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You’ve Got Some Gall

These green tendrils are not a normal part of the branch they’re sprouting from. •

A colony of tiny aphids has spurred the growth of this gall and lives inside it. Despite their small size, aphids—also called plant lice—are among the critters www.hhmi.or most destructive to plants. Feeding on sap through long mouthparts, aphids not only drain plants of their nutritional resources but also spread viruses from plant to plant. Gall-forming aphids, like the members of Tuberaphis taiwani that

formed this gall in Taiwan, use their self-built home as a place to hide from g predators and rain. HHMI investigator David Stern, an evolutionary biologist, studied aphids for his Ph.D. and still finds them fascinating (see page 5). Visit the Bulletin online to see more photos of galls and aphids.

Still Learning From Darwin vol. vol. how much has selection shaped us? 22 / no. no. /

David Stern In This Issue Parrot Detectives Community College Bridges Evolution in the Classroom 03 O b s e r v a t i o n s

Where Darwin Left Off

This November marks the 150th anniversary of the publication of Charles Darwin’s magnum opus, best known by its shortened title The Origin of Species. In this Year of Darwin, celebrating the bicentennial of the English naturalist’s birth, it is fitting to revisit his poetic and passionate words, which, in light of a century and a half of scientific findings, sing with as much relevance today as ever.

It is interesting to contemplate an entangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent on each other in so complex a manner, have all been produced by laws acting around us. These laws, taken in the largest sense, being Growth with Reproduction; Inheritance, which is almost implied by reproduction; Variability, from the indirect and direct action of the external conditions of life, and from use and disuse; a Ratio of Increase so high as to lead to a Struggle for Life, and as a consequence to Natural Selection, entailing Divergence of Character and the Extinction of less-improved forms. Thus, from the war of nature, from famine and death, the most exalted object which we are capable of conceiving, namely, the production of the higher animals, directly follows. There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.

20 From On the Origin of Species by Means of Natural Selection, or the Preservation Loved by bird-enthusiasts for their beautiful bright colors, intelligence, of Favoured Races in the Struggle for Life, by Charles Darwin. Published by John and affection, parrots are the quintessential pet bird. But a mysterious Murray, London, 1859. and contagious virus is threatening parrot aviaries around the world. One team of biochemists worked with some concerned veterinarians to solve the 30-year mystery and name the deadly virus. Susan Clubb Sophie Kern vol. 22 august ’o9 no. o3

DEPARTMENTS

P RESIDENT’S LETTER 0 3 Through Evolution’s Prism

C ENTRIFUGE 0 4 Something to Say 0 5 Study Aphids, See the World 0 6 Serious Softball

U PFRONT 0 8 The E Word 1 0 The Pay-Off of Persistence 1 2 Folding Phenoms

P ERSPECTIVES AND OPINIONS 3 8 Robert J. Alpern 4 0 Mark Davis 4 2 Q&A – Name an example of evolution at its finest, when an elegant efficiency is selected over time, that you’ve come across in your research.

C HRONICLE

Science Education 4 4 Next-Generation Scientists 4 5 HHMI Gives Research Training Awards Institute News 4 6 Janelia Farm to Expand Campus Housing 4 7 HHMI Doubles Postdoctoral Fellowships 4 7 In Memoriam: Alexander G. Bearn L a b B o o k 4 8 The Power of One 4 9 No More Worming Around 5 0 Finding the Off-Switch Ask a Scientist 5 1 How do we laugh? Is it the same as speaking or coughing? To o l b ox 5 2 Sticky DNA N o t a B e n e 54 News of recent awards and other notable achievements

O BSERVATIONS Where Darwin Left Off

FEATURES 14 20 26 32

Wrestling with A Curious Building Solid Proceed with Darwin Catastrophe in the Bridges Caution Jonathan Pritchard has Parrot World Community college For each man with prostate been an arbiter in one of the An HHMI team enters the students interested in cancer, which treatment gets most contentious debates mysterious domain of parrot pursuing science are on the green light? in biology: How much has breeding to decipher the virus surer footing, thanks to natural selection influenced that’s killing exotic birds. welcomed support. human traits? [COVER STORY]

V I S I T T H E B U L L E T I N O N L I N E FOR ADDITIONAL CONTENT AND ADDED FEATURES: www.hhmi.org/bulletin COVER IMAGE: pa ul s ahre 2 hhmi contributors

When he’s not chasing parrots, chasing he’snot When (2) Aioli. cat, her cosmoswith the pondering and romantic comedies, bike1990s rides, typi nel the surrealist painter René Magritte, whose work Baltimore. This issue’s story on teaching evolution (“The E Word,” page 8) inspired her to chan- Art, of College Institute Maryland the graduateof recent A proud father oftwins.Heworks from hisof the dad, new a also He’s champion. foosball design graphic world the organizer,and munity SahrePaul ington ington Post page 20) works as a freelance science journalist in Washington, D.C. He’s written for both biology and journalism. She lives Virginia. She Arlington, in (4) journalism. and biology both in training academic has yearsand eight reporterfor a worked as She magazines. and papers page 26) has covered a range of scientific researchand science-related news for variousnews From quarks to stem cells to health policy, writer policy, health to cells stem to quarks From associatenews editorfor Fiduciary Trust Company International Director, Retired Chairman & CEO Tatlock M. Anne Dean / Howard Esq. University School of Law Schmoke, L. Kurt Former Head of Global Investment Banking, J.P. Morgan & Co. Senior Lecturer, Harvard Ph.D. Business School Rose, S. Clayton The University of Cambridge Vice-Chancellor Ph.D. Richard F. Alison President / The Rockefeller University F.R.S. Nurse, Paul The Prudential Insurance Company of America Former Vice Chairman & Chief Investment Ofﬁcer Chairman / SeaBridge Investment Advisors, L.L.C. Keith L. Garnett The University of Chicago Distinguished Service Professor of History President Emeritus & Harry Pratt Judson Ph.D., Gray, H. Hanna University of Texas Southwestern Medical Center at Dallas M.D. Regental Professor & Chairman, Department of Molecular Genetics Goldstein, L. Joseph WilmerHale Senior International Barshefsky Partner Charlene Ambassador Senior Partner / Baker Esq. & S Botts III, E Baker, E A. T James S U R T I M H H bulletin f e s his sometimes humorous representational use of objects. In her free time, she enjoys she time, free her In objects. of use representational humorous sometimes his s

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Va s f t Science ce inNew York City. (1) ag (“A Curious Catastrophe in the ParrotWorld,”(“A the in Catastrophe Curious Chri , , among other publications, and is a former Ceci n’est pas une pipe (This is not a pipe) s t i n Na Kim Kim Na e Suh Suh is a freelance illustrator in freelance a is (“Building Solid Bridges,” Solid (“Building or official policies of the Howard Hughes Medical Institute. Medical Hughes Howard the of policies the official in or authors by www.hhmi.org expressed • Bulletin HHMI viewpoints and Institute beliefs, 215.8863 opinions, Medical The (301) Fax Hughes • Howard 215.8855 ©2009 (301) Telephone S & S R E C I F F O I M H H Finlay Printing Finlay NYC Partners, VSA Pines Maya Williams C.P. Sarah Projects WebSpecial for & Foster Patricia Widener Andrea Keeley Jim Vanchieri Cori I Gardiner T E Beth L Mary L U B I M H H Zimmerman Landis Ph.D. Rubin, M. Gerald Palmerino J. Edward Meehan A. Avice Esq. Leonard, S. Joan Ph.D. Dixon, E. Jack Ph.D. Bruns, J. Peter Alexander A. Craig R obert Tjian, Ph.D. Tjian, obert Heather McDonald, Anne Sommer Anne Kresge McDonald, Nicole Heather Cissell, Michelle I T Butler, I D Cay A d . (3) . do not necessarily reflect the opinions, beliefs, viewpoints, viewpoints, beliefs, opinions, the reflect necessarily not do o / Science Editor Science / / Contributing Editor Contributing / n The Wash- L A / Story Editor Story / / Printing / / Associate Director of Communications of Director Associate /

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Paul Sahre, Na Kim, Brian Vastag, Christine Suh Barbara Ries anniversary of the publication of 150th the honoring prose, magisterial Darwin’s with We conclude traits.humanselection natural on ofimpact the gauge Pritchard to Jonathan investigator HHMI by used models mathematical the to students their to concepts basic introduce teachers how from tion: the of issue ability to adapt and survive over huge spans of time. Throughout this tion, the process of ceaseless experimentation that drives an organism’spredictable foundation without Charles Darwin’s insights into evolu- and begin assembling a transcript? that makes messenger RNA—to latch onto the right snippet of DNA polymerase—theenzyme RNA enable cues What vary?machinery the Does assemble? molecules essential the do How process? the scriptionfascinatingso betterforyears.than30 Whatevents initiate processevolution.suchashavefoundreason onetran- thatIisAnd trial-and-error random a through only hold take could assembly Goldberg-like Rube almost this Rather, opportunity. the given if roommate’s lecture notes—each and every time. yourcopyingbegin todown sit can youbefore chair and desk a for to whittle the pencil, make the paper, and assemble the components process of “transcribing” a gene is so ornate that it’s rather like having the biochemical the that Except genes. specific generate activate to instructions to required steps the encompass transcription—to running. And that’s only stage one. cell a keep to needed proteins the making for instructions precise deliver to produced be can RNA messenger named aptly the and so that the right piece of DNA can uncoil from its protective cocoon ofmolecular players must mobilize in ahighly orchestrated manner y l e r decodethe genetic information we carry s inside ourselves. l Hundreds l e c r u O Through Evolution’s Prism Science, Evolution and Creationism and Evolution book the Science, in Sciences of Academy National the at colleagues by compiled been have examples everyday Such individuals. to other relationship its in predictable and related yet unique is signature genetic person’s each because play into comes evolution of edge knowl- suspects, potential screen to scene crime a from DNA of sample a uses scientist forensic a time each Likewise, season. upcoming flu the for strategy vaccine a map and path its assess evolutionary can adapt—researchers and survive virus the help that virus—changes the of at surface the dot that looking proteins the in By changes humans. and birds, Americas, the and pigs Eurasia infect in that viruses from drawn genes of pot mixed a is enza influ- of strain H1N1 The world. the sweeping is that influenza of strain new the by stumped utterly been have evolu- would scientists of tion, understanding firm a without all, After the approach. best often is examples concrete relevant on has focusing Black discovered, Suzanne teacher As tenets. its accept to whether and Nothing we study in biology and medicine would have a rational, This isn’t a manufacturing process that an engineer would devise, Scientistseverydayborrowedfromsimplehavewordspeech— a Many Americans struggle with the fundamentals of evolution evolution of fundamentals the with struggle Americans Many , we consider different aspects of evolu-differentconsiderof aspects weBulletin HHMI , o n c o m m x e l p The Origin of Species o , a survey of modern evolu- modern of survey a , l t y r e n i h c a m r a l u c e . o

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Peter Arkle Adi Lavy see theworld. University. Andthey were histicket to an HHMIinvestigator at Princeton history ofbiology, says David Stern, have played an“outsized role” inthe aphids are afascinating odditythat mid-1800s. the Great French Wine Blightofthe legendary industry to nearcollapse in known as“plantlice,” brought France’s plants. The tiny, soft,green insects, ing pests that cansuckthelife outof To gardeners, aphidsare disease-carry- Study Aphids, See the World to cut off branches where soldier- where branches off cut to poles long to clippers attached also He leaves.” over flipping road, the along walk would I “So plants. roadside on abundant weremost sapsuckers The admits. Stern sounds,” it as romantic as history. evolutionary aphids’ in emerged had soldiers the times many how determine to evidence DNA used then He days. those in process time-consuming DNA—a their sequencing and aphids ing collect- years several spent and 1989 in Japan for bags his packed Stern behavior. social Intrigued, of tion evolu- the about questions interesting raised had taxonomist Japanese a by 1970s the in soldiers aphid of in thefield. Indonesia, andTaiwan to study aphids five-year sojourninJapan, Malaysia, during hisgraduate studies, hetook a six, aphids were merely a nuisance until, legs.” fat hind their with submission into enemies their essay, “squeezeadmiring others while an wrote in Stern horns, sharp with them stab some predatorsand their poison variants Some sterile) warriors. (but “soldiers”—fierce of castes breed species hideaways. aphid aphid Some growthsserve hollow as that beautiful, sometimes galls—bizarre, forming provoke aphids Certain intothem. trees without or wings with offspring spawn can mateand a of help the without example, or reproduce they can with environment.” the Foron depending phenotypes, make different theycan acteristics Stern describes aphids’ unique char- unique aphids’ describes Stern To evolutionary scientists, however, The fieldwork for his Ph.D. “was not not “was Ph.D. his for fieldwork The caste sterile the of discovery The To Stern, anavid gardener since age :

“With the same genome, genome, same the “With the evolutionary history of a sterile caste of plant-sucking aphids. plant-sucking of caste sterile a of history study to lands evolutionary the far-flung to traveled Stern David student, graduate a As p hunt for methods powerful devised and shifted. Hebeganto study thefruitfly development inaphids,buthisinterests Stern continued to study evolution and cal to this day.” body part. imaginable I remain skepti- of,strongly tasted to,and every tical iden- looked but curd bean from made whereeverything was supposedly restaurant vegetarian a “and recalls, Stern stall,” roadside a in soup chicken and noodles homemade outstanding most the eating remember “I foods. indigenous many Lumpur,sampled and Kuala like cities in apartments rented domiciles. their inside aphids the bag could he so roducing species had formed galls, galls, formed had species roducing After completing hisdoctorate, in himself based scientist lone The i ng genes that he plans to use in in use to plans he that genes ng years.” —Richard Saltus putting itoff—at least for acouple of development,” heconfesses. “ButI’m plans to attack theproblem ofgall “I must admitIstill harborsomecrazy on several trees that are forming galls. Princeton lab, hechecksdailyprogress his to walk mile-and-a-half his on completion. genome, aproject that isnow nearing for fundingto sequence theaphid however. Backin2001, hepushedhard disappeared from hisradar screen, enthusiasm—behavior. Aphidshaven’t reproductive rate, and—Stern’s current span, life size, body as such traits, quantitative of control the probing And thelifelong gardener says that from Stern’s aphid-collecting travels and more. : A R T X E B E W Visit the uut 2 August Bulletin oo 9

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bulletin 5 6 hhmi throw California, SanFrancisco. HHMI investigator at theUniversity of an easy laptogether,” says Locksley, an infield warm up. “Okay, everyone take his near-constant chatter duringan and laughing,theplayers respond to Morgan and Sydney. In between jostling includes his twin 13-year-old daughters, from theside.” Throw it hard over the top, don’t sling it please, hard throws. Way to stay down. girls teenage of cluster nologist Richard Locksley isdrillinga It’s asunny Aprilweekend andimmu- Serious Softball review thegameduringcarride says hestill takes itseriouslyenoughto that goalittlebit.” seriously ifwe won orlost. Now I’ve let “At the beginning Itook itmuchmore fundamentals of the game—and has fun. coached team isonethat knows the years, he’s come to realize that awell- about his coaching style. But after seven do fine.” and getthemcomfortable. Then they’ll to stop coaching, diffuseeverything, uptight aboutthegame. Then it’s time do next, that Iknow that they’re too too quietlyorlookingto mefor what to Locksley says. “It’s whenthey’re sitting game,” a for knowthey’re ready centrifuge “If the girls are goofing around, around, aregoofing girls the “If Locksley coaches a softball team that Maybe alittle, butdaughter Sydney Locksley hasn’talways beensoclear

