almost an instinctive In optogenetics, we take genes encoding light-responsive part of science culture, particularly in the United States. proteins from microbes and introduce them into neurons, As it becomes universal, students come to see this disease- even within freely moving mammals. Using a variety of pro- relevance aspect as essential to the scientific process, and the teins, we have shown that we can stimulate or inhibit neurons resulting value judgments color the scientific process and with millisecond-precision flashes of light. By switching spe- guide national and global priorities. But I have long made it cific populations of neurons in the brain on or off to define a point to underscore to my students and postdocs the impor- what they do, we’ve obtained insights into neural circuit tance of undirected research. ­function relevant to Parkinson’s disease, anxiety, substance For me the question of basic versus applied research is not abuse, depression, narcolepsy, and autism. a choice. Translational work is essential. But every funding But the roots of the field extend to 1971 when the first agency—even those with a disease focus—should examine its light-responsive microbial opsin protein, bacteriorhodopsin, portfolio, and if all is translational or even disease inspired, this was identified. Scientists studying microbes for their own sake should be viewed as a serious weakness. Despite shrinking bud- characterized more opsins in 1977 and 2002. They did not gets, undirected basic science funding must be preserved and give a thought to neuropsychiatric disease; attempts to link even encouraged if we are to reach our disease-curing goals. their work with psychiatry would have been laughed at. These researchers were simply studying an elegant biological system. Interview by Elise Lamar. Karl Deisseroth is a member of No disease-driven donor or agency would have funded them. the Institute of Medicine.

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38 science EDUCATION There had to be a faster way to silence genes in skin Going Viral / 2011 Holiday Lectures on Science stem cells. Elaine Fuchs managed to do it, carving years off the process, by using a well-timed injection of 40 institute NEWS lentivirus—loaded with an RNA hairpin—into a mouse Rosenfeld To Lead HHMI Documentary Initiative / amniotic sac. HHMI Teams Up for Open Access Journal / Plant Science Gets a Boost The virus infects the embryo’s outer layer of skin cells,

42 lab BOOK which differentiate into the multilayered epidermis and The Buzz on Bee Viruses / Memory Cells at the hair follicles. One or more target genes in the resulting Ready / Leading a Double Life skin stem cells are silenced through this method. This image shows the fluorescently labeled viral payload 45 ask A SCIENTIST reaching the inner skin cells, confirming specificity of Can stimulants exercise your heart and make it delivery. To read about the method and its many uses, stronger, just like lifting weights will make your visit www.hhmi.org/bulletin/aug2011. body stronger?

46 nota BENE Eight Elected to National Academy of Sciences / Medzhitov Wins Shaw Prize Fuchs lab Fuchs

August 2o11 | hhmi bulletin 37 38 hhmi ing, eachoftheseschoolshascommitted to continuing toofferthe so that eventhough their three years of HHMI support are end- Genomics ResearchInitiative, shareFindley’s enthusiasm.Somuch pioneered HHMI’s phagecourse,formallyknown astheNational it inexciting wayswenevercouldhaveimagined.” novice studentscandoresearch ataveryhighlevelandbenefitfrom among honorsstudents.“We’ve beenabletoprovethateven truly research-based program would succeedonly at elite universities or peer leadersoncampus,” says Findley. Theassumptionwas thata set footinascience lab. Coming from ruralschoolsystems,manyofthestudentshadnever theycouldmeetthechallenge. ana atMonroe,shewasn’tcertain teaching aresearchcoursetofreshmenattheUniversity ofLouisi- Wh SEA’ Going Viral science education Participants from the10othercollegesanduniversities that “Not onlyhavetheysteppedup,they’vesoaredandbecome en bulletin s b

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its universities andcolleges. of the phage course model to include other organisms and other to createanetworkthatsupports theexpansionanddiversification 6 fromthe second—to securea National Science Foundation grant the effort with 17 other institutions—7 of them from the first cohort; Madison University inHarrisonburg,Virginia. Temple isleading of the Integrated Science & Technology Department at James ences; it’s justsoexciting andvaluable,” saysprofessorLouiseTemple the programtoothercolleges. opportunities toupperclassmenattheir own institutions,andspread working toofferthecoursemorefreshmen,expandresearch bio labof“experiments”withpreordainedoutcomes. world ofresearchinsteadparkingtheminthemoretraditional course. Theintroductorybiolabcoursethrustsfreshmenintothe “We reallywanttogoviralwiththisideaofearlyresearch experi- thisfall) is This first cohortof schools(the fourthcohort starts o wn .

