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Home , 2011 in science, Wiley Prize

M AY ’11 VOL.24 • NO.02

RESEARCHERS ARE ON A PATH TO DISCOVER BETTER DRUGS TO TREAT SKELETAL FLAWS.

CLEARING KEEPING OPEN ICONOCLAST MARK BEAR SEEING WHAT OTHER PEOPLE DON’T POSTDOC LIFE THE JOYS AND CHALLENGES in “Wired forSmell”atwww.hhmi.org/bulletin/may2011. groupsinteracttosendmessages isthenextchallenge.Readmore of relatedneuronsformsaunique howthese structure.Understanding but visualizethemoneatatime (asabove)andit’s clearthateachgroup The lobeisamishmash of olfactory neuronsnormallyhardtodistinguish, sent totherestofbrainsoflycanreact—Eat! Follow! Fly away! In theantennallobeofafly, smellsareprocessedand environmental

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Liqun Luo lab

Brett Ryder tails that entertain and inform. Through thebook,White says, natural history, creating vignettes ofdarners,clubtails,andpetal­ ­anecdotes withsubstantial knowledge ofdragonfly biologyand natural habitat. Inhisnew book,White weaves observational of hisfree timeobservinganddocumentingtheinsectsintheir Biochemist HalWhite isadragonfly enthusiast, spendingmuch Strong Fliers almost three inches long,theShadow Darnercan move swiftly or busy office, theeffect canbedramatic. Being strong fliersand in openwindows onwarm days. Whenthishappensin a classroom seems to attract attention most inthefall whenitsometimesflies Although present throughout thesummer, theShadow Darner things, includinghumans. he hopesto illuminate biologicalprinciplesthat applyto allliving Observations

by theUniversity ofDelaware Press, ©2011. Damselflies: Essays of aLifelong Observer, by HalWhite. Published Excerpted from Natural History of Delmarva Dragonflies and attacking andterrorizing aschoolof fish. dragonflies slice backand forth through clouds of smallinsects—like the wind.Sometimes,ifconditions are right,hundreds of feeding that often flyinclearingsor at theedges of fields protected from They leave thishabitat to feed on midges andother smallinsects where malespatrolling for females flylow and follow theshoreline. Normally, however, Shadow Darnersprefer smallwoodland streams, a giantwasp andwithacorresponding sting. about aroom, inadvertently frightening humanswhomay thinkitis may ’11 vol. 24 · no. o2

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nih’s national research service award stipend for starting postdocs, PERCENT WHO HAVE which many institutions use as a guideline, has risen. HEALTH INSURANCE: POSTDOC STIPEND: POST- (based on nih) 2000 DOCS 75% 90%* a doctorate holder in a average42 age that 1986 2006 $26,916 temporary research job, scientists get a first receiving mentoring research grant *postdocs often pay the tab themselves 2010 and training needed for the next career stage. PERCENT WHO ARE THE BEST GIVEN RETIREMENT $37,740* *stuck in the mid-$30,000 80-100 BENEFITS: range since 2003 OF TIMES 43,000– hour work weeks Web Only Content 30% AND 50% Explore the scientific images behind a THE WORST 89,000 mosaic portrait of Gregor Mendel. u.s. trained postdocs OF TIMES 1986 2006 Learn how researchers can follow real- 2.2 time neuron growth in a . by dance PERCENT OF FORMER POSTDOCS K99/R00: the nih “kangaroo”award See the stunning variety of dragonflies that postdocs balance the joys WHO AIMED TO BE A TENURE- of pure research with YEARS Hal White has photographed. tough working conditions. TRACK PROFESSOR: median length of a 150– single postdoc in the 200 life sciences Join us at www.hhmi.org/bulletin/may2011. nih k99/r00, or PERCENT WHO HELD TWO 61% “kangaroo” 24 awards per year POSTDOC SLOTS: 30 PERCENT OF WHO ACTUALLY NIH DIRECTOR’S 60% EARLY 29% ACHIEVED THAT GOAL: INDEPENDENCE PERCENT WHO HELD AWARDS: THREE OR MORE: 10 superstar ph.d. recipients are sixty percent of u.s. postdocs Features chosen to skip Departments the postdoc and are foreign citizens 37% go straight to pi 11% 40 cover story PRESIDENT’S LETTER Summer Institute Expands with HHMI Support Bone’s Balancing Act 03 Learn, Show, and Tell 1 2 Searching for cures, scientists are 41 Institute Launches Documentary CENTRIFUGE revealing the biological complexity Film Unit 04 Ode to Dragonflies of bones. 41 Measuring Quality: HHMI Announces 05 History as Art $60 Million Competition for Colleges Charting New 06 From Bench to Brahms 1 8 The same daring drives Mark Lab Book UPFRONT Bear to win sailboat races and to craft 42 The Pace of Evolution 08 A Crowd in the Kitchen treatments for fragile X syndrome. 43 The Very Hungry Mouse 1 0 Neuro2genesis 44 Nourishing Neural Stem Cells The Best of Times and PERSPECTIVES AND OPINIONS the Worst of Times Ask a Scientist 34 24 Postdocs balance the joys of pure The Future of Science 45 How did evolve from a research with tough working 36 Q&A—What do you wish you had universal common ancestor? known before you started your lab? conditions. Nota Bene CHRONICLE The Next Statin 46 News of recent awards and other Science Education 30 Could new findings on how the notable achievements 38 Industrial-Strength Training human body regulates cholesterol OBSERVATIONS lead to a better drug? Institute News Strong Fliers 39 HHMI Selects Nine Students for Gilliam Fellowships 40 Kotak Elected HHMI Vice President and Chief Financial Officer

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

When my brother was small, he jumped off the My father is not exempt. At 92, he’s dealing with back of our living room sofa, in some ­superhero-​ weakening and compression of his spinal vertebrae. inspired game, and fractured his leg. Broken bones Two of his sisters have experienced the same fates, are a right of passage for many kids, but he stands both of them developing noticeable “dowager’s out in the history of our family—the only one of humps”—a forward curvature of the upper back four siblings to ever wear a cast. His junior by three due to osteoporosis—in their later years. years, I was so impressed by the event that I have Genetic odds say that I will face a similar destiny. always steered clear of ski slopes. The thrill of My frst bone density test, which I had last year, shushing downhill never outweighed the prospect showed mild bone loss. Ever since, with almost of hobbling on crutches. religious zeal, I’ve taken a calcium plus vitamin D Most of the time, we take our bones for granted— supplement at breakfast, chased by a bowl of until something goes wrong. Our cover story high- yogurt. I’m hoping this daily routine will at least the work of researchers trying to understand postpone further bone loss. Like missing out on the mechanisms behind normal bone buildup and the thrill of skiing, it’s a small concession I’m happy breakdown and what happens when that process to make for the health of my bones. goes awry. What they are learning about bone Meanwhile, I will count on researchers like my repair, genetic bone disease, and of the sister and the ones described in this issue to con- bone tells us that the pathways involved are much tinue making headway in understanding bone more complicated than once thought. biology, which will no doubt lead to better treat- These days my family is keenly aware of the ments for all types of skeletal faws. I hope you effects of aging on bones. My mother, now 89, was fnd the work as fascinating as I do. And for those diagnosed with osteoporosis several years ago. of you with iPads, be sure to download the free Initial treatment with the drug Fosamax proved Bulletin app for a deeper dive into the topic as well disappointing, due to side effects. After careful as a fun twist on the story’s design. assessment of other available options by her doc- tor and my sister, a bone researcher, my mother is now facing her second treatment with the once-a-year drug Reclast. Time—and her next bone density test—will tell if the drug is doing its intended job of slowing bone loss.

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

Paul Nurse, F.R.S. Additional Co ntrIButors President / The Royal Society of Cay Butler, Michelle Cissell, Dame Alison Richard Nicole Kresge, Heather McDonald Professor / The VSA Partners, NYC / Concept & Design Clayton S. Rose, Ph.D . Finlay Printing / Printing & Binding Professor of Management Practice, Former Head of Global Investment Banking, J.P. Morgan & Co. Kurt L. Schmoke, Esq., Chairma n Dean / Howard University School of Law Anne M. Tatlock Director, Retired Chairman & CEO Fiduciary Trust Company International Telephone (301) 215.8855 • Fax (301) 215.8863 • www.hhmi.org ©2011 Howard Hughes Medical Institute

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

2 hhmi bulletin | May 2o11 James Kegley an impact—particularlybecause itcancreatetheimpressionthat conversation inside the scientific community doesn’t have much of found tobeonlypartiallycorrect. Yet keepingthissortofproductive nificance, evenifaspecific model,finding, orassumptionislater We recognize thattheweight ofaccumulated evidencehassig- knowledge. the worldsometimesbasedonpartialorfragmentary conclusionsabout sense tousthatourcolleaguescanreachcertain and revisingourunderstandingofthephysicalworld. ourselves abouthow discovery isanongoing exercise inassessing ing whatwedo,how wedoit,andwhy. We openlyamong talk understanding fornonscientists andscientists alike. How dolivingorganisms evolve?Thesearebigquestions andworth or bad?How canweknow thattoday’s miracle drugwillbesafe? to climatechangeandwhatdoesthatmean? public conversationaboutscience. Hashumanactivitycontributed bine to create confusion among individuals who try to follow the way. Conflictingclaims,newinformation, and misuse offactscom- up tryingtomakesenseofthefloodinformationthatcomestheir forscience inAmericaandaroundtheworld. important other media. ofdevelopment,is This initiative, still inthe early stages and disseminate itinternationallythroughtelevision,classrooms,and initiative. Wedocumentary willcreatehigh-quality programming spot on the tennis court, cation havebecomeanintegralpartofourmission andculture. investmentsofmorethan$1billion,programsinscience edu- total but went beyond that commitment many years ago. Today, with over a10-yearperiodonanactivityrelatedtoitsresearchmission ­Ho issues thathaddoggedthe settlement with the to supporting programs inscience education. gro  I M Learn, Show, andTell Department ofScience has beenanHHM reach innewdirections. commitment needstoextendbeyondtheclassroomandlaboratory forschoolsthatwe’vesupportedmanyyears. new expectations with otherinstitutionstocreatecomprehensiveprograms,andset tion objective, made it clear that we’ll reward those who partner have askedschoolstounify their proposalsaroundasingleeduca- asking ourpotentialcollaboratorstothinkbigandbecreative.We in newgrantsaboutayearfromnow. We aresettingthebarhigh, ties thatfocusonundergraduates—andplantoaward $60million collegesanduniversi- education competition—thisonetargeting and students.Thisspring,weannouncedoureighth undergraduate cational “sweet spot” in programs aimed at undergraduate faculty nstitute reorganized itself and entered a period of exponential o ward wth inscientific research,the As scientists, wehaven’tdoneaparticularlygoodjobofexplain- Science hasgottensocomplicatedthatmanypeoplehavegiven As anavid tennis playerwho’s alwaysseekingthatelusivesweet This is good, important work.Butit’sThis isgood,important clearthatHHM r e tha R . Hughes.HHM n tw o d e I investigatorformanyyearsandnow headsour cad I nternal E I e U du c s ag nder the leadership of Sean Carroll, who nder theleadershipofSeanCarroll,who an tell you that HHM I cation, the agreedtospendanextra$100million I nstitute duringthelifeofitsfounder, o R , asth evenue Service and resolved tax I nstitute alsomadeacommitment I e nst

Ho itute will launch ascience w I ard s mammography good s mammographygood I I t stemmed froma h H ugh as found its edu I ’s educational I t alsomakes e s M e d i ca l -

­Holiday LecturesonSc on more screens—and at alevel ofquality on par with HHM extend ourscience educationoutreachonalargerscale—certainly experts onOctober6and7. humanevolutionwithHolidayLecturesfromatrioof we’ll tackle tohighschoolteachersandstudents.Thisyear, on topicsimportant used videoasatoolforexpanding knowledge throughourpopular science reportingunit on thePBSNewsHour. Andwehavelong NOVA scienceNOWandprovidedmodestsupportforthenew gramming. We have helped fund the public broadcasting series widen thegulfoftrust. tended barriers that can often alienate nonscientists and further we aresmug aboutourown “superior”knowledge anderectunin- belief. That’s aninvestmentwefeelobligationtomake. that makeitpossibletodistinguish observabletruthfromopinion or the naturalworld,how accumulatedcanleadustoinsights data more: Show how science isdone,how experimentstestideasabout andrelatededucational materialswilldosomething documentaries dow intotheessenceofscientific process.Butwehopethese that’sto spinalivelytale scientifically accurateandopensawin- books andacolumnist forThe NewYork Times,Carroll knows how nourish . Asanaccomplishedauthorofpopularscience scientists’ lives anddiscoveries, storieswith the power toinspireand create televisionprogramming builtaroundcompellingstoriesof program in scientific research. Carroll and his colleagues aim to “ It’s clear that HHMI’s educational Ro in newin directions. the classroom and laboratory reach to commitment needs extend to beyond We initiative will significantly expect that the new documentary HHM bert I T hashadsomelimited experiencewithtelevisionpro- jian ience, whichprovidein-depthinformation ” president May 2o11

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s letter hhmi bulletin I ’ s 3 centrifuge

parents and the Pennsylvania for a playground. “I got to roam unsu- pervised, catching animals, damming streams, harvesting berries, climbing mountains.” Later, in his formal educa- tion, “those experiences were real to me, not abstractions.” “But today, students are no longer interested in a walk in the woods,” he says. “They’ve been conditioned to be afraid of poison ivy, mosquitoes, those sorts of things.” White’s offce is decked with ­dragonfy-themed artifacts, among them a door knocker, an oversize kite, and a Tiffany-style lamp. Here he opens up about the concerns that sparked his book: “Science comes from feld observation; feld biologists like Darwin make observations that lead to experiments that otherwise would never happen.” Everyday people lack boots-in-the mud experience, too, he says, and the Ode to Dragonflies consequences are dire: The jewel-like creatures lyrically depicted in his book In his small, quiet book about large, A self-described “enthusiastic stand for all of “our fellow earthlings charismatic insects, Hal White ­amateur,” he’s published a swarm of whose survival we threaten—not through a persuasive alarm about our vanishing articles on dragonfies and damselfies deliberate actions … but through our connections with the natural world. and was proud to coauthor descrip- relentless destruction and disruption “As people forget their sense of the tions of the rare ringed boghaunter of fragile and unique habitats.” outdoors, it’s being destroyed,” he says. and pygmy snaketail larvae, which he He writes, “Our seemingly innocent “And nobody will even see it go.” His tracked down (and dredged up) in routine activities of building houses, book is Natural History of Delmarva ­Massachusetts and Virginia. fertilizing lawns and crops, salting roads Dragonflies and Damselflies: Essays of a White’s university duties include in the winter, cutting down stream-side Lifelong Observer, published this spring directing an HHMI-supported program vegetation, tapping ground … con- by the University of Delaware Press that makes calculus more accessible tribute far more to the demise of certain with the Delaware Society. to biology students by substituting than most people realize.” It’s a leisurely ramble through a biological examples for physics and “This book is a plea to humankind,” rich patch of natural history, featuring engineering problems. “It’s surprising White says, to return to the wonder almost 200 razor-sharp portraits of the how often kids who love biology are of the woods, the mountains, and the spiketails, emeralds, darners, and other taken aback by math requirements. If marshes—to experience biodiversity aquatic insects that have fascinated they can understand how math relates directly, and to appreciate just how him since he was a teenager in the to their feld—if math anxiety doesn’t ­vulnerable and precious it is. 1950s. He rounds out his reminiscences, stife their attitude of inquiry—I call it —George Heidekat feld notes, and observations with a great success,” he says. sketches of dragonfy hunters he has He traces his own attitude of inquiry WEB EXTRA: To see a slideshow of photos from White’s book, visit www.hhmi.org/bulletin/may2011. known—and the occasional haiku. to a childhood lived with educators as White is a University of Delaware biochemist who spends weekends and holidays with net and camera prowl- “I’d rather be up to my knees ing the wet places of the Delmarva ­Peninsula between the Chesapeake in a swamp than cooped Bay and the Atlantic . “I’d rather up in an office. be up to my knees in a swamp than cooped up in an offce,” he says. Hal W hite ” Ping Zhu

4 hhmi bulletin | May 2o11 Science History as Art For neurobiologist Julie Simpson, ing image tiles against his portrait, researching scientists and Midgley beauty is microscopic. In her second- numerically ranking and sorting the writing code. The collection grew foor offce at HHMI’s Janelia Farm tiles into a logical layout to fll up the as colleagues at Janelia lobbied for Research Campus, circuit diagrams of picture. Tile by tile, the new portrait must-haves, like Freeman Dyson fy are neatly framed. Simpson’s emerged, composed of about 5,000 and Maria Goepfert, and voted down favorite t-shirt is an Andy Warhol-style images that convey Mendel’s work. others (sorry, B.F. Skinner). shot of fy images, in four squares. At a distance, the mosaic Mendel “It was a huge hit. Our scientists “I’m not tempted to buy a Monet,” thoughtfully gazes, same as always, loved it,” says Kim Ripley, special proj- she remarks, “but I do like a good from a simple background. Draw ects manager at Janelia Farm, who Golgi stain.” closer, however, and you see that his coordinates exhibits. “In fact, we’ve Now, Simpson can get the best of dance with a motley mix of tiled decided to make the images a perma- big portraits and tiny science. She and images of peas, the DNA double helix, nent collection,” just outside Janelia’s her partner Frank Midgley, a scientifc a butterfy, chromosomes, garden popular dining room. computing expert at Janelia Farm, images, monk robes, and thousands of Back on the second foor, Simpson have created a one-of-a-kind art other illustrations, pieced together like is identifying brain cells that con- exhibit, “MacOSaiX Scientifc Heroes.” a giant crossword puzzle. trol fy behaviors, such as grooming. They generated mosaic portraits of “What’s cool is that these por- ­Midgley is developing computer tools 35 scientists—from Gregor Mendel to traits are driven by the real work the to allow Simpson and other scientists E.O. Wilson—assembled from Google scientists did,” Midgley says. Equally to make sense of huge data sets on search images of key research terms. satisfying, Simpson adds, is learn- those behaviors. Midgley wrote a software program, ing the history behind that work. The You can try out Midgley’s free MacO- using the Macintosh operating sys- couple wrote short biographies to SaiX program at http://web.me.com/ tem, that cranks out the portraits. To accompany each portrait. knarf. Midgley notes that your creation remix the classic portrait of Mendel, Simpson and Midgley got the idea will be your own: image search results for instance, the program performed for their MacOSaiX project in the spring constantly change. No two portraits are a Google search for images chosen to of 2010 as they stopped in Janelia’s art ever the same. —Kathryn Brown describe Mendel’s work: “genetics,” gallery and began thinking of ideas to “peas,” “heredity,” “law of segregation,” dress the walls in art with a scientifc WEB EXTRA: To see how Gregor Mendel’s and “law of independent assortment.” twist. Soon, they were spending week- portrait came together, visit www.hhmi.org/bulletin/may2011.