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“Hard throws “Hard 9 signed onascoach. the girlsfor softballthenext spring,he softball coach. Andwhenheregistered Olympic U.S. byformer a led clinics throw theballrightto thegirls.” ously enoughto even learnhow to someone wouldn’t take thegameseri- required insoftball.“Itbuggedmethat instead ofusingtheunderhandstyle girls withabaseball-style overhand, Their first softball coach pitched to the But after oneseason,that changed. and watch softballfrom thesidelines. content to help thegirls’soccer coach ball andsoccer through college, was Locksley, who played competitive base- soccer andsoftballasyoung kids, them out.” cated sotheotherteam can’tfigure he thinksthey have to beall compli- he getsmadwhenwe forget hissigns; home. AndMorgan smiles So he took a couple of coaching coaching of couple a took he So When thetwinsstarted playing : “Sometimes the season undefeated. undefeated. season the called, won thegame, andthey finished is team Locksley’s as Angels, SF The horse!” your on get “Morgan, position coaching third-base his from hollers Locksley base, second rounds she As slam. a grand for field right to ball fly long a hits Morgan third, the of bottom the In field. Ketcham on happening what’s on focused are Locksleys when they lose.” when they win,how collected they are develop, seeinghow happy they are just my daughters—watching them so funworking withallthesegirls—not says he’llmiss histimewiththem.“Itis happens andthey move on,Locksley dad ascoach. Whentheinevitable school team orkeep playing withtheir choose whetherto switch to theirhigh Best Coach oftheYear Award. to wintheSanFrancisco LittleLeague’s Locksley became the first softball coach and they continue to win.In2007, of the same girls come back each year— the basicsanddoingpretty well. Many Right now, however, Right three all Next spring,thegirlswillhave to Before long,histeam was learning —Rabiya Tuma —Rabiya

Peter Arkle upfront

08 The E Word Teaching evolution in high school often means a soft sell.

10 The Pay-Off of Persistence What began as a side project has become a primary focus for this physician researcher.

12 Folding Phenoms Some computer gamers are proving to be valuable partners for protein biologists.

While researchers explore the imprint of evolution on individuals, species, and populations, teachers must find innovative ways to present the subject in the classroom. Evolution and religion coexist uneasily in some minds, and students often arrive in biology classes with reservations or even a set notion about evolution’s improbability. Many teachers have thoughtfully devised ways to reach their students in the face of such resistance. And they’ve got some great resources to help them.

August 2oo9 | hhmi bulletin 7 upfront

The E Word Teaching evolution in high school often means a soft sell.

T w e n t y -six weeks in t o S u zanne Black’s 10 t h - g r a d e b i o l o g y class in a Seattle suburb, she drops the bomb. ¶ Evolution. ¶ Black didn’t purposely avoid the word before then, but in 25 years of teaching she’s She adds, “It was great that he asked, learned to minimize conflict by presenting information about evolution because you know 10 other kids were thinking the same thing and just not asking.” gradually. ¶ Though the principles of evolution underlie biology from Years ago, Black remembers taking a genetics to ecology, the religious beliefs of some students can make different tack, with dreadful results. She inaugurated a student teacher with a unit teaching the topic difficult. Experienced course. “[Some students] have been misled on evolution. “That was a mistake,” she says. high school educators have learned to get to think it’s something else, and they don’t “The kids ganged up on her and were liter- past the controversy by working up to the see what all the fuss is about.” ally firing questions at her like, ‘Were you important concepts and keeping lessons The same day Black formally introduced married in a church? How could you do that relevant to the students’ lives. the “E” word, a student asked a question and believe in evolution?’” Black also trains teachers as part of about intelligent design. Black’s own early attempts were “too the HHMI-supported Science Education “I explained that intelligent design is a textbook,” she adds. “I came across as too Partnership, a professional development religious viewpoint that says that some things confrontational. With high-school students, program for high school teachers based are so complex that you can’t explain them, it has been more successful to present at the Fred Hutchinson Cancer Research and that it’s not scientifically supported,” learning experiences that let them construct Center. She and others like her build their she says. “The kids wanted to know what their knowledge from evidence they can see, case with each day’s lesson until the bigger I meant, and I asked how we could design hear, touch, and analyze.” picture forms. Then they let on that they’ve experiments to test the ideas behind intel- Taking that approach, teachers say, can been teaching evolution. It’s like adding ligent design. And that was it.” be the tipping point between keeping high shredded zucchini to a homemade choco- late cake. No one knows it’s there, and once it’s pointed out, people realize it’s not at all Know Your Audience what they thought. Ev en in the title of its revised book, Science, Evolution, and Creationism, the National Academy “We start with evidence that’s based in of Sciences (NAS) and the Institute of Medicine faced the controversy head on. But the book’s molecular biology and genetics and slide developers went to its audience to make sure its messages were on target, and made big changes in the ‘evolution’ word later on,” agrees as a result. “The book is very different than I expected it would be,” says Jay Labov, NAS senior Ann Findley, professor of biology at the advisor for education and communications. Several focus groups in Indiana and South Carolina led the editors to downplay legal decisions, focus on how science works, and present real- University of Louisiana at Monroe. She world examples of evolution. The book, released in 2008 (nap.edu/sec or nationalacademies. teaches college students as well as high org/evolution), includes quotations on the compatibility of religion and evolution from several school seniors and high school biology scientists—including Francis Collins, former director of the National Human Genome Research teachers in an HHMI-supported summer Institute, an evangelical Christian—as well as Pope John Paul II and other religious leaders.

8 hhmi bulletin | August 2oo9 Na Kim Carolinians for Science Education after after Education Science for Carolinians tion affects life every day,” she says. family trees. “It helps them see where evolu- anemia,evolution,cellsickleorbird tance, resis- antibiotic discuss example, for might, Teachersevolution. on “unit” a during just not and instruction throughout embedded evidenceinteresting,and relevant examples evolutionarypair to state districtandher in South Carolina, encourages science teachers City, Lake in teacher a Whittington, Deb Make it Relevant turning them off for good. and science in interested students school In 2005, she helped organize South South organize helped she 2005, In their families andfriends,aswell. to and students to doors open can myths Clemson. at studies undergraduate and programs dean summer of associate Speziale, J. concept,” Barbara says abstract some not day, every to happening that’s try something as action, it present in evolution them show University. Clemson at teachers biology for topic the on courses summer pated in, and helped run, HHMI-supported partici- also has Whittington classroom. the in evolution about presenting apprehensive were teachers fellow some that realizing Providing information and dispelling dispelling and information Providing labs, the into teachers the take “We Na Kim’s illustration, see Contributors on page 2. page on Contributors see Kim’s Na illustration, teachers. about for more advice learn and To information find TION: N O I AT M R O F N I E R O M R O F along the way.” the along get might you barbs the of any worth that’s … theory power of and beauty evolutionary That’s community. I’d what achieve.” to like her in dialogue a start least at can great—she was that thought I tion. evolu- about father her to go talk to and home excited the was of she said end she the program, “At says. Findley ters,” minis- Baptist were grandfather and father whose woman young a had we program, Black agrees. “For a student to see the the see to student a “For agrees. Black precollege our in ago years few “A uut 2 August W

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uut 2 August oo 9 A college project studying how elephant seals’ fat cells change after the seals are weaned weaned are seals the after change cells fat seals’ elephant how studying project college A triggered Vivien Cheung’s long-time interest in how different human traits appear. traits human different how in interest long-time Cheung’s Vivien triggered

Jason Varney The children came to the clinic usually before the age of two. They had difficulty walking or even sitting upright. In some, angry red veins bulged in the corners of their eyes. ¶ Vivian Cheung, then a pedi- “That told me that ATM wasn’t the only atric neurologist at Children’s Hospital of Philadelphia, recognized the gene responsible for radiosensitivity,” she remembers. signs of ataxia telangiectasia (AT), an inherited disorder. The good Cheung still does some clinical consul- news was that it was rare; the bad news was that there was no cure. tation at Children’s Hospital. But for the past several years, and with support from The AT gene defect normally rendered its have inherited two mutant copies of a HHMI since early 2008, she and her victims wheelchair bound by the age of 10 gene known as ATM (ataxia telangiec- colleagues have been trying to understand and plagued them with respiratory ailments tasia mutated). The gene normally codes the genetic underpinnings of radiosensi- and cancers until they succumbed, often for an enzyme whose most evident role tivity in AT patients as well as in the wider before turning 30. is to act as the foreman of a special repair population. In a study published in Nature Cheung had been on track for a medical crew—called into action after the gravest in April, Cheung and her lab members career. “My dad was a surgeon,” the HHMI of cellular events, a double-stranded DNA looked at gene expression responses to irra- investigator says now, with a dutiful daugh- break. The “ATM crew,” which includes diation in a large sample of human cells. ter’s smile. But while working as a clinical several powerful tumor-suppressing mole- They were able to link individual differ- fellow at Children’s, a teaching hospital cules, must either attempt DNA repairs or ences in these responses to DNA-sequence affiliated with the University of Pennsylvania trigger a cellular self-destruction process variations in more than a dozen master School of Medicine, she began doing known as apoptosis, lest the damaged DNA regulators of the radiation response, which research in her spare time to unravel the lead to runaway cancerous growth. Cells were found throughout the genome. mysteries of this heartbreaking disease. that lack this repair capacity are much “One goal of this is to develop a It was a journey that would eventu- more susceptible to damage from radia- DNA-based test to determine how radio- ally make her one of the world’s foremost tion and are more likely to turn cancerous. sensitive a person is likely to be,” she says, experts on the genetics of DNA repair. In AT patients, a defect in an important repair- “One goal of this is to develop a DNA- related gene leaves them vulnerable to a bewildering variety of bodily dysfunctions: based test to determine how radiosensitive balance and motor-control problems, spider a person is likely to be. veins in the eyes, diabetes and infertility, immune system defects, and—perhaps Vviani C h e u n g ” strangest of all—an extraordinary sensitivity to ionizing radiation. “Even ordinary background radiation, from adding that such information is becoming “I had long been interested in how cosmic rays and radon gas, can contribute more important, given the rapid increase different traits appear,” Cheung says. As an to cancers in AT patients,” says Cheung. in the use of radiation for CT scans and undergraduate at the University of California, AT occurs in fewer than 1 in 40,000 cancer therapies over the past two decades. Los Angeles, majoring in microbiology, children, yet Cheung soon realized, as her Detailed knowledge about the molecular she had studied how fat-cell metabolism lab grew, that radiosensitivity was a trait first responders to radiation damage could changes radically in young elephant seals to not confined to these rare patients. Gene- help, too, in the development of drugs to enable them, after weaning, to hunt fish at expression studies in her lab suggested that make tumors more sensitive to radiotherapy. half-mile depths. Later, in medical school at AT carriers, who have one nonworking Cheung also has a deeper goal in mind, Tufts University, she took part in a multiyear copy of ATM (and represent fully 1 percent which broadly relates to the popular concept epidemiological project in Turkey to study of the population), are also more sensitive of personalized medicine: “We can apply the genetics of lipoprotein levels. to radiation. In fact, Cheung noted from the same tools developed for this study to At Penn, Cheung set up a small labo- the literature that more than 10 percent of see how people differ in their responses to ratory to study the genetic havoc of AT, all patients receiving radiation therapy for drugs or environmental toxins that they are and she quickly focused on the radiosen- cancer showed signs of excessive damage or exposed to in their ordinary lives,” she says. W sitivity problem. Patients with the disorder secondary cancers. – J i m S c hna b e l

August 2oo9 | hhmi bulletin 11 upfront

Folding Phenoms Some computer gamers are proving to be valuable partners for protein biologists.

s T e v e Ple t s c h i s n ’ t a b i o c h e m i s t. The 32-year-old elec t r i c a l designer from Mesa, Arizona, spends his working hours planning how to wire fire alarms and security systems. So it might seem surprising

that researchers at the University of Washington in Seattle invited him fold-off called CASP (Critical Assessment to show them how to fold proteins. ¶ Though not a scientist, Pletsch is of Techniques for Protein Structure a whiz at “Foldit,” a computer game designed by HHMI investigator Prediction). But predicting the shape of a protein that comprises hundreds, or maybe David Baker and colleagues in which players rack up points for thousands, of amino acids can overwhelm sculpting an on-screen protein into the most stable conformation. even a supercomputer. To speed up the work, Baker and col- The Foldit team has been analyzing often nail down a protein’s shape experi- leagues parceled out the analysis in 2005 the skills and strategies of prodigies like mentally through x-ray crystallography and through Rosetta@home, a project in Pletsch—so-called folding savants—for nuclear magnetic resonance spectroscopy, which some 200,000 people have allowed guidance on how to teach computers better but these laborious techniques can’t keep their computers, during downtime, to per- ways to predict protein structure. And up with all the new proteins being discov- form a portion of the folding calculations. through a new version of the game, these ered, says Baker. Baker says that the inspiration for Foldit virtuosos and other Foldit fans now have a As an alternative, researchers often came from Rosetta users who watched the chance to take on a bigger task: designing hand the job over to a computer, which program’s progress on their screen savers proteins that might become the next gener- can make folding predictions based on the and reported that it wasted time testing ation of treatments against diseases such as amino acid sequences of proteins. Over the obviously incorrect configurations. The influenza, cancer, and HIV/AIDS. past decade, Baker’s team has devised some researchers wondered whether humans Every protein folds into a characteristic of the best algorithms for making these could do better. Computers are stuck with shape that dictates what job it can perform. forecasts, consistently topping a biennial a big limitation, says Baker—they select the Like the seating arrangement at a dinner party, the conformation reflects attractions and repulsions. Water-shy amino acids, “People won’t be moving around for example, huddle in the interior of the randomly. They will use insight to molecule. Some pairs of amino acids make find the best step. good neighbors, whereas others don’t mesh because of their bulky side chains. Scientists dvi a d b a k e r ” University of Washington

