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One Lump or Two? in this issue Once again, those fast-growing yeast find a way to turn a The Silicon Marvel

long-held theory on its head. This time, it’s about prions,

• Prions for Good which aren’t as universally nasty as once suspected. Some may

actually help organisms evolve. The yeast colony shown here www.hhmi.org A Kaleidoscopic View contains a in its prion form. Because the prion, known as PSI+, is self-replicating and forms fibrous amyloids, the yeast look lumpy and bumpy—strikingly different from normally smooth yeast. ’s group has found 19 yeast

that can switch back and forth between a normal and a prion version. The prions are thought to help the yeast adapt to changing conditions (see “A Silver Lining,” page 22).

LIGHT MOVES v ol. ol. 23 Heather True / Lindquist lab / no. no. / 02 O b s e r v a t i o n s

16 Secret Agent Man cells do more than just cover our bodies. As a neurology resident, Stanley Prusiner saw Creutzfeldt–Jakob agent began to emerge. These data established, for the first time, that , for example, anchor immune cells disease kill a patient in a matter of months. Researchers knew the rare a particular macromolecule was required for infectivity and that this within the epidermis, move and proliferate during neurodegenerative disease and scrapie, a similar disease in sheep, macromolecule was a protein …. wound healing, and even secrete inhibitory molecules were infectious but not as a result of a typical virus. At the University of California, San Francisco, Prusiner set out to determine the molec- Once the requirement of protein for infectivity was established, as part of the immune response. has ular structure of the elusive infectious agent. Hypotheses about the I thought that it was appropriate to give the infectious pathogen of delved deep into the of skin cells, including nature of the agent ranged from DNA viruses to membrane fragments scrapie a provisional name that would distinguish it both from viruses their elaborate cytoskeletal networks that support to proteins. Prusiner published the surprising answer in 1982 and set and viroids. After some contemplation, I suggested the term “prion” movement. In the shown here, the blue- off a firestorm of skepticism. He turned out to be right, which earned derived from proteinaceous and infectious. At that time, I defined stained nucleus is surrounded by microtubules (red) him the 1997 Nobel Prize in Physiology or Medicine. prions as proteinaceous infectious particles that resist inactivation by crosslinked by the protein ACF7 (yellow), which procedures that modify nucleic acids. I never imagined the irate reac- plays a critical role in migration. As reproducible data began to accumulate indicating that scrapie tion of some scientists to the word prion—it was truly remarkable! infectivity could be reduced by procedures that hydrolyze or modify proteins but was resistant to procedures that alter nucleic acids, a From Stanley Prusiner’s Nobel Prize Lecture. ©The Nobel Xiaoyang Wu / Fuchs lab Dan Haskett family of hypotheses about the molecular architecture of the scrapie Foundation 1997 may ’1o vol. 23 · no. o2

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web only content Hear Pat Brown discuss our society’s dependence on animal agriculture. Watch fossil hunter Jason Osborne in action on Maryland’s coast. Read how Dan Goldberg and Alan Cowman, on two different continents, zeroed in on an enzyme critical to the malaria parasite’s infectivity. Join us at www.hhmi.org/bulletin/may2010. 22 28 Features Departments cover story p r e s i d e n t ’ S L E t t e r I n stit u t e N e w s Light Moves 03 Biomolecular Crowdsourcing 40 Lummis Elected HHMI Trustee 12 Light is becoming the tool of choice 40 c e n t r i F U G E Jibrell Selected as Vice President of for researchers who want to precisely Information Technology 04 For the Long Haul manipulate neurons and other cells. 4 1 HHMI Investigator Sean Carroll 05 Fossil Hunter Named Vice President for Al K a e idoscopic V i e w 06 She Floats Through the Air 16 Elaine Fuchs brings an eye for the Science Education U P F R ont creative to the many-colored facets of L oa b B o k 08 Scratching the Surface her life and work. 42 Young Again 01 Live Long and Prosper A S i lv er Lining 43 Lab-Grown Liver PERSPECTIVES A N D O p i n i o n s 22 Sure, some prions can cause diseases, 44 Going Solo 34 Peering Back in Time but others are turning out to be A s k a S c i e n t i s t 36 Q&A—If you were to take a year off beneficial. to “change the world,” what would 45 How do scientists learn about plants T h e S i l i c o n M a r v e l you aim to do? that are extinct? 28 The new Janelia computing cluster Nt o a B e n e c h r o n i c L E puts a premium on expandability S c i e n c e E d u c at i o n 46 News of recent awards and other and speed. 38 The Heart of a Snake notable achievements