Andrew Cutraro The program then compared the result- end hours on the project, with Simpson

May 2o11 | hhmi bulletin 5 6 hhmi LS and scientists. For many, though, the strain theschedulesofbusy doctors practices for hospices, andrehabilitation centers. it bringsmusicto patients inhospitals, disorders. Also, through “LS rosis, disease, Alzheimer’s andgenetic research onamyotrophic lateral scle- medical organizations that support raises awareness and funds for nonpro entertainment; through performances, it sprinkle theranks. engineers, andbiotech workers also Architects, teachers, dentists, software violinist andLS cal institution inMassachusetts, says ­r ­Mas Walker, anHIV-AIDS researcher at in thelabofHHMIinvestigator Bruce Jia isanHHMImedicalresearch fellow Jia, aviolinist andLS tic yet just asful to pursue anotheravenue that isartis- recharge after alongday ofwork, and use musicto enrichtheirlives, to f passion that endedupplaying second they’ve found anoutletfor alifelong O ativity withtheLongwood Symphony bedside to unleashtheirmusicalcre- community escapethelaboratory or and scientists from Boston’s biomedical At least oneevening aweek, doctors to Brahms From Bench epresent nearlyevery majorbiomedi- ddle to theirdemandingcareers. rchestra (LS centrifuge O The weekly rehearsals plusextra For theLS The orchestra’s 120musicians “A lotofscientists andphysicians In thisac sachusetts General Hospital. , f bulletin ounded in1982,isahighpriority. claimed amateur orchestra f O

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, musicismor O May 2o11 ). f president LisaWong. lling,” says Sherman O concertmaster. O e than onCall”

f t t before was tryingto squeeze intherehearsal research at Children’s HospitalBoston, to arehearsal. Zon, headofstem cell trumpet Leonard Zon rushedinlate and joinedtheLS But he’s happy hebecame ascientist about playing violinprofessionally. Cepko. “Istarted playing in laboratory ofHHMIinvestigator Connie Emerson, apostdoc intheHarvard time Ivisited asachild,” recalls Mark and aviolinist—he would play every music isafamily tradition. cells,’” Zon recalls. Congress andeducate themonstem to the conductor senthimoff:“‘Go people inneed.” and ithasawonderful mission to help everyday life asaphysician-scientist, venue for relaxing amidthepace of says Zon. “The orchestra isagreat legislators onstem cell research. HHMI investigator andLS affair withmusic.Emersonsays Zon’s a I thinkabouthimevery timeIplay in and my grandfather gave mehisviolin.

concert.” At onepoint,Emersonthought “My grandfather was adoctor For many, aswith science, classical “I doeverything Icanto getthere,” Several years ago, for instance, f ying to Washington to brief O O n that day, however, to maintainhis O principal f fth grade, me.” — Richard Saltus ticing, helikes to stand upandconduct violin,” says Emerson.“WhenI’mprac- down thegiftofmusicto hischildren. tion; like hisgrandfather, heishanding Another motivation isthefamily tradi- munity outreach work,” Emersonsays. ily life, andtheorchestra. successfully jugglinghisresearch, fam- for LS I’m thought aboutitalot.Butfor now, really like to come back,” shesays. “I’ve has afamily, forcing herto resign. “I’d career hasintensi sional,” Lehtinen says. However, her unless you’re avery seriousprofes- opportunities to play inanorchestra the LS Hospital Boston. Shewas thrilledto join gator Christopher Walsh at Children’s a postdoc inthelabofHHMIinvesti- to give. Sheisaviolinist, apianist, and could balance thetwo.” ­example “was what mademethinkI “My son,who’s four, hasalittle “ Comings andgoingsare afact oflife For Maria Lehtinen, somethinghad

just too busy.” WEB EXTRA: wgbh/nova/secretlife/scientists/len-zon/. plays shofar aswell astrumpet,visitwww.pbs.org/ O ne of the main reasons is the com- O O members.Sofar, Emersonis in1999. “There aren’t many To learnmore aboutLeonard Zon, who f ed andshenow

Ping Zhu upfront

08 A Crowd in the Kitchen A global team of researchers showed that potassium channel mutations promote tumor formation and hypertension.

10 ne URO2GENESIS An ancient cellular program to protect cells when is low seems crucial for the production of brain cells.

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Wired for Smell Complex circuits of excitation and inhibition help the brain interpret odors. Read the story at www.hhmi.org/bulletin/may2011.

The human body is full of fine-tuned sensors and circuits that respond to changes in the environ- ment. Some are self-explanatory: in the cold, the body shivers to warm up. Others take probing to understand. Scientists scrutinizing how cells react to low oxygen found a complicated response pathway linked to aging and disease. And researchers have discovered that a mutation in an ion channel triggers cells to proliferate out of ­control, causing a rare type of tumor—and high blood pressure. When it comes to biology, the ­tiniest imbalances can have surprising implications.

May 2o11 | hhmi bulletin 7 upfront

A Crowd in the Kitchen A global team of researchers showed that potassium channel mutations promote tumor formation and hypertension.

Whoever said too many cooks spoil the broth must not have been a geneticist. ¶ According to HHMI investigator Richard Lifton,

a kitchen full of cooks—plus some very high-end cookware—was removed the tumors, and then meticu- exactly what was needed to define the molecular defects under­ lously stored tumor specimens to preserve lying a severe form of hypertension, and a specific type of tumor. their DNA. Lifton then did a high-tech search Lifton, a human geneticist at Yale School laborators recently discovered the surprising through the 23,000 or so in the of , has long been interested in cause of a subset of those adrenal tumors: patients’ tumor cell DNA to find culprit a type of adrenal gland tumor that causes mutations in a encoding an ion chan- mutations. That analysis, called whole high blood pressure. Normally, the adrenal nel . Normally that channel, known exome sequencing, was a two-step process. gland, located atop the kidney, secretes the as KCNJ5, allows potassium ions to pass First, the team used gene microchips to steroid hormone aldosterone into the blood. in and out of cells. But in the tumor cells, “capture” the approximately 1 percent of The hormone instructs the kidney to retain the channel also allows sodium ions to leak a cell’s 3 billion DNA letters that contains water and salt (and hence elevate blood through, which activates signaling pathways genes (the exome). Second, they sequenced pressure) in times of acute physiological that stimulate tumor cell growth and unreg- that relatively small portion of the stress, such as blood loss or salt imbalance. ulated aldosterone production. using next-generation machinery at the Yale Some 5 to 10 percent of patients with “It seemed so obvious that these tumors Center for Genome Analysis. extreme hypertension, however, have tumors were caused by somatic mutations,” says Lif- Choi took on the daunting task of devis- of the adrenal gland. These benign, some- ton, referring to mutations that are acquired ing computer programs (see Web Extra, times massive tumors pump out unregulated rather than inherited. “But it wasn’t until “Dedication Personified”) to make sense of levels of aldosterone into the bloodstream. we could sequence all the DNA in a all that DNA data—including whole exome Unrestrained aldosterone production causes tumor that we could identify what those analysis of four patients and partial analysis the kidney to retain sodium, keeping blood mutations were.” of 18 more. In the end, his analysis iden- pressure high. The condition is curable only That’s where all the cooks come in, start- tified eight patients harboring mutations by surgical removal of the adrenal gland. ing with physicians at Uppsala University in the KCNJ5 channel gene. According to Lifton lab postdoctoral fellows Murim in , who diagnosed hypertensive Lifton, the odds of that happening by Choi and Ute Scholl and a team of col- patients with adrenal tumors, surgically chance are 10–30.

8 hhmi bulletin | May 2o11 Pietari Posti U investigator building blocksthatformagate—aso- through duetotheconfiguration ofprotein ionstopass allow onlycertain tions madeinthe1990sbyfellow HHM beautifully thisstorymeshedwithpredic- ruary 11,2011,inScience. into thecells.TheworkwasreportedFeb- allowed sodium ions to flow abnormally in culturedcelllines,shefoundthatthey When shestudied themutantchannels answered thequestion experimentally. York Medical CollegeinValhalla, Scholl laborating withWenhui Wang atNew the mutantKCNJ5channelsleaky?Col- niversity. MacKinnon hadshown that channel Particularly toLiftonwashow notable But wasitstructuraldamagethatmade R od MacKinnonof R ocke ­ feller I

this typeofadrenaltumor. de time, tumors remainstobeseen. lead tolessinvasivetreatment for adrenal of tumors.Whetherthisknowledge will unbridled cell proliferation characteristic of anionchannelplayingaroleinthe slip throughthemutantchannel,headds. tectural explanationforwhysodium ions MacKinnon’s workoffersasatisfyingarchi- tivity forsimilar channels,” saysLifton. selec- had definedascriticalforpotassium tumors wasinaresiduethatMacKinnon in 2003. was awarded theNobelPrizein Chemistry called “selectivityfilter.” For thatwork,he tect KCNJ5 mutations to help diagnose The KCNJ5storyisthefirstreport “One mutationwefoundinKCNJ5 Lifton envisionsasimpleblood testto ­ I n themean-

treat thesepatients.” Lifton. “We must figureout abetter wayto improve underthatkindofcontrol,” says about two-thirdsofthosepatientsdon’t use threeormoredrugsperpatient,and major riskfactorforheartdisease andstroke. patients worldwidewhohavehypertension,a strategies fortheapproximately1billion investigations willleadtobettertreatment regulation ofsaltbalance.He’s hopingthese pressure. All,including KCNJ5,control so genesthatwhenmutatedincreaseblood of hypertension,hislabhasidentified10or began hisefforttodiscover the genetic basis “To treathypertensivedisease, weoften Now, almosttwodecadesafterLifton

w Murim Choi, visitwww.hhmi.org/bulletin/may2011. e b e xtra: For moreontheexomeanalysisbypostdoc May 2o11 W –E li

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ar bulletin 9 upfront

NEURO2GENESIS An ancient cellular program to protect cells when oxygen is low seems crucial for the production of new brain cells.

Celeste Simon has shown that some cells need low oxygen to function well.

In the brain, that finding offers clues on depression. Antony Nick

10 hhmi bulletin | May 2o11 F or more than two billion years on this planet, O2 has been the go-to gas for generating efficient cellular energy. But life on never takes oxygen for granted. “When it runs low, cells how exercise affects oxygen distribution in swiftly adapt,” says cell biologist Celeste Simon. ¶ This ancient these stem-cell-rich regions of the hippo- campus,” she says. adaptive reaction, known as the low-oxygen, or hypoxia, response, The clinical possibilities don’t end there, typically involves a cascade of protective changes in cells: protein given the links between decreased neuro- genesis and both Alzheimer’s and aging. synthesis drops and cells switch to a less efficient process of energy “We haven’t yet had a chance to investigate production that doesn’t require oxygen. But organisms have evolved in this area, but naturally we’re intrigued by uses for the hypoxia response that are not merely protective. the possibility that age-related declines in the hypoxia response help to drive the age- Simon, an HHMI investigator at the their voracious intake of oxygen? Simon related functional declines we see in the University of Pennsylvania, recently found and her team found that the usual habitat brain and other organs,” says Simon. evidence that the response is crucial for for stem cells in the mouse hippocampus is It might seem odd that a protective maintaining the health of stem cells in riddled with low-oxygen zones, where the response to low oxygen has ended up being the hippocampus, a key memory region signs of activity are particularly adopted by some cells so that they actually of the brain. The discovery could alter our evident. “It seems that these lower-oxygen need a bit of hypoxia to function normally. understanding of a host of stem cell-related zones are essential for maintaining neural But most of Simon’s prior research in the brain conditions. stem cells’ healthy activity,” she says. “In field has aimed at understanding such adap- “It’s a seemingly puzzling finding, but fact, these stem cells appear to be spread tations. “Embryonic cells, for example, can the normal functioning of neural stem cells out, in and near these zones, with different grow so quickly that they create a hypoxic in the hippocampus does appear to require activities depending on the oxygen level, zone around themselves,” she says. “This low oxygen levels and consequent hypoxia suggesting that the stem cells’ activities are switches on their hypoxia response, which responses,” says Simon. The neural stem cells in question are “ meant to keep the population of hippocam- It seems that these lower-oxygen zones pal replenished. A certain level of are essential for maintaining neural stem cells’ this replenishment, or “neurogenesis,” is healthy activity. increasingly thought to be important for a healthy mood and memory. Interruption of Celeste S imon ” neurogenesis causes depression-like behav- ior in mice, while in humans antidepressant being regulated by the local oxygen levels.” among other things promotes the sprout- appear to work largely by boost- The hypoxia response may be acting as a ing of new blood vessels toward them, so ing neurogenesis. Alzheimer’s disease, as growth signal for the stem cells. that they can continue to grow.” Her work well as ordinary aging, features a decline in Preliminary tests on the engineered no- has helped to show, too, how the hypoxia this replenishment process. hypoxia-response mice suggest that they response is used in some cells and In an October 2010 Nature Cell Biology do have behavioral defects consistent with also directly regulates stem cells in the paper, Simon and her colleagues reported those seen in other mouse models of depres- developing bone marrow and heart. that neurogenesis markedly declined in sion. Simon and her colleagues now are “It’s been clear for some time now that mice when their brain cells were genetically trying to determine whether inadequate hypoxia signaling is relevant in many areas altered to knock out their ability to produce hypoxia responses in the hippocampus of biology,” she says. “But it could turn the hypoxia response. “We saw fewer stem might be at least partly to blame for depres- out to have more importance for health cells, fewer of the immature daughter cells sion in humans. and disease than we’d ever imagined.” that stem cells produce, and fewer connec- Some activities are known to promote W –Jim Schnabel tions coming from these daughter cells,” neurogenesis—such as physical exercise— says Simon. and here again Simon wants to know web extra: For other work related to hypoxia Why would the hypoxia response even whether hypoxia signaling is a factor. “One and the heart, see the sidebar “ and HIFs” at matter to brain cells, which are known for of the things on our to-do list is to determine www.hhmi.org/bulletin/may2011.