Jamie Cullen The phage course is a relatively simple concept based on work departments will explore the effect of mercury on embryonic by HHMI professor Graham Hatfull at the University of Pittsburgh. ­development in frogs. Students isolate novel viruses that infect bacteria, called bacterio- One of the most exciting ways the phage course is evolving takes phages or phages, from soil, and then purify them, isolate their the effort to upper classmen. The first cohort of schools faced a genomic DNA, and send it away for DNA sequencing. When the “problem” when students were eager to continue pursuing ques- sequence comes back, the students employ bioinformatics tools to tions arising from the phage course work and the schools had annotate and ­characterize their new-found phages. nothing to offer them. From start to finish, there are no guarantees of success or “Once you’ve sequenced and annotated a phage genome, this right answers. Students endure the pitfalls of true research, such is just the beginning of discovery,” says associate professor Aaron as contaminated bacterial plates and inscrutable results, along Best of Hope College in Holland, Michigan. The annotation pro- with the thrill of discovery and eureka moments small and large. cess sheds light on new avenues of exploration that truly engaged “Just because something is effective, doesn’t mean that it’s always ­students want to pursue. “We had a student at the end of the course a comfortable experience to go through,” says Grant Hartzog, throw up her hands and ask if this was IT?” laughs William & Mary a professor at the University of California, Santa Cruz. “These biology professor Margaret Saha. Like most of the first cohort of [students] are getting pushed to think hard in ways that they schools, Hope and William & Mary are developing courses for aren’t used to.” upperclassmen designed to explore gene expression patterns in the And the phage course is effective. As the first initiative of HHMI’s phages they’ve annotated. Science Education Alliance (SEA), which now encompasses 67 “People always ask how we afford to offer this experience,” Saha schools, participants have been documenting their experiences: says. “It’s really not that expensive when you consider what it gives ­students participating are more likely to continue in science courses the students and the institution. It’s mostly time and it just works and perform significantly better in lecture courses than peers in so well.” W –Lisa Chiu traditional laboratories, says Tuajuanda Jordan, former director of SEA who was instrumental in getting the program off the ground. Jordan notes, “We are born naturally curious and the SEA course engages that curiosity and really helps students develop higher thinking skills.” 2011 Holiday Lectures on Science The quality of those thinking skills and the significance of the Bones, Stones, and science produced was on full display in the January 27, 2011, Genes: The Origin issue of the peer-reviewed journal PLoS One where 192 coauthors of Modern Humans ­composed of students from the first cohort of SEA schools and from the University of Pittsburgh identified and characterized 18 previ- Some 150 years after Charles Darwin proposed that ously unknown phages. At the time, their work represented a fifth of we have a common ancestor with great apes, human evolution remains one of the most debated topics all bacteriophage genomes characterized. in all of science. In HHMI’s 2011 Holiday Lectures on The ability to adapt the course to best fit the students and cur- Science, three world experts will delve into millions of ricula of an individual school is part of what makes it so effective years of evidence that scientists use to study human at institutions ranging from elite universities to regional colleges, evolution and the fact and fction of this important according to Jordan. topic. ¶ John J. Shea of Stony Brook University will While the course has been built around phages that infect explain how ancient stone tools provide evidence of problem solving. Sarah Tishkoff of the University Mycobacterium smegmatis, a cousin of the bacterium that causes of Pennsylvania will examine the genetic heritage of tuberculosis, some schools are switching to different organisms modern humans and human evolution. And Timothy because they are less expensive or easier to work with or repre- D. White of the University of California, Berkeley, sent “uncharted” territory. For example, the University of Mary will describe the fossil evidence that links modern Washington, in Fredericksburg, Virginia, through a collaboration humans to our earliest relatives. ¶ This year’s lecture with the Naval Surface Warfare Center at Dahlgren, will look for series—Bones, Stones, and Genes: The Origin of phages that infect spore-forming bacillus bacteria—common and Modern Humans—will take place in front of an audi- ence of high school students October 6–7 at HHMI’s easily maintained organisms that could inform the Navy’s work on headquarters in Chevy Chase, Maryland. Sign up now anthrax bacteria. for the live webcast at www.hhmi.org/biointeractive. At the College of William & Mary in Williamsburg, Virginia, the biology department will institute a Helicobacter pylori genom- ics lab course and the environmental science and neuroscience

August 2o11 | hhmi bulletin 39 40 hhmi ate, andefficient publishingmodel.” excellent journals,butthereis need foradifferent, moreappropri - HHMI president Robert Tjian. “We are fortunate tohave many that bettersuitstheneedsofresearchers. cluded thattherewasaneedformodelofacademic publishing attended byanumber ofleading scientists. Theparticipants con- a workshop in 2010 at HHMI’s Janelia Farm Research Campus lishing, andaneditorial teammadeupofactivescientists. 2012. Thejournal’s tenetsincludeafastreviewprocess,onlinepub- and thefirstissueisexpectedtobepublishedinsummer of journals. Thethreeorganizations announcedthejournalinJune sciences research thatbreaksthemoldsetbytraditional scientific intend tolaunchanopen-accessjournalforbiomedical andlife HHMI HHMI Teams UpforOpenAccessJournal EmmyAwards.documentary graphic. Hehaswon—orledteamsthatwon—nearly40newsand supervisory writing and production positions at National Geo Channel, PBS,andworldwide.Overtwodecades,heheldvarious programming ayear,whichairedonNationalGeographic mentary oversaw theproductionofmore than130hoursoftelevisiondocu- tion outreachtoaglobalTVviewership. television. Theinitiative willextendtheInstitute’s science educa- February, aimstobringhigh-quality, compellingscience featuresto sion joined theInstituteinJuly asheadoftelevisionandfilm. filmmaking. TheformerpresidentofNationalGeographic Televi- M HHMI DocumentaryInitiative Rosenfeld To Lead icha institute news “The message from the research community was clear,” says The plansfortheyet-to-be-namedjournalweredevelopedafter As presidentofNationalGeographicTelevision, Rosenfeld HHMI’s filminitiative, $60million announcedin documentary bulletin , th e l R e os