39 2010 Gilliam o b s e r vAT i o n s Secret Agent Man

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: J e ssica H ay e a nd C l ar k H s iao 2 hhmi contributors Fiduciary Trust CompanyInternational Director, RetiredChairman&CEO A Dean /HowardUniversitySchoolofLaw Esq Schmoke, L. Kurt Former HeadofGlobalInvestmentBanking,J.P. Morgan&Co. Senior Lecturer,HarvardBusinessSchool Ph.D Rose, S. Clayton The UniversityofCambridge V A President /TheRockefellerUniversity F.R.S Nurse, Paul Platform Partners LLC Chairman &CEO Lummi R. Fred The PrudentialInsuranceCompanyofAmerica Former Vice Chairman&ChiefInvestmentOfficer Chairman /SeaBridgeInvestmentAdvisors,LLC Keit L. Garnett The UniversityofChicago Distinguished ServiceProfessorofHistory Chairma President Emeritus&HarryPrattJ Ph.D., Gray, H. Hanna University ofT M.D Regental &Chairman,DepartmentofMolecularGenetics Goldstein, L. Joseph WilmerHale Barshefsky Senior InternationalP Charlene Ambassador Esq Senior P III, Baker, S A. E E James T S U R T I M H H

and homeswhere heonce lived. (4) apartments in live now who people 18 the photographing is project current His Chemex. the bered for: his chainsaw, a collection of handgun, typewriter, Burroughs: William shoes, author quilt. This led latehim to ponder what the personal possessions he of would most like possessions to be remem­ the photographed recently He others. among corporations, and websites, magazines, for portraits making City, P in appeared has work her then, Since2000. in pen the for biologist, fallen A a celebration oftheway science imagerymakes theinvisible visible. (2) written has severaland hundredsarticles of latestHe His books. book, world. the about know not does he much how of aware more ever becomes he work, his do to world the about more learning in that, laments sometimes technology,he Although hunky whether and humanoid robots anxiety, make thebest husbands.(1) death, God, like topics big about writing Magazine, Times York at writer contributing a become and (Pandora’sBaby) book eighth her writtenshe’s Manhattan, to movedtake and museums, and theatre,art loveof her indulges 2002she where in roots up pulled husband her and 16) View,” page scopic Takomain Maryland, daughters Park,two raising After digital media.Sarah lives inAnnapolis,Maryland,withherhusbandandtwo dogs.(3) and electronic publications at HHMI, she now works at the bustling intersection of science and The Dallas Morning News , and online at bulletin ice-Chancellor nne M. Tatloc M. nne Ph.D Richard, lison eter artner /BakerBottsLLP R oss(“A KaleidoscopicView,” portraitphotographera worksNew as 16) Yorkin page