May 2o11 | hhmi bulletin 11

ones are the body’s about how their owners flew, ran, swam, and ate. Bone can do framework and support, all that—but only if it stays in balance. our strongest tissues. Unlike the scaffold of a The Magic in Bone building, however, bones Early in embryonic development, our bones are mostly cartilage, are anything but inert. and it’s the cartilage-filled ends of bones that lengthen as we They pulse with life and grow. As we mature and growth slows, bone gradually replaces their mainte­nance requires that cartilage.­ The thick, hard outer layer of bone resembles rein- a surprisingly delicate bal- forced concrete in its structure, deriving strength from fibrous ancing act. proteins called collagen encrusted with crystals of a calcium-­ Throughout our adult lives, containing mineral. Even hard bone is plumbed with blood the body works day and night to vessels and wired with nerves. And inside the outer layer sits clear away patches of weak bone and build up new and stron- marrow, a softer tissue packed with immature cells that can form ger bone. When that balance falters in either direction, it spells blood, bone, and cartilage cells. trouble. Osteoporosis, which literally means porous bones, occurs In 1992, Kingsley reported a pivotal discovery about how the when bone breakdown outpaces bone buildup. Just bending or body constructs bones. He examined a mutant line of mice with coughing can cause a fracture. Too much bone, on the other very short ears, a wide skull, and a reduced ability to heal frac- hand, can lead to rare bone diseases or even bone cancer. tured ribs in search of something that had been hinted at two A small army of bone researchers, including several HHMI decades earlier. An orthopedic surgeon named Marshall Urist had investigators, is exploring the cellular pathways that strengthen made an extract of rabbit bone and implanted it under the skin of weak bones and support healing in broken bones. Their efforts a living rabbit. It produced an intact, marrow-filled bone under are yielding new drugs to treat osteoporosis, heal severe fractures, the rabbit’s skin. The discovery meant, Kingsley says, “that there and treat rare hereditary bone diseases. They’re working on new is some magic in bone that could induce formation of new bone.” precision therapies to stop bone cancer, as well. He found that the short-eared mice had a mutation in a gene The work is essential. By 2020, half of all Americans over age that produced that magic ingredient, called bone morphogenetic 50 will have weak bones and the low bone mass of osteoporosis, protein (BMP). Today 20 related BMPs are known, many of according to a 2004 Surgeon General’s Report. Roughly 4 in 10 which induce the body to make bone or cartilage. BMP-2 is the white women age 50 or older in the will experience active ingredient of a drug that grows new bone after spinal fusion a hip, spine, or wrist fracture, most likely due to osteoporosis. And surgery. Surgeons a biodegradable sponge soaked with the problem isn’t limited to women. Up to one in four men over the drug, called INFUSE Bone Graft by . The proce- age 50 will break a bone due to the disease. The consequences dure replaces an older, painful, and infection-prone method in are profound: one in four patients over 50 with a hip fracture will which surgeons transplanted bone from the patient’s hip. die within a year. The same drug is used for other dental and orthopedic “Skeletal diseases are incredibly common,” says developmen- ­problems: to bolster bone that anchors crowns or teeth, to heal tal biologist David Kingsley, an HHMI investigator at Stanford foot and ankle injuries, and to repair gunshot wounds to the jaw. University School of Medicine, noting that patients with less It can help knit shin bones shattered in motorcycle accidents, common but devastating bone diseases desperately need effective for example, or replace sections of cancerous bone that have treatments too. been removed in children, according to bone cell biologist Hari Studying bone also sheds on fascinating and fundamen- Reddi, of , Davis, who purified the first tal biological questions, Kingsley adds. The development of bone BMPs in the 1980s. reveals how “just a few cell types can be organized into highly However, the drug must be implanted with the sponge, rather specific shapes and sizes that underlie the things that animals than given as a pill or injected into the bloodstream, because it do.” The forms of animal skeletons, past and present, offer clues doesn’t easily circulate to where it’s needed, according to Reddi.

14 hhmi bulletin | May 2o11 Clinicians would like better alternatives, and they need treat- in solid bone, sensing and directing the others. For all these cells, ments that preserve and repair bone when it gradually deteriorates “the quest is to find out how signaling works and start design- throughout the body, as it does in osteoporosis. ing therapies around that,” says bone biologist Alex Robling of ­Indiana University School of Medicine. Building Bone Bulk Today, several targeted therapies are available to prevent and Even when bone is healthy, it’s always growing, dying, chang- treat osteoporosis by blocking bone breakdown. They include ing. To build and maintain healthy bone, we need weight-bearing four members of a class of drugs called bisphosphonates—­ exercise such as tennis, hiking, and walking; a healthy diet with Fosamax, Actonel, Boniva, and Reclast—and Denosumab, which calcium-rich food such as milk, cheese, and certain vegetables; blocks the Rank ligand pathway. These bone-preserving drugs are and vitamin D, from dairy products and sunlight, or a supple- also used to treat osteogenesis imperfecta, which causes children ment. This is true during childhood and adolescence when the to produce weak, defective bone. body builds 85 percent of adult bone mass, and it’s true during But while bisphosphonates and Denosumab are effective at adulthood to prevent bones from thinning and weakening. preventing bone resorption, they also cripple the bone-degrad­ ing The only reliable detection method for osteoporosis before cells that are supposed to clean out weak or damaged bone. Over a fracture is a bone density scan. Such tests have shown that a time this can make bones even more brittle, increasing the risk of full 44 million Americans have low bone mass and 10 million, fractures and, rarely, cause the jawbone to decay. Researchers are most of them women, have osteoporosis. In men, the disease is now investigating ways to get around this dangerous side effect, linked to low testosterone levels, and alcohol use, and such as giving patients drug holidays after a few years. lack of physical activity. In women, it is linked closely to meno- Bone endocrinologist and geneticist Gerard Karsenty of pause, when estrogen levels in the body drop. In the 1980s and Medical Center likens osteoporosis to a 1990s, doctors recommended that postmenopausal women pre- house fire and antiresorptive drugs to water. I“ f you come with vent osteoporosis and fractures by taking estrogen supplements, water you are going to stop the destruction, but you still need to which jam two cellular pathways used for bone resorption—one rebuild,” he says. Just one drug exists to rebuild lost bone—Forteo pathway involves compounds called cytokines and a second is (teriparatide), a synthetic form of human parathyroid hormone. called the Rank ligand pathway. But in 2002, researchers running Although the drug looks safe in humans so far, long-term treat- a long-term trial called the Women’s Health Initiative reported ment with high doses of it caused bone cancer in ; as a result, that estrogen plus progestin supplements raised the risk for breast doctors stop giving it to patients after two years. New drugs that cancer and stroke; two years later, estrogen alone was found to build bone would be helpful. “That’s where the need is,” says also increase the risk for stroke. Estrogen use plummeted. endocrinologist and bone expert Sundeep Khosla of the Mayo Fortunately, by then researchers had begun uncovering cel- Clinic in Rochester, Minnesota. lular signaling pathways that maintain bone’s thickness and strength. Three types of bone cells balance breakdown and repair: Learning from Overgrowth osteoclasts, which clear away patches of weak or defective bone; Researchers have identified at least three ways to build bone. osteoblasts, which build it; and osteocytes, which are entombed Two involve a cellular signaling pathway called Wnt. In 2001,

May 2o11 | hhmi bulletin 15 an international consortium led by HHMI investigator Matthew release compounds that recruit osteoblasts to lay down more Warman, a pediatrician and geneticist at Children’s Hospital in bone. Warman’s collaborator, Robling, at Indiana University, Boston, showed that a Wnt pathway gene called LRP5 is mutated anesthetized the mice and then mimicked the effects of weight- in a disease called osteoporosis-pseudoglioma syndrome, which bearing exercise by repeatedly bending their forelimbs. Mice with causes people to develop brittle bones. overactive Lrp5 in their osteocytes produced three times more A year later, HHMI investigator Richard Lifton of Yale Univer- bone than normal mice put through the same exercises. sity School of Medicine reported a different LRP5 mutation that “That tells us that the high bone mass mutation works in makes the LRP5 protein overactive, leading patients to make too very mature bone cells,” Warman says. “And, if we can think much bone. His team showed that the mutation causes high bone of a way to make an LRP5 receptor in mature bone cells think mass by preventing the natural antagonist Dkk and, by inference, that it has a high bone mass mutation, then you and I can have the related protein sclerostin from inhibiting LRP5 function. more bone.” At least three companies have looked for and found Warman and Lifton later found other LRP5 mutations in patients a compound that tricks the LRP5 receptor in just this way. For with syndromes characterized by high bone density. example, Amgen is running phase 2 clinical trials on its version of Since loss of LRP5 causes brittle bones and people with over- an antibody to sclerostin. Eli Lilly and Company has developed active LRP5 build extra bone, drugs that boost LRP5 activity a chemical compound that keeps sclerostin from blocking LRP5. could boost bone growth without keeping damaged bone from Warman is eager to develop bone-building drugs to help some being recycled. This is why Warman says that “LRP pathways in of his youngest patients—children with osteogenesis imperfecta. bone are very exciting targets.” This hereditary disease can kill before birth or make children Warman has studied bone building in patients who make too so susceptible to fractures that they must spend their lives in a much bone to better understand—and ultimately enhance— wheelchair, Warman says. bone building. What happens in these patients resembles an As Warman’s team tries to build bone by targeting LRP5 in extreme version of what happens during weight-bearing exercise bone cells, Karsenty’s team is trying to build it by blocking pro- like hiking or weight lifting, which spurs the body to bolster bone duction of a compound called serotonin in the gut. In 2008, his where it’s needed. (In a famous 1977 study, the upper arm bones team found to their surprise that LRP5 blocks gut cells from pro- of professional tennis players were 30 percent thicker in the arm ducing serotonin, which normally signals bone-building cells to they used to hit the ball than in their other arm.) stop multiplying. Last year, they reported in Nature Medicine that Recently, Warman’s team engineered mice to produce the a drug that blocks serotonin synthesis in the gut builds bone in overactive version of Lrp5 but only in mature osteocytes in hard mice. The results seem to conflict with Warman’s, but “it’s pos- bone. Osteocytes are believed to sense mechanical stress and sible that both groups are in part correct, and more needs to be done to sort out that whole story,” Khosla says. While most researchers seeking bone-building drugs have tar- geted Wnt signaling, including LRP5, HHMI investigator Gerald Crabtree, at , has discovered a second path- way that seems to help the body build bone. A few years ago, Monte Winslow, an HHMI predoctoral fellow in Crabtree’s lab, was investigating why the anti-rejection drug cyclosporine causes bone loss. They knew that cyclosporine indirectly changes the shape of a protein called NFATc that typically sits in the cell’s cytoplasm but moves into the nucleus to activate genes. When they engineered mice with a mutant version of NFATc that stays in the nucleus just 10 percent longer, the result was “the boniest mouse anyone ever produced,” Crabtree says. Unlike a normal mouse, which feels “soft and cuddly,” Crabtree says, these mice “felt like a bag of bones.” Now, he and biochemist and HHMI investigator Stuart Schreiber of Harvard University are hunting for chemical compounds that tweak normal NFATc to act like the nucleus-loving version. Such compounds will shed

16 hhmi bulletin | May 2o11 Clockwise from left: Matt Warman targets LRP5 to build bone, Brendan Lee linked Notch signaling to bone cancer, and David Kingsley placed BMPs in the center of early bone-building efforts.

light on how the NFATc pathway leads to bone growth and, with darker on x-rays, which suggested they had low bone mass—an luck, may lead to drugs that boost bone growth in a new way. observation that Lee corroborated with bone density scans. Lee knew that genes in a signaling pathway known as Notch were Immature Bone and Cancer mutated in this disease and that Notch signaling helped imma- Sometimes bones lose their balance by overgrowing and becom- ture stem cells in the bone marrow decide which of two types ing cancerous. Brendan Lee, a pediatric geneticist and HHMI of blood cells to become. He suspected that Notch might help investigator at Baylor College of Medicine in , pursues another type of bone marrow stem cell decide whether to become therapies for osteosarcoma, the most common type of cancer that a bone- or cartilage-forming cell. originates in the bones, from which about 60 percent of patients Sure enough, his lab group discovered, it did. Mice with over- recover. To do so, he draws on insights gained by treating patients active Notch in their bone marrow stem cells developed far too with hereditary bone, cartilage, and joint diseases at the Skeletal much bone in their skull, ribs, and leg bones, the team reported Dysplasia Clinic at Texas Children’s Hospital. in Nature Medicine in 2008. But it was immature bone, not the Among them are children with spondylocostal dysostosis, a strong, layered bone that supports the healthy adult skeleton. rare disease in which babies are born with fused and misshapen Lots of immature bone forms in human osteosarcoma, too. That vertebrae and a rib cage several sizes too small. Children who “helped us make the leap to bone cancer,” Lee says. survive often can’t breathe without a ventilator and sometimes To see if Notch signaling was also altered in bone cancer, Lee’s need a hole inserted in their , or major rib and chest sur- group tested lab-grown human bone cancer cells, including tis- gery, just to breathe. “It tugs at your heartstrings,” Lee says. “Their sue cultured directly from patients’ bone tumors. As anticipated, brain is okay, but they’re kind of trapped in a body.” Notch signaling was overactive, suggesting that the pathway con- Lee noticed that many patients with spondylocostal dysostosis tributed to human osteosarcoma. And compounds that block

Warman: Matt Kalinowski Lee: Pam Francis Kingsley: Davis Tower Kingsley Kingsley: Davis Tower Francis Matt Kalinowski Lee: Pam Warman: weren’t growing. What’s more, their bones were “washed-out” or (continued on page 48)

May 2o11 | hhmi bulletin 17 18 hhmi bulletin | May 2o11 Charting new wat e r s The same daring spirit drives Mark Bear to win sailboat races and to craft treatments for fragile X syndrome.

by madeline drexler

The is not built for leisurely sailing. With a sleek hull just under “But what really separates great sailors from less great sailors,” 14 feet long, a tall mast, simple sail, and minimal controls, this craft adds the HHMI investigator, “is that they see things that other has one purpose: to race. The singular helmsman—almost always a people don’t.” “he” because of the physical demands—must scramble, in a race on He should know. On the water, in a boat inaptly named “Fat high seas, from one side of the craft to the other, suspend himself ­Bastard,” Bear has won the U.S. Masters National Championship outboard straight-legged against a stiff wind, and torque his body in and the New Championship. In the lab, he’s challenged response to every wave. Since all are structurally identical, reigning dogmas in neuroscience. winning or losing lies entirely in his hands. Over a quarter century, Bear has tacked toward elusive problems Mark Bear—a champion helmsman and neuroscientist at the in his field. His main obsession has been brain plasticity: the process Massachusetts Institute of Technology—says he applies the same by which neurons change in response to experience. Early on, he principles to racing and research. explored neural connections in the hippocampus, which plays a key “You begin with probabilities. You don’t know a priori whether role in long-term memory and spatial navigation. Controversially, he heading off to the left side of the racecourse or the right is the way used these findings as a model for a very different part of the brain, to go. So you collect information, make observations, test hypoth- the visual cortex. eses. You do a few pilot experiments, sailing upwind a little in either More recently, Bear has applied his discoveries in brain plasticity direction, to see what looks promising. You make a plan, and take to understanding fragile X syndrome, an inherited form of mental measurements of whether or not the plan is working. If you made a impairment. He has described surprising mechanisms underlying wrong guess, you make on-course corrections. fragile X and has shepherded a promising treatment through phase 2

photographs by jeff barnett-winsby

May 2o11 | hhmi bulletin 19 clinical trials testing for efficacy in patients. The course he has adaptive plasticity extends into adulthood. And this plasticity charted may yield the first neurobehavioral targeted pharmaceu- is centered in the synapse—the junction across which a nerve tical treatment that grew from the bottom up: from gene discovery impulse passes from one neuron to another. At the synapses, to an understanding of pathophysiology to a targeted drug. axons—the long, slender projections of nerve cells that conduct electrical impulses to target cells—connect to dendrites, the short- Early Inspiration branched extensions of nerve cells that ferry impulses toward the On November 22, 1963, the day President John F. Kennedy was cell body. The terminus of the sending cell contains neurotrans- assassinated, six-year-old Mark Bear was glued to the television. mitters, chemicals that diffuse across the gap and activate sites on What transfixed him, even then, were the early conjectures from the target cell, called receptors. Synaptic plasticity is the ability of newscasters about what Kennedy’s life would be like if he survived the connection between two neurons to change in strength. the gunshots to his head and neck. “I remember being astounded: Figuring out the basis of this plasticity has been Bear’s mission so much resides in the brain,” Bear says. The next Christmas, he from the start. To convey how he has gone about that quest, he asked his parents for a human brain modeling kit. switches metaphors from the sea to the casino. “Imagine nature Now 53, Bear has the look of an ageless East Coast postdoc: neat as a deck of cards,” he says. “The first experiment you do should but decidedly casual—khakis, crew neck sweater, hiking boots. He not be one where you peel off a card from the top. It should be is tall and fine-featured, with a slightly receding hairline and an the deck-splitting experiment. The most incisive experiment. The early morning hint of a five-o’clock shadow. His eyes often have experiment that most narrows the range of possibilities and will an abstracted and amused expression, as if he’s formulating a joke. define your subsequent course.” Across the street from where he works on the MIT campus, Bear launched his career as a doctoral student at Brown Uni- dominating the view through his lab’s plate glass windows, is versity, followed by a postdoctoral fellowship with Wolf Singer at Frank Gehry’s Stata Center: big and boxy, with defiantly jangled the Max Planck Institute for Brain Research, in Frankfurt, and angles. It’s an odd panorama. In his unassuming office, Bear— a return to Brown with his own lab. His research spun off from sometimes slouched, sometimes leaning forward to explain a fine a well-studied phenomenon known as long-term potentiation, or point of science—is soft-spoken but plainly passionate about the LTP. When a rapid train of strong nerve impulses hurtles down mysteries of the brain. an axon, the synapses that connect the axon to the dendrites of In the decades since JFK’s death, neuroscience came of age, other neurons are strengthened, or “potentiated.” LTP is one and Bear caught the wave. Researchers learned that the brain’s of the cellular processes underlying learning and memory.