12 hhmi bulletin | August 2oo9 VSA Partners he doesn’t stick to a script when he folds, but says He moves. best his off showed Pletsch to 20- October, last two sessions computer 30-minute In debriefings. for Seattle to members, Hour Another several including savants, Foldit of handful a invited have Point” team. Another star Hour “Another the the on performers of one he’s and website, the on posted challenges the of 30 than more on May in score top the set Foldinghas he 2008. solo, release Internet its after shortly step.” best the find to randomly. use insight will They ing around next step at “Peoplerandom. won’t be mov- Over the last year, Baker and colleagues colleagues and Baker year, last the Over Foldit playing started he says Pletsch such as having though, really good clear, three-dimensional already are players master these of attributes Some emulate. could computer a thatsteps reveal to playsavants’ the over poring are colleagues his But and he proteins. folding at computers than ability.” visual enal shape. According to Baker, that requires “phenom- efficient it more a in up piecing together and back breaking onscreen for molecule facility the his was play configuration. efficient more a into which can good the shakes, jostle molecule few a protein the giving by starts usually he Forexample, plan. rough a follow does he Baker won’t say that humans are better better are humans that say won’t Baker Pletsch’s about Baker impressed What to take a crack at some usable solutions.” usable some at crack a take to try. “It allows someone with a casual interest a feature design the give to eager he’s says Pletsch infection. an start to cells entering from it prevent and virus flu the jam can soon, will ask players to craft a molecule that release to plans team the which challenge, diseases. other and malaria, AIDS, first The for treatments furnish possibly could that designing their compounds brains: tickle to and other Foldit aficionadoswith a new way 13-year-old son trounces him. middling—hisis game the on performance all,”atadmits helpownwho Baker,his says visualization skills. “Being a scientist doesn’t hh – M i The team recently provided the savants savants the provided recently team The t c L e e i l s uut 2 August oo 9

hhmi

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Jonathan Pritchard has been an arbiter in one of the most contentious debates in biology: How much has natural selection influenced human traits? Wrestling with Darwin

by Steve Olson | photography by Kevin J. Miyazaki forefront of these controversies throughout The discovery of natural his research career. But he has served more in the role of mediator than combatant. Pritchard is an expert at the mathematical selection was both a techniques needed to determine how natural selection has influenced our genomes. While others argue in the abstract triumph and a burden about how genes might affect human traits, Pritchard focuses on facts: what historical processes could have produced the for Charles Darwin. sequences of genetic letters in our DNA? Through careful observations of the living It’s also a problem with many practical world, he concluded that most organisms applications. Selection modifies genes An Extra Year have many more offspring than can that influence our phenotypes—our Pritchard’s proficiency in both mathemat- survive. Those offspring with advanta- biological forms and functions—includ- ics and biology can be traced in part to a geous characteristics tend to live while ing susceptibility to disease and responses bum knee. He and his father, William G. others succumb to disease, are eaten by to environmental toxins. If geneticists like Pritchard, an applied mathematician who predators, or otherwise fail to reproduce. Pritchard can identify places in our moved the family from England to the This “struggle for life” tends to perpet- genomes shaped by selection, they might United States to take a faculty position at uate favorable traits, enabling populations shine a spotlight on genetic regions impli- Pennsylvania State University, shared a of organisms to adapt to their environ- cated in some of the major scourges of love of running. Pritchard’s first scientific ments. Yet the struggle reveals an amoral humanity. “Selection could influence paper, which he wrote as an undergradu- ruthlessness at the heart of nature. When common diseases—like diabetes, hyper- ate with his father as coauthor, analyzed Darwin reflected, late in life, on his loss of tension, and stroke—that fill up hospital the effects of wind on sprinters and faith, one consideration he cited was “the beds,” says his University of Chicago concluded that the women’s world record sufferings of the millions of lower animals colleague Anna Di Rienzo. in the 100 meters, set by Florence Griffith- throughout almost endless time.” More controversial issues are at stake. Joyner at the Olympic Trials in 1988, Humans are not exempt from this Some biologists claim that the biological should have been disallowed because of a competition for reproductive success. The differences between human populations strong tailwind. However, the anemome- miscarriage of a fetus, the death of a child are largely the product of selection. They ter, which recorded a wind speed of zero, from disease, a young couple’s inability to say that skin color, body shape, and even appears to have malfunctioned. (“Running have children—all are more than human certain dispositions such as aggressiveness officials have occasionally asked us about tragedies; they also prevent particular and intelligence are the product of people our results,” says Pritchard, “but they don’t versions of genes from passing into future with particular heritable traits having want to change the record.”) generations. As Darwin said of his theory, more successful offspring. Pritchard planned to run the 1500- and “the vigorous, the healthy, and the happy Other biologists scoff at these claims. 5000-meter track events for Penn State survive and multiply.” They insist that complex characteristics when he entered as a freshman. But a Jonathan Pritchard, an HHMI investi- like intelligence depend much more on a knee injury forced him to redshirt for a gator at the University of Chicago, has person’s experiences than on the genetic year, which meant he was in college for been fascinated by evolution and natural differences between individuals or groups five years. That gave him plenty of time to selection ever since he began collecting of people. And they claim that, for most double-major in biology and mathematics insects and watching birds near his child- traits, factors like the movement and growth while still competing on the track and hood home outside London. “Understand- of human populations are more likely than cross-country teams. A freshman class ing the role of selection in any species selection to determine genetic inheritance. taught by Andrew Clark on population is one of the fundamental questions in Pritchard, a lanky ex-athlete who exudes genetics—the study of changes in DNA biology,” he says. the calm of a serious runner, has been at the sequences in populations of organisms

16 hhmi bulletin | August 2oo9 Jonathan Pritchard, fascinated by evolution since childhood and gifted in math, combines compu- tation and population genetics to learn how natural selection has influenced our genomes.

team of researchers who used structure to analyze genetic data from more than a thousand people drawn from 52 world- wide populations. At the time, geneticists thought the extensive genetic overlaps among all humans would make it difficult to divide people into categories. But structure clearly sorted the people into groups centered on continents or parts of continents, including sub-Saharan Africa, western Eurasia, eastern Asia, and the Americas. The resulting paper, published in Science in 2002, was named “Paper of the Year” by The Lancet. Newspaper stories heralded the results as providing a biological basis for tradi- tional racial classifications, but Pritchard interprets the results somewhat differently. For him, the patterns in our genomes reflect the earth’s geography and the history of populations as much as they do the classifications societies use to divide individuals into groups. Anatomically modern humans evolved in Africa some- time before 150,000 years ago. They spread into the rest of the world and gradually replaced the more archaic forms of humans living in other parts of Africa and in Eurasia, including the Neanderthals in Europe, Homo erectus in Asia, and the over time—intrigued him. “He was tremen- could use the mathematics of population most recently discovered Homo floresiensis dously gifted mathematically,” Clark says. genetics to learn about human history,” in Indonesia. “When a student like that comes along, Pritchard says. As modern humans colonized the you pay attention.” In 1998, he returned to England for world, groups developed genetic differ- After graduating from Penn State, a postdoctoral fellowship at Oxford ences that make it possible to distinguish Pritchard moved to Stanford University to University, and there he wrote a computer Africans, Asians, and Europeans today— work with Marc Feldman, a prominent program that dramatically changed how both visually and by using computer geneticist who had also been Clark’s grad- geneticists think about the genetic relation- programs like structure. People, however, uate adviser. In Palo Alto, Pritchard ships among people. Known as structure, have continued to move within and quickly fell in with the vibrant community the program analyzes the differences in among continents throughout history, of students and faculty members surround- DNA sequences in a sample of individuals. blurring the genetic differences among ing Feldman and Luca Cavalli-Sforza, It then sorts the individuals into groups populations. In some cases, the move- who pioneered the use of population based on their genetic similarities. ments were extensive, as between Europe genetics to study the movements of human Pritchard and Noah Rosenberg, a and Asia. In others, they were small but populations over broad historical periods. friend from Stanford who’s now a geneti- continuous, as between Asia and the “I was fascinated by the idea that you cist at the University of Michigan, led a Americas across the Bering Strait. Today,

August 2oo9 | hhmi bulletin 17 all human groups appear to be the product team found two genetic variants involved southeastern Asia moved north, but there, of complex mixings and movements of in resistance to malaria that appeared to different sets of variants became respon previous groups, not isolated populations have increased dramatically in frequency sible for lighter skin. that have remained separate and immo- over the past few thousand years—about Pritchard and other geneticists also bile for long periods. the same time frame when the develop- began to find signs of selection in parts of ment of agriculture caused populations of the genome with unknown functions. In a Signs of Selection? malaria-carrying mosquitoes to explode. 2006 paper, for example, he and a group of Pritchard moved from Oxford to the Soon other signs of selection popped colleagues found selective signals scat- University of Chicago in 2001, the same up in DNA data. For example, the stron- tered throughout the genome. Some year the full sequence of the human gest signal of selection in the entire signals were associated with genes of genome was published. Completion of human genome emerged from the gene known function, but others appeared in the Human Genome Project marked a that encodes the enzyme lactase, which genes of unknown function or even in milestone in the history of science, but it breaks down the sugar in milk, lactose, areas that had no genes. was just one genome and population into more easily digested sugars. Most Meanwhile, other studies suggested geneticists wanted more. They wanted to people in the world make lactase when that the rate of selection markedly know how DNA sequences differ from they are children so they can digest their increased in recent human history. A person to person, both to gauge the effects mother’s milk, but the gene shuts off research team led by anthropologist John of those differences on health and to learn when they become adults. Many people Hawks at the University of Wisconsin more about human history. with European, Middle Eastern, or concluded that selection was more than They did not have to wait long. In the African ancestry have a variant of the 100-fold faster in recent human history 1990s, Cavalli-Sforza at Stanford had initi- lactase gene that remains active in adult- than before the movement of modern ated an effort known as the Human hood, so that they’re able to digest milk humans out of Africa. Two members Genome Diversity Project to gather their whole lives. These versions of the of that team, anthropologist Henry hundreds of human DNA samples from gene are most common in populations Harpending and physicist Gregory around the world; the data Pritchard that domesticated animals for milk, which Cochran, have used the data to speculate analyzed with structure were some of the would have created a selective pressure that many features of modern popula- first results from the project. In 2002, the for a lifelong ability to digest lactose. The tions—such as the higher average scores National Institutes of Health launched a genetic variants in these populations of Ashkenazi Jews on IQ tests—reflect the more intensive effort that identified began to increase in frequency at about influence of selection. millions of common DNA differences in the same time that dairy animals were At this point, arguments about selec- several hundred people with African, domesticated. tion often acquire political overtones. But European, and Asian ancestry. Another strong selective signal turned Pritchard has avoided those arguments. As data on human genetic differences up in genes that affect skin color. As He wants to know whether selection actu- flooded into databases, population geneti- modern humans expanded out of Africa ally produced the signals he and others cists scoured the data for signs of selection. into more northern latitudes, their dark have detected. Recently, he’s come up For example, a group led by Pardis Sabeti skin became a distinct disadvantage, prob- with some surprising answers. at Harvard University developed a mathe- ably because in high latitudes it blocks matical technique to look for large too much of the sunlight that humans Ambiguity sections of DNA that were unusually need to synthesize vitamin D. Genetic Last year, a group of researchers at Stanford similar in many people. Nearly identical variants that produced lighter skin there- used a new technology to measure dif blocks of DNA suggested that the sections fore gained a significant advantage. In ferences in DNA sequences from the contained a genetic variant that had early Europeans, variants in several genes Human Genome Diversity Panel at many conferred an advantage on individuals that lighten skin color began to increase more genetic locations than in the past. with that variant, causing the representa- in frequency. Meanwhile, the same With postdoctoral fellow Graham Coop, tion of the variant to increase in the process was occurring on the other side of graduate student Joseph Pickrell, and population. For example, Sabeti’s research Eurasia as dark-skinned people from several collaborators at Stanford, Pritchard

18 hhmi bulletin | August 2oo9 “I was fascinated by the idea that you could use the mathematics of population genetics to learn about human history.” —jonathan pritchard

began searching the data for signals of migration of modern humans out of Africa Sabeti, however, finds Pritchard’s selection. and by the continued movements of conclusions convincing. “There has to be Previously known signals jumped out people since then. a false-positive threshold,” she says. “We right away, including the lactase and skin Pritchard’s team has concluded that don’t really understand the demography pigmentation genes. Pritchard and his selection in the human genome is often of these populations, and there are lots of colleagues also found several interesting overwhelmed by the movement and question marks.” signs of selection where they hadn’t been expansion of populations. “Selection is a New data will help answer some ques- seen before, such as in a set of genes weaker force than people thought,” says tions. The 1000 Genomes Project will soon involved in the development of heart, Pickrell. Populations that are closely begin delivering full DNA sequences—not neural, and mammary tissue. Geneticists related genetically, because they split just the most common DNA differences— have few clues about how these genes recently or exchange many migrants, have of more than a thousand people from operate and why they might have been very few genetic variants that are markedly around the world. Geneticists also will selected, but “we’re keen to learn what different. With more distantly related learn more about the genes that have been these genes are and how they work,” says populations, demographic processes have selected, which will help them separate Coop, now an assistant professor at the usually had a greater influence than selec- true examples of selection from misleading University of California, Davis. tive pressures. Selection may be driving signals. “As functional studies go forward, In a paper published in PLoS Genetics groups of genes that all influence a trait in people will start figuring out the pheno- on June 5, 2009, Pritchard, Coop, Pickrell, particular directions, but “simple models types that are associated with selective and a group of colleagues, including of strong selection pushing single variants signals,” Coop says. “That will be very Feldman and Cavalli-Sforza, describe an to high frequencies appear not to be the important, because then we can figure out unexpected result of their analysis. case,” Pickrell says. what the selection pressures were on these Beyond the clearest signs of selection— As a result, it may be difficult to deter- phenotypes.” like lactase persistence, skin color, and mine which human genes have genuinely Pritchard remains cautious about resistance to several infectious diseases— been affected by recent natural selection. whether new results will answer every there appear to be few unambiguous cases “It’s hard to be confident about individual question. “For lots of these historical ques- of strong selection in the human genome. signals beyond the top 10 or so,” says tions, some things are fundamentally “Natural selection may shape the human Pritchard. unknowable,” he says. But he acknowl- genome much more slowly than previ- Some dispute these conclusions. “It edges that geneticists may be on the verge ously thought,” says Pritchard. In fact, depends on the model of population of answering a historic question: To what some of the DNA sequences identified history that you use,” says Hawks. “We extent has selection shaped both our earlier as possible signs of selection look believe that populations were larger in bodies and our minds? If Darwin were like something else to Pritchard. They the past, which means that there was alive today, he would be eagerly awaiting look like the patterns generated by the more selection.” the answer. W

August 2oo9 | hhmi bulletin 19 a c u r i o u s catastrophe

in the parrot world

an hhmi team enters the mysterious domain of parrot breeding to decipher the virus that’s killing exotic birds.