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Robin Henig, Ivan Amato, Sarah Goforth, Chuck Gonzales Barbara Ries a subsequent stint as a visiting scientist at HHMI’s Janelia Farm Janelia HHMI’s at scientist visiting a as stint subsequent a Paris in 2005, a collaborative project with a Berkeley colleague, and molecule bymolecule,andinsome caseseveninlivingcells. time, real in unfolds it as transcription witness to possible it make microscopy fluorescence in developments now But genes. specific at cells individual in place taking events real-time mysterious and In short, biochemists like me have been missing the rapid, dynamic, locus. gene single a at or cells individual in place taking reactions the not events, average only detect can we types, cell of mixtures from derived extracts in events transcriptional measuring by ple, exam- For limits. inherent has bucket contributors, tion, andheartdisease amongthem. inflamma- cancer, diabetes, occurs: disease wrong, goes regulation gene when surprisingly, Not cells. blood red in oxygen carries that products like generate hemoglobin, important the iron-rich protein to on go RNAs “messenger” transcribed The genes. transcribe and andstopsignalsrecognized bytheenzymesthatread marks”—start specializedas proteinsrecognize sequencethat DNA “punctuation factors transcription of think Youcan genes. our all of activity the denigratedonce DNA of regions short control fact in that “junk” as Sp1. or 1, specificityprotein called we something cells, human in factor tion transcrip- first the found then and viruses with Westarted cells. in as bait, hunting for a match among the tens of thousands of proteins DNA Weof cells. segments in short used information biological of flow the control that proteins regulatory factors—key transcription target: molecular specific very a for fishing went I and colleagues my Berkeley,California, of University the at subsequently and tory Labora- Harbor Spring Cold the at Watson Jim with postdoc a as years my during Starting scientific. been have expeditions fishing work ofunderstandingthemachinerylife. nanograms of scarce proteins that researchers need to begin the real biological material, such as liters of HeLa cells—the nugget is a few information. In biochemistry—which often requires real buckets of of nugget pure a yield to filters powerful and input vast a requires parallels with old-fashionedbucketbiochemistry (mykindofscience). Each interesting some coining—has to claim lays Howe Jeff tions inprotein folding. a distributedRosetta@home, network dedicated to solving big ques- solu- with basis daily surprising a on it sees often Baker David investigator HHMI tions. provide to footing equal an on compete amateurs and Professionals happens. what watch and community digital vibrant a into challenge a out toss ideas: soliciting and lems prob- complex E solving to N approach effective and cheap relatively g A Biomolecular Crowdsourcing A convergence of serendipity—involving a sabbatical detour in in detour sabbatical a serendipity—involving of convergence A Like collaborations in cyberspace that rely on many anonymous We’ve learned that transcription factors work by interacting with successful most my of some but passions, my of one is Fishing journalist that term crowdsourcing—a of phenomenon This e r a t i N O

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s letter s hhmi bulletin 3 4 hhmi Club. Then apostdoctoral fellowship single scullwiththeBaltimore Rowing and duringgraduate schoolherowed a high schoolhewas onthetennis team, to 80miles. throughout theweek, for atotal of 70 20 ing seasonhefollows upwithanother partners. Duringthepeakofhistrain­ tainous trails—with ahandful of training 30 miles—onnarrow, winding,moun­ O that stretch between 30and100miles. marathons, gruelingtests ofendurance his Saturday morningsto train for ultra­ ­S to catch himyou’ll have to move fast. Diablo. He’llbeonfoot, butifyou want Mountains orhalfway upnearby Mount dozens ofmilesdeepintheSantaCruz a Saturday morning,focus your search If you’re trying to findChrisGarcia on For the Long Haul tanford SchoolofMedicine, reserves n anaverage Saturday, heruns25to centrifuge - Garcia wasn’t always arunner: in Garcia, anHHMI investigator at miler onSunday andshorter runs bulletin

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May 2o1o May morning temperatures. The 100 4:00 a.m.to take advantage ofcool States. Races usuallystart around peted intriathlons andmarathons. took him to SanDiego, where hecom­ 10 orsomiles. food andwater stops offered every the following night,pausingonlyat He wears aheadlamp andrunsthrough and how mountainous theterrain is. “I just remember being totally trans story onultramarathons,” says Garcia. the channelsonmy TVandseethis to take Garcia between 20and30hours ing nine100 more than75 ultramarathons, includ­ that.’ For me, itmadecomplete sense.” crazy, oryou think‘Hey, Ishouldgodo tions: you eitherthinkit’s completely 100 miles,you have oneoftwo reac­ When you hearaboutpeoplerunning f “Then oneday, I’m In thepast decade, Garcia hasrun nish, dependingontheelevation - milers, allover the f ipping through - U milers nited f x ed. of theseraces. “Mybodyisde is starting to feel thestress ofadecade —Sarah C.P. Williams chaos. At the lems inhisresearch—a break from life’s to process information andsolve prob­ encounter, andprecious solitarytime views, anoccasional mountainlion look forward to it.” self,” says Garcia. “Infact, you have to hours andonthetrail by your­ one. “You have to notmindspending and mentalchallenges,isn’tfor every­ to see the morning,” hesays. “Whenyou just start the sunsets,andthenat sunriseinthe races are actuallyat dusk,rightbefore 100 lons. Notyet, though.He’s gotthree to shorter races—marathons andtriath­ hips may eventually sendGarcia back rary discomforts. Butchronically sore that hecanpushthrough thosetempo­ marathon. Experience hastaughthim come inthelatter stages ofanultra­ fuzzy thinking,andsore musclesthat not bothered by thepuking,shivering, getting pretty beat up,” hesays. He’s in perspective,” hesays. than at any othertime. “Itjust putslife race, Garcia says heismore himself of therace, you’re gettingclose.” know that you’re on thedownhill slope U The trails offer himbreathtaking “My favorite timesduringthese Garcia says his40 - milers onhissummercalendar. ltramarathoning, withitsphysical f icker ofsuncome upyou f nish lineofa100 - something body f nitely - mile