20 hhmi bulletin | May 2o11 In his research on brain plasticity, Mark Bear asks questions and designs experiments that challenge conventional views.

What piqued Bear’s interest was the opposite process: synap- “He was willing to stick his neck out,” says Richard Huganir, tic weakening, a phenomenon known as long-term depression, an HHMI investigator and neuroscientist at Johns Hopkins Uni- or LTD. He was inspired by classic experiments performed in versity, coauthor on several of Bear’s papers and a longtime friend. the early 1960s by Harvard University’s David Hubel and T­ orsten Bear had used discoveries about how LTD takes place in the hip- Wiesel that won them the 1981 Nobel Prize in Physiology or pocampus—where it wasn’t even clear what effects that plasticity Medicine. They temporarily sealed one in infant kittens. had—and applied it to the visual cortex, where the end results When the eye was reopened weeks later, neurons in each animal’s were obvious: blindness. The conceptual leap drew flak from fel- visual cortex no longer responded to stimulation, while brain low scientists. As Bear drily recalls, “I can still remember someone cells compensated by responding more strongly to inputs from saying, ‘The visual cortex is not a hippocampal slice with eyes.’” the open eye. In effect, the kittens’ brains had rewired themselves Yet his findings were later replicated.I ndeed, Bear’s lab is under visual deprivation—enough to cause permanent blindness. still working on the problem, publishing important papers in The kitten experiment “was the most exciting demonstration of 2009 and 2010 that explore molecular mechanisms for percep- experience-dependent brain plasticity ever,” says Bear. “I wanted tual learning and the mechanisms of visual cortex plasticity. “We to understand the mechanisms at the synaptic level and ulti- half-joke about ‘the curing blindness experiment,’” he says. “We mately at the molecular level.” He focused on a group of receptors haven’t quite succeeded yet, but we’re going to, I hope.” known as metabotropic glutamate receptors, or mGluRs, which “He’s one of the few neuroscientists who pays any attention are especially active during periods of high plasticity. to theoretical arguments,” notes Leon Cooper, director of Brown But he took an unconventional route to the answer. He University’s Institute for Brain and Neural Systems and Bear’s employed a formula in computational biology known as the BCM mentor at Brown. (Cooper—the “C” in the BCM theory—shared theory—for Bienenstock, Cooper, and Munro—a model of how the 1972 for studies on the theory of super- synapses change and respond selectively to stimulation. This theory conductivity.) “Mark developed a rather deep understanding of suggested that LTD is a consequence of synaptic activity that fails to theories of synaptic modification and realized that they depended strongly activate the target neuron. Using stimulating and recording on assumptions about cell behavior that hadn’t been checked. , Bear and his graduate student Serena Dudek looked for He set out to check them—and in the process, discovered some LTD in the hippocampus, an easy site to study synaptic physiology. remarkable new phenomena, including LTD.” They eventually were able to reliably trigger LTD in hippocampal Cooper says this approach to discovery sets Bear apart from slices freshly prepared from mice and rats, with both electrical stim- many scientists. “They say seeing is believing, but Mark had to ulation of synapses and with chemicals that stimulate glutamate believe in order to see.” receptors. Further experiments showed that LTD was widespread in slices from different brain regions—including the visual cortex. Daring Experimentalist Next, he temporarily deprived young kittens of sight in one Fragile X syndrome is the most common inherited form of eye in two different ways, either by anesthetizing the or ­intellectual impairment and the most common known genetic by closing the eyelid, which allowed the retinal cells to continue cause of . Though its symptoms vary among individuals, firing nerve impulses randomly. A few days later, after the anes- they are profound and devastating: low IQ, , autistic thesia wore off and the closed eyes were reopened, the scientists behavior, anxiety, attention deficit, and sometimes an abnormal displayed visual patterns to each eye and measured brain activity. In animals whose eye had been closed temporarily, synapses had predictably weakened. But in animals whose had been “what really separates anesthetized—and therefore sent no signals to the brain—the cortex responded about equally to stimuli from both eyes. This great sailors from suggested it wasn’t the absence of visual stimulation that caused less great sailors blindness—“use it or lose it”—but a mismatch of activity between the signals the brain was getting from the open and closed eyes. is that they see Synaptic strength declined through the active process of LTD. things that other Bear had illuminated the mechanisms of the famous Hubel and Wiesel experiments decades earlier. people don’t.” Mark Bear

May 2o11 | hhmi bulletin 21 to Neuroscience” class, Bear began one experiment after experiment.” Every time Sc ientist lecture by wheeling in a cart on which she brought her dismal findings to Bear, & a hospital sheet was draped over large, he showed her promising new direc- round objects. A hush of anticipation tions. “I was finally able to debug the M entor swept over the students. Bear donned a lab protocol and make it work. It turned out coat and surgical gloves. In a solemn voice, to be a robust protocol, and simple, too. “Professor Bear’s Patented Fundamental he reminded the students that they were Nowadays, people use it widely, which Brain Tonic & Cure All,” proclaims the lucky to have materials to demonstrate the makes me very happy. It’s all because Victorian-lettered notice on a bulletin brain’s structures, and that it was important Mark was inspirational, getting me board in Mark Bear’s suite of labs. “For the to respect the sanctity of the donors. through the hardships of the project.” immediate relief of Scientific Thought, He then pulled away the sheet. Under­ Kim Huber, now associate professor of Enlightened Ideas, Secular Reasoning, neath were honeydew melons adorned neuroscience at the University of Texas Humanist Morality, and the General with Mr. Head accessories. Southwestern Medical Center, as a Confusion of having to think for yourself.” postdoc performed the decisive laboratory “He’s a great lecturer,” says Lee, now asso- The occasion was a graduate student pre- experiments proving the mGluR connec- ciate professor of biology at the University sentation at the lab—poking fun at Bear’s tion to synaptic weakening. “Even now of Maryland. “And he changed my career enthusiasm for mGluR5 as a broad thera- when I see Mark—and I’ve been out of direction. He turned me on to how inter- peutic target. Among his grad students his lab for 10 years—I still want to tell him esting it is to study the molecular basis for and postdocs, Bear is known as an encour- about findings in my lab, because he was memory formation. I decided that this is aging, enthusiastic, and joyful mentor. always so enthusiastic.” what I want to do for the rest of my life.” Hey-Kyoung Lee was impressed by this “Science is fun,” Bear says. “If you’re not As a graduate student with Bear, Lee side of him even as an undergrad at having fun, then maybe you shouldn’t be worked for two arduous years to figure . In an “Introduction doing science.” —M.D. out a chemical way to depress synapses. “I spent two years getting no data, running

physical appearance. It strikes 1 in 4,000 boys and 1 in 8,000 girls. high levels of LTD, not the wild type. “I swear to God, I thought There is no cure—only treatments for problems such as anxiety somebody had mixed up the code,” says Bear. They repeated the and impulsive behavior. experiment: same incongruous result. Fragile X is caused by a mutation in the FMR1 gene, discov- “If you’re doing an experiment, and you’ve worked very hard ered in 1991, which leads to loss of a protein, the fragile X mental at it, and you get a bizarre result, chances are 99 out of 100 that retardation protein, or FMRP. Under a , the defective the bizarre result is just some kind of fluke,” explains Cooper. X chromosome looks broken—fragile—where the FMR1 gene “But 1 time in 100 it’s not a fluke. That’s up to the taste, the is disrupted and mutated. In 1994, researchers created an Fmr1 discretion, the daring of the experimentalist. And Mark is a knockout mouse. daring experimentalist.” At an HHMI science meeting in 2000, Bear unexpectedly After pondering the results for several months, Bear came up crossed paths with fragile X. In a prepared lecture, he explained with an explanation that turned the conventional wisdom on its the link between protein synthesis and memory. When he head. Simply put, it states that mGluR5 drives protein synthesis returned to his seat, the stranger next to him leaned over, com- to keep up with the demands of the cell. FMRP acts as a brake plimented him on the talk, and offered to send him some fragile on protein translation. Without FMRP, mGluR5-triggered protein X knockout mice, which lack the Fmr1 gene. The stranger was synthesis goes unchecked, eventually disrupting synaptic function. then-HHMI investigator Stephen Warren, the geneticist at Emory In 2002, Bear presented the idea at a conference on fragile University who had discovered the mutation for fragile X. X at Cold Spring Harbor Laboratory. “I was the last speaker of Bear enthusiastically accepted. The conventional wisdom was the meeting. I laid out this idea. And there was a sort of stunned that LTD’s synaptic weakening was a result of protein synthesis silence. I felt relieved that I hadn’t been laughed at.” and that one of those LTD proteins was FMRP. That meant that In 2004, based on this single experiment and an exhaus- Warren’s Fmr1 knockout mice would presumably show fewer tive literature search on the downstream effects of mGluR5, he signs of LTD. In Bear’s lab, postdoc Kimberly Huber, a gifted published a paper in Trends in Neurosciences boldly titled “The physiologist, performed experiments comparing hippocampal mGluR theory of fragile X mental retardation.” It suggested that LTD in the knockouts with that in wild–type mice. The experi- a vast array of fragile X symptoms—, cognitive impair- ments were blinded—that is, she didn’t know at the outset which ments, developmental delays, loss of motor coordination, animals were the knockouts and which were wild type. anxiety, autistic behavior, habit formation, sensitivity to touch, When the experiment was completed and the scientists finally even changes in gastrointestinal motility—could be accounted genotyped the animals, Bear and Huber were dumbfounded. for by runaway effects of mGluR5. Fragile X, Bear wrote, was a Contrary to expectations, it was the knockout mice that showed disease of excess: excessive sensitivity to environmental change,

22 hhmi bulletin | May 2o11 ­excessive neural connectivity, excessive protein synthesis, exces- sive excitability, excessive body growth. Was it possible to undo “Being born with a this cellular chain of events? developmental brain Bear and his colleagues at MIT later performed a genetic res- cue experiment in mice—“rescuing” normal behavior through disorder may not DNA manipulation. They crossed mice that were heterozygous be an irrevocable for the gene that encodes mGluR5 with Fmr1 knockout mice, which lacked the gene for FMRP that restrains protein synthesis. sentence.” Mark Bear The offspring had only half of the normal mGluR5 receptors and so produced only half the normal amount of mGluR5 protein. The company has received federal regulatory approval to Reducing mGluR5 compensated for the lack of FMRP and elimi- undertake larger trials of children with fragile X and autism. nated many of the symptoms of fragile X. It was as if the genetic Meanwhile, another Seaside drug—STX107, which selectively manipulation had compensated for lack of a protein synthesis blocks mGluR5—is in the pipeline. Other companies, including brake by taking the foot off the gas pedal. Novartis and Roche, are also working on glutamate inhibitors for In the genetically engineered mice, seven of eight fragile X fragile X. phenotypes similar to those in humans were corrected or pre- How would a treatment that could ease the symptoms of frag- vented. (The only phenotype not corrected was abnormally large ile X change people’s lives? “It’s like asking: What would it be testes.) The animals didn’t have exaggerated LTD, they didn’t like to have the best dream you could ever have come true?” says suffer seizures when exposed to a loud noise, they didn’t gain Katie Clapp, parent of a 21-year-old son with the disease. Clapp abnormal weight, and their neurons didn’t show the abnormal cofounded the FRAXA Research Foundation, which is dedicated dendrites seen in the Fmr1 knockout mice. to finding treatments and a cure for fragile X syndrome and has While the results are encouraging—suggesting global effects funded some of Bear’s work. of a single —“the behavioral manifestations of fragile But Bear cautions that there may be limits to the mGluR X are different in a mouse than in a human,” Bear says. “It is hard ­theory. Most neurodevelopmental disorders are not diagnosed to know a priori which aspects will be helped and which will not.” until well after symptoms begin, suggesting that doctors may not The experiment did demonstrate that mGluR5 was a valid target be able to give drug treatments early enough to stave off the worst for drug therapy. Other investigators have found that the interac- effects of the disease, such as severe cognitive impairments. As tion between FMRP and mGluRs is highly conserved in evolution, Bear conceded in a 2008 paper in Neuropsyc­ hopharmacology, showing up in fruit flies and zebrafish in addition to mammals. “derailment in brain development might be difficult to reverse This evolutionary conservation boosts confidence that pharmaco- retrospectively.” Some drugs may also carry intolerable side logic approaches successful in animals may fare well in humans. effects. In early clinical trials of glutamate inhibitors, a small proportion of patients suffered adverse events such as upper respi- Trial Treatments ratory infections, sedation, and headache. In 2005, Bear cofounded Seaside Therapeutics, Inc., a Cambridge, Despite these cautions, the recent clinical trials represent Massachusetts-based company dedicated to creating treatments a dramatic shift in thinking. Scientists had long assumed that to correct or improve the course of fragile X syndrome, autism, genetically based developmental disorders of the brain were per- and other disorders of brain development. In July 2010, Seaside manent. But Bear has shown that treating the functional deficits announced positive data from a randomized, placebo-controlled with small therapies may alter one’s fate in life, even if phase 2 study of pediatric patients with fragile X syndrome. Sea- the gene remains unchanged. “Being born with a developmental side used an experimental drug dubbed STX209, or arbaclofen, brain disorder,” he says, “may not be an irrevocable sentence.” which inhibits glutamate signaling. And fragile X may just be the start. “The big splitting-the-deck The trial showed that the drug reduced outbursts and tan- question now,” he says, “is whether other rare, single-gene causes trums and boosted sociability and communication. In September of autism—such as Rett syndrome and tuberous sclerosis com- 2010, the company announced promising results from an “open plex—share similar characteristics with fragile X syndrome.” Even label” phase 2 study of the drug in young patients with autism autism without a known cause may respond to the treatment. If disorders, where the participants knew what drug they so, mGluR5 blockers (or, with some disorders, enhancers) could were receiving. These patients likewise were less irritable and less have wide applications. Returning to a familiar metaphor, Bear socially withdrawn. calls this new line of thinking—and of hope—“a sea change.” W

May 2o11 | hhmi bulletin 23 POST- DOCS a doctorate holder in a temporary research job, receiving mentoring and training needed for the next career stage. THE BEST OF TIMES 43,000– AND THE WORST 89,000 OF TIMES u.s. trained postdocs by amber dance postdocs balance the joys of pure research with tough working conditions.