by brian vastag illustration by riccardo vecchio

doctoral position with two HHMI investigators, Joseph DeRisi and Don Ganem, attracted to the operation they had built to link viruses to human diseases. (See “Modern Day Virus Hunters,” HHMI Bulletin, August 2006.) Ganem, the physician of the operation, had found in the late 1990s that human herpesvirus 8 causes Kaposi’s sarcoma, a tumor found in many AIDS patients. DeRisi, the lab polymath, is a pioneer in DNA microarrays—glass slides spotted with thousands of genetic fragments. In 2002, DeRisi and David Wang, a postdoctoral fellow in his lab at the time, invented the Virochip, a DNA array for detecting every virus found in plants, animals, insects, and humans. The Virochip can also identify unknown viruses if they share a smat- tering of genetic code with a known virus. In 2003, the Virochip pinned severe acute respiratory syndrome (SARS) on a previously unknown coronavirus, proving the worth of the chip in a pressure-cooker international outbreak he tiny patient that killed hundreds of people. was feathered and failing. The prognosis: grim. On a hot Friday Since then, Ganem and DeRisi had received stacks of entreat- before Labor Day 2008, Amy Kistler fought holiday traffic to make ies from researchers wanting to tap their technology. In 2006, two a house call. She was greeted by a high cyclone fence and snap- unusual requests arrived. Both asked the researchers to help ping rottweilers. When the owner opened the gate and dismissed unravel the mystery of a parrot disease, PDD. the guard dogs, Kistler stepped into the world of a parrot breeder. “Parrots seemed kind of off the subject, so at first we just filed Behind the house, dozens of cages—some as big as 6 feet the letters,” Ganem recalls. square and 8 feet tall, with wooden nesting boxes inside—littered the yard. Each held a pair of parrots. Majestic macaws, big cream- E l u s i v e Bird Killer colored crested cockatoos, African grays with blood-red tails. At the time, Kistler was studying upper respiratory illnesses with As the owner showed Kistler around, the birds screamed and the Virochip, but she had a growing interest in animal viruses. shrieked—a cawing cacophony. “There were more than 100 When she got wind of the letters, she read up on PDD and discov- birds, and they absolutely flipped out,” Kistler says. “I had never ered the disease first appeared in macaws imported to the United seen anything like it before.” States from Bolivia in the 1970s. Since then, veterinarians had Ignoring the riot, the owner explained the situation: A young recorded it in more than 50 species of Psittaciformes, the avian macaw was sick. It had stopped eating and was losing weight. order that includes many pet species, such as parrots, macaws, During the past six weeks, other parrots in his collection, mostly cockatoos, cockatiels, lorikeets, parakeets, budgerigars, conures, chicks that lived inside the house, had wasted to the bone and parrotlets, and lovebirds. The disease jumps between birds in died. Kistler collected the red bird, put its carrier in the backseat close contact, suggesting an infectious agent. of her car, and drove to a local bird veterinarian, Jeanne Smith. Under the microscope, veterinarians see tiny round specks in At Smith’s office, the pair euthanized the sick bird and opened it tissue from sick birds, specks that resemble virus particles. up. Smith pointed to one of the digestive organs, the proventriculus. Veterinarian Susan Clubb had written one of the letters pleading Situated in the upper gastrointestinal tract of birds, the proventriculus for a viral investigation of PDD. “For a very long time, researchers normally passes partially digested food farther down the line. In this all over the world have been trying to find the agent that causes macaw, though, the organ was grotesquely swollen and clogged with the disease,” says Clubb, who has a bird clinic in Loxahatchee, food. This young bird had PDD, proventricular dilatation disease. Florida. “It’s been very elusive.” This and the other dead birds meant an outbreak was spreading. Clubb calls PDD an obsession. Over her 30-year career, she’s PDD is the AIDS of the parrot world, devastating captive treated hundreds of birds with it. She’s watched PDD wipe out flocks and stigmatizing breeders whose birds carry it. How Kistler, whole indoor aviaries in Canada and the northern United States. a virology postdoctoral fellow at the University of California, San “It’s devastating,” says Clubb, who counts 280 parrots in her own Francisco (UCSF), got involved is a story of DNA chips, persever- breeding flock. ance, and good timing. Like AIDS, PDD is a wasting disease. Inflammation attacks the nerves at the base of the proventriculus, paralyzing the organ. T h e V i r u s H u n t e r s As the organ swells, birds stop eating, regurgitate, and pass When she arrived at UCSF in 2003, Kistler had never heard of undigested food in their feces. Affected parrots often become PDD, let alone touched a bird. She had signed on for a post clumsy and fall off their perches. Seizures sometimes strike. But

22 hhmi bulletin | August 2oo9 symptoms can wax and wane, and birds might rally for a time connection with a condition called achalasia. In this disease, the after treatment for secondary bacterial and yeast infections. esophagus—analogous in form and function to the proventricu- Most cases are diagnosed symptomatically. Owners sometimes lus of birds—is affected, impairing the peristalsis that normally spring for an arduous and costly crop biopsy, in which veterinar- propels food along the digestive tract. The cause is unknown, but ians search for tell-tale inflammation of the gastrointestinal esophageal biopsies of achalasia patients show “active inflamma- nerves. Even then, biopsies miss about half of positive cases, says tion of the nerves and ganglia,” Ganem says, “which in fact is the Clubb. A definitive diagnosis—as confirmed by the inflamed exact pathology of PDD. I realized this wasn’t just important for nerves—can be made only via necropsy. parrot owners, it actually had relevance to human disease.” There are cultural parallels to AIDS, too. PDD is freighted Buttressed by Ganem’s findings and the enthusiasm of Kistler with stigma. No breeder wants a reputation for keeping birds with and Alexander Greninger, an M.D./Ph.D. student who joined the the disease. Organizations of parrot lovers have sprung up to raise project, the team decided to make PDD the first veterinary awareness, some launching a campaign called Stop PDD, which disease they would study with the Virochip. Clubb sent tissue made a PDD quilt, each square hand-sewn to recall a parrot that from birds that died of PDD and birds that died of natural causes. had passed. The writer of the second letter, an Israeli veterinarian named Ady As Kistler discovered, parrot breeding is a big backyard business, Gancz, sent his own samples. exploding after a 1992 law banned the importation of most wild In January 2007, Kistler selected one of the samples Clubb parrots. Now, virtually all the estimated 12 million pet parrots in the had sent from Florida, extracted the genetic material, added fluo- United States are captive bred, providing income for several thou- rescent tags, and then washed the mixture over the Virochip. She sand breeders, according to the American Federation of Aviculture. slipped the chip into a scanner, which reads each of its 20,000 Rare, hard-to-breed, “super-exotics,” such as the magnificent spots, and watched bright dots scroll up the screen: green spots hyacinth macaw, can fetch $10,000 to $15,000. African grays, known are hits, white spots are strong hits. for their intelligence and longevity, typically cost $1,200 retail. Kistler noticed a white spot on the right edge, one she’d never seen in the hundreds of human disease Virochips she had N e w T e r r i t o ry processed. The computer identified it as “bornavirus.” She’d Ganem delved into the pathology of the parrot disease to deter- never heard of it. An Internet search revealed that “Borna disease mine whether it resembled any human ailment. He made a virus,” named for the town in Germany where a peculiar outbreak

AK MY Istler KNOWS MORE ABOUT BIRDS THAN SHE EVER INTENDED WHEN SHE JOINED THE GANEM AND DERISI LABS. HER RESEARCH ON A DEADLY AVIAN VIRUS HELPED SOLVE

Lenny Gonzalez A 30-YEAR PUZZLE AND OPENED HER EYES TO VETERINARY RESEARCH.

August 2oo9 | hhmi bulletin 23 DONG AneM AND JOE DERISI WEREN’T PLANNING ON STUDYING A BIRD DISEASE, BUT AN ENTERPRISING POSTDOC AND SIMILAR PATHOLOGY TO A HUMAN AILMENT MOVED THEM TO TAKE A CLOSER LOOK AND PINPOINT THE VIRUS THAT CAUSES PDD.

in horses was first described in 1885, causes poor balance, motor That’s when bird doctor Jeanne Smith called. She suspected control problems, and abnormal behavior in horses, sheep, and an active PDD outbreak. Did the researchers want to play other livestock. The virus latches onto nerves and can cause disease detective? At this point, Kistler had worked only with encephalitis. tissue samples from dead parrots. She jumped at a chance to The association to PDD was striking. Five of the 8 samples, investigate live cases, and on that scorching Friday in August but none of the controls, lit up with bornavirus. 2008, she drove three hours and met Smith at the breeder’s “That was it,” says DeRisi, recalling when he and Kistler compound. watched the first data roll in. “That was a thrilling moment. It The facts of the case: Several months earlier, a female African gave us an answer that was pretty clear cut.” In two days, the team gray named Kiwi had fallen ill, lost weight, and developed a nasty and their Virochip had solved a 30-year mystery. fungal skin infection. The breeder isolated Kiwi outside, but Next, Kistler fished out segments of the virus’s genetic code. brought her inside to the kitchen to medicate her. Too close, it The segments confirmed that they had found a bornavirus turned out, to where he kept the hatchlings, 50 chicks, stacked in unlike any seen before. The viruses recovered from horses and cages in the erstwhile living room and dining room and in the sheep all closely resembled each other at the genetic level, but pantry, next to the kitchen. In July, some of the chicks started the parrot viruses looked much different from those viruses and showing symptoms; a few quickly died. from each other. The team called them avian bornaviruses Kiwi also died, and the necropsy tissue was positive for PDD. (ABVs). After analyzing samples from more dead birds, the team “He introduced a sick bird with PDD into the nursery. He wasn’t discovered five ABV subtypes across a range of parrot species. washing his hands, washing the counters, taking precautions,” Kistler, Ganem, and DeRisi eventually spelled out the entire Smith says. “So it just spread like wildfire.” genome—all six genes—of one strain of the new virus. They had The breeder was worried. He agreed to let Kistler take samples, found their quarry. but only if he could remain anonymous. On Kistler’s first visit, she collected the young red macaw, and T h e O u t b r e a k she and Smith sampled nearly every organ. At the UCSF lab, The team published the discoveries in Virology Journal in July Kistler ran the tissue through a polymerase chain reaction (PCR) 2008. “We became rock stars of the parrot world,” Ganem says. test she had developed with the ABV genome data. The test can Soon the calls began. Veterinarians asked if a diagnostic test was quickly fish out bits of ABV. The brain and digestive tract were available. (“Nothing commercially available.”) Breeders hoped marinating in virus. Kistler returned to the compound for another

the discovery somehow meant a cure was at hand. (“Not yet.”) dying bird. Same results. Lenny Gonzalez

24 hhmi bulletin | August 2oo9 The breeder panicked. He wanted all the indoor chicks tested. from an independent testing service before you buy a bird, it will In mid-September, Kistler and Smith arrived armed with vials for help clear that up.” blood and a batch of large Q-tips for swabbing the birds’ cloaca, DeRisi, Ganem, and Kistler are convinced that ABV causes or backsides. They started with the African grays and spent three PDD. In late 2008, Gancz, the Israeli veterinarian collaborating hours wrangling screeching parrots. When Kistler ran the samples with the HHMI team, injected three cockatiels with an extract at the lab, she found virus in 12 of 46 chicks. She e-mailed the from ground-up ABV-infected parrot brain. One rapidly died from results to the breeder. He never wrote back. The breeder also cut severe PDD, and the other two got sick. The group expects to off contact with Smith, his veterinarian for 10 years. “He went publish its findings in an upcoming issue of the journalVirology . into denial,” Smith says. A host of other questions now come into play. DeRisi wonders There were still more casualties. Another client of Smith’s, a where the parrot outbreaks originate. Do wild ducks or geese second breeder, had boarded three hatchlings at the first breed- carry it? “Maybe parrots are just the dead end,” he says. “What er’s house earlier that summer. After the second breeder brought about poultry?” the chicks home, one of them displayed symptoms and died. Kistler discovered that some asymptomatic birds test positive Kistler and Smith found ABV in 8 of 10 other birds exposed to the for the virus. Does that mean they’re carriers, spreading the infec- dead chick, even though some were asymptomatic. It was the tion? And is ABV like HIV, infecting the host for a long period same strain found in the first breeder’s birds. The case was a slam before causing symptoms? How accurate is the PCR test that dunk. “We linked the strains,” says Ganem. “We proved the birds Kistler produced? Can a vaccine be developed? in the second aviary caught the strain we saw at the first place.” Already, the veterinary research community is jumping in, The second breeder wanted the virus gone, the birds out; she with teams in Canada and Germany also finding ABV in dead needed to protect her flock. She asked Smith to quarantine the parrots. Any company can now license the technology that UCSF exposed birds. Kistler and Smith watched the birds for a few patented and commercialize a PCR diagnostic test. An accurate months, but Smith eventually euthanized all of them to search test could help eradicate PDD by identifying birds that need to be for virus in their tissues. quarantined. Though they were long-time friends, the two breeders no Ganem and DeRisi plan to back off PDD to focus on their longer talk. The second breeder, who eliminated the virus from work on achalasia and other human diseases. Ganem wants to her flock, also doesn’t want to be identified. “It’s one of those know if a virus like ABV triggers achalasia, the human disease things that can severely damage my reputation,” she says. “I’d eerily similar to PDD. To that end, he has obtained esophagus never sell another bird again.” biopsies from 10 patients, which he has begun scanning for viruses. A n swers Breed Questions Kistler, though, might just make a career of it. She’s looking DeRisi acknowledges that it is a complex situation. It’s a small for a faculty position at a university with a strong veterinary world and breeders are a close-knit community. “Maybe someday research program. “I’m going to work on it for a while,” she says. when birds have certificates of health, and you get a test result “There are a lot of interesting questions left unanswered.” W sn av i g With the cause of in the world. The last wild Spix’s, into the viral cause of PDD t h e a deadly viral spotted in Brazil in 2000, is might just save the species. After r a r e s t disease in hand, presumed dead. ¶ Veterinarians months of red tape wrangling, o f HHMI researchers at Al Wabra breed the powder DeRisi won approval to import b i r d s at UCSF and blue birds, and in 2008 the samples from the Spix’s. He colleagues have a chance to save compound’s owner bought a tract plans to run them through a a bird that exists only in captivity. of land in Brazil with plans to battery of tests to search for signs ¶ On a lush island of vegetation reintroduce the Spix’s there. But of avian bornavirus. If the tests in Qatar’s desert lies an ark of proventricular dilatation disease identify birds carrying the sorts, Al Wabra Wildlife (PDD) is stalling his plans. disease, the animals can be quar- Preservation. Owned by a Veterinarian Susan Clubb, a antined, reducing the risk to member of Qatar’s royal family, PDD expert, flew to Qatar and their flock-mates. “This is a case the park shelters 2,000 animals found the disease in several birds where finding PDD could make from 100 rare species—including (she won’t say how many). a difference in whether a species 50 Spix’s macaws, the rarest bird Ganem and DeRisi’s research survives,” Clubb says.

August 2oo9 | hhmi bulletin 25

Building Solid b y christine suh illu stration by paddy molloy Bridges Community college students interested in pursuing science are on surer footing, thanks to welcomed support.

August 2oo9 | hhmi bulletin 27 R yan dosumu- The funding for such programs comes government provides them with less than from organizations, including HHMI, the one-third of the funding that it gives johnson Virginia-based Jack Kent Cooke public four-year colleges, according to a had a big decision to make the spring after Foundation, the National Science report released in May by the Brookings his 18th birthday: apply for a promotion Foundation (NSF), and the National Institution. with RadioShack or enroll in classes at a Institutes of Health (NIH). These institu- Second, their students are not always community college. Though he came tional programs are experimenting with accepted at four-year institutions with from a well-educated family—his father is different formulas to see what it takes—in open arms. Harvard and Princeton a doctor and his sister a medical anthro- addition to financial aid—to find and currently do not accept any transfer pologist—in high school he barely eked nurture future scientists among the ranks students, says Emily Froimson, director of out a C average. But, craving an intellec- of community college students. higher education programs at the Jack tual challenge, he decided to give school Teasing apart the winning components Kent Cooke Foundation, a private organi- another try, and in the fall of 2003 he of these endeavors is no simple task. The zation that provides assistance to enrolled in classes at southern California’s strategies and goals are as diverse as the low-income students. At highly selective Orange Coast College. students, who often are from groups schools that do accept transfers, a shrinking This spring, Dosumu-Johnson faced an underrepresented in the sciences. But lots handful come from community colleges. altogether different kind of choice: enroll of close attention and advising for the A national study partially funded by JKCF in the joint M.D./Ph.D. program at students, plus a hands-on research experi- and published in 2006 found that, between Harvard University and the Massachusetts ence, appear to be essential. And for 1984 and 2002, the number of transfer Institute of Technology (MIT), or accept students like Dosumu-Johnson, these students accepted at elite institutions admission to the tri-institutional program efforts are well worth the investment. dropped from 10.5 percent of entering at Weill Cornell Medical College, “The range of student talent at commu- students to 5.7 percent. Rockefeller University, and Memorial nity colleges is extraordinary,” says Chris Those schools that do accept transfer Sloan-Kettering Cancer Center. Craney, director of undergraduate and students generally do so simply to make Clearly, school suited him just fine. sponsored research at Occidental College, up for attrition rates, and once accepted, Dosumu-Johnson’s story offers a lesson a four-year private college in Los Angeles. students often receive inadequate finan- to educators as they search for the next In the mid-1980s, Craney, a chemistry cial aid, according to Froimson. generation of scientists: don’t forget professor, started a summer research “That’s not a very proactive approach,” community colleges. program at Occidental for community she says. A handful of educators have built college students interested in science. At the same time, Froimson notes, “bridge programs” between community col- Over the years, he drew from a variety of research has demonstrated that high- leges and four-year institutions. The Bridges funding sources, including HHMI. He says achieving, low-income students are more to the Baccalaureate program that steered some of his best students transferred to likely to graduate if they attend selective Dosumu-Johnson toward a Ph.D. is based at Occidental via the research program. schools. the University of California, Irvine, and “It tapped a talent pool that’s often Chances are, many more will attempt includes an undergraduate summer overlooked,” he says. this route as families turn to community research program at the university. It’s one Two-year colleges have long been colleges to cut education costs for their of dozens of similar initiatives administered undervalued in two significant ways. First, baccalaureate-bound kids. Indeed, enroll- by four-year colleges and universities to help they lack federal support. Although ment in community colleges has swelled community college science students suc- community colleges serve nearly half the during the economic downturn, making cessfully transition to four-year institutions. undergraduates in the country, the federal bridge programs increasingly important