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T ntary rust - biologist attheUniversity ofCalifornia, Berkeley. chief. SchekmanisanHHMIinvestigator andadistinguished cell National AcademyofSciences,hasbeennamedfounding editor in share content,anddirectly engagethereader. tunity toexploit thepotentialofnewtechnologiestopresentdata, form endlessadditional experimentsbeforeapapercanbepublished.” will be toavoid asking authors to makeextensive modifications orper- Mark Walport, Directorofthe Wellcome Trust. “Theethosofthejournal online alongwithanonymousreviewers’comments. revision and rapidpublication.Accepted articles will be published who willensureatransparentpeer-reviewprocessaimedatlimited team ofhighlyregarded,experienced,andpracticing scientists scription andcellsignaling. investigator atUniversity ofCalifornia, SanDiego,whostudies tran- Michael G.Rosenfeld,known tohisfriendsasGeoff,isan HHMI our excitement aboutdoing greatscience television.” proposals frombroadcasters,producers,andfilmmakerswhoshare Rosenfeld says.“We willdevelopourown ideasbutwill alsolookfor the waypeoplethinkaboutscience andtheworldtheylivein,” for teachersandstudentsatthehighschoolcollegelevels. intomaterials teamtorepackagethefilmfootage the documentary work ofHHMI’s own researchers. science, especially biology andmedicine, butwillgobeyondthe Randy Schekman,currentlyeditor oftheProceedings As thejournalwillexistonlyindigitalform,itoffersanoppor - “This will be a journalfor scientists edited by scientists,” says Sir Editorial decisions fortheplannedjournalwillbemadebya Rosenfeld isthesecondMichaeltojoin HHMI. “My goalwillbetofindprojectsthatcanhaveanimpacton HHMI’s educationalresources group andotherswillworkwith cation. Thefilmswillcoverallareasof HHMI’s vicepresidentforscience edu- that grabtheviewer,saysSeanCarroll, will betotellintriguingscience stories making. TheHHMIfilm division’s priority film- its firstexperiencewithdocumentary reporting onPBSNewsHour.Butthisis series ects, including thepublicbroadcasting be liketomakeadiscovery themselves.” ple imagine—inavividway—whatitwould adventure. Throughfilmwecanhelppeo- it is like to be a scientist and to be on an they giveviewersavicarioussenseofwhat of discovery,” Rosenfeldsays.“Attheir best, HHMI hassupportedtelevisionproj- “Good science filmscapturethepassion W NOVA scienceNOWandscience W

James Kegley Plant Science Gets a Boost

Imagine wheat engineered to be resistant to disease and resources,” says Vicki L. Chandler, chief program officer for sci- packed with extra, essential nutrients. Now picture a mustard plant ence at GBMF. that reveals biology’s secrets—secrets that pertain to plants and “People in the developed world have sort of lost touch with how, humans—of gene regulation and gene silencing. every day, plants are part of their lives—from food, shelter, clothing, These scientific achievements are a reality, thanks in part to and fuel to the simple beauty of a garden,” says Jeff Dangl, of the the work of 15 researchers who have been chosen to join a new University of North Carolina at Chapel Hill. His appointment as an initiative supported by HHMI and the Gordon and Betty Moore HHMI-GBMF investigator will help him recruit smart and creative Foundation (GBMF). The investment provides much needed fund- young scientists to his lab to tackle what he considers the big ques- ing for research in fundamental plant science. tions and exciting problems in plant biology. W HHMI and GBMF are supporting this initiative at $75 million total, offering 5-year, potentially renewable grants to the 15 investi- The HHMI-GBMF I nvestigators gators so they have the flexibility to move their research in creative

directions. Despite funding constraints that have plagued plant Philip Benfey, Ph.D. Duke University researchers for decades, this group of scientists has made impres- Dominique Bergmann, Ph.D. Stanford University sive discoveries, opening up new research fields and improving crop Simon Chan, Ph.D. University of California, Davis engineering. They represent 13 institutions from across the United Xuemei Chen, Ph.D. University of California, Riverside Jeff Dangl, Ph.D. University of North Carolina at Chapel Hill States and were selected on the basis of individual scientific excel- Xinnian Dong, Ph.D. Duke University lence from a group of 239 applicants. Jorge Dubcovsky, Ph.D. University of California, Davis “We think the creation of our joint program underscores the Joseph Ecker, Ph.D. Salk Institute for Biological Studies importance of investing in fundamental plant science and we Mark Estelle, Ph.D. University of California, San Diego hope it will encourage others in the United States to make analo- Sheng Yang He, Ph.D. Michigan State University gous commitments,” said HHMI President Robert Tjian. “We are Robert Martienssen, Ph.D. Cold Spring Harbor Laboratory Elliot Meyerowitz, Ph.D. California Institute of Technology as excited as these scientists are to begin putting their best ideas Krishna Niyogi, Ph.D. University of California, Berkeley into action.” Craig Pikaard, Ph.D. Indiana University at Bloomington “GBMF and HHMI believe the research will generate high- Keiko Torii, Ph.D. University of Washington impact discoveries with implications for a range of intertwined concerns facing society: food production, human health, protec- FOR MORE INFORMATION: To learn more about the scientists and their work, visit tion of the environment, and identification of renewable energy www.hhmi.org/news/plantscience20110616_list.html.

Scientists study pattern and orientation of plant cells, which is often predictable and tied to function. In the mustard plant’s flower, the patterns and proportions of cells develop progressively from the center outward (left). Stomata, valve- like structures on the underside of the plant’s leaves that regulate exchange of gas and water, are typically spaced at

, 8, e1000367 Right: Kylee Peterson / Torii lab / Torii Peterson Left: Adrienne Roeder, PLoS Biology , 8, e1000367 Right: Kylee regular intervals. When activity of a genetic transcription factor is elevated, all epidermal cells become stomata (right).

August 2o11 | hhmi bulletin 41 lab book The Buzz on Bee Viruses Technology designed for human viruses is helping solve a bee riddle.