60%

up to sixty percent of u.s. postdocs are foreign citizens nih’s national research service award stipend for starting postdocs, PERCENT WHO HAVE which many institutions use as a guideline, has risen. HEALTH INSURANCE: POSTDOC STIPEND: (based on nih) 2000 75% 90%* average42 age that 1986 2006 $26,916 scientists get a first research grant *postdocs often pay the tab themselves 2010 HOW MANY GET RETIREMENT $37,740* *stuck in the mid-$30,000 80-100 BENEFITS? range since 2003 hour work weeks

30% 50% 1986 2006 2.2 FORMER POSTDOCS WHO K99/R00: the nih AIMED TO BE A TENURE- “kangaroo”award YEARS TRACK PROFESSOR: median length of a 150– single postdoc in the life sciences 200 percent who held 61% nih k99/r00, or “kangaroo” awards per year two postdoc slots: PERCENT WHO ACTUALLY NIH DIRECTOR’S EARLY 29% ACHIEVED THAT GOAL: INDEPENDENCE percent who held AWARDS: three or more: 10 superstar ph.d. recipients are chosen to skip the postdoc and 37% go straight to pi 11% part 2 of 2: in part 1 of this series, readers learned how principal investigators find and train the most promising postdocs. (see hhmi bulletin, february 2011)

resh from a Ph.D. in virology, Nancy training they deserve. With these positions stretching four years or Van Prooyen is carving her own sci- much longer, some enthusiastic young scientists molder in a kind entific niche. She’s taking on the of postdoctoral purgatory, hoping for a career that seems further little-known fungal pathogen, Histo- away with each passing experiment. plasma capsulatum, as a postdoctoral Even so, a postdoc that doesn’t drag on is well worth it for fellow at the University of California, the to untangle biology’s mysteries and a shot at the San Francisco. professor’s chair, Van Prooyen says. Her graduate work on human Postdocs have won some victories lately, asking for and get- —supported by an ting employee benefits and other perks with help from national HHMI Gilliam Fellowship at Johns associations and unions (see Web Extra, “Who Speaks for the Hopkins University—was interest- Postdocs?”). But a big worry still looms large: what comes next? ing, but the virology field is saturated At the end of that long, hard slog, the desired reward may turn out with seasoned researchers. As a young to be just a mirage. scientist, Van Prooyen wanted to do “Getting out of the gate continues to get harder,” says Sean B. something new. Far fewer researchers Carroll, HHMI’s vice president for science education. With study Histoplasma, which causes an intense competition for grant monies, moving from a postdoc to infection called histoplasmosis. a faculty position can take a few cycles to achieve funding and The also appeals to Van get a new lab going. He’s seen some talented young scientists Prooyen because it is a real challenge faced with these frustrating facts forgo academic research for to work with. No one has built genetic other options. libraries or developed the standard tools that other scientists can rely on. Sifting through hundreds of Histoplasma to find interest- The Postdoc: Defined and Counted ing mutants is a puzzle Van Prooyen relishes. “postdocs are an invisible work force for a university,” says Like many postdocs, she’s thrilled to focus her time on science Elizabeth Johnson, president of the Postdoc Association at Duke alone—no classroom teaching or lab management to distract her. University in Durham, North Carolina, from 2004 to 2008. It’s an opportunity many professors would envy. Today Johnson is associate director of the Duke Institute for But Van Prooyen is also realistic about her position and she Brain Sciences. has no intention of being a postdoc—with the typical 80- to 100- “They do science, write grants, mentor grad students,” John- hour workweek—for any longer than a few years. Her wages are son says. “And yet they don’t have full status as core members of paltry, as well, even with her recent postdoctoral fellowship from any institution.” Instead, postdocs inhabit a sort of career limbo— the A.P. Giannini Foundation. a vague midpoint between student and independent professional. Low wages are the norm. The National Institutes of Health In 2004, Duke started working on its own postdoc policy. The (NIH) National Research Service Award stipend for starting post- first task was to figure out who the postdocs were. Johnson asked docs, which many institutions use as a guideline, has been stuck around for numbers and heard estimates as low as 70 and as high in the mid-$30,000s since 2003. “We’re all in our 30s, we have a as 2,500. With postdocs often hired by a handshake and just as lot of education, and we’re still scraping by,” Van Prooyen says. easily cut loose, no one knew. Once the committee defined who Add to that the constant stress of the publish-or-perish lifestyle on was and wasn’t a postdoc, and performed a head count, the actual what is usually a year-to-year contract. “It’s a sacrifice,I think, to number was between 600 and 700. do a postdoc.” No one has a solid figure of the number of postdocs in the Once an optional pit stop on the road to professorship, a United States. A 2008 National Science Foundation (NSF) sur- postdoc position like Van Prooyen’s has become a required vey counted more than 54,000 postdocs, up 6.5 percent from apprenticeship. Because their positions are temporary, it’s easy for 2007, but included only those at degree-granting institutions. postdocs to go unappreciated, and some simply don’t receive the The National Postdoctoral Association (NPA) cites a range of

26 hhmi bulletin | May 2o11 43,000 to 89,000 postdocs. That includes scientists who got their ­continue as postdocs but may be hired as regular employees. degrees outside the United States; NSF data show 55 percent to And while they’re postdocs, they get health care benefits and 60 percent of U.S. postdocs are foreign citizens. ­retirement savings. One key advance, says NPA executive director Cathee John- Similar policies are coming together at institutions across son Phillips, was defining what a postdoc is.I n 2007, the NPA, the country. For example, according to the NSF’s 2006 Survey NSF, and NIH agreed that a postdoc is a doctorate holder in a of Doctorate Recipients, 90 percent of postdocs received health temporary research job, receiving mentoring and training needed insurance in 2006, up from 75 percent in 1986 (these data do not for the next career stage. indicate how many postdocs must pay for their own insurance). The number receiving retirement benefits has risen from 30 per- Spotty Progress cent in 1986 to 50 percent in 2006. in 2005, then-hhmi president thomas cech and others exam- For the more than 700 postdocs that HHMI supports in the ined the needs of postdocs in the National Research Council laboratories of HHMI investigators and HHMI early career sci- report “Bridges to Independence.” The goal was to identify ways entists, pay is scaled to NIH and other postdoctoral fellowships, NIH and other funding agencies could help postdocs—who work says Pamela Phillips, HHMI’s director of research operations. under an advisor—transition to an independent position. The Starting HHMI postdocs make between $37,500 and $50,000, at authors recommended, for example, that NIH allocate funds to their advisor’s discretion. They also receive health insurance and support postdocs as individuals rather than as simply part of an retirement benefits. Vacation time is at the advisor’s discretion, advisor’s grant. but Phillips notes that postdocs so rarely take time off that it usu- They also recommended that research institutions provide ally isn’t an issue. postdocs with more than a lab bench: they need mentoring and career advice. And with fellowships lasting longer, the authors F inancial Help ToWARD Independence suggested that there should be a time limit. To find out whether satinder singh, a former hhmi predoctoral fellow, put in postdocs’ needs are met, the committee recommended that NIH her time as a postdoc at Health and Science University in collect data on the postdocs it funds, including whether they con- Portland, working on the bacterial version of a neurotransmitter tinue in research. transporter. She divided her time between experimenting with Since the Bridges report, change has been spotty, says Cech, cells and lipid vesicles, exploring the protein’s structure, mentor- an HHMI investigator at the University of Colorado at Boul- ing students in the lab, and writing papers. der. Some universities have implemented postdoc policies In 2007, Singh applied for the Pathways to Independence and support postdoc offices and clubs; the NPA reports that 160 Award, one of the initiatives NIH launched in the wake of the institutions have acted on at least some of its policy recommen- Bridges report. Announced in 2006, the award, a K99/R00, is dations. In 2010, NIH began requiring grantees to identify their affectionately referred to as the “kangaroo” award. It provides five postdocs by name, so it could track their appearance on subse- years of funding designed to bridge the end of a postdoc and the quent grants. beginning of a faculty position. The idea, Cech says, is to wean Duke is ahead of the curve; the administration took seri- postdocs from mentored to independent research. Each year, ously its postdocs’ plight and spearheaded the policy effort, NIH offers between 150 and 200 of these grants, with various Johnson says. Still, it took from 2004 to 2008 to craft a policy, dollar amounts. which undergoes regular revisions. Now, all Duke postdoc slots Just writing the application was a useful process, Singh says, are paid positions; no postdoc is a volunteer. They get vacation, because she had to organize her thoughts for an independent pro- sick leave, and parental leave, just like regular employees. They gram. Her plan to study the human version of the transporter she receive annual progress reviews. As recommended by the Bridges worked on as a postdoc earned her a kangaroo award. And Singh report, they won’t be postdocs forever; after five years, they ­cannot suspects the award helped during her final interviews for faculty positions in early 2008; she already had evidence that her ideas were grant-worthy. “T hey do science, write grants, Singh got a job offer from , but she still wanted to finish up some papers in her postdoctoral lab and take a couple mentor grad students,” Johnson of neurobiology courses. With the kangaroo funding, she was able to work mostly independently in her postdoc lab, and Yale waited says. “And yet they don’t have until she was ready to start. She used the extra time to collect preliminary data before starting the Yale tenure clock—with all full status as core members of its associated responsibilities in the classroom and on commit- any institution.” tees. Since July 2010, Singh has been living the postdoc’s dream at Yale: a lab of her own, with two of her own postdocs to train.

May 2o11 | hhmi bulletin 27 A handful of current graduate students may realize that dream Some advisors don’t take their role as mentors seriously, treating much faster. In 2010, NIH director Francis Collins announced their trainees as cheap hands in the lab. “Some fraction of postdocs the new Director’s Early Independence Awards. They allow do not get much career advice,” Cech says. “They’re mostly being superstar Ph.D. recipients to skip the postdoc and move straight employed for the purpose of doing a certain set of experiments.” to the principal investigator level. NIH plans to make 10 awards, And that lack of training shows when postdocs apply for jobs, each with a budget of $250,000 a year for five years. says HHMI investigator Celeste Simon of the University of Penn- sylvania School of Medicine. When she interviews applicants for Meaningful Mentoring faculty positions, she can tell when postdocs from big labs didn’t neal sweeney was a postdoc at yale for three years. He had a get all the help they needed in preparing their application and good relationship with his advisor, but the advisor was always busy, job talk. “Sometimes postdoctoral fellows can fall through the juggling a lab with more than 20 people plus teaching and grant cracks,” Simon says. writing. “I didn’t really feel like I was getting enough mentorship that UC postdocs and their mentors are now expected to design my research could move forward at the pace I wanted it to,” he says. an individual development plan (IDP), with short- and long-term In 2009, to be closer to an ailing family member, Sweeney goals, and hold regular meetings to assess progress. Making an took a second postdoc at the University of California (UC), Santa IDP is the greatest factor in postdoc satisfaction, according to a Cruz. He’s now studying how stem cells morph into the neu- 2005 survey by the scientific research honor society Sigma Xi. For rons required for vision. He’s in a smaller lab, with fewer of the example, postdocs need to know what part of their projects they high-tech facilities Yale offered. But he’s been able to learn new can take to a new job. techniques, achieve more responsibility, and practice grant writ- Postdocs who become professors also need to learn how to ing in the cozier environment. manage a lab. “You’re going from pure science to running a At first he felt like he was starting over, Sweeney says, but he’s small business,” says Maryrose Franko, senior program officer for now excited about his new projects. He spends his days fiddling HHMI’s department of science education. with DNA strands, growing cells in dishes, or sitting at the micro- With its successful weeklong training course of new lab heads, scope. And he’s gotten involved as a leader in the UC union, the HHMI—in collaboration with the Burroughs Wellcome Fund— UAW Local 5810. turned the information into a highly popular book, “Making the Finding a mentor is a big concern among postdocs and was Right Moves.” HHMI now works with partner institutions to sup- one of the issues noted in the Bridges report. One of the UC port similar training on their campuses. union’s key interests in negotiating its new contract, Sweeney says, was to make sure postdocs get the mentoring they need for Where Are the Jobs? both their current research and their future career. “This is one of none of those efforts, however, solves the most crucial issue: the things that came up again and again,” he says. not enough academic jobs for the academically trained scientists

left to right: satinder singh aimed high for an nih kangaroo award, and landed at yale; nancy van prooyen vows not to let her postdoc go too long; elizabeth johnson helped usher in duke’s progressive postdoc policy. Singh: Chris Jones Van Prooyen: Tom Kochel Johnson: Jeff McCullough Jeff Johnson: Kochel Tom Prooyen: Van Singh: Chris Jones

28 hhmi bulletin | May 2o11 With the expanding postdoc timeline, Tilghman says, a sci- “AT FIRST, IT’S REALLY fun,” ROHN entist’s most creative years are spent toiling on someone else’s project. In 2009, the average age at which scientists got a first SAYS. “ONCE YOU GET INTO YOUR FIFTH research grant was 42. On the flip side, science-loving under- graduates who observe graying postdocs look to other careers, OR SIXTH YEAR OF THE POSTDOC, such as medicine. “I was finding it harder and harder to convince ONE STARTS TO GET A BIT ANXIOUS.” the brightest young Princeton students to go into biomedical sci- ence,” Tilghman says. In December 2010, NIH’s Collins proposed a working group to address the lopsided science workforce. He enlisted Tilghman out there. “I was not warned about this,” says Jennifer Rohn, a to run the project. She plans to come up with a workforce model postdoc at University College London, who wrote a March 2 that better matches the nation’s science needs and uses finan- column in Nature News on the subject. She spends her days cial incentives to alter the science landscape (see Perspective, sorting through images of cells, looking for conditions that page 34). The group has yet to assemble, however, so recommen- change their shape. dations are still to come. “We may be overproducing biomedical scientists,” agrees Shirley Tilghman, president of and an Looking Beyond the Bench HHMI alumna. richard ting is in the third year of his postdoc in the UC San There’s no quick fix. “Science would grind to a halt without all Diego laboratory of HHMI investigator Roger Tsien. He came to these people working,” Rohn says. She suggests that universities Tsien’s lab because it was a multidisciplinary group with plenty of hire more permanent, nonfaculty scientists. These researchers— good ideas. Even then, Ting was thinking about his post-postdoc sometimes nicknamed “perma-postdocs”—offer huge value to a career. Tsien is a Nobel laureate, and as Ting notes, “It definitely lab because, unlike trainees who come and go, they are always up helps to have some name recognition on your reference letters.” to speed and able to assist newcomers, Rohn says. But they’re a Ting spends most of his time synthesizing new that bit different from a postdoc in that they have a decent salary and might be useful in positron emission tomography (PET) medical often work normal hours. “Once you hire a permanent scientist, imaging. “The synthesis, by itself, is pretty boring,” he admits. you can’t treat them like a slave,” Rohn says. “But being able to personally test the impact of these new mol- The tight job market also means that postdoctoral periods can ecules on a PET scanner makes the job worthwhile.” stretch for years. “It’s very, very rare for the postdoc training period Right now, things are going well—but the future is a big ques- to run shorter than four years these days,” says HHMI president tion mark. “That’s the stressful part,” he says. “You don’t really Robert Tjian, who has seen postdocs stick around for six or seven know what you’re going to do.” years. It doesn’t help that publishing in top journals requires Ting has applied for the kangaroo award. However, he’s realis- more data than ever before, he adds. “There’s a lot of pressure to tic about his chances. If he doesn’t receive the funding he’s after, knock something out of the park … to do something that will be he’ll likely consider a career in the biotechnology industry as well. the beginning of a whole career.” In his hopes, Ting is like many of his compatriots. Accord- The median length of a single postdoc in the life sciences ing to the 2010 Science Careers survey, 61 percent of former is 2.2 years, according to the NSF’s 2006 Survey of Doctorate postdocs went into the apprenticeship aiming for a tenure-track Recipients. But many postdocs string together multiple posi- professor job. Only 37 percent achieved that goal. tions; 29 percent of postdocs who responded to a 2010 survey by With the tough job market, many postdocs are considering Science Careers had held two postdoc slots and 11 percent had more than one career. “We have to get away from thinking that already done at least three. we are only training postdocs to be professors,” Cech says. “That’s “At first, it’s really fun,”R ohn says. “Once you get into your just a false premise.” Postdocs today have lots of options: journal fifth or sixth year of the postdoc, one starts to get a bit anxious.” editor, policymaker, attorney, and more. Van Prooyen, for Plus, this extended training period comes just as researchers are example, is considering science writing. Ph.D.s would make great reaching the age when they’d like to settle down, perhaps start a science teachers, Carroll adds. family. Yet they bounce from position to position, and who can Given the challenges of making it in academia, is it worth afford day care on a postdoc’s salary? ­signing on for a postdoc? “I don’t want them to get discour- The conflict between postdoc-ing and parenting is “just unac- aged by the fact that the slope is very steep,” Tjian says. “I still ceptable,” says Tom Rapoport, an HHMI investigator at Harvard think that doing science is one of the most rewarding careers Medical School in Boston. Given the stark choice between sci- you can have.” W ence and family, many female postdocs leave the lab, Rapoport says. He suggests that subsidized day care would be the best way web extra: To read about who’s speaking for postdocs and explore some atypical to keep talented women in science. fellowships, visit www.hhmi.org/bulletin/may2011.

May 2o11 | hhmi bulletin 29 the Next Statin

Could new ndings on how the human body regulates cholesterol lead to a better drug?