28 hhmi bulletin | August 2oo9 Dosumu-Johnson: Mark Harmel Gaines: Jeffrey Salter of what’s out there, of what’s available in in available what’s of there, out what’s of active weren’t they research scientists. but Ph.D.s, had he professors college where community His from stood. possibility a even was research scientific in career a that realize didn’t Dosumu-Johnson science, for tion not justmemorizefacts,hesays. science, understand to students lenged chal- and engaged they and passionate, were they matter, subject the knew They been really introduced toresearch. hadn’t but classes science altered hisgoals. figure out whether research is for them. engage students in science and toto help them Program directors say it’s an effective way to bridgeprograms is undergraduate research. componentsofcommon most the of One Chan A educational experience. inclusive and rich a students giving for an U c r F o o n

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Mendoza: Chris Jones Craney: Darcy Hemley the classes are offered only one semester of “I’ve lost students to Stanford—that’s “I was sure once I got here I could find the academic year—for example, Biology I not such a bad thing,” he quips. good opportunities, and it ended up being is offered in the fall and Biology II in the The program, which Gaines spear- true,” she says. spring. If students miss or have to retake headed in 1994, supports about 15 new Dosumu-Johnson says the UC Irvine one of the classes, they might not be in a students per year. Most complete bache- bridge program was largely responsible for financial position to wait another year for lor’s degrees in the sciences. More than a lighting his research ambition. In his final it to be offered again. quarter go on to Ph.D. programs, Gaines year at UCLA, he earned a spot in the Community colleges and four-year insti- says, and about 30 percent go to medical HHMI Gilliam fellowship program, tutions sometimes attempt to address school. which provides full support for up to five transfer issues with articulation agreements, Mendoza credits the Miami bridge years toward a Ph.D. for outstanding which are designed to make curricula the program for propelling her to New York students from underrepresented groups in same at the partner institutions. With the University, where she is working toward the sciences. exception of a few states, such as California, her Ph.D. in developmental genetics. She He could be working in retail—but this that have developed a well-oiled transfer had moved to the states from Venezuela in summer, he is on his way to becoming a mechanism, Packard says these agreements search of a science education and career. physician-scientist at Harvard and MIT. W can be signed and filed away with no follow-up—and no effect. Bridge program directors, like Mike F or the Profs Gaines at the University of Miami, go Though bridge programs focus on student development and assistance, heavy on the advising. Gaines makes a the University of Miami and Occidental College offer something for point of talking to students and their community college teachers as well. ¶ Miami hosts one faculty member teachers regularly. each semester in a research lab to keep the hands-on and inquiry aspects “I started seeing Mike [Gaines] as a of science fresh. Occidental, a private four-year college in Los Angeles, father figure,” says Mendoza. “He was has taken this idea a step further and recently made research by commu- really involved and always catching up nity college faculty a top priority. ¶ “There is good evidence in the with us.” literature that says if faculty stay active scholars, they are more effective Bridge partnerships like the one at teachers than those who rely on what they learned ‘X’ number of Miami–Dade College and the University years ago,” says Chris Craney, head of Occidental’s bridge program. of Miami make students’ transition from one to the other seamless by, for example, ¶ Chemistry professor Dennis Mitchell from Los Angeles City College making sure there is no room for uncer- says it worked for him. Last year, he became the first of two community tainty about transferring credits. college faculty members to receive support from Occidental’s HHMI “Both sides have totally bought in,” grant. Becoming a teacher, he says, didn’t mean he was done learning. says Carter Burrus, director of the honors ¶ “I talked to Chris and came up with my own project,” says Mitchell, college on Miami–Dade’s north campus. who studied the use of porphyrins for solar energy storage. “The amount Almost all the students who participate of insight you get [from research] is incredible. Chemistry is more than in the Miami bridge program—supported just what’s in the book.” ¶ This summer, Asmik Oganesyan, a chemistry by grants from HHMI, NSF, and NIH— instructor at Glendale Community College, became the second teacher transfer to four-year institutions, including to take advantage of the experience offered by Occidental’s program. highly selective colleges and universities, Her students are seeing the benefits. —C.S. Gaines says.

August 2oo9 | hhmi bulletin 31 proceedFor each man with prostate cancer, which treatment gets the green light? By Sarah C.P. Williams illustration By with the heads of state caution

32 hhmi bulletin | August 2oo9

antigen—is little help in predicting how a ters and grandkids, not deciding how to Valentine’stumor will progress. PSA levels can be just treat his cancer. as high in men with slow-growing cancers, or no cancer at all, as in men with aggres- Lots of Opinions sive tumors. Because doctors tend to err Foley’s diagnosis came after an annual on the side of caution, patients with PSA test, which men are encouraged to nonaggressive tumors are often treated the undergo beginning at age 50. A PSA of up same as those with more high-risk cancers. to 4 (measured in nanograms per milli- As a result, the value of the PSA test has liter) is generally considered normal. long been debated. Higher levels can be okay too, though—it D y2001, Jim Foleya learned he had prostate “It’s a major clinical challenge,” says varies from person to person. The rate at cancer. Suddenly, the 56-year-old engi- HHMI investigator Arul Chinnaiyan, at which PSA changes is often more indica- neer from a New York City suburb faced a the University of Michigan Medical tive than its level. The red flag for Foley daunting dilemma: What next? Though School. “We end up overtreating because came when his PSA rose from 4 one year he can explain the ins and outs of physicians can’t tell the difference to 10 the next. compressors and steam turbines effort- between these aggressive tumors and not- In December 2008, the New England lessly, Foley was clueless about prostate so-aggressive ones.” Journal of Medicine presented the case of cancer. He knew no one with the disease, With Chinnaiyan’s recent discovery of a 63-year-old man with rising PSA scores he says, and was unprepared for the lack of a gene that drives more than half of pros- and polled more than 3,000 doctors on clarity his diagnosis—and prognosis— tate cancers, however, and work by other how they would treat him. They were split offered. HHMI investigators, physicians may soon three ways: about 39 percent said they Of the roughly 190,000 men diag- have new tools to predict the course of would remove the patient’s prostate; about nosed with prostate cancer in the United prostate cancer and identify the most 33 percent would treat the tumor with States every year, many have slow- aggressive tumors. radiation; and about 29 percent would growing tumors that are unlikely to They’re developing new treatments, wait and monitor the patient’s PSA levels. spread. Without treatment, men with too, and Foley can attest to their success: With this lack of consensus, the deci- nonaggressive tumors will likely live for In 2008, during a recurrence of his cancer, sion often comes down to a gut reaction by decades and eventually die of something he was one of the first patients to enroll in an informed patient. Foley and his unrelated. But others will have cancers a clinical trial for a novel prostate cancer doctors—including oncologist Michael that spread to lymph nodes and bones. drug developed in part by HHMI investi- Morris at MSKCC, who became his Predicting, on initial diagnosis, which gator Charles Sawyers at Memorial primary prostate cancer doctor—weighed tumors are deadly is a matter of guess- Sloan-Kettering Cancer Center the options after considering his PSA levels, work for physicians. (MSKCC). Today, Foley’s cancer is in his age, general health, and MRI scans. The blood test used to screen men for remission. When he thinks “What next?” For Foley, an MRI technique consid- prostate cancer—called PSA because it he’s planning his retirement or his next ered experimental at the time revealed measures the level of prostate-specific trip to Virginia or Iowa to visit his daugh- that his cancer had already spread to his

34 hhmi bulletin | August 2oo9 seminal vesicles, so a course of radiation and hormone therapy seemed the best option. In his case, PSA was a valid warning sign that caught his cancer before it spread even further. PSA and scans leave others in the dark as to whether their cancer is growing and how aggressive treatment should be. There is a lack of useful diagnostic tests to classify a prostate cancer. In the near future, though, genetic Jim Foley (left) has battled prostate cancer several times with analysis of tumors may fill this void. the help of oncologist Michael Morris (right) and a clinical trial Chinnaiyan’s team studies genes that, that’s had him in remission more than a year. when rearranged incorrectly, cause prostate cancer. His research relies on a large genes in a sample—Chinnaiyan has cancers. But Chinnaiyan didn’t think bank of prostate cancer tissue samples at looked at the molecular signatures of hun- that was the best approach. Instead, he the University of Michigan. Using micro- dreds of prostate cancers. Traditionally, looked for genes that were expressed at arrays—a technology that can quickly researchers sort through such data by high levels in some, but not necessarily analyze the activity of massive numbers of looking for genes expressed in all the all, of the cancers. He calls these genes “outliers” and reasons that typical aver- aging techniques would cause scientists to miss them. His analysis paid off—it found parts of two normal genes that had been combined P rostate Pirates into one single cancer-causing “fusion gene” in about half the tumors he Like the liver and just a few other organs, the prostate gland has the ability analyzed. One of the normal genes was in to regenerate itself. In castrated mice, the prostate shrinks to a tenth of its a family of transcription factors; the original size. But giving the mice testosterone restores the prostate. HHMI proteins produced by these genes bind investigator Owen Witte, at the University of California, Los Angeles, directly to DNA and can activate cancer- thinks some prostate cancers may be co-opting the gland’s regenerative causing genes that are turned off in a properties. ¶ “The majority of cells in the gland require testosterone for healthy prostate. This “ETS transcription their maintenance but there is a group of cells that can survive in the factor” was fused with the on-off switch absence of testosterone and re-grow the whole organ,” explains Witte. He from an unrelated prostate gene—one has created numerous prostate cancer cell lines and mouse models that regulated by male hormones. So when- can report what genes and proteins are activated when prostate cancers ever this fusion gene came into contact grow. With the help of these tools, he is studying what role stem cell- with testosterone, a constant presence in the prostate, the ETS transcription factor related proteins in the prostate might play in cancers. He has found one was switched on and went into action protein—dubbed prostate stem cell antigen—in higher levels in prostate turning on other cancer-causing genes. cancers, a hint that cancers could be pirating the prostate regeneration Chinnaiyan’s work was published in system. By understanding how different molecules interact at different 2005; his fusion gene was the first to be points during prostate cancer growth, Witte hopes his research will lead to linked to prostate cancer, and the treatments to stop the tumors at their earliest stages. —S.W. discovery drew wide acclaim from the prostate cancer community. Chinnaiyan believes the fusion gene could lead to

Chris Jones treatments and, even sooner, to new ways

August 2oo9 | hhmi bulletin 35 36 hhmi haven’t been able to see the CTCs.” the see to able been haven’t we but bloodstream, the through spreads cancer that known always says. we’ve “Really, Haber blood,” her in cells tumor breast advanced cancer was found to have with woman a when 1800s, the to back the bloodstream. enter and tumors off break CTCs—that or cells, tumor circulating cells—called emergingtechnology todetect rare cancer an to turned he costly, and invasive often are tumors of biopsies repeated because and, cancers various in mutationsgenetic most other cancers. Haber wanted to study for also but cancer prostate for only not General Hospital, thinks blood holds clues investigator Daniel Haber, of Massachusetts types, unlike cancer PSA—is also on the horizon. HHMI differentiate potentially could cancer—which prostate of markers blood tests for PSA. monitordisease,to ofinstead alongsideor sarcosine levels, he says, for could be one way urine men’s Screening sarcosine production. boosts gene fusion ETS one Chinnaiyan, to According exists. called cancer prostate when metabolite elevated that’s a sarcosine urine, in cator gene canbemonitored inbloodorurine. the if cancer prostate track and detect to ere’s got to be something better than T right) right) have set their sights on finding it. finding on havesights their set

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investigators ( u b, b, C h ar l e s L. L. s S l a e wyers, wyers, ft to By July 2006, it was 13, higher than when than higher 13, Julywas By it 2006, rising. started PSA his therapy, hormone and treatment radiation finished after Foley day the to years five almost 2006, In them. to resistance evolve eventually cells cancer enterprising that is Casodex PSA tolessthan1. Foley’s lowered drugs the conjunction, so that the hormone itself cannot. Used in works by binding to testosterone receptors, Casodex while circulatingtestosterone, of fusion gene. gene; rogue fusion the off turns testosterone blocking cancer-causing the on the (in works turns causes)—testosterone it that cancers this why explains now Chinnaiyan by discovered gene fusion one way to treat cancer.prostate The ETS was cells on acting from hormones male thwarting that century known 19th late the since had Physicians prostate. the and in testosterone block to aim Both drugs—Lupron Casodex. anti-hormone common two cells and directed, it’s wherever cancerous kills which radiation, first the course of treatment for through his prostate cancer: went coming Foley 2001, In O new place and cause a metastatic cancer? a in lodge to likely more cells circulating ver The problem with Lupron and and Lupron with problem The amount the decreases directly Lupron R esistance

Haber: Darren McCollester / PR Newswire, ©HHMI Chinnaiyan: Don Alley / PR Newswire, ©HHMI Golub: Paul Fetters Sawyers: Liz Baylen / PR Newswire, ©HHMI he’d first been diagnosed. His doctor put receptor. One compound emerged: Between February 8 and 15, 2008, him back on the anti-hormone drugs, but MDV3100, a drug that blocks testosterone thanks to MDV3100, Foley’s PSA dropped the PSA dropped only slightly and then receptors, like Casodex, but blocks them from 22 to 12. In the next month it started rising again. earlier in their activity cycle—before they dropped to 2 and then a month later to “Essentially 100 percent of men who transition from being free in the watery less than 1. It’s been undetectable since, go on these drugs eventually develop resis- interior of a cell to being inside a cell’s and his lymph node tumors have all but tance to them,” says Sawyers, who turned nucleus and able to bind DNA. disappeared. He’ll continue on the drug his attention from drug-resistant leuke- By February 2008, Foley’s PSA had until it stops working, Foley says, which he mias to drug-resistant prostate cancers risen drastically—hitting 22—and his hopes is many years away. after developing a drug that overcame cancer spread to half a dozen lymph “When you first get those high resistance to the successful drug Gleevec nodes. He had just returned from a confer- numbers, you never think you’ll see low in leukemia patients. What happens in ence in California, where more than 700 numbers again,” says Foley. “But it just prostate cancers, Sawyers found in mouse prostate cancer patients met to share dropped like a rock. I was blown away.” models, is that cancer cells start overpro- stories, learn about how to live with their ducing testosterone receptors. There are disease, and hear about new treatment Making Predictions still trace amounts of testosterone in the options. “It was so encouraging to hear that Not all prostate cancers are the same. In the prostate, even when patients are being the fact that I had slipped into advanced clinical trial that Foley attributes with giving treated with Lupron. If the number of prostate cancer wasn’t a death sentence,” him a second life, some patients didn’t see receptors begins to increase, those tiny says Foley. “There were still treatments such dramatic improvements. Sawyers is amounts of testosterone eventually find that would allow me to keep going.” collaborating with Haber to determine free receptors and once again turn on When Foley returned to New York, whether there are different markers in the cancer-causing genes. Morris presented him with an alternative CTCs of patients helped by the drug versus Sawyers’ drug-hunting mind went to to chemotherapy: Sawyers’ MDV3100 was those who saw less improvement. They work. “What we needed was a new drug in clinical trials, and Foley qualified to be want to develop a rapid screening test to that’s not perturbed by higher levels of the one of the first patients to try it. He joined show who the drug might benefit. receptor.” So Sawyers’ lab made a cell line the trial—a dose escalation trial in which To complicate matters, there may be overexpressing the receptor and screened patients are put on increasing doses of the variety within a single patient’s cancer. it for compounds that would still block the drug and checked for side effects. “One individual might have multiple distinct cancers within the prostate gland that are independently arising,” says Todd Golub, an HHMI investigator at the N ow researchers must Dana-Farber Cancer Institute. Instead of one tumor that spreads, he hypothesizes, a cancer-ridden prostate could often have turn [C hinnaiyan’s separate tumors, each genetically distinct. “So if you sample one of these tumors,” discovery of the fusion Golub says, “it’s not necessarily going to be predictive of how the other ones are going to behave. The tumor you die of gene] into detection may not be the tumor that was biopsied and genetically analyzed.” methods, ways to monitor It’s a vexing problem—to analyze all these potentially different tumors in the prostate, the whole gland would need to the disease, and be removed, and then there would be no measure of which tumors grew. This situ- new treatments for ation is, in part, leading to dead ends in prostate cancer research, Golub believes. He’s collaborating with a group of prostate cancer. (continued on page 56)

August 2oo9 | hhmi bulletin 37 38 hhmi

A Prescri A bulletin for for rethinking

| Physici

uut 2 August oo 9

the Robert J. Alpern J. Robert F

college u ture ture

curriculum s n o i n i p o & s e v i t c e p s r e p p a t n ion ion s .