In 2006, bee colonies started failing at a rate never seen before. By the end of the year, the team had tracked all known bee Entire colonies died. Farmers feared a shortage of bees to polli- viruses and identified four more, they reported in PLoS One on nate their crops. The cause of this phenomenon, known as colony June 7, 2011. Two in particular stood out. The scientists named collapse disorder, remains a mystery despite intense effort. HHMI them Lake Sinai virus 1 and 2, after a South Dakota lake near where investigator Joe DeRisi is using his expertise on viruses to tackle the bees were collected. Surprisingly, Lake Sinai virus 2 was found the problem. to be the most abundant pathogen in the bees, reaching levels of “Attempts to examine the cause of the bee colony collapses were greater than 1 billion copies per bee in the winter. confounded by the fact that very little was known about viruses in The data collected by the DeRisi lab don’t solve the bees, period,” says DeRisi. mystery of why bees are dying. But they offer a baseline for sci- So DeRisi and his colleagues at the University of California, entists who continue to track bee viruses. “This study provides a San Francisco, decided to follow a convoy of semitrailer trucks with ­foundation from which to 70,000 beehives as it drove around the country during its annual work,” says DeRisi. Now trek to pollinate crops. With the help of experienced commercial the team can continue beekeepers, bee samples from 20 designated hives were collected following bees and each week throughout the year. Using a specially designed micro- begin correlating viruses array that allows rapid screening for viruses and other pathogens with colony collapse of insects, they monitored pathogen incidence at different times of to better understand year in different hives. current and emerging

“We were leveraging a lot of the same skills and technology that Understanding the pathogens that normally threats. It’s a step toward we use to look at human medicine and veterinary medicine,” says inhabit beehives provides a baseline to look keeping bees healthy. for the cause of colony collapse disorder. DeRisi, “and now applying that to insects.” W –Sarah C.P. Williams

IN BRIEF

When Copies Don’t Match sequence. The researchers repeated the School of Medicine led by HHMI investi- For a cell to function properly, it needs experiment in skin and brain cells of infants gator Evan Eichler looked at 20 affected to copy DNA—the most basic blueprint and adults to rule out the effect of age and children in their latest study. They com - of proteins—to RNA strands that encode cell type on the phenomenon. They found pared the genes of the children with those proteins. It’s long been assumed that RNA similar results, they reported May 19, 2011, of their parents to fnd mutations that were must code for the protein in exactly the in Science Express. unique to the child. same way as its complementary DNA for Known RNA-editing molecules could The team turned up 21 spontaneous this process to work smoothly. Mistakes explain only about half of the RDDs the sci- mutations, 11 of which altered protein at any step were always thought to be entists found. Their next step is to explain sequences. In four children, the research- detrimental—and rare. Now, new research how the rest arise, why the cell lets these ers pinpointed severe mutations that have suggests that DNA blueprints aren’t always sequence differences persist, and whether been linked to autism, intellectual disabil- followed to the letter. the RDDs in different individuals contribute ity, and epilepsy. The fndings, published “The idea that RNA and protein to variations in disease susceptibility. in the June 2011 issue of Nature Genetics, sequences are nearly identical to the hint that the same mutations can manifest corresponding DNA sequences has not Homing in on Autism Genes themselves in different ways in different been questioned in the past,” says Vivian A team of HHMI researchers has identi- individuals. They support the idea that hav- Cheung, an HHMI investigator who led the fed new gene mutations linked to cases ing more than one mutation can change or study. To investigate this question, Cheung of autism spectrum disorders (ASDs). The worsen symptoms of ASDs. and her colleagues at the University of fndings suggest that 20 percent of cases “The idea that multiple genes are com- Pennsylvania School of Medicine analyzed of sporadic autism—where neither parent ing together in what’s called an oligogenic the DNA and RNA sequences from B cells, of an affected child has a family history of model of autism is, I think, an exciting but a form of white blood cell, in 27 individuals. the disorder—can be explained by sponta- also daunting prospect,” says Eichler. The team found more than 10,000 dif- neous gene mutations. ferences in base pairs—the letters that ASDs cover a wide range of defects A Delicate Balance Protects make up genes—between the DNA and in language, social ability, and movement Against Leukemia RNA. The RDDs (RNA-DNA differences) and vary widely in severity and symptoms, When it’s turned up too high, the cellular were found in about 40 percent of genes making them hard to study as a group. Notch signaling pathway causes leuke - and often led to a change in protein Scientists at the University of Washington mia. Now, HHMI researchers have found Mark Bowler / Photo Researchers, Inc.

42 hhmi bulletin | August 2o11 Doyun Lee and Brenda Shields / Lee lab nl theyalsohadasignificantly lower thresholdforfiring. ingly received inputsthansilentcells,butsurpris- moreexcitatory cells asaratexplorednewmaze,hefoundthatplace When Leemeasuredtheelectricalactivityinsidehippocampal threshold. the interiorandexteriorofcell)aboveacertain push itsmembranepotential(adifferencebetween involtage silent cells. electrical activity inside place cells with that in neighboring new spatialmemories.To findout,hisgroupcomparedthe chargeofwas curiousaboutwhatdetermines whichcellstake environments but remain silentcells in in others, certain Lee facts, andevents.Sincemosthippocampalneuronsactasplace cells in the human brain that store memories of people, places, destined formemorystorage. chargeofthenextpieceinformation areprimedtotake the total, leagues foundthatthesecells,whichrepresent25–50percentof the hippocampus.JaneliaFarm groupleaderAlbertLeeandcol- by firingafewselectcellsinthememory-forming regioncalled map As arodentnavigatesanenvironment,itsbrainformsmental u S Memory CellsattheReady pecial p IN BRIEF For a neuron to fire, inputs from neighboring cells must The cells, known as place cells, are considered analogous to