BY SARAH C.P. WILLIAMS ILLUSTRATION BY GAVIN POTENZA

30 hhmi bulletin | May 2o11

are, you know someone with high The body can make cholesterol, absorb it from food digested in cholesterol. A parent, a friend, yourself. Too the gut, move it around, and excrete it as bile. many fatty molecules pulsing through the bloodstream, stick- At any given point, each of these processes can be turned up ing to the sides of blood vessels, and doubling—or more—the or down depending on a cell’s needs. “If the cell is deprived of chances of a heart attack. In the United States, one in six adults cholesterol, you turn on uptake, and you turn on synthesis,” says has cholesterol levels considered too high and doctors write DeBose-Boyd. “When the demands are met, synthesis and uptake more than 200 million prescriptions a year for cholesterol- are both turned off.” But when cholesterol levels from the diet get lowering drugs. too high, the body’s system to deal with it becomes overloaded, Statins, the most widely prescribed cholesterol medications, and molecules idle dangerously in the arteries. have been successful in curbing cholesterol levels for many peo- Statins work by halting cholesterol production in cells. They do ple. But in some, statins lead to severe joint and muscle pain or it by blocking hydroxymethylglutaryl-CoA (HMG-CoA) reductase, inflammation.I n others—perhaps due to genetic quirks— an that carries out an early step of cholesterol synthesis. statins don’t lower cholesterol levels enough. And when one But the cell reacts to those falling cholesterol levels by making statin was compared with sugar pills in a clinical trial, the drug more reductase in an attempt to revive cholesterol synthesis. lowered the risk of heart attack by only one-third. “Statins are basically inducing accumulation of the very pro- Although clinicians have firmly established the link between tein they’re targeting,” says DeBose-Boyd. “We could improve cholesterol levels and heart disease, there are still more questions their effectiveness if we can stop that accumulation.” That’s his than answers when it comes to the nitty-gritty molecular details of lab’s goal. this connection. Unraveling the genetics and of the When they are replete with cholesterol, cells not only stop body’s natural cholesterol-control mechanisms would do more producing HMG-CoA reductase, they also speed up the enzyme’s than satisfy scientists’ curiosity: It could provide targets for better degradation. In cells deprived of cholesterol and other sterols, cholesterol drugs and fresh ways to predict earlier in life who is at reductase molecules stick around, churning out cholesterol, for risk for high cholesterol and related heart disease. an average of 10 or 11 hours, says De-Bose Boyd. But with lots of “This is one of the most tightly regulated systems in biology,” cholesterol around, reductase survives only about an hour. says Joe Goldstein of the University of Texas (UT) Southwestern DeBose-Boyd wants to coax cells to turn on this degrada- Medical Center at Dallas. Goldstein, an HHMI Trustee, shared tion process even in the low-cholesterol state induced by statins. the 1985 Nobel Prize in Physiology or Medicine with Michael This would prevent the reductase buildup that limits the drugs’ Brown for their discoveries about cholesterol metabolism. “It’s effectiveness. regulated at so many levels, in so many ways that there’s no short- “It looks like there is a switch for this whole cholesterol system age of questions about how it works,” he says. That means no where it’s either on or it’s off,” says Goldstein, just down the hall shortage of potential drug targets. from DeBose-Boyd’s lab. “Understanding this switch is really fun- Goldstein, Brown, and a handful of other HHMI scientists damental to understanding the system.” HMG-CoA reductase is are still piecing together the full picture of how the human body normally located on the outer membrane of a cell’s endoplasmic manages cholesterol. In the process, they’re revealing new ways to reticulum (ER), a packaging center that directs newly made pro- stop atherosclerosis and heart attacks: by controlling cholesterol teins to their destinations in the rest of the cell. production, absorption, and the ’s response. DeBose-Boyd discovered that in times of high cholesterol, a protein called Insig binds to reductase and removes it from the Finding Balance ER, according to work published June 2010 in the Journal of Despite its bad rap, cholesterol isn’t harmful in moderation. “It’s Biological Chemistry. From there, the reductase ends up in lipid absolutely required,” says cholesterol researcher Russell DeBose- droplets. “They’re basically little balls of fat in the cell,” he says. Boyd, an HHMI early career scientist at UT Southwestern who Exactly how this happens, he’s not sure, but somewhere in the was a postdoc in the Brown–Goldstein lab. The human body lipid droplet or the cell’s watery cytosol, the reductase is broken needs cholesterol to function properly—it’s integrated into cel- into pieces, no longer functional. lular membranes, in bile it aids digestion, and it plays a key role DeBose-Boyd’s lab has also revealed that it’s not cholesterol in the connections between neurons in the brain. But too much that triggers Insig to bind to reductase and ship it out of the cholesterol is toxic for a cell and for the body as a whole. So cells ER. It’s a molecule related to cholesterol, called dihydrolanos- have a complex feedback system to regulate cholesterol levels. terol (DHL). Because it’s not identical to cholesterol, DHL can

32 hhmi bulletin | May 2o11 ­potentially turn on HMG-CoA reductase degradation without the following the genetics and cholesterol levels of almost 3,500 peo- risk associated with increasing cholesterol levels. ple as part of the Dallas Heart Study, her large-scale attempt to “If we were to get a drug from this work, it’d have to be find genetic causes of heart disease. So her team tested a hand- designed after DHL,” says DeBose-Boyd. But such a drug is still ful of participants for mutations in the PCSK9 gene. They found hypothetical. No pharmaceutical company will pursue it until them—in 2 percent of their African-American participants. They DeBose-Boyd or others reveal the full picture of how reductase repeated the work in a larger population and showed that PCSK9 degradation works—the role of the lipid droplets, how DHL mutations were associated with a 28 percent reduction in LDL mediates Insig, and how the final degradation happens. and an 88 percent decrease in coronary heart disease. “Studies like the Dallas Heart Study are absolutely key to this Genetic Targets field,” says JoeG oldstein. “The way to find interesting mutations Other researchers are aiming new drugs at the part of the system is to find a population and look at those extremes.” that imports cholesterol. When it travels in blood, cholesterol The research team led by Hobbs then relied on basic bio- is packaged inside lipoproteins—either low-density lipoproteins chemistry to piece together PCSK9’s function. They discovered (LDL), considered the bad guys for their accumulation in arter- that the protein encoded by PCSK9 is required to degrade the ies, or high-density lipoproteins (HDL), the “good” lipoproteins LDL receptor—the protein that pulls LDL from the bloodstream that carry cholesterol to the liver for excretion. People with low into a cell’s interior. Removal of functioning PCSK9 protein is an levels of LDL and high levels of HDL have the lowest chance of ideal recipe for treating high cholesterol: LDL receptors increase, atherosclerosis and heart disease. These days, cholesterol reduc- LDL in the bloodstream decreases, and atherosclerosis risk drops. tion is measured by tracking LDL; the role of HDL is not as “This is the single biggest story in the translational medicine clear-cut. side of cholesterol research right now,” says Goldstein. “Hobbs For more than three decades, HHMI investigator Helen Hobbs has taken PCSK9 all the way from a finding in a population to has been tracking down individuals with extreme LDL and HDL learn the real importance of the protein to medicine. And now we levels—either low or high—and analyzing their genetics. Hobbs, have a really good drug target.” a physician and researcher at UT Southwestern, got her start in Hobbs identified a person in the Dallas Heart Study who has research with a postdoctoral fellowship in the Brown–Goldstein no PCSK9 and appears to be completely healthy, which has reas- lab. She hopes to uncover genetic mutations that hint at new sured pharmaceutical companies about the safety of the protein drug targets for managing cholesterol. She’s already revealed as a drug target. A PCSK9 inhibitor is now in early phase human one promising candidate—a protein that sweeps the bloodstream studies with the pharmaceutical company Regeneron. It blocks clear of LDL—and it’s in the pharmaceutical pipeline. PCSK9 from binding to and degrading the LDL receptor and In 2003, a research group in identified a gene called results in a dramatic reduction in LDL levels. PCSK9 that helps control LDL levels. Hobbs had already been (continued on page 48)

Research by ­ Russell DeBose- Boyd, Helen Hobbs, and Peter Tontonoz (l-r) on how the body ­manages choles- terol is ­revealing new ­targets for cholesterol-­ lowering drugs. DeBose-Boyd: UT Southwestern Medical Center at Dallas Hobbs: UT Southwestern Medical Center at Dallas Tontonoz: Paul Fetters Paul UT Southwestern Medical Center at Dallas Hobbs: Tontonoz: DeBose-Boyd:

May 2o11 | hhmi bulletin 33 perspectives & o pinions

Shirley Tilghman Th e FuTURE of Science getting realistic about biomedical trainees Jesse Winter Jesse

34 hhmi bulletin | May 2o11 Shirley Tilghman is an outspoken advocate for young scientists. She was an HHMI investigator at Princeton University from 1988 until 2001, when she was named university president—the first woman and first scientist to hold the position. Tilghman will have a hand in modernizing the prospects for scientists as the recently appointed chair of a National Institutes of Health (NIH) study on the future of the biomedical workforce in the United States.

What are your goals for the NIH biomedical workforce panel? science feeds the applied science pipeline. They are Ultimately, we want to create a biomedical enterprise that deeply complementary to one another. Everyone knows produces the best science and brings out the best in the the applied work is important, but frankly, you can’t do it people engaged in it. Today the training path has become without the basic stuff. too long. The average age of a biomedical scientist receiving a first IN H grant is 42. I don’t know a single person who Speaking of tighter budgets, how do you feel about cuts thinks that’s optimal for generating good science. So the to the research and development budget pushed by many question is, why does the path take so long? And are there in Congress? things that could be done to speed it up? There are many aspects of the budget cuts proposed by the House of Representatives that give me great concern. At Do other people agree this is a problem? the highest level, the cuts have the potential of undermining Definitely. There has been welcome recognition that busi- the future prosperity of the United States, by consuming ness as usual is not acceptable, and changes must be made our “seed corn”—the innovation that has been the basis for if we are to sustain the vibrancy of the U.S. biomedical the staggering vitality of the U.S. economy. The cuts to the research enterprise. Many feel that significant changes in Department of Energy and the Environmental Protection how NIH supports the biomedical workforce must be on Agency certainly fall into that category; green technology the table, including reducing the number of trainees and is likely to be one of the biggest growth industries in the changing the way they are supported. future, and it would behoove the United States to be in the forefront of that economic wave. On a deeper level, Could you elaborate on the solutions you have in mind? investing in green technology is so important because the At the root of the problem is the fact that we are overproducing future of the globe depends on our finding economically Ph.D.s. As a consequence, there are too many people chasing viable alternatives to fossil fuels. I don’t know a single serious too few jobs and too few grant dollars. This problem will only research university today that is not making major invest- get worse in the next decade, given the current federal budget. ments in research and education in these areas. I believe there could be changes made to the structure of the typical biomedical research laboratory. The typical Are policy makers open to hearing from young investigators? lab consists of about 10 trainees, a technician, and a prin- Yes, in fact, I think the public discourse on science is better cipal investigator. The majority of those trainees will not now than any time in my memory. Under this administra- become principal investigators, because those jobs are not tion, we have highly distinguished scientists in important multiplying. And at the moment, there aren’t enough career positions, who speak effectively about science. We have an alternatives to capitalize on the time investment of these administration that is pro-science and makes a clear distinc- trainees. So I think we need to change the scenario. tion between what is scientifically knowable and what can From years of being a mentor, I know that not all students be known only through religious faith. I welcome the disap- want a career running their own lab and raising money. pearance of politics from science that many of us found Instead, they want to do what they love: research. Perhaps disturbing in the past. more members of a lab could be permanent employees, and fewer could be trainees. We need to explore such options. How has research prepared you for being a university president? For a long period university presidents were economists, but With tighter budgets, should graduate students still focus I think a scientific background is actually beneficial. Science on unapplied research? taught me how to ask questions, collect data, and analyze Absolutely. There will be no jobs in applied science in information. In that way, what I do now is not so different 20 years if we are not doing fundamental research. Basic than what I did before.

Interview by Amy Maxmen. Shirley Tilghman is a member of HHMI’s Science Education Advisory Board.

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38 science EDUCATION 46 nota B ENE Industrial-Strength Training Wiley Prize Goes to Lily Jan and Yuh Nung Jan / Bassler Wins Lounsbery Award 39 institUTE NEWS HHMI Selects Nine Students for Gilliam Deep in the brain, neurons grow, form branches, and Fellowships / Kotak Elected HHMI Vice President then shrink as memories are created and forgotten. and Chief Financial Officer / Summer Institute The surrounding blood vessels change in concert with Expands with HHMI Support / Institute Launches the neurons. For the first time, scientists have been Documentary Film Unit / Measuring Quality: HHMI able to watch these long-term changes in the brains Announces $60 Million Competition for Colleges of living mice. This snapshot of what they saw in one mouse illustrates the complexity of the branching: 42 laB B OOK blood vessels in red and pyramidal neurons—critical The Pace of Evolution / The Very Hungry Mouse / for long-term memory—in green. To read more about Nourishing Neural Stem Cells the new method and what the scientists saw, visit 45 ask A SCIENTIST www.hhmi.org/bulletin/may2011. How did viruses evolve from a universal common ancestor? Yaniv Ziv and the Schnitzer Lab Ziv and the Schnitzer Yaniv

May 2o11 | hhmi bulletin 37 38 hhmi by the merging ofthe two fields, Yang immediately joined them Knowles tostudytheneurobiology ofAlzheimer’s disease. have goneontomedical orgraduateschool. students excited to do research,” sheexplains.“Mostof the students RI ist, workedforCiba- Petrack aboutAlzheimer’s talk disease. Petrack, aretiredbiochem- program’s inceptionin1980. 2008. The scientists have mentored about 250students since the 10 studentsayear,hasbeenpartiallysupportedbyHHM research while introducing undergraduate students to life in the lab. lab spaceandequipment atDrew sotheycancontinue doing and telecommunications companies acrossNewJerseywhoreceive program. Charles A.Dana industry veteranswhowere part ofaspecial programatDrew:The decide wheretofocusherefforts. was interestedinbothbiochemistry andneuroscience. Shecouldn’t A a R Industrial-Strength Training explained thatshecollaborates withDrewneuroscientist program asuccess. s a etired u science education S E Yang saw new possibilities when she heard The When Yang approachedPetrack Petrack afterherpresentation, E niversity f arly thatyear,Yang attendedaseminar byasmallgroupof

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VSA Partners institute news

HHMI Selects Nine Students for Gilliam Fellowships

After fleeing Zaire as a refugee, in 1996, Espoir Kyubwa by supporting Ph.D. research by students from groups traditionally struggled to learn English at his new elementary school in Califor- underrepresented in the sciences. “Our goal is to train tomorrow’s nia. Many subjects were difficult, but he found comfort in science leaders in science and education,” says William Galey, director of class because it relied on a language he already knew: math. HHMI’s graduate and medical education program. Now 24, Kyubwa still has the love of science he discovered as a This year, HHMI doubled the number of the Gilliam fellow- child. He will be using his HHMI graduate student research fellow- ships available after realizing that they had more top applicants ship to study how the body repair’s itself, as part of an M.D./Ph.D. than they could fund. “The talent pool is amazingly deep. We’ve program at the University of California, San Diego. seen spectacular students who go on to great schools and are Kyubwa is one of nine students chosen this year to receive very promising,” says Sean B. Carroll, HHMI’s vice president for HHMI’s Gilliam Fellowships for Advanced Study. The fellowships ­science education. “We think it is really important to support are aimed at increasing the diversity of college and university faculty these outst­ anding students.” Gilliam fellows are chosen from among students who have participated in HHMI’s Exceptional Research Opportunities Program (EXROP), which places under- graduate students from minority or other groups traditionally underrepresented in the sciences in the labs of HHMI investigators and professors. The expansion of the pro- gram will allow up to 10 students each year to become Gilliam Fellows, an increase nicolas altemose andria ashmore nadia herrera from five in previous years. duke university university of california, university of texas at los angeles el paso That means more support for doctoral students like Gloria Tavera, who is start- ing an M.D./Ph.D. program this fall to study infectious diseases after spending a year doing research on dengue fever on a Fulbright fellowship in Mexico. And for stu- dents like Sandra Jones, who was inspired to study neuroscience after hearing a seminar on the science of anesthesia. Among the new Gilliam fellows, five have jessica cabral jimenez sandra jones benyam kinde graduated from college or will graduate this university of california, spelman college harvard medical school year and are applying to graduate school. los angeles The remaining four awardees are in their first year of Ph.D. or M.D./Ph.D. programs. As for Kyubwa, he hopes to eventually go back to his native country, now called the Democratic Republic of Congo, where he can use his doctoral research on medical trauma and injury to help heal the strife- torn country. “I have a lot of aspirations to develop something, maybe a teaching hospital or espoir kyubwa chinweike okegbe gloria tavera university of california, columbia university university of florida something along those lines,” he says. “I’m

Altemose: Jim Bounds for HHMI Ashmore: Rene Macura for HHMI Herrera: Victor Calzada for HHMI Jimenez: Rene Macura for HHMI Calzada for HHMI Jimenez: Rene Macura Altemose: Jim Bounds for HHMI Ashmore: Rene Macura Herrera: Victor for HHMI Wass Nick for HHMI Okegbe: Charles Sykes Tavera: Denis Poroy Kyubwa: Barnett-Winsby Amis for HHMI Kinde: Jeff John Jones: san diego really interested in helping.” W

May 2o11 | hhmi bulletin 39 40 kno hhmi HHM going it would never reach enough faculty,” says Sean B. Carroll, up thissummerinNewHaven, ,Boulder,andMinneapolis. $3 million providedbyHHM centers acrossthecountryovernextfiveyears,withhelp of a singlesiteinWisconsinwillincludeuptonine regionaltraining to learn the techniques as behind successful teaching. What started of thetraining program.“ herownso excited localversion by whatshelearnedthatstarted shows facultybetterwaystoteach. for Virginia LLE h “ M Summer InstituteExpandswithHHMISupport from the team andwe’re pleasedtowelcome himtothe chief operatingofficer. “Heisastrongaddition toourmanagement ance,” says Cheryl Moore, HHM significant experienceinfinancial analysis,reporting,andcompli- ­P was chieffinancial officerandtreasurer. Hesucceeds  I T and ChiefFinancialOfficer Kotak ElectedHHMIVice President Kot  nstitute’s nextvicepresidentof financeandchieffinancial officer. I h almerino, whohadheldthepostsince2006. i hadbeentryingtolearnhow toteachbetter,but institute news c e “The Summer Now theSummer Then shewenttotheNationalAcademies Summer A nativeof “Nitin comestouswithgreatenthusiasmforourmission and U ak, 53, joins HHM w what to do,” says Withers, now a biology professor at West