Derek Dudek A revolution in biomedical science has transformed medicine, yet premed course requirements have not changed in decades. Robert J. Alpern, dean of Yale University School of Medicine, served as co-chair with Sharon R. Long, former dean of Humanities and Sciences at Stanford University, of the 22-member Committee to Establish the Scientific Foundation for Future Physicians. Organized by the Association of American Medical Colleges and HHMI, the committee was charged with making recommendations to bring standard premedical and medical school curricula in line with the practice of modern medicine.

Why change medical school preparation for undergraduates now? For instance, undergraduates need much more prepara- The same premedical requirements have been in place for tion in statistics and the handling of large databases, yet the 40 years or more, and while many students have made it bulk of students take calculus, which is much less important. through the curriculum and gone on to become good physi- Similarly, biochemistry is so much more important for cians, others who could have become outstanding physicians medicine today than organic chemistry, yet it is not univer- have been held back. The courses are often too difficult or sally required in undergraduate programs. not interesting enough. They’re seen as barriers rather than opportunities to teach material in exciting ways. Organic Ultimately, won’t this come down to a specific set of courses chemistry in particular is perceived as the course that deter- or some other well-defined requirements a student will need to mines who should go into medicine, but we don’t want prepare for the MCAT [Medical College Admission Test]? course requirements to be the gate that keeps students out. The appearance of this report couldn’t have been better And the issue is larger than medicine. When premed timed because another committee is reviewing the MCAT. students are unhappy with required courses, all too often To be frank, the MCAT will define specifics of the compe- other undergraduates thinking about research careers tencies to be tested. Changes to the test will drive changes become dejected along with them. That’s driven many in the curriculum—they need to change together to bring aspiring scientists away. about reform. The critical element will be changing the MCAT and giving colleges enough lead time to rewrite The committee called for replacing premed course requirements courses to prepare students for the changed test. with what it terms “scientific competencies.” What do you mean by that? Changing undergraduate and medical school curricula Physicians today need to be scholars of science whether won’t be easy, will it? they pursue research or not. So we started out by defining We thought there’d be enormous resistance to the proposed specific competencies all physicians should attain in medical changes, but every medical school dean we surveyed was school. We then worked back from there to define the broader wildly enthusiastic. The same is true for most undergraduate competencies an undergraduate will ideally acquire before faculty. The students I have spoken with have all said, entering medical school, like applying quantitative reason- ‘Can’t you do it faster?’ Resource-rich schools are not waiting; ing and mathematics to describe phenomena in the natural they’re making changes already. With the help of HHMI world or explaining how biomolecules contribute to the and other organizations, we want to make sure less wealthy structure and function of cells. colleges have the resources they need to make the changes. For medical school applicants, competencies might be Underrepresented minorities come disproportionately from achieved through a variety of courses or educational experi- those schools, and we don’t want to cut off that pipeline of ences. We want to give colleges freedom to teach in the future doctors and researchers. most interesting ways they can. This will make the courses Realistically, it will take at least five years and some say more relevant for undergraduates interested in medicine ten to have every student arrive at medical school with the and biomedical science in general and bring students to competencies we’d like. It’s not going to happen overnight, medical school better prepared to learn the science they’ll but when it does, I think it will represent a major transfor- need throughout their careers. mation in medical education.

I n t e r v i e w b y M a r c W o r t m a n . A physician-scientist, Robert Alpern focuses his research on the regulation of kidney transport proteins. The AAMC-HHMI report, published in June, is available at www.hhmi.org/grants/sffp.html.

August 2oo9 | hhmi bulletin 39 40 hhmi

nter nter C bulletin the the e

uut 2 August S oo 9 y I Mark Davis Mark stem m mune mune S t s n o i n i p o & s e v i t c e p s r e p a g e: e:

Mark Likosky The field of immunology is stuck in the lab and needs a major overhaul to become more relevant to human health, says Mark Davis, an HHMI investigator and immunologist at Stanford University. He argues that now is the time for large-scale human studies of the immune system—a human immunology project.

The immune system is one of our major health systems and years of evolution separate mice and men, a vast divide. is just as important as our cardiovascular system or nervous Researchers can regularly cure cancer and autoimmunity in system. If your immune system goes haywire, you’re in deep mice, but almost none of those cures work in people. trouble. But for many years, the immune system has been a Here’s one example: Recently, an antibody developed as black box. That situation has now changed dramatically over an antitumor therapy showed outstanding results in laboratory the past few decades in that enormous progress has been mice, leading to human trials. But after hundreds of millions made in basic immunology. But unfortunately, very little of of dollars and two large human studies, only 14 percent of this knowledge is being applied medically. After decades of patients showed any benefit. Everyone involved with this study, immunologists still can’t define what constitutes a therapy had great hopes for it. But it’s been very disappointing, healthy human immune system. and it’s unclear if the Food and Drug Administration will We know a lot about what the immune system can do ever approve the drug. Dozens of similar examples litter the and should do, but no one has put together a test that can drug development landscape. identify whether a patient’s immune system is working Part of the solution is that some of the money spent on correctly. Such a test would be more complicated than, say, mouse research should be funneled into explicating the a cholesterol test, but it would serve a similar vital function: differences between human and mouse immunity. Defining providing clinicians with an easy-to-understand readout of this gap would be incredibly valuable. Another part is to the health of the patient. That way, trouble could be spotted begin a human immunology project focused on defining early and interventions taken when necessary. Cholesterol immunological health, taking some important cues from the tests are a good model because they’re proactive. We need a human genome project. In the 1970s, human genetics was similar, proactive test for immune function that lets physi- a very limited field with almost no ability to inform medical cians and patients know when a big problem lies ahead. care. But after a huge investment in sequencing and If such a test were developed, it might help reduce the cataloguing the human genome, genetics is now at the burden of the almost 90 known autoimmune diseases and center of the search for cures. the 120 known immune deficiency diseases. More recently, A large-scale human immunology project could work immune dysfunction has been found to play a role in big similar wonders. Such a project would focus the field on killers such as Alzheimer’s disease and atherosclerosis, the human, instead of mouse, immunology. The project would inflammation and hardening of the arteries that causes heart create or ease access to large banks of blood samples from disease. These diseases could be handled better if we had a clinical trials. And it would encourage researchers to mine deeper understanding of how the human immune system these large samples for critical information on immune works and what goes wrong with it. function in healthy and ill people. Much of the lack of progress in human immunology is As a step toward that goal, I’ve helped organize the due to the tremendous success of inbred mice as a scientific Human Immune Monitoring Core at Stanford. Clinicians model. As a result, the whole field is severely tilted toward running human trials are encouraged to send patient samples studying mice, with some 80 percent of articles published in to the facility, where we can collect data across patient popu- immunology journals involving rodents, not people. Yet the lations. We also aim to combine data from dozens of such mouse is a poor clinical model. studies to learn a lot in a hurry and to uncover previously Sure, the thousands of immunology studies conducted on unrecognized similarities between diseases. mice have provided, and continue to provide, major insights More projects like this are needed. Immunology has into how the mammalian immune system functions. Yet mice always held the potential to be clinically useful across a broad aren’t people, and the mouse immune system does not accu- spectrum of devastating diseases. But it’s going to take a rately mimic the human immune system. Sixty-five million serious rethinking of the whole field to achieve that potential.

I n t e r v i e w b y B r i a n Va s ta g . Mark Davis is director of the Stanford Institute for Immunity, Transplantation and Infection.

August 2oo9 | hhmi bulletin 41 Q & A What is an example of evolution at its finest, when an elegant efficiency is selected over time, that you’ve come across in your research?

There are countless examples of how natural selection explains not only how entire organisms evolve but also how the organs, behaviors, and intricate molecular parts within an organism have been perfected over time.

—IE E D T D B Y S a r a h C . P. W i l l i a m s

T anya T. Paull E rich D. Jarvis C atherine L. Drennan C arlos D. Brody HHMI Invest i g at o r HHMI Invest i g at o r HHMI Invest i g at o r HHMI Invest i g at o r U n i v e r s i ty o f T e x a s D u k e U n i v e r s i ty a n d P r o f e s s o r P r i n c e t o n U n i v e r s i ty at A u s t i n M e d i c a l C e n t e r M a s s a c h u s e t t s I n s t i t u t e “The brain is clearly a o f T e c h n o l o g y “I think the perfect micro- “A remarkable example of marvel of evolution: using “The class II ribonucleotide cosm of efficient evolution evolution at its finest is that only some 20 watts, it seems reductase (RNR) from is the virus. A virus uses of song and spoken language to effortlessly accomplish Lactobacillus leichmannii every nucleotide of its in birds and humans. myriad tasks that we cannot is a perfect example of evo- nucleic acid, sometimes Human language is often yet imitate using our fastest, lution. RNRs are proteins many times over, to store all considered a pinnacle of biggest, and most energy- essential to all organisms— the information it needs in evolution, a source of our hungry computers. But is it they help make DNA. In the smallest space. A virus civilization, and a final an elegant, perfect example higher organisms and many can change over the course frontier of science. But of evolution? Most experi- micro-organisms, RNRs of many years to reproduce humbling to me, we find ments reveal an extremely work together in complexes, successfully in its host that the required brain noisy, bewilderingly com- with two or more proteins but also has the ability to pathways and associated plex thicket of interacting attaching to one another to change during the course genes in distantly related components. It is easy to do their job. But for some of a single infection to song-learning birds and in imagine the brain as a Rube micro-organisms, simplicity suppress a host’s defenses. humans have undergone Goldberg device, chock-full is the key to life. L. leich- The random changes that a remarkable parallel of irrelevant peculiarities mannii has an RNR that are constantly introduced evolution. In both, the picked up through a long has neatly evolved to do into the virus genome show pathways appear to have evolutionary history. But I its job with only a single us that the virus has evolved evolved similarly multiple don’t think so. I prefer to molecule of protein present. to evolve—one of the best times using an old trick believe that the brain holds We recently showed that examples of the power of similar to gene evolution: hidden elegance that we this single RNR chain works natural selection that exists the duplication and then are working to reveal.” in nature.” modification of existing because it contains a helix- brain pathways involved in shaped structure that typical learning.” RNR proteins can form only when joined together. This simple RNR in L. leichman nii is a perfect example of evolution.” Paull: Jack Plunkett / AP, ©HHMI Jarvis: Jonathan Fredin / AP, ©HHMI Drennan: Robert E. Klein/AP, ©HHMI Brody: Christopher Barth / AP, ©HHMI

42 hhmi bulletin | August 2oo9 CDC Public Health Image Library ota Bene ota 54 oolbox 52 Scientist a sk 51 Book ab 48 News nstitute 46 Education cience 44

they mature into adults and reproduce (see page 49). page (see reproduce and adults into mature they before them kill to aims drug new a but tricky, is parasites of the rid Getting disease. causing and reproducing, intestines, small the in burrowing eventually foot, bare human’s a through millimeter-long This Award Dimes of March Share Kunkel and Campbell Friedman to Goes / Prize Shaw Sciences / of Academy National to TenElected N DNA Sticky T coughing? or speaking as same the it Is laugh? we do How A Off-Switch the Finding Around Worming / More No PowerOne of The / L Bearn G. Alexander – Memoriam In Fellowships Postdoctoral / Doubles HHMI Housing / Campus Expand Farmto Janelia I H / Scientists Next-Generation S HMI Gives Research Training Awards Training Research Gives HMI Strongyloides Strongyloides

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bulletin 43 science education