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43 44 hhmi cells liningthebladder. appear to play arole inrepair of Developmental signalingproteins P Leading aDoubleLife increased inmultiple celltypes. of theprotein Sonic hedgehog increased;Wntpathwayactivityalso in response toeither typeofinjurytheir proliferationandtheir levels identified stemcellsinthelining ofthebladderandnoticedthat the bladder or to a chemical that harms the organ. The researchers strain ofEscherichia colithatinfectstheurinarytractanddamages development, alsocontributetobladderrepairinadult mammals. r lab booklab IN BRIEF Beachy andhiscollaboratorsexposedadultmice either toa o tal for Sick Children in Torontoin toChildren wanted Sick for tal re now is Salter Michael scholar research down.Newresearchinternational byHHMI dialed is receptor NMDA the of activity the schizophrenia, in that hypothesize to scientists led observation The voices. inner thinking, disordered hallucination, disease: the of symptoms develop they receptor—NMDAreceptor—the cell brain speci a of action the blocks that drug a takeschizophrenia without people When S N down thecell’s energy to give itanedge. cells as well. The virus needed viperin to turn infect longer no could CMV viperin, lacked chemical energy withincells. transports that ATP—amoleculeproduce ef longer no can cell The duction. pro- energy sabotages it where cell, the of mitochondria the to protein the sends not only turns on viperin production, it also in 2011,

teins chizo bulletin ew f ning that explanation. Salter and his colleagues at the Hospi- the at colleagues his and Salter When Cresswell’s team created cells that 27,May published work, latest their In M , the team shows that CMV thatshows team the Science, i p dd

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embry well known forregulatingembryo hog andWntprotein families, University revealsthattheHedge- tigator PhilipBeachyofStanford there maybesomeanswers. has puzzledscientists, butnow themselves. How thishappens than nottheymanagetoheal harmful bacteria,moreoften Though regularlybombardedby bodies comewithaself-repairkit. Lucky for us, the organs in our f A studyledbyHHMIinves- ciently o devel f c patients—and how losartan alters it—wasn’t Marfan in aneurysm aortic of mechanism exact the But problems. heart to lead can that disorder tissue connective a drome, syn- Marfan of cases in aneurysms aortic decreases it that suggestedhave losartan called drug a using experiments Mouse tic S A the in activity NMDA low for account could molecules these by signaling thought receptor.NMDAThey the ErbB4—on and schizophrenia—neuregulin in implicated know the effects of two proteins previously other regions. in occurs it whether investigate to next prefrontalcortex,researchers the plan and the and hippocampus the brain, the of regions different two in true held ecules issue ofNature Medicine. They reported their results in the April 2011 activity.receptorNMDA squelches turn in whichactivity, Src down turn ErbB4 and molecule called Src is to blame. Neuregulin yn or o

h rltosi bten hs mol- these between relationship The a that found instead team Salter’s But disease. d pment rome A neurysms in E

x als p laine o therapies forcancerpatients,” hesays. future, whichcouldprovidesomeinsightsintohow todesign better inappropriately activated. “That’s an area we’ll be exploring in the in other organs and, conversely, if they promote tumor growth when ployed tohelprestorepatterninadultorgansduringregeneration.” cellpatternduringembryodevelopment are rede- establishing rolesinNature, suggestthat“signalingproteins withimportant problems thatinvolvetherestorationoftissues,” says Beachy. replace damagedones.“Thismayhaveimplicationsformedical underlying cell layer, which then stimulates growth of new cellsto in thebladderlining triggersincreasedWntprotein expressioninan other organs. for bladderregeneration,italsopreventsmicrobes frominvading cate that not only is Hedgehog-dependent proliferation required accumulated tenfoldmorebacteriathannormal.Theresultsindi- cell replication was delayed and reduced, and the mice’s kidneys ing theGli1protein, acomponentoftheHedgehogpathway, repair d Beachy wants to find out if these molecules promote tissue repair Beachy wantstofindoutifthesemoleculespromotetissuerepair According toBeachy, theresults,publishedApril7,2011,in The researchersobservedthatSonic hedgehogprotein expression When theydid thesameexperimentwithmutantmice lack- M arfan o rgans . Harry C. Dietz, of the Johns Hopkins Johns the of Dietz, C. Harry investigatorclear.HHMI Now, byresearch cations to test inthefuture,” hesays. medi- aneurysm],againstwhich aortic and protect [to now use to medication which regarding choices informed more make to aneurysms. halt to drugs for targets specific, more and new, offers says, Dietz finding, new The suppressed. was aneurysms causes ­Scienc of issue 2011, 15, April the in reported they syndrome, Marfan of model mouse a in molecule either blocked scientists the When TGF-beta. on rely that JNK, and ERK called molecules, signaling two to linked was one which know didn’t ers different signaling pathways, and research- of handful a through works TGF-beta But signaling. TGF-beta blocks Losartan sion in a mouse model of Marfan syndrome. progresaneurysm- drivesTGF-beta called the connection. out spelling is Medicine, of School versity

aneurysms. “I really think we’re going to be able be to going we’re think really “I pinpointed colleagues his and Dietz It was already known that a molecule a that known already was It , the abnormal aortic growth that growth aortic abnormal the e, W –Ja nelle W e av e r U ni-