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­Secret the Summer members from 94 institutions havegone through instructional staff work inalargelecture-styleclassroom. Since2004,304facultyand assessment.Theyalsolearnhow to make it groups withconstant learning techniques, including interactiveprojectsanddiscussion who co-leadstheSummer the waytheyweretaught,” saysJoHandelsmanatYale behind successfulteaching.“People haveastrongtendencytoteach report concludedthatbiologyfacultyneededtolearnthescience National AcademyofSciences’ Bio2010reportasatouchstone.The of thiseffortisaimedatchangingbiologyteachingacrossthecountry.” ticipate andbringwhattheylearnbacktotheir campuses.Thescale we hopetogreatlyincreasethenumber offacultymemberswhopar- the a senior member ofthree major professional institutes in remains wife, Dipti,liveinSilverSpringandhavetwosons.Kotak Kali Temple, an great responsibility.” “ the controller’s office, treasury, internal audit, and procurement. to teachifyoucareaboutstudentlearning.” of Colorado,Boulder. “Butweknow thatlecturesaretheworstway community,” “ saysKotak. standing organization andworkinaspiritofgivingbacktothe undergraduates eachyear. I a The expandedSummer alsoservesaspresidentoftheMaryland-basedWashingtonKotak At theSummer At HHM I m very excited at this opportunity to be apart of this out- nstitute of Chartered Accountants, the nstitute ofCharteredAccountants, aries, andthe I , Kotak will overseebudgetandfinancial analysis,, Kotak I n stitute. I ndian religiousandculturalcenter. Heandhis I nstitute, facultylearnhow toincorporateactive- I nstitute ofCostandWorks Accountants. I facturer ofgenericpharmaceuticals. Laboratories, Toys, asubsidiary ofMattel, He hasalsoworkedat 500 company British American Tobacco. Limited, the variety offinance-relatedpositionsat He spent more than 17 years working in a class honorsinaccountingandauditing. intelligence agencies. defense, homelandsecurity, military, and technologies andservicestotheNational 2008. Technest providesadvancedsensor chief financial officerandtreasurerin for finance and operations and became in Bethesda,Maryland,asvicepresident I nstitutes ofHealthaswellnational t s graduates teach approximately 100,000 I W I nstitute withBillWood atthe n 2005, Kotak joined Technest,n 2005,Kotak located I feelhonoredtobeselectedforthis I nstitute willcontinue tousethe I ndian associate oftheFortune I nc., adeveloperandmanu- I nstitute ofCompany I ndia-based Mattel I nc., andAble U U niversity, niversity I ndia— W I TC

James Kegley Institute Launches Documentary Film Unit

At a meeting in February that brought together scientists, their potential for powerful narrative, but HHMI’s staff—primarily educators, and entertainment industry professionals, HHMI its Educational Resources Group—will work hand-in-hand with the announced the launch of a $60 million documentary film initiative executive producer and filmmakers to repackage the film footage that aims to bring engaging science features to television. into materials that can be used by teachers and students at both the “Film is the most powerful medium for bringing ideas, knowl- high school and college levels. edge, and stories to life and communicating them to any audience,” “Compelling films have the power to inspire people and nour- says Sean B. Carroll, HHMI’s vice president for science education, ish curiosity—which also happen to be central goals of our science who spoke at the meeting. “HHMI can harness that power by produc- education program,” says HHMI President Robert Tjian. ing high-quality, compelling documentary films on scientific topics.” Carroll, who took over as HHMI’s vice president for science HHMI has funded television projects on a more modest scale education in 2010, has a longstanding interest in public science edu- in the past—including support for the public broadcasting series cation. In addition to writing several popular books on science and NOVA scienceNOW and science reporting on PBS NewsHour—but a regular column for The Times, he has participated in this is its first foray into the documentary film arena. The HHMI numerous television documentaries. film ivision’sd priority will be to tell intriguing science stories that Although Carroll has not identified specific film topics, he grab the viewer, Carroll says. They will cover all areas of science, says that most scientists and science educators agree that the pub- especially biology and medicine, and will go beyond the work of lic would benefit from access to engaging materials that provide HHMI’s own researchers. better insight into how science works, how evidence is weighed The institute will collaborate with broadcasters and other part- and tested, and how conclusions are reached. “We want the ners to develop, produce, and disseminate programs and specials public to understand the process of science and gain an apprecia- internationally. The documentary film initiative also includes a tion for it so they can trust its results and use them in their daily major educational component. Subjects will be chosen based on lives,” he says. W

Measuring Quality: HHMI Announces $60 Million Competition for Colleges

Challenging colleges and universities to think creatively often led schools to “check the boxes” rather than encouraging about how they teach science, HHMI has invited 215 undergrad- them to think strategically about a more global objective. uate-focused institutions across the country to apply for a total of Under the new guidelines, the grant proposal must support the $60 million in science education grants. institution’s larger science education goal. Asai hopes this new, The new round of grants differs from previous HHMI edu- focused design will make it easier for grantees to measure and cation grants in that they include a focus on collecting better understand which components of a program are successful. information about which programs succeed in developing the “We want to get away from just counting the numbers of stu- talent and leadership skills of students. Institutions will be asked dents who do research. We want to find out what schools are doing to identify an overarching educational objective for their pro- that is preparing undergraduates to be successful as future scientists, gram, and schools will be encouraged to create joint programs teachers, or members of a scientifically literate public,” he says. I“ t with other institutions to build on shared science education inter- is a harder question, but it is an important question.” ests. In addition, colleges and universities that have previously The grants will range from $800,000 to $1.6 million over four received four or more education grants from HHMI will be asked years for individual institutions and up to $4.8 million over four to share the cost of their ongoing programs to demonstrate their years for programs run jointly by multiple institutions. commitment. “Grants of this size can have a big impact at small schools,” “The question is not whether we can produce more scientists says Sean B. Carroll, HHMI’s vice president for science education. and science teachers, but whether we can produce better ones,” “A small number of faculty working together can quickly make says David J. Asai, director of HHMI’s precollege and undergradu- changes that will have an immediate impact on the quality of sci- ate program. “That is our goal with these changes.” ence education for their students.” In the past, HHMI’s grants have allowed applicants to submit Applications are due October 4, 2011, and grants will be projects in four categories: student research, faculty development, announced in the spring of 2012. W curriculum and laboratory development, and outreach. Although schools were not expected to put forward a program in every cat- FOR MORE INFORMATION: To learn more about the competition and how to apply, visit www.hhmi.org. egory, Asai notes that the modular design of the grant competition

May 2o11 | hhmi bulletin 41 lab book The Pace of Evolution A close look at the human genome shows the slow and steady beat of adaptation.

Here’s how scientists have typically explained the emergence of a see more highly conserved regions around mutations that had func- new genetic trait: A genetic mutation randomly occurs that gives its tional effects. Yet they saw no differences between the variability carrier an advantage in reproducing. Over a handful of generations, surrounding functional mutations compared with the rest of the the mutation becomes more prevalent in the population, quickly genome, they reported on February 18, 2011, in Science. becoming ubiquitous. It’s called a “selective sweep” and has been This finding must mean that “not many adaptations in our his- the predominant explanation for how most new human genes have tory have proceeded through sweeps,” says Przeworski. “Selective surfaced. Now here’s Molly Przeworski’s take: evolution is slow and sweeps must be really rare.” complex and few human traits have ever emerged through such a She suggests two alternatives that could explain how adapta- speedy takeover. tions might spread more often. Preexisting mutations across the Przeworski, an HHMI early career scientist at the University population can face a new selective pressure from a change in of Chicago, relied on the fact that if a gene mutation moved that the environment—this process is called “selection on standing quickly across the human population, most everyone would have ­variation.” Or, a trait can inherited the identical genetic material bordering the mutation. If a rely on many gene changes mutation spread slowly, on the other hand, or arose more than once, rather than one change with it would gradually pick up other mutations in surrounding genes as a large effect. “Height, for it broadened throughout the population. example, is controlled by Using this reasoning, Przeworski and her team analyzed 179 thousands of loci,” says Prze- human collected through the 1000 Genomes Project. worki. “If the environment They looked at 40,000 genetic changes that set humans apart from is selecting for height, that

their primate ancestors—some that might change a protein’s func- Scientists looked at 40,000 genetic will happen through hun- tion, others that are essentially silent. If the “selective sweep” model changes to determine the pace of dreds of gene locations.” W human evolution. had dominated throughout human history, Przeworski’s team would –Sarah C.P. Williams

IN BRIEF

Cellular Stress Pathway Linked of PACAP gene activity in regions of the mouse, however, a separate group of to Traumatic Stress Disorder brain associated with stress and fear, sug- neurons switched on—and the aggression- Researchers have discovered a genetic gesting that estrogen controls this activity, linked neurons appeared to be actively marker for post-traumatic stress disor - the team reports in the February 24, 2011, suppressed. der (PTSD) in women. They found that issue of Nature. Next the researchers engineered the the gene’s effect relies on the hormone This result provides the frst evidence male mice so that they could control the estrogen and therefore is not linked to linking the PACAP pathway to PTSD. The aggression neurons with bursts of light the disorder in men, who have very low pathway is normally linked to cellular coming through an optic cable into the levels of estrogen. Led by HHMI investiga- response to stress. brain. When the light came on, the mice tor Kerry Ressler at Emory University, the immediately fought—with a male, a female, multi-institutional study could lead to the Mating Trumps Fighting or a nearby object. When researchers frst blood test for PTSD susceptibility. In a tiny area deep in the mouse brain, a set blocked the neurons from fring, the mice Ressler and his collaborators began of neurons ensures that mice don’t mate refused to fght, even around another male. with blood samples from 64 men and and fght at the same time. Crude experi- Moreover, when researchers allowed a women in a highly traumatized popula- ments from the 1920s had hinted that mouse to mount a female and then shined tion. Levels of a protein called pituitary both behaviors were controlled by neu- the light, the mouse did not engage in adenylate cyclase activating polypeptide rons in the brain’s hypothalamus region. attacks. The results, published February 10, (PACAP) were higher in women who had Now, HHMI investigator David Anderson 2011, in Nature, suggest that the VMHv1 been diagnosed with PTSD than in women has used modern techniques to resolve neurons activated during mating might without the diagnosis. A study in a larger the details. inhibit fght behavior. group of women yielded the same results. In his lab at the California Institute of To understand PACAP’s role in PTSD, Technology, Anderson and colleagues Flash-Freezing Cells Reveals the team looked for variations of the gene began by inserting electrodes into an area Backward encoding the protein in more than 1,200 of the hypothalamus called VMHv1. Then A new technique of freezing cells in liq- women at high risk for PTSD. They found they recorded the behavior—and fring pat- uid nitrogen allows scientists to view how that a mutation in the gene is associated terns of 104 neurons in the region—of the a cell accesses information encoded in with the presence of PTSD. The researchers male mice over the next several months. genes. The technique has allowed HHMI then compared PACAP levels in female rats When one male mouse encountered scientists to make fundamental discover- lacking ovaries, and thus estrogen, and in another male mouse and began to fght, ies about transcription—the process a cell such mice receiving estrogen replacement. a group of neurons in VMHv1 began fring. uses to copy strands of DNA to single-

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42 hhmi bulletin | May 2o11 BSIP / Photo Researchers, Inc. ing them would cause mice to eat less. POMC neurons,wouldhavetheoppositeeffect—thatis,activat- stopped eating. the moremice ate.Whenthelightwasquenched, themice times the usual meal. The more neurons that were activated, researchers switched on the light, the mice ate—more than 20 fire whenilluminated bybluelightfromanopticalfiber. When to activateneurons.TheyengineeredA But theneuronshadneverbeenactivateddirectly. related moleculeisinjectedintothebrainofamouse,iteatsmore. called agouti-related peptide (A that feeding habitsmight bestronglyaffectedbyoneneurontype, rons canmodulateacomplexbehavior. Previousresearchsuggested R off theneurons. Themousecontinuesas ifstarved. overeatinguntilscientists turn that themouseiswellfedandit’s notmealtime,iteatsvoraciously, brain, theanimal headsstraightforitsfooddish. Despitethefact Within minutes oftheactivationspecific neuronsinamouse’s ATING makes A The Very HungryMouse esearch Campus,thisdisplay isproofthatasinglegroupofneu- ctiv IN BRIEF I Sternson andhisteamreliedonoptogenetics,theuseoflight For ScottSternson,agroupleaderatHHM t wasthoughtthatactivatinganotherneurontype,called iu, ecie Jnay 0 21, in 2011, 20, January described nique, con areresearchers The restart. and stop to likely most is speci found also They cell. the by discouraged actively be to appeared process the but direction, wrong the in happening tion them how transcription isprogressing. tell strands“frozen” the of sequences The mid-transcription.strands RNA purify can activity,researchers all stopping cell, the sequencing (NET-seq). nique they call native elongating transcript tech- a using transcription in bumps these study to way a found Francisco, San nia, W investigatorbyHHMI led team Jonathan research A direction. wrong the in launch even and restart, pause, can RNAP the research: recent to according smoothly, RNA new the releases and removesitself RNAP gene, a of moves.end reachesthe it When it as RNA of strand complementary a ing produc - sequence, gene a along way its works and DNA the to attaches enzyme strands. Then the itsRNA polymerase (RNAP) expose to unwinds DNA stranded isa o the of eissman The team found instances of transcrip- of instances found team The go always doesn’t process This double- when begins Transcription

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in the brainthat controls eating behavior. lations that A acting throughmelanocortinreceptors. Neuroscience The mice stillracedtotheir food,theresearchersreportedinNature output ofPOMCneuronsandthenactivatedtheA cortin receptorsignaling,” says Sternson. Sohisteamblockedthis A “We wantedtoknow ifthe POMC and A to teaseaparttheeffectsof neurons. ofPOMC tors, akeytarget blocked melanocortinrecep- abolished inmice with in oneday. Thiseffectwas percent oftheir bodyweight ate 40percentlessandlost7 rons optogenetically, mice team activated POMC neu C GR ells Sternson’s nextgoalistoidentify thedownstream neuronpopu- The researchers decided P neuronswereactivatingfeeding bysuppressingmelano- Ap f ar rst pro- GR t in March2011,showing thatA GR P neuronswork through andconstruct a full circuit P neurons. a class of tumor-causing tyrosine kinases. tyrosine tumor-causing of class a of activity the impeding for responsible is PTPN12 called enzyme An phosphatase. the on in zero to cells tumor negative triple- of screen genetic a used School phosphatase ismutated. tyrosine a called molecule a cases these of many in that shown has Elledge Steve investigatorHHMI drugs. current by geted tar- be can that traits three the of any for so named because they fail to test positive cancer.areTriple-negative breast tumors aggressive of cases some of pinnings under- genetic the revealsresearch New N A ger destroyed. lon- no are cells cancer blocked, areCD47 and calreticulin When them. eliminate and cells cancer recognize to macrophages CD47 could getthejobdone. at aimed therapeutic a But place. in puts CD47 that block overcomethe to enough unfortunately,protein,isn’t of level higher The outcomes. clinical worse with cancers in highly more expressed is calreticulin that note also researchers the Medicine, of issue 2011, 22, ber egative Positive leg’ ta a Hrad Medical Harvard at team Elledge’s Reporting their Reporting - mice eat ravenously. When certain neurons are turnedon, C F ancer inding for f ndings in the Decem- the in ndings May 2o11 Science TranslationalScience W – GR S arah P neuronsarenot T

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a m s 43 44 hhmi darkest like thoseshown here inthe brain andfillsits central cavities, Cerebrospinal fluidsurrounds the C Nourishing NeuralStemCells tissue fromembryonic ratsandbathedtheminCSFfromold ral stemcells—theprecursorstobraincells.Theytookbitsof work, theylookedathow theseproteins might affectthebrain’s neu- 2007, hundredsofproteins suspendedinthefluid. roles when they identified,in pected that CSF has such important brain development,growth, andhealth. more—it holdsproteins thatplayirreplaceablerolesincontrolling erebr lab booklab IN BRIEF Walsh andhiscolleaguesatChildren’sBostonsus- Hospital triple-negative . of cases other explain may phosphatases different whether investigating are and affectedkinases PTPN12 bythe in changes all identify to working are scientists The cancers. breast triple-negative with mice in growthreversed tumor and slowed tors inhibi- kinase these of two of combination reported in reported researchers The cancers. colorectal and pancreatic, lung, head, some in implicated been also have which kinases, these of many of activity the inhibit drugs existing the kinasesinitiate tumorgrowth. off, turned or deleted, mutated, is PTPN12 Elledge and his colleagues found that when outer layer. an to other the push and skin of layer innermost the in cell daughter one leave divisions asymmetric stratification, as protect an organism. In this process, known thatlayers many the into skin of layer gle of skin stem cells are required to turn a sin- skin, for example, asymmetric cell divisions mammaliandeveloping In paths. different dividing cell needs to send daughters down a sometimes, But cells. daughter equal two producing evenly, divide to is goal their divide, cells when time the of Most T

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q A How did Fossil records can help us understand produce proteins. And some viruses how complex organisms evolved, but, have RNA genomes, which is difficult to viruses evolve unfortunately, viruses are too small explain by the regressive theory. and fragile to withstand the processes The cellular origin hypothesis suggests from a required for extremely long-term pres- that viruses began from rogue molecules universal ervation. As a result, we are left to infer of DNA or RNA that jumped ship and their origins by studying how present left the host cell’s genome. Circular DNA common viruses evolve. The genetics of today’s molecules called plasmids are known to ancestor? viruses and their hosts can give us hints churn out RNA even though they are not about their evolution: viruses often con- part of a genome and can move between tain bits of genes that they have picked cells. And scientists have discovered trans- Asked by a science-curious lifelong learner up from a previous host, and there is posons, sequences of jumping DNA that evidence that host cell genomes can can copy and paste themselves within likewise be changed by a viral infection. a cell’s genome. These examples lend But modern-day viruses vary dramati- validity to the idea that a section of DNA cally from species to species, and no or RNA could leave a cell’s genome and single gene is shared by all viruses. So continue to function, which may explain genetic relatedness can only teach us how a virus could first emerge. so much. Finally, the coevolution hypothesis There are three main theories that proposes that the first viruses originated attempt to explain how viruses origi- from self-replicating molecules, such nated. The time frame for them probably as ribozymes, some of which can store would have been between two and three genetic information but also possess the billion years ago, after life arose and ability to copy themselves. They would cells developed the ability to duplicate have appeared on earth at the same and metabolize. Since viruses depend time as the first cells. Over time, these on other cells for replication, they likely pre-virus molecules could have hijacked appeared shortly after the first cells, the machinery of emerging cellular life though this cannot be proven. and transitioned to parasitic viruses. The first hypothesis, known as the Viroids, small RNA molecules that regressive hypothesis, proposes that can infect plants, may be examples of viruses evolved from small cells that this phenomenon. acted as parasites—relying on larger Most likely, viruses have arisen numer- cells. Over time, these parasitic cells ous times (and may even continue to would have lost genes they no longer arise!) by one or more mechanisms and, required. Eventually, they would become as a result, may not possess a common a cell-dependent virus. Chlamydia bac- universal ancestor in the same sense as teria—which cannot reproduce outside cellular life. their host cell—may have evolved simi- larly. But unlike a bacterium such as Answer Researched by Nathan Yozwiak, Chlamydia, viruses never encode for a graduate student in the lab of ribosomes—the cellular organelles that HHMI investigator Joseph DeRisi.