Since 2003, EXROP has placed 359 students from 97 colleges and universities in the labs of 130 HHMI investigators and HHMI professors. The hope is that students who experience the excitement and intensity of a top research lab and see other students like them doing the same thing will be inspired to one day become academic scientists—and serve as examples for others. “I’ve experienced the positive impact Next-Generation Scientists that highly talented faculty from diverse Expi er encing the realities of a research lab backgrounds can have on students can be life-altering for some students. in science departments,” says Peter J. Bruns, HHMI’s vice president for grants When Shearman Jabari M i ller looked around the biology and special programs. “We desperately need more professors like department during his undergraduate years at Georgia State that, and EXROP is part of that effort.” University, he saw mostly white and Asian faces among the graduate So far, 189 EXROP students have completed their undergrad- students, postdocs, and professors. uate degrees. Of those, 93 percent are still in science: 38 percent But this summer the graduating senior and biology major, who are pursuing a Ph.D. or M.D./Ph.D., and 29 percent an M.D. The is African American, took a step toward changing that picture, remaining students are working as research technicians or science through HHMI’s Exceptional Research Opportunities Program teachers, or are studying for a master’s degree. (EXROP). EXROP’s talent scouts, as Bruns calls them, are the direc- EXROP gives undergraduate students from groups underrepre- tors of HHMI’s undergraduate grants at colleges and universities sented in the sciences or from disadvantaged backgrounds a chance across the country. They identify top students who could someday to work in some of the world’s top research labs run by HHMI become academic leaders and who are ready for the challenge of investigators and HHMI professors. Miller was one of 62 students working in an intense research environment, both academically selected this year to participate in EXROP, the largest group in the and emotionally. program’s seven years. The program is popular among the HHMI lab hosts. Every year, “Jabari has enormous potential as a scientist, and yet he has more of these high-profile scientists volunteer to host students than never been exposed to the kinds of opportunities that are available,” are needed. says Barbara Baumstark, a biochemist at Georgia State and the EXROP students Jabari Miller (right) and Alexandra Boye-Doe (left) HHMI program director who nominated Miller for EXROP. “Now shared stories with former EXROP student Ana Cristancho (center)

he will be.” at a program meeting at HHMI headquarters last May. Paul Fetters

44 hhmi bulletin | August 2oo9 science education

HHMI Gives Research Training Awards

I n 1985, the H o wa r d H u g h e s M e d i c a l I n s t i t u t e first gave medical students the chance to spend a year working in a research lab on the Bethesda campus of the National Institutes of Health (NIH). Twenty-five years and more than 2,000 students later, HHMI remains committed to encouraging medical students, including dental and veterinary students, to hone their scientific skills and prepare for possible careers in research. This year, 112 students from 44 institutions will spend a year in the laboratory, either at the NIH through the HHMI–NIH Research Scholars Program or at a research center anywhere else in the United States through the HHMI Research Training Fellowships Program. This year, HHMI has joined in a partnership with the Ben and Catherine HHMI President Robert Tjian has hosted three EXROP students Ivy Foundation to support four HHMI–Ivy research at his University of California, Berkeley, laboratory. “Working in training fellows who are studying glioma, a deadly and a lab as a college sophomore really is the thing that got me into incurable brain cancer. science, so I can’t imagine a more interesting pathway for students “These programs give the students a chance to understand what real research is about,” he says. “And EXROP is to immerse themselves in research,” says Peter J. special … You could be anywhere, and if you show some promise Bruns, HHMI’s vice president for grants and special you could end up in one of the best labs in the world.” programs. “For many, this will be a pivotal experience Miller, 22, is just one of those students. Inspired by Bill Nye the that helps them decide whether to pursue a career in Science Guy, Miller grew up loving science, but his high school in research.” And many do: nearly 45 percent of alumni Atlanta didn’t provide many opportunities. “We didn’t really have are still doing research 15 years or more after partici- any labs, just bookwork,” he explains. pating in the scholars or fellows program. Despite that, Miller decided to major in biology at Georgia Scholars and fellows who pursue an academic State. Though he struggled through required physics and chem- research career have a chance for more HHMI istry courses, his professors recognized his talents and recruited him support. Since 2006, former fellows and scholars have into an HHMI-sponsored biotechnology program. He worked in a been eligible for Early Career Physician-Scientist research lab studying how bacteria change their genes in response awards, grants totaling $375,000 over five years. to the environment. That experience lit his fire. The funds help these researchers set up their labs In June, Miller joined the lab of HHMI investigator David and commit to science at a vulnerable time in their G. Schatz at the Yale School of Medicine, who studies how the careers, when many are pushed to abandon research immune system makes antibodies that fight invading pathogens. so they can spend more time seeing patients. Schatz has hosted three previous EXROP students, all of whom More than 50 physician-scientists have received have gone on to graduate school in some field of science. “These HHMI support through the program. And it appears are serious kids who want to learn and want to make a difference, so to be working—among the 2006 award recipients they come in ready to work,” Schatz says. “They have been fun to half of them later successfully competed for an RO1 work with and they have been productive.” award, the NIH’s main research funding vehicle. This The EXROP program has almost doubled in size since its year, 11 new early career physician-scientists from beginning, and the Institute continues to consider ways to grow the seven institutions were chosen, with research inter- program while maintaining the factors that make it successful. ests ranging from cancer to obesity to autoimmune Miller says he was excited to have the opportunity this summer diseases. W – A n drea Widener to learn a new subject and new techniques, and to meet people who have the same interests and background. “I used to hate school,” FOR MORE INFORMATION: To learn more about the new HHMI–NIH says Miller, who is beginning a master’s degree program in biotech- research scholars, visit www.hhmi.org/news/20090507scholarsfellows.html. For more on the new early career physician-scientist awardees, go to nology at Georgia State this fall. “Now I can’t get enough of learning www.hhmi.org/news/ecps20090707.html. about biology.” W – A n drea Widener

August 2oo9 | hhmi bulletin 45 46 hhmi L. Waters, whose Broad Run District encompasses the Janelia Janelia the campus. Farm encompasses District Run Broad whose Waters, L. Lori Supervisor County scientists Loudoun for says goal,” that in us housing help will Expanding community. our in home and at welcome feel them making requires County Loudoun and one apartments. include of floors will three and it parking covered of floor building; research nearby the of shape the echoes that design curved slightly a have will building four-story The Farm. Janelia to entrance main the near building, research the of southeast just lies that campus the of portion a on building Farm’sdirector. Janelia Rubin, Gerry nity,”says commu- research vibrant a building and world the around from candidates talented most the recruiting in element important an is housing on-campus of expansion result, a As laboratories. their to close living on value high a place they and time of period short late for planned is September. early or project August the for career breaking early Ground other and scientists. researchers, postdoctoral students, uate grad- of recruitment the support will apartments one-bedroom 60 a h The Virginia. Ashburn, in Campus Research Farm Janelia the at i m h h Janelia Farm to Expand Campus Housing wall. corridor interior the along located be will areas, kitchen and bath, storage, as such functions, Core wall. exterior the along spaces living loft-like for allows layout horizontal The areas. living in light natural the maximizes that design wide long, a incorporate drawing architectural this in units residential individual The institute news institute “Attracting the best and brightest graduate scientists to HHMI HHMI to scientists graduate brightest and best the “Attracting 80,000-square-foot an in located be will apartments The relatively a for us with are postdocs and students “Graduate

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develop al u o h l na o i t i d d a p o l e v e d o t s i g n well as postdoctoral researchers and graduate students. students. graduate and researchers postdoctoral as well as countries 15 from the scientists visiting 100 anchor and who program research heads laboratory 33 scientists—including 240 approximately to home is campus The analysis. data and imaging for technologies new of development the and behaviors complex enable to together work cells brain of networks how studying tists for scien- environment Farm research an interdisciplinary provides project costs. building related and apartment the finance to bonds tax-exempt in million $21 to up for Authority Development Industrial County tists who typically come to Janelia Farm for short-term collaborations. scien- visiting for intended apartments—are multibedroom 32 and studios21 of mixunits—a Those plan. campus original the of part nearby. located be will spaces parking handicap and Visitor areas. common plus residents, to dedicated an spaces with parking covered ones 61 include will larger complex The 12 den. added and units one-bedroom ments—eight and project. the design build to selected were D.C., Washington, of Architecture Opened in 2006 as HHMI’s first freestanding campus, Janelia Janelia campus, freestanding first HHMI’s as 2006 in Opened Loudoun the with application an submitted has HHMI as developed village housing the augment will apartments The apart- 20 contain will floors residential three the of Each WDG and Group Construction Dietze Ashburn-based W

WDG Architecture HHMI Doubles Postdoctoral Fellowships h h m i announced in June that it i s from universities across the country—based Each fellowship will have a three-year increasing support for outstanding postdoc- on its own criteria. The foundations focus term. Start dates will vary, but most of the toral researchers through expanded on basic biomedicine, general life sciences, new funding will take effect in 2010. When collaborations with four foundations. Since and cancer research. the initiative is at full capacity, HHMI 2007, HHMI has supported four postdoc- “These organizations consistently select will be supporting 96 postdoctoral fellows toral fellows a year through the Jane Coffin outstanding scientists for their prestigious through this program at an anticipated Childs Memorial Fund, the Helen Hay fellowship programs, and this support annual cost of about $5 million. HHMI Whitney Foundation, the Damon Runyon comes at a critical moment in the young separately funds postdoctoral associates at Cancer Research Foundation, and the Life scientists’ careers,” says HHMI President the Janelia Farm Research Campus. Sciences Research Foundation. The new Robert Tjian. “We are pleased to expand “By expanding its funding for this initiative doubles the number of fellows to our partnership as well as the funding program, HHMI will enable these organiza- eight per organization each year. needed to develop and nurture some of tions to offer 32 additional fellowships each As is already the case, each group will the most talented among a new generation year,” says Jack E. Dixon, HHMI vice presi- competitively select candidates—who come of scientists.” dent and chief scientific officer. W

In Memoriam Alexander G. Bearn 1923–2009

Former HHMI Trustee, Alexander G. Bearn, a distinguished brain. He also demonstrated that the disease was associated with physician, scientist, and author, died May 15, 2009. He was 86. decreased function of a blood protein that binds copper. Bearn served as a Trustee of HHMI for 18 years, from 1987 to After nearly 30 years in academic medicine, Bearn joined 2005, providing wise counsel and thoughtful guidance during a Merck & Co. as senior vice president for medical and scientific period of sustained growth and transformation for the Institute. affairs of its international division from 1979 to 1988. Born in England, Bearn received his M.B., B.S., and M.D., In addition to serving as a Trustee of HHMI, Bearn was a degrees from the University of London. He came to The Trustee of The Rockefeller University, the Helen Hay Whitney Rockefeller University in 1951 and in 1966 moved next door Foundation, and the Josiah Macy Jr. Foundation and was an to The New York Hospital, where he served for 11 years as overseer of The Jackson Laboratory. In recent years, Bearn physician-in-chief and as chairman of the Department of wrote biographies of three scientists: Archibald Garrod, Sir Medicine for the Cornell University Medical College. He Clifford Allbutt, and Sir Francis Fraser. founded the first human genetics laboratory at the Medical Bearn was a member of the National Academy of Sciences, College and, with colleagues at Rockefeller, initiated the joint the Institute of Medicine, the Harvey Society, and the American M.D./Ph.D. program at the institutions. Society of Human Genetics. He was also a member of the An expert on the genetics of rare metabolic diseases, Bearn American Philosophical Society and served as the organiza- defined the genetic nature of Wilson’s disease—an inherited tion’s vice president from 1988 to 1996 and then as executive disorder that causes copper to accumulate in the liver and officer from 1997 until his retirement in 2002.

August 2oo9 | hhmi bulletin 47 lab book

The Power of One Atingl er a single neuron causes a surprisingly sweeping change in the rat brain.

Maybe the flapping of a butterfly’s wings in Brazil can’t really cause of the individual.” There are a tornado in Texas, but this whimsical idea may be an apt analogy for 100 billion neurons in the how the brain works. Perturbing one single neuron, HHMI human brain, she points out, researchers have discovered, can change the electrical landscape of with only weak connections the whole brain. between them. But with Yang Dan, an HHMI investigator at the University of California, each neuron connected— Berkeley, didn’t set out to show this. She wanted to probe how the albeit weakly—to thousands strength of connections between neurons changes over time. So she of other neurons, a signal

and her colleagues set up an experiment: they would activate single can spread like wildfire. The frequency of brain waves sets neurons one at a time in a rat brain and then measure local connec- Why activating a single two states of the brain apart. tions from nearby neurons. neuron would cause such a They found that instead of just tweaking how it interacted with drastic change throughout the entire brain, Dan can’t fully explain. other nearby neurons, activating any one neuron flipped the anaes- “So far what we have is a fascinating observation,” she says, “but in thetized rat’s entire brain between two states. In one state, which terms of explanations we only have speculation.” resembles deep sleep, brain waves are slow and synchronized Dan’s research, published in the May 1, 2009, issue of Science, throughout the brain. In the other state, which resembled rapid eye suggests that the cortex—the part of the brain where her team was movement (REM) sleep—a less deep state of sleep—neurons were perturbing neurons—plays an important role in controlling the less synchronized and fired faster and more often. The flip worked in state of the brain. Previously, scientists had focused mostly on other both directions. areas—the hypothalamus and brain stem. To further flesh out the “This is surprising,” says Dan, “because it shows that the weight issue, Dan hopes to study rats that are awake, rather than anaesthe- of a single neuron is so much greater than we thought. It’s the power tized. W —Sarah C.P. William s

I N B R I E F

Heartbeat to Heartbeat that did just that. The compounds, it the soil-dwelling and in the human The first beats of an embryo’s heart do turned out, also increased blood flow, pathogen versions of the bacteria. They more than pump blood, HHMI investiga- corroborating Daley’s observation. Since identified one protein—SigB—that controls tors George Q. Daley and Leonard I. Zon, then, Zon has discovered drugs that allow genes Listeria use to adapt to the intes- both of Children’s Hospital Boston, have developing zebrafish embryos that lack a tines and another protein—PrfA—that shown. The force of the beating heart trig- beating heart to produce blood cells. helps the bacteria survive in the blood. gers production of blood stem cells, which Daley’s results appear in the June 25, The bacteria switch between expressing give rise to new red and white blood cells. 2009, issue of Nature and Zon’s results are SigB and PrfA, depending on which The effect can be mimicked with drugs, in the May 15, 2009, issue of Cell. surroundings they sense. the researchers also discovered. More surprisingly, the scientists found Daley first noticed in 2001 that Listeria’s Two Sides that some of the genes important to the streaming a fluid across embryonic stem With the flick of a few genes—some on, switch don’t code for proteins—they are cells compels them to develop into blood others off—the bacterium Listeria monocy- small noncoding RNAs. They also discov- cells. A later collaboration—with a scientist togenes can turn from a harmless soil ered long antisense RNAs and other RNA who invented a system to expose cells to dweller into a dangerous human pathogen. elements that highlight new regulatory different degrees of fluid flow—helped HHMI international research scholar Pascale mechanisms in bacteria. The findings Daley take a closer look. They put embry- F. Cossart has made headway into under- appear in the June 18, 2009, issue of Nature. onic stem cells into the setup and showed standing this transformation by investi- that when fluid flowed over the cells with gating what parts of its genome Listeria Ultraviolet’s Cellular Killer the same force as blood in a developing expresses in different environments. When a cell is exposed to ultraviolet radia- heart, blood stem cells formed. Cossart, at the Pasteur Institute in Paris, tion from the sun, two things can happen: Meanwhile, Zon was looking for compared Listeria grown in the lab with the cell can stay alive but accumulate DNA compounds that boost the production of bacteria from the intestine of Listeria- mutations that may lead to cancer, or the blood stem cells within bone marrow, to inoculated mice as well as bacteria from inoc- cell can sacrifice itself, preventing the treat patients with weak immune systems ulated samples of human blood. Her team spread of the possibly cancer-causing or blood diseases. To test thousands of also compared normal bacteria with bacteria mutations. An HHMI researcher has unrav- drugs for whether they increase blood cell genetically altered to be less virulent. eled the molecular pathway that leads a production, Zon used a technique that The analysis turned up many surprises, cell to head down the self-sacrificing path. stains new blood stem cells purple. In says Cossart. First, they revealed that Alberto R. Kornblihtt, an HHMI interna- 2007, his team found a class of compounds different groups of genes are expressed in tional research scholar at the University of PHANIE / Photo Researchers, Inc

48 hhmi bulletin | August 2oo9 No More Worming Around Dsruptingi a worm’s life cycle could be the key to ending parasitic infection.