David M. Phillips / Photo Researchers, Inc. ask a scientist

q A Can stimulants The best place to start answering this increase cardiac output by up to 40 per- question is to discuss what makes a cent, clearly reflecting a stronger and exercise your strong heart. A useful measure of the more efficient heart. heart’s efficiency is cardiac output: how Stimulants such as amphetamine heart and make much blood the heart can deliver to the and cocaine increase heart rate by it stronger, body with each heartbeat. At rest, about increasing the stimulation of the heart 5 liters of blood are pushed out of the through ­neurons from the brain, which just like lifting heart every minute. During aerobic also occurs during exercise and even weights will exercise like running and swimming, in anticipation of exercising. This so- the heart can increase its cardiac output called sympathetic stimulation increases make your to 25 liters per minute to deliver more both the heart’s output volume and its oxygenated blood to the body. rate and therefore increases cardiac body stronger? Exercise can certainly make your output. Long-term use of stimulants, heart stronger, but it also optimizes the however, may lead the heart to become Asked by Ryan, a high school student way the heart functions. The heart is less sensitive to the signals of sympa- from Massachusetts a specialized type of contractile mus- thetic stimulation, possibly making it cle, best visualized as sets of muscles more ­difficult to initiate an appropriate ­encircling a series of chambers; con- response to true exercise. At high doses, traction of the left ventricle of the heart some stimulants can increase heart rate squeezes blood into the circulation like to such a degree that they increase the toothpaste from a tube. The volume of risk for heart attacks and seizures. blood that can be delivered to the cir- With the exception of judicious use culation per beat depends primarily on for treating conditions like attention the volume of blood that fills the cham- ­deficit hyperactivity disorder (ADHD), ber while the heart is relaxed and the the potential adverse effects of using fraction of blood that is ejected during stimulants exceed their short-term ben- contraction. The heart can optimize efit. Cardiologists use drugs that modify these two parameters by maximizing the heart’s contractile force to help indi- contraction to eject more blood from the viduals whose hearts are intrinsically ventricle, followed by rapid relaxation to failing. But the best conditioning for allow the ventricle to refill with oxygen- the heart will always be aerobic exer- rich blood. With consistent exercise the cise, which enables the heart to adapt heart becomes a more efficient pump for over time in the context of the chang- greater cardiac output per minute. ing physiology of the entire body—no What about heart rate and condi- drug will likely ever be able to precisely tioning? Long-term aerobic training mimic that. in fact slightly decreases heart rate, as a rapid heartbeat may not give the left ventricle enough time to fill with an Answer Researched by Jeffrey T. Ehmsen, optimal volume of blood. But increasing an M.D./Ph.D. student in neuroscience the volume of blood the heart pumps, at the Johns Hopkins University School even without changing heart rate, can of Medicine.

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

August 2o11 | hhmi bulletin 45 46 General Hospital; and General Hospital; proteasome complexinregulating the Aifantis studies therole oftheubiquitin- the Society for Hematology and Stem Cells. the 2011McCullochandTill Award from scientist atNewYork University, received hhmi nnis I G K are of ArtsandSciences. Theinvestigators fellows electedtotheAmerican Academy Eight HHMI investigators are among 212 The Children’s Hospital of Philadelphia. The Children’sofPhiladelphia. Hospital Massachusetts InstituteofTechnology; Medical School; Institute ofTechnology; Boston; San Francisco; sity ofPennsylvania SchoolofMedicine; a evan eorge nota bene s ­ R is J. Nussenzweig, The Rockefeller Angeles; Luis F.Luis Medicine; of School Technology;of Institute Academy of Sciences. The investigators are David scienti HHMI’s of ber investigators,researchinternationalscholar,mem- HHMI one one Six and Bo t Academy ofSciences Eight ElectedtoNational p

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: August 2o11 A s A m . mita , anHHMIearlycareer c , University ofCalifornia, camm H , d U , Children’s Hospital ­ therine K aber dietz P. niversity of Texasniversityof Dallas. SouthwesternatCenter Medical a ­ o Davi C ehgal n , orey , Massachusetts f , jac Steven E. Jacobsen E. Steven n c review board have been elected to the National the to elected havereviewbeen board c u d U , California U ssenzweig o

niversity of California, San Diego; and Diego; San California, niversityof Harry C. Dietz C. Harry bsen niversity of Buenos Aires. The board member is member boardThe Aires. Buenos niversityof C , Harvard , Univer- A . Page. . H U , igh kingsley niversity. The international research scholar , Ko , , ­

rnblihtt C ­ Chapel Hill named HHMI investigators The University ofNorthCarolinaat ferentiation andmalignanttransformation. balance betweenphysiologicalstemcelldif- feller Un HHMI investigator regulate social behaviors. to thediscovery ofchemosensorycircuits that award recognizes the scientists’ contributions 11th Perl/UNC Neuroscience Prize.The of HarvardUniversity, co-recipients ofthe proteins andcellsintheimmune system. tomography, andbiophysical methodstostudy man uses x-ray crystallography, electron Technology, Engineering,andMath).Björk- Most Powerful Moms inSTEM(Science, featured as oneof of theCalifornia InstituteofTechnology, was

ornelia , The Johns Hopkins Johns The , U niversity School of Medicine; of School niversity , U , P n iversity, and iversity of California, Los California, of iversity arad I P . . a B Bartel, Massachusetts argmann Working Mother magazine’s Pamela J. C atherineDulac U , of the Rocke Michel C. Michel niversity ­Bj örkman ­ , , HHMI investigators for herresearchonretinaldegeneration. of its 2011 Bressler PrizeinVision Science gator atHarvardMedical School,recipient HHMI investigator Farm AdvisoryCommittee, wasalsoselected. tance C Peter J. HHMI investigator Paloma C T 2011) on the anatomy and physiology ofthe Gonzalez-Bellido’s article (PNAS, March8, ogy Capranica Prize.Theaward recognizes the 2011InternationalSociety forNeuroethol- group leaderAnthonyLeonardo, wasawarded research associate inthelabofJanelia Farm program used by x-ray crystallographers. program usedbyx-raycrystallographers. refinement the softwaresuiteCNS,adata biology. Brungerwaschosenfordeveloping ogy thatenhancesresearchinmolecular award honorscreatorsofcomputertechnol- Award Biosciences. The forComputational Molecular Biology’s inauguralDeLano American Society forBiochemistry and University,of Stanford received the the SalkInstituteforBiologicalStudies, and ­ The JewishGuildfortheBlindnamed changes inbiologyeducation. revolutionary for hisleadershipincatalyzing in Science Education.Brunswasrecognized Biology’s BruceAlbertsAward forExcellence year, received the American Society for Cell president forgrantsandspecial programslast reverse diseases andconditions. ing ofthepotentialstemcellstotreator - were honoredforadvancing understand tute ofCardiovascular Disease.Thescientists of Kyoto University andtheGladstone Insti- Wisconsin–Madison, andShinyaYamanaka, with JamesA.Thomson,oftheUniversity of medical Research. Fuchs shares the prize Medical CenterPrizeinMedicine andBio- scientists toreceive the11thannual Albany Rockefeller University, wasoneofthree of their exceptionalcontributionstoscience. lowship oftheRoyalSociety inrecognition were electedasforeign membersoftheFel- homas ons arla J. arla B A S runs T hatz . . S L G teit . onzalez- C , who retired as HHMI vice , whoretiredasHHMIvice , amemberoftheJanelia e E p z laine A ko Joanne , ofYale University, xel , anHHMIinvesti- T F B . uchs elli B C runger hory , ofthe d o , of , a , ,