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?

May 2o11 | hhmi bulletin 45 46 Biophysical Chemistry. fellowship attheMaxPlanck processes. He’s now doing apostdoctoral using fluorescencetovisualizecellular prize winner,developednewmethodsof around theworld.Bates,2010grand ognize promising young molecular biologists winner andthreefinalistseachyeartorec- Science sponsored jointly by while intheZhuanglab.The for Young LifeScientists forworkhedid Zhuang, won the 2010 in thelabofHHM hhmi J. James M P.James Lagrange-C g treating sometypesofmelanomas. development of adrug—ipilimumab—for and cancers.Hisfindings haveledtothe on theinterplay between theimmune system nologists. Allisonwaschosenforhisresearch from theAmericanAssociation of won the2011LifetimeAchievementAward at MemorialSloan-KetteringCancerCenter, ator at Boston ark Batesark nota bene s Yu Wiley PrizeGoestoLily JanandYuh NungJan p bulletin otli h magazine—goes toonegrandprize Nu A ng C llison R ollins J T F g

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HHM CML. resistant as wellfurtherresearchintoimatinib- ment forchronic myeloid leukemia (CML), both scientists thatledtoimatinib, atreat- gation. The award recognizes the work by the American Society for Clinical J.KorsmeyerAwardthe 2011Stanley from rial Sloan-KetteringCancerCenter,share HHM the Salk investigator Academy of was also elected a member of the National various biologicalnetworksfunction.Collins howground inengineeringtounderstand on complexsystems.Collinsuseshisback- 45 years of age for achievement in research annually, theaward honorsascientist under and of OregonHealth&Science ence. Fuchswaschosenforher research outstanding contributionstomedical sci- ents thisaward toascientist whohasmade Foundation. the 2011 Passano Laureate by the Passano R ockefeller C I I harles investigator investigators I nstitute forBiologicalStudies. T E E U errence J. errence ngineering, alongwithHHM ach year,thefoundationpres- niversity, hasbeennamed L . E S laine a Brian J. Brian wyers heart arrhythmias, deafness, andotherdiseases. epilepsy,to channels potassium of have mutationslinked scientists then, Since channel. potassium a of sequence ity.1987,wereIn the Jans the activ neuron control that channels ion potassium on researchtheir for WileyFoundation, the bygivenprize, annual receivedthe pair Francisco.The San California, the at lab a share who team husband and to HHMI investigators The 2011 Wiley Prize in Biomedical Sciences was awarded S e Fu j nowski , ofMemo- chs U D niversity, r I , ofthe u nvesti- ker , of I ,

award was and HHM sored bytheNationalAcademyofSciences a co-organizer of the Summer U HHM in neuroscience. that supportsminority studentsandmentors HHM dent ObamapresentedHHM I cellular decision. has discovered keypathwaysthataffectthis become askincellorhairfollicle.She on how skinstemcellsdecide whetherto of theDana-Farber Cancer some tumors. to oxygenlevels—aprocessthat’s affectedby how cells in the body monitor and respond proteins andtheir roleincancers,hasshown ics. Kaelin,whostudies tumor-suppressor Alfred the NationalCancer Mentoring (PA in Science, Mathematicsand a H L n aceremonyattheWhiteHouse,Presi- 2011 Presidential Award for ily andelsman ndergraduate Y I . I G -funded programatDavidsonCollege investigator Jan . Knudson Award inCancer f J rst to determine the DNA the determine to rst I and . Also receiving a PA u lio E E Y , ofYale ducation inBiology, spon- S uh R M amirez W N I E nstitute’s 15thAnnual illiam ung Jan, a wife M U ). Handelsman is niversity ofniversity U niversity, with , director ofan I I nstitute, won professor E G I E ngineering nstitute on . x E K cellence SM aelin G - enet- E Jo Jo M ,

Gabriela Hasbun Paul Fetters tigator HHM ment fordiabetes. become pancreascellscouldleadtoatreat- with type 1 . Coaxing stem cells to creatic cells that are destroyed inpatients embryonic stemcellsgiverisetothepan- helped advanceunderstandingofhow R tific 2010 David N D egg andspermthroughoutadulthood. become stemcellsthatcontinue toproduce are specified inanembryoandhow they in Lehmann studies germcelldevelopment Biology.the Society forDevelopmental of the Ru cal School, wonthe2011William C. of the annual award recognizes outstandingcon- chemistry andMolecularBiology. The Award fromtheAmericanSociety forBio- esearch Foundation. Melton’s researchhas o ew York Drosophila, investigating how germ cells s th u Bo Bassler Wins LounsberyAward E p glas I xcellence fromtheJuvenile Diabetes L otli E investigator nnie U at Harvard ehmann dwin niversity ofMassachusettsMedi- U L.B A niversity, is the 2011 recipient R . g G umbough Award forScien- M assler ht rant ConklinMedalfrom elton , anHHM U M niversity, received the elissa J. elissa , anHHM I investigatorat M I oore inves- R ose ,

man activity, andintermolecularinteractions. life, conformation,localization,enzymatic ways, including changingthetarget’shalf- proteinscan affecttheir indifferent target of otherproteins inacell.Different like proteins ( how a class of molecules called ubiquitin- Health. Schulman’s researchhasrevealed with Wei Yang oftheNational the Protein Society. Shesharestheaward Dorothy Crowfoot HodgkinAward from scientist whohasalsomadeexceptionalcon- The award isgivenannually toaprotein Brändén Award from the Protein Society. Baltimore County, wonthe2011Carl Hospit tigator atthe HHM machinery that processes newly transcribed ies thespliceosome,partofmolecular to training youngerscientists. Moorestud- biology researchaswellacommitment tributions tobiochemistry andmolecular M R NA strands. ichael , ofSt.Jude Children’s I implications in together.importantact toresearchrequireprocesseshas cells that Her our carry tobehavior their change theymass, critical havea reachedria bacteriabehavegroup. discovereda She as bacte-groupof a when that howand other each communicatewith individual howstudies research.Basslermedical and achievementbiologicalrecognition of in Theprizegiven is alternatein years Frenchtoand American scientistsin Princetonof Bassler, AcademyinvestigatorTheNationalScienceshonored HHMI of investigator al, is the 2011 recipient of the F . U Su BLs) controlthefunctioning U mmers niversity ofMaryland, Brenda f ghting pathogenic bacteria. , anHHM U I A niversity, with the 2011 Richard Lounsbery Award.niversity,LounsberyRichard 2011 the with nstitutes of . R S esearch I ch inves- U BLs u l - e The Society for Neuroscience named HHM in science. ate abouttraining undergraduatestudents of proteins related to H Summers studies themolecularstructures tributions toscience educationorservice. of theJohnsHopkins 2010 Young of HarvardMedical School,recipient ofits tal, pancreatic, andbraincancers. tal, development ofcancers,including colorec- acterized numerous genesinvolvedinthe oncological research.Vogelstein haschar- tion for outstanding contributions to basic the Charles R R Medicine, isarecipient ofthe2011Charles HHM about odors. the fruitflybrainprocessesinformation within thepast10years.Wilsonstudies how of neuroscience whocompletedaPh.D. is givenannually toaresearcherinthefield arly career scientist esearch. Thebiennial award isgivenby odolphe BrupbacherPrizeforCancer I investigator R I nvestigator Award. Theaward odolphe BrupbacherFounda- May 2o11 Bert R U achel niversity Schoolof I V

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47 continued from page 17 Research. “We’re very excited because we’ve got what we think is a (bone’s balancing act) more authentic model of osteosarcoma,” Lee says. Notch signaling dramatically slowed the growth of human tumors Now they’re testing whether blocking Notch genetically in mice implanted in immune-deficient mice, the group reported in Human will prevent bone cancer. If so, then compounds that block Notch Molecular Genetics in 2009. signaling could also stop the disease. And if that works in mice, Lee Since then, the researchers have engineered a line of mice plans to test them on osteosarcoma patients. with an intact immune system that would be better than immune-­ As with other bone diseases, treating bone cancer is also a matter of deficient mice at predicting how potential drug compounds might regaining balance. Lee thinks it’s possible: “If we could inhibit Notch affect tumors in people, Lee says. Notch is activated continually in osteosarcoma, that would be spectacular.” New drugs for bone in these mice, and the animals develop bone cancer, Lee’s team cancers, childhood skeletal diseases, fracture healing, and a major reported last October at the American Society for Bone and Mineral disease of aging may all come from these pathway explorations. W

continued from page 33 2003 paper showing that LXR also has anti-inflammatory effects. (the next statin) Tontonoz has since discovered that mice without LXR are more A Role for Inflammation susceptible to a host of diseases, including listeria and tuberculosis. Cholesterol build-up causes inflammation too, which is a risk factor Other studies have shown that drugs increasing the activity of LXR for atherosclerosis. That inflammation pathway offers another target in macrophages have the potential to stop the formation of a foam for drug developers. cell—by pumping cholesterol out—and to decrease arterial inflam- When cholesterol accumulates along walls, macrophages— mation. The combination could stop atherosclerosis. immune cells that recognize foreign material—are the first cells to As Tontonoz has explored the pathway of LXR, he’s also discov- encounter the clumps. The reaction of the macrophage to the cho- ered how it arrests cholesterol input, and it’s a familiar mechanism: lesterol can either help clear the artery or make problems worse. degradation. In a July 2009 paper in Science, Tontonoz reported that “A macrophage is a scavenger for extracellular garbage,” says one of the proteins that LXR turns on is a protein called Idol. Idol in HHMI investigator Peter Tontonoz of the University of California, macrophages has the same job as Hobbs’s PCSK9 in the liver—deg- Los Angeles. “And when there are cholesterol deposits, they’re rec- radation of LDL receptors. So Idol, like PCSK9, could be a target ognized by the macrophage as junk that it wants to clear.” Normally, for new pharmaceuticals. Already, compounds activating LXR are this is a good thing—macrophages help remove LDL from the in the pharmaceutical pipeline. artery wall. But when a macrophage is overwhelmed with too much cholesterol to process, it turns into a foam cell—so named because Pieces of the Puzzle the LDL in its interior looks like foamy bubbles. For every 10 milligrams per deciliter of blood that you decrease your Foam cells are the first sign of an atherosclerotic plaque. The LDL, you have a 10 percent decrease in coronary heart disease risk, foamy macrophage produces inflammatory molecules and recruits says Hobbs. Statins have been an effective way to achieve this LDL other immune cells to the site, setting up an inflammatory response, reduction, but for some patients, they’re not effective enough to stop a hallmark of coronary artery disease. “The reason the plaque even- heart disease. The network of proteins and genes that regulate cho- tually gets so big and complicated is that the macrophage talks to lesterol in the body is complex and far-reaching. Statins affect only and recruits other cell types,” says Tontonoz. one part of this system. But what scientists have struggled to understand is why the The next cholesterol drug—be it a compound that blocks PCSK9, macrophage recruits inflammatory molecules when it fills with cho- degrades HMG-CoA reductase, or turns on LXR—will likely be used lesterol. When the macrophage eats other foreign material, it clears in concert with statins to come at the problem from two angles. them with no inflammation. You can’t predict which aspect of the field will lead to the next Tontonoz has an answer: a protein called LXR. Originally breakthrough, says Goldstein. “You have to wait and see. But the identified by HHMI investigator David Mangelsdorf, of UT South- important thing is to keep looking at this from new angles.” western, LXR switches between an inactive form, in the presence of As scientists forge ahead in probing those new angles and reveal- low cholesterol, and an active form, in the presence of high choles- ing each part of the cholesterol puzzle, they get closer to that next terol. In its active form, LXR causes the cell to pump cholesterol out breakthrough, and the promises of the next drug come into focus. W and stop taking cholesterol in. There are different versions of LXR in different cell types, web extra: To learn more about cholesterol research and cholesterol-related diseases, visit

including macrophages. Mangelsdorf and Tontonoz published a www.hhmi.org/bulletin/may2011.

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48 hhmi bulletin | May 2o11 in “Wired forSmell”atwww.hhmi.org/bulletin/may2011. neuron groupsinteracttosendmessages isthenextchallenge.Readmore of relatedneuronsformsaunique howthese structure.Understanding but visualizethemoneatatime (asabove)andit’s clearthateachgroup The lobeisamishmash of olfactory neuronsnormallyhardtodistinguish, sent totherestofbrainsoflycanreact—Eat! Follow! Fly away! In theantennallobeofafly, smellsareprocessedand environmental

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Brett Ryder almost three inches long,theShadow Darnercan move swiftly or busy office, theeffect canbedramatic. Being strong fliersand in openwindows onwarm days. Whenthishappensin a classroom seems to attract attention most inthefall whenitsometimesflies Although present throughout thesummer, theShadow Darner things, includinghumans. he hopesto illuminate biologicalprinciplesthat applyto allliving tails that entertain and inform. Through thebook,White says, natural history, creating vignettes ofdarners,clubtails,andpetal­ ­anecdotes withsubstantial knowledge ofdragonfly biologyand natural habitat. Inhisnew book,White weaves observational of hisfree timeobservinganddocumentingtheinsectsintheir Biochemist HalWhite isadragonfly enthusiast, spendingmuch Strong Fliers Observations

by theUniversity ofDelaware Press, ©2011. Damselflies: Essays of aLifelong Observer, by HalWhite. Published Excerpted from Natural History of Delmarva Dragonflies and sharks attacking andterrorizing aschoolof fish. dragonflies slice backand forth through clouds of smallinsects—like the wind.Sometimes,ifconditions are right,hundreds of feeding that often flyinclearingsor at theedges of fields protected from They leave thishabitat to feed on midges andother smallinsects where malespatrolling for females flylow and follow theshoreline. Normally, however, Shadow Darnersprefer smallwoodland streams, a giantwasp andwithacorresponding sting. about aroom, inadvertently frightening humanswhomay thinkitis

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Dem Bones “Bone’s Balancing Act,” page 12). Balancing “Bone’s normally enters a product of the gene called NFATc1 bone growth. But in the mouse on the right, NFATc1 NFATc1 bone growth. But in the mouse on the right, On the outside, these two mice have the same sleek fur, have the same sleek fur, mice two On the outside, these resemblance ends. A CT scan reveals drastically different resemblance ends. A CT scan reveals drastically it’s a hint at how osteoporosis may one day be treated (see a hint it’s ultrastrong bones. Every bone, from the mouse’s skull and mouse’s ultrastrong bones. Every bone, from the skeletons and the reason lies with a single gene. The protein skeletons and the reason lies with a single dainty whiskers, and thin tails. Look inside, however, and the tails. Look inside, however, and thin dainty whiskers, was engineered to stay in the nucleus longer, and the result is longer, engineered to stay in the nucleus was spine to its toe bones, is thicker than normal. For researchers, than normal. For is thicker to its toe bones, spine cell’s nucleus only occasionally to turn on genes that encourage nucleus cell’s

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