The trick to killing roundworms—such as hookworms and thread- their metabolism low until they sense a friendly environment inside worms, which infect humans—may be to force the parasites to a host. Taking hints from the C. elegans pathway, Mangelsdorf and grow up too quickly. HHMI investigator David J. Mangelsdorf his collaborators treated the iL3 parasites with dafachronic acid. It discovered that the molecular pathway governing how the harmless forced the worms out of their infectious state but not fully into the roundworm Caenorhabditis elegans exits a hibernation state next life cycle stage—the worms died before they could reproduce, controls the transition between life stages in many parasitic worms. the team reported in a Proceedings of the National Academy of He’s figured out a way to intervene in that pathway and kill larvae— Sciences article that appeared online on June 2, 2009. something existing drugs can’t do. The current drug of choice to kill S. stercoralis targets adult In 2006, Mangelsdorf’s team at the University of Texas parasites—eggs and larvae inside Southwestern Medical Center at Dallas identified molecules— the host remain viable. Using dafachronic acids—that bind to DAF-12, a receptor involved in C. dafachronic acid to force larvae elegans longevity. They found that the receptor is a checkpoint for out of their infectious state and worms exiting dauer diapause—a dormant state that C. elegans kill them could end the hard-to- larvae enter when they perceive low temperature, crowding, or a lack stop cycle, says Mangelsdorf. His of food. When the worms sense more favorable times, they produce lab is screening synthetic dafachronic acids, which activate DAF-12, ending dauer diapause by compounds for drugs that could turning on genes involved in reproduction and food metabolism. mimic dafachronic acid’s effects Mangelsdorf’s group has now shown that the parasitic worm and is looking more closely at Strongyloides parasites increase Strongyloides stercoralis, among others, also has DAF-12. While the biochemical pathways that their metabolism and express these parasites don’t enter dauer diapause, they do go through a DAF-12 controls. W a whole new set of genes once they’ve entered a host. similar dormant stage. So-called stage 3 infective larvae (iL3) keep —Sarah C.P. William s

I N B R I E F

Buenos Aires and the National Research deadly—cancers that have spread, or metas- jumbled mess, but each cell must be in the Council of Argentina, zapped cells with a tasized, from one area to another account right spot at the right time for an organism strong form of radiation, called UV-C, for 90 percent of cancer deaths. HHMI to develop correctly. Faulty cellular orien- which is normally blocked by the ozone investigator Joan Massagué, of Memorial tation can lead to problems such as spina layer. He and his collaborators looked Sloan-Kettering Cancer Center, has bifida, polycystic kidney disease, and inside the cells to determine how the radi- published the first account of just what it metastatic cancer. Two genes that help ation affected gene expression. takes for breast cancer to invade the brain. cells determine their orientation have now The UV radiation affected many genes, Massagué implanted tumor cells from been identified by HHMI international among which were two genes involved in an advanced breast cancer patient into research scholar Jeffrey L. Wrana. The apoptosis—cell suicide. The messenger mice. His team then isolated cells that genes—Smad ubiquitin regulatory factors, RNAs from the genes, Bcl-X and caspase-9, spread to the animals’ brains. They found or Smurfs—help cells move and distin- can be spliced into two forms—one that 243 genes expressed at abnormal levels guish front from back as well as top from promotes cell suicide and one that blocks it. and narrowed them down to 17 by looking bottom. The UV-C caused the switch from the form at their activity in clinical tumor samples. Wrana and his colleagues at the that keeps cells alive to the form that kills Knowing which genes allow a cancer to University of Toronto genetically engi- cells. Even in cells missing a protein that spread may help doctors predict how neered mouse embryos that lack the two normally triggers the switch in Bcl-X and in likely an individual patient’s tumor is to Smurf genes and observed what caspase-9, the UV-C was enough to make metastasize and could lead to targeted happened. The embryos failed to develop the change. The team further explained drugs. Already, Massagué’s group has correctly—appearing short and wide how the switch was made, and their results discovered that patients with breast when they should have been long and thin appear in the May 15, 2009, issue of Cell. cancer expressing some of the 17 genes and improperly forming the tube that Kornblihtt plans to repeat the experi- are more likely to experience brain metas- becomes the spinal cord. The anomalies ments with UV-A and UV-B, the lower tases. The research appeared in Nature on didn’t stop there: hair cells in the inner ear, energy forms of UV radiation, which are June 18, 2009. The researchers hope to normally organized neatly, were scattered the reasons we slather on sunscreen. further characterize the roles of the genes in all directions. within the cancer cells. To explain how Smurf genes control a Th e Breast–Brain Barrier cell’s sense of space, or polarity, the It takes a special set of skills for breast From Side to Side researchers looked for other proteins that cancer to spread to the brain and grow into To the untrained eye, the mass of cells interact with Smurf gene-encoded a new tumor. The spread is slow, but that make up an embryo may look like a proteins. They found two, the team reports Dr. Mae Melvin / CDC Public Health Image Library

August 2oo9 | hhmi bulletin 49 50 hhmi zoom in on an ideal drug target. drug ideal an on in zoom researchers let genes Huntington’s of sequences the Gathering onlyexists that target drug a find tounableResearchers beenhave elusive. been has gene and one cure healthy version that allows for limited motor genetic function. a Huntington’s 1993, patients have one abnormal version of in the discovered was neurodegenerative disorder that causes jerky, random movements— disease—a Huntington’s causes that mutation gene the Although KING B Finding theOff-Switch p ati l lab book lab F E I R B N I o types of promoters, with 20 in each set. set. each in 20 with two promoters, of of types parts libraries created these They use together. to how for guidelines create off—to and on turn to when genes tell which promoters, parts—gene of set one test and create to out set colleagues his interact.and will differentCollins parts how predicting is network biological new play” and a “plug parts. developed generate to has strategy at University, Collins, J. Boston James investigator of HHMI process the systems, new into together in parts putting time some save To together. pathways—work signaling and proteins, cells—genes, of parts how about more understand scientists as easier gets that one it’s But task. difficult consuming, Play time- a is and purposes, study for laboratory, the in systems biological novel Creating Pl on onesideofthecell. they proteins the of one destroying imbalance, by found, necessary this create cell. a of sides opposite on of issue 2009, twoproteinshealthycells,the accumulate 17, April the in

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Nature . It was far rarer in healthy copies of the gene—either Current Biology The results were published online, on on online, June published were results The needed. when only expressed are genes that ensure tags These them. unwrap to when cell the telling likely tags, different needed in development, the histones carry are genes the when on Depending sperm. onic development are bound to histones in embry- in needed genes of number a that found He proteins. protamine to bound was DNA was which and proteins histone which to bound analyzed and donors human from sperm used Cairns mation, roledevelopmental passing along in infor- when to express various genes. sperm about information much mature along pass don’t that hinted finding tighter. This even DNA the protamine, compacts which protein, different a around ping around histones, wrap- DNA primarily winds than rather sperm, mature in that the around histones iseasierfor acell to access. wound loosely more histones— that’s of DNA DNA. for form spools form that the proteins in zygote the to information along passes sperm a that if the only difference from the healthy copy healthy the differencefrom only the if To test whether histones still played a played still histones whether To test noticed had researchers Previously, Universitythe of Cairns, foundUtah, of

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How do we Laughing, speaking, and coughing all suddenly rush outward. This rush of originate at our larynx, or “voice box,” air is a cough. laugh? Is which serves as our primary sound Another, less-well-understood reflex it the same producer. It contains paired vocal is the hiccup; the respiratory muscles cords that vibrate when air passes over pull in air, but the vocal cords slam as speaking or them. When we’re quietly breathing, closed, resulting in the “hic” sound. our vocal cords are completely open. Laughter is probably the least coughing? Completely closed vocal cords stop understood airway-related reflex. The airflow. Slightly open vocal cords cause mechanics are simple, but why we Adrienne, a high school student from California exhaled air to pass through very quickly, laugh is more mysterious. The sound of which makes a vibration that we shape laughter happens when we are exhaling with our mouth and tongue to create and the vocal cords periodically close. speech. By adjusting the tension on the As they get close together, laughing vocal cords, we can adjust our pitch. occurs. Periodic activation of the respi- Stretching out vocal cords creates a ratory muscles produces the rhythmic higher pitch—like tightening the string airflow that helps make the sound. of a violin. Everybody has a unique laugh, and Speaking is a voluntary act. We there is evidence for a laughter “pace- choose what we say (although we maker” that controls how fast or slow are capable of making “involuntary” the beats of our natural laugh occur. sounds, such as when we are startled). This action is similar to hiccups, which Coughing and laughing can also be also occur at a frequency that tends to voluntary, if we choose to clear our be constant within individuals. throat or want to fake laughter, but are In the brain, laughter involves many more typically involuntary. regions—those needed to understand Coughing occurs in response and process the humorous stimuli (a to stimulation of the airway and is joke or situation) and those that tell designed to clear out something the larynx and respiratory muscles unwanted, like mucous or a piece what to do. This system is distinct from of popcorn. This action protects that used to control voluntary speech. the airway from getting clogged. Of In fact, some patients with speech course, this reflex is not perfect— production disorders related to the sometimes we cough when our larynx larynx can still produce involuntary is stimulated by spicy foods or irritated sounds like laughter. by a virus. When we cough, the vocal cords Aw n s e r re s e a r c h e d b y A l e x first close completely. The diaphragm L a n g e r m a n , M . D. , a former HHMI and other respiratory muscles build medical student fellow, now a resident up air pressure below them. Then the in Otolaryngology and Head and Neck vocal cords release, allowing air to Surgery at the University of Chicago.

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, find helpful Web links, or toss your question into the mix. What’s been puzzling you lately?

August 2oo9 | hhmi bulletin 51 toolbox

Sticky DNA Problem-solving chemists begin to build three-dimensional tissue. developing organisms know just where to position Bertozzi’s lab and colleagues in the chemistry department have been various cells so they can communicate and cooperate with their exploiting this property of DNA to create simpler, two-dimensional neighbors to establish three-dimensional structures. For biologists, patterns of cells. By linking a strand of DNA to a cell, and a comple- emulating the body’s architectural dexterity, even for simple tissues, mentary DNA strand to a spot on a flat surface, the researchers can has been a frustrating pursuit. direct the cell to bind there—a useful strategy for tasks such as “The spatially encoded information in tissues is very difficult to designing cell-based biosensors or drug-screening technologies. replicate outside the body, but also really important for function,” When Gartner joined the lab in 2006, he realized the approach says HHMI investigator Carolyn Bertozzi at the University of could be taken, literally, to another dimension. California, Berkeley. To jump from two to three dimensions, Gartner linked comple- “In the lab, we typically culture cells on flat substrates like tissue mentary strands of DNA to the outer membranes of different culture plastic. But we don’t live in a flat world,” adds Zev Gartner, types of cells. Then he allowed those cells to interact so they who began to study cell-to-cell interactions as a postdoctoral fellow could bind to one another. By varying the length of the DNA in Bertozzi’s lab. “Cells in our bodies are surrounded on all sides strand, the complexity of its sequence, and its abundance on a by their neighbors and by an extracellular matrix, and the behavior cell’s surface, he could control how quickly the cells came of cells in 3-D is very different from when they are grown on these together and how stable the resulting complexes would be. He rigid, inert surfaces.” incorporated fluorescent markers so that, after the cells had If they could control tissue assembly, researchers could design mingled, the sought-after multicellular assemblies could be sorted biomaterials to replace or repair injured tissue and would have more from cells that remained solo. true-to-life models of tissues, both healthy and diseased, for study in Gartner used the approach to create a tiny sphere in which two the lab. To Bertozzi and Gartner, the challenge of organizing cells onion-like layers of cells encase one another. The innermost cells into more complicated structures looked like the kind of problem secrete a protein growth factor that the outer layer of cells needs to they solve best: a chemistry problem. Chemists synthesize complex survive. This intercellular signaling depends on the close proximity molecules by performing a series of reactions with simpler building of the cells to one another due to their DNA “glue.” The team calls blocks. The team’s building blocks were short single-stranded the structure a “microtissue”—simpler than most of the tissues the sequences of DNA linked to the outer surface of cells to make the body builds but a useful model for studying specific cell-to-cell cells selectively “sticky.” interactions in the lab. The contact-dependent exchange of The approach relies on DNA’s discriminating nature: because survival factors in their system mimics signaling that spurs the each building block or nucleotide that makes up a DNA sequence growth of tumors and immune cells, according to their paper, has a preferred partner, a strand of DNA will bind only to another published March 24, 2009, in the Proceedings of the National strand whose sequence is complementary to its own. For years, Academy of Sciences.

52 hhmi bulletin | August 2oo9 Courtesy of PNAS and Zev Gartner way inwhichcells are combined. the or glue DNA featuresthe byof the manipulated altering be can “microtissue” this of stability of red- and green-labeled cells promotes theirassembly into adefined structure. The shapeand ROW: using complementary strands ofDNAastheir“glue.”BOTTOM ROW: TOP less, Gartner says. says. Gartner less, for directingthe possibilities different limit- are virtually assemblies type,” cell individual the with do to nothing has “really block ing build- cellular each of surface the on “glue” DNA the because and to accessible readily be researchers in other labs who want to design their should own microtissues, method The works. technique This first microtissue demonstrates that Bertozzi and Gartner’s and Bertozzi that demonstrates microtissue first This Researchers coax cells ofdifferent typesto findand form contacts with oneanother, basic idea,” he says. says. he idea,” basic the push can we further much how see to “We’retrying skin. the in cells of layers the as such assemblies, orientation asymmetric construct and their direct can researchers so cells the into mation infor- structural more encoding and types, cell more include that microtissues larger building with experimenting is Francisco, San Gartner, now a faculty member at the University of California, California, of University the at member faculty a now Gartner, That “glue” onthesurfaces W

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C of the University the of ch K o . T u ckefeller University and and University ckefeller j M nkel identified dystrophin, the protein mutated in mutated protein the dystrophin, identified nkel a i e a , an HHMI investigator at the University of Iowa Iowa of University the at investigator HHMI an , r llo llo n d a ; HHMI HHMI ; vice- , c D of the of o evelopmental b s - Jeffrey Jeffrey and publicservice. chemistry as well as his teaching, mentoring, to contributions scientific Zare’s recognizes HHMI investigator HHMI School ofMedicine. was awarded to HHMI professor professor HHMI to awarded was bestowed by the American Chemical Society, honor highest the Medal, Priestly 2010 The in Neuroscience. Lawrence Katz Prize for Innovative Research University,the Rockefeller won The at gator Research. Cancer for Association American the Research from Cancer Translational for Prize received the 2009 Dorothy P. Landon-AACR of Memorial Sloan-Kettering Cancer Center rry K slie B. B. slie L N e e . Z a r B e e M R iology. They were chosen to of Stanford University. The honor honor The University. Stanford of e . B ssler ssler V o o ston, received the 2009 e F e J ssh uut 2 August f r of the Emory University University Emory the of les les C a h y l L

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aw bulletin i el, y a ers ers r 55 continued from page 37 He’s also working—as many researchers prostate cancer support group in his home- (Pro ceed with caution) are—to create drugs to target the fusion town and is active in online message researchers in Sweden, where the wait- gene identified by Chinnaiyan. boards, touting his success with MDV3100. and-see approach is used much more As for Foley, he’s become an outspoken Though Chinnaiyan’s discovery of the often than in the United States. Golub’s advocate for prostate cancer patients fusion gene is heralded as the greatest leap Swedish collaborators have followed a learning about their disease and staying in understanding prostate cancer in the large cohort of prostate cancer patients informed of the latest drugs and clinical past decade, it’s only half the battle toward from early diagnosis to see whether their trials. “Do the research, read the data, talk changing the way prostate cancer is dealt tumors worsen—this approach is more to doctors. If my cancer rears its head again, with clinically. Now researchers must turn difficult in U.S. cohorts as the prostate is I’ll look to other trials.” In January, on inau- that discovery into detection methods, more often removed. To identify differ- guration day, he and one of his prostate ways to monitor the disease, and new ences between prostate cancers, Golub is cancer groups sent a petition to President treatments for prostate cancer, so that the using DNA chips to quantify the genetics Obama requesting more federal funding for disease can be managed in a more person- of bits of biopsied tumors. prostate cancer research. He’s also started a alized way. PSA needs a helping hand. W

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56 hhmi bulletin | August 2oo9