Bartel: Kelly Lorenz Dietz: Paul Fetters Jacobsen: John Hayes / AP, ©HHMI Kingsley: Davis Tower Kingsley McCammon: Paul Fetters Nussenzweig: Paul Fetters Kornblihtt: David Rolls Parada: UT Southwestern Medical Center Chris Jones HHMI investigator cess and managethatinformationovertime. the brain’s cellularandcircuitry systemspro- ies how neurons store information andhow their achievement and service. Kandel stud- who embodytheuniversity’s idealsthrough Eastman Medal,giventohonorindividuals Surgeons, won the University of Rochester’s Columbia University College of Physicians and the movementsofsinglebiomolecules. transfer techniques tocontrol and visualize work usingfluorescenceresonanceenergy the NobelPrize,award wenttoHaforhis Widely regardedastheKoreanequivalent of from the Ho-Am Foundation of Korea. received the2011Ho-AmPrizeinScience University ofIllinois atUrbana–Champaign, Davi HHMI investigator tion inthefieldofneuroethology2010. to be most scientifically significant publica- eyes oftwospecies offlies, whichwasjudged Physicians: theGeorgeM.KoberMedal. est honoroftheAssociation ofAmerican of DukeUniversity, wasawarded thehigh- HHMI investigator plex problemsinbiology. techniquesadvanced computational tocom- in thefieldofbioinformatics, whichapplies of biomathematicians. Haussler is a leader a prestigiousaward thatrecognizes thework receive the2011Weldon MemorialPrize, was chosenbytheUniversity ofOxfordto at theUniversity Cruz, ofCalifornia, Santa s Ru Medzhitov Wins ShawPrize p d otlight slan

H aussler M.M edzhit R , anHHMIinvestigator obert J.

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efkowitz an H a d , ofthe el , of , process, andrespondtosensoryinformation. understanding how highermammalsacquire, Newsome’sUnited States. researchfocuseson cal Society, theoldest learned society inthe was electedtotheAmericanPhilosophi- University SchoolofMedicine,tor atStanford Stanford University,Stanford and Davi W enzymes, proteins, andsignalingpathways. G protein–coupled receptorsandrelated Lefkowitz was honored for his research on sented The AmericanSociety forCellBiologypre- of super-resolutionmicroscopy. accolade forherdevelopmentandapplication and structuralbiology;Zhuangreceived the microfluidic techniques usedinbiophysics University. Quakewashonoredfordeveloping national PrizeinBiophysicsfromTel Aviv 2011 RaymondandBeverlySacklerInter- of Harvard University, are recipients of the award withStuartKornfeld,oftheWashington est honor for science. Schekman shares the Berkeley, withtheE.B.WilsonMedal,itshigh- investigator at the University ofCalifornia, HHMI investigators their studies onXandYchromosomes. Wessex RegionalGeneticsLaboratory, for ampton University Medical Schoolandthe award with Patricia Ann Jacobs, of South Biology.in Developmental Page sharesthe ogy, won the 2011 March of Dimes Prize at theMassachusettsInstituteofTechnol- illiam d growth oftumors. Toll-like receptors play in infection control, chronic in keyrolesthe Medzhitov’s of understanding expandedour researchhas pathogens. against defense of line first immunity,the innate of nism mecha- molecular discoverythe their ResearchInstitute,of for Scripps Hoffman Jules with prize million $1 the shares He Medicine. and Science Life in PrizeShaw receive 2011 to scientiststhe three of one became Medicine, investigator HHMI June, In R

C an . Page . T . d N y ewsome W of the of , anHHMIinvestigator . S S te chekman X p , anHHMIinvestiga- iaowei hen U niversity of Strasbourg and Bruce A. Beutler of the of Beutler A. Bruce and Strasbourg of niversity R . , an HHMI Q Z uake huang , of Yale School of YaleSchool of Medzhitov, M. Ruslan , of , of - , abundance inthecell. localization and the regulation of organelle fornia, SanFrancisco. Walter studies protein HHMI investigatorattheUniversity ofCali- C Biomedical University. Sciences fromStanford and Paul BergLifetimeAchievementAward in also recentlyreceived theArthurKornberg ing researchonprotein transport.Schekman Rothman, ofYale University, fortheir pioneer- University SchoolofMedicine, andJamesE. Donk Warburg Medalto Molecular Biologywillaward the2011Otto The GermanSociety forBiochemistry and discover naturalproductantibiotics. Van derDonk usesgenomic approachesto of theAmericanAcademyMicrobiology. Champaign, wasrecentlyelectedafellow HHMI investigator mutations thatcausehumanheartdisease. the biannual award forherresearchongene University.Ohio State Seidman received stein prizeincardiovascular science from was awarded theJayandJeanie Schotten- tigator atBrighamandWomen’s Hospital, HHMI investigator in vertebratecells. RNA–protein complexesingeneexpression Steitz studies the roles played by noncoding dinary AchievementinCancerResearch. Annual Medical ResearchAward forExtraor- and ClairePasarow Foundation’s 2011 Yale SchoolofMedicine, wonthe hristine , of the University of Illinois at Urbana– E . S August 2o11 ei f ammation, and the d W man Peter Joan ilfre , anHHMIinves-

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47 continued from page 23 Corey said that the sun was hurting his eyes. “That had never hap- (seeing is believing) pened before. It was a pretty big deal,” Ethan recalls. But best of all, he Down the line, it’s likely that the field will be choosing from a range says, was the day Corey tried out the maze. “To see him navigating this of vectors and using both in vivo and ex vivo approaches, depend- obstacle course without difficulty—it was the most dramatic thing.” ing on the disease, according to Kay. “There’s not going to be one In the two years since, Haas says he’s been pressing the research- vector that’s going to be perfect for all applications. They all have ers to repeat the procedure in Corey’s other eye. He’s slated for their niche.” (See Web Extra sidebar, “Taking Down Bad Genes.”) surgery this fall. W The AAV procedure, for example, transformed Corey’s life. His father, Ethan Haas, knew the surgery was the right decision four days web extra: For more about the work described here and to see a timeline of events in the

after Corey left the hospital, when the family took a trip to the zoo and field of gene therapy over the last 30 years, visit www.hhmi.org/bulletin/aug2011.

continued from page 29 in the fall. She interviewed at several institutions and believes her (Time to teach) teaching experience was a key factor in her appeal. and research postdoc is the ideal for the greatest depth of academic Her advice? “Find a place that has top notch research facilities jobs.… They are getting supervisory experience, they are getting but cares enough about teaching that it will not count against you,” multitasking experience.” Haynes says. “Those universities do exist.” W That’s how it turned out for Haynes. After three years as a research postdoc at Harvard University, web extra: Postdocs can learn to be science education researchers too.

she starts a tenure-track faculty position at Arizona State University Visit www.hhmi.org/bulletin/aug2011.

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48 hhmi bulletin | August 2o11 Read morein“LastingMemories” atwww.hhmi.org/bulletin/aug2011. Ryohei imageslivingspines assignalingoccurs,seeninthis seriesofphotos. what’sunderstand happening inthoseextendedmoments,biophysicistYasuda minutes orlongerare thought toencodelong-termmemories.To better as spines. Signalingstrength canfluctuaterapidly, butsomechangeslasting When neuronsfireinthebrain,theyexchangesignalsthrough tiny budsknown

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Yasuda lab

Jing Wei exclusive!). The motivation to doresearch hasto bemuch stronger A’s orearning aVarsity letter (thoughby nomeansare thesemutually rewarding thanotherhighschoolactivities,suchasgettingstraight Being ableto contribute to thepoolofhuman knowledge ismore common? Apleasure indiscovering somethingfor themselves. what they learnintheclassroom. What do thesestudents have in ­r Some students may notbecontent with just memorizingand progressively more sophisticated. conducting scientific experiments—and theirprojects are becoming researchers are younger—more secondary students thanever are ful female andmalescientists range from 10to 90years old.Today’s the stereotypical moldof“old, beaker-carrying men.” Infact, success- how-to. Earlyon,they reassure readers that scientists nolongerfit experiences ascompetitors. Theirbookishalfencouragement andhalf school science fairs—decided to give backandshare theiradvice and A motivated group ofHarvard undergrads—all winnersofelite high A G egurgitating scientific facts. Othersmay never blindlyagree with Observati uidi n g o ns L ig h t

by permission ofResearch Corporation for Science Advancement. Kominers, Dayan Li,Carol Y. Suh.©2011 Research Corporation. Used Research, by withMariaElenaDeObaldia,Scott ShivGaglani Duke From Success withScience: TheWinners’ Guideto HighSchool applications, networking andmakingprofessional boards and posters. tant life skillssuchasgivingpresentations, writingresearch papersand not just provide bookknowledge. Italsoenablesoneto develop impor- would inthree monthsofschoolwork. Unlike homework, research does one monthofresearch astudent canoften learnasmuchheorshe relationship between research andclass work iscloseto 1:3.That is,in most fulfillingactivityof your highschoolcareer. The stoichiometric and quite frustrating at times.At thesametime, though,itcanbethe By nomeansisresearch easy: itcanbeasubstantial timecommitment high schoolstudents whodoresearch eachyear. than that, however, ifwe are to account for thetens ofthousands HHMI

BULLETIN A u g . ’11 VOL.24 • NO.03

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4000 Jones Bridge Road

Chevy Chase, Maryland 20815-6789 Howard Hughes Medical Institute www.hhmi.org

Special Delivery What if a cancer patient’s own immune cells could be loaded with tumor-fighting drugs? Engineer and materials scientist Darrell Irvine has found a way. Irvine’s lab group has devised tiny drug-loaded

nanoparticles and strapped hundreds of them to the surface of T-cell •

lymphocytes. When tested in mice with metastatic melanoma, the www.hhmi.org enhanced T cells rapidly reproduced, moved through the body, and zeroed in on the spreading tumors. The tumors shrank and the mice lived longer than untreated mice. The team has also used the technique to send drug-studded blood stem cells to restore depleted bone marrow in mice. Fascinated by the complexity of the immune system, Irvine is working to remodel the surface of cells with synthetic materials to treat disease and reduce treatment side effects, with more applications in sight (see “T-Cell Booster Kits,” page 10). v ol. 24 / no. 03 Matthias Stephan / Irvine lab