Peter Arkle James Kegley ized marine life, for studying thebrain. imaging andelectrophysiology tools Research Campus,where hehelpsbuild rication team at HHMI’s JaneliaFarm part oftheinstrument designandfab­ in hishand.The mechanicalengineeris no wonder thescrewdriver feels natural what Ineeditto,” hesays. the tool ofchoice. logical dig.Butfor thisfossil hunter, it’s tool that comes to mindfor apaleonto­ coastal waters in prehistoric times. marine snail that inhabited Maryland’s tive curves of an of embedded sand to reveal the distinc­ carefully scrapes away millions of years tly into a craggy, waist screwdriver. Kneeling, he pushes it gen­ into his pocket and pulls out a b Cold waves lapping Fossil Hunter ooted feet, Jason A self Considering “It A screwdriver mightnotbethe f ts inmy pocket anddoesjust - taught a O O Ecphora sborne’s day job, it’s f sborne spendsmost cionado offossil­ O at his rubber s borne - h igh rock and —an extinct f s f hes a thead - f rst O weekends onthebeaches were like backthen.” amazing to imaginewhat theseas from asharkattack. It’s absolutely you seetheserrations andlacerations says. “You lookat aribfragment and cows andporpoises. from marinemammals,suchassea teeth, mollusks,andbonefragments with asharpeye canspotancientshark are soabundantthat any beachcomber rock onto thebeachesbelow. Fossils of seacreatures preserved insandand cliffs periodicallydisgorge theremains some 10to 23millionyears ago. The when thearea was covered by ocean, its, composed ofsedimentlaiddown amateur andprofessional. Chesapeake Bay from mid cliffs that linethewestern coast ofthe waterways. The Calvert Formation— Maryland’s hundreds ofmilesinland southern Virginia—is afavorite spotfor sborne andotheravid fossil hunters, “Everything tells astory,” Those cliffscontain Miocene depos­ - f Maryland to anking O sborne shark that measures 5 has onespecimenfrom amegatooth some ofhis collection— be big—really big.Inhispersonal O on theriverbed, andyou’re the you crawling around onthebottom and ern Virginia. that hefound whiledivinginsouth­ fossil top to bottom. He’s alsomadelarger “That’s cool. That’s de grinning ashelowers thebinoculars. I can’timagineonethat big,” hesays, Marine Museum. “It’s aheckoffeeling.” person to seeitandtouch it,” hesays. yet last New Year’s Day, andtheskull ofa uncovered alongthePotomac River brae from theEocene epochthat he partial association ofseasnake verte­ vertebrae ofabaleenwhale, arare —Mary BethGardiner the to investigate, heplansto report him from climbingtheunstable cliff the side. Though state laws prohibit be white extensions coming outof chalky circle withwhat appear to ful glasses, hecanmake outa for hisbinoculars.With thepower­ be something,” hesays andreaches of white catches hiseye. “That might cliffs risingabove thebeach.Aglint his trained eye upward, to thesteep sil remnants. After atime, heturns tiny tiger sharkteeth andotherfos­ sborne scours thetidelinefor Some ofthosesharkteeth can O “There’s nothinglike itwhenyou’re “It could beabigradius [bone] but - : A R T X E B E W fossil fossil his of some of exhibit an of tour virtual take a to and Formation, Calvert tothe trip collection f to f n thisbriskmidwinter day, nd to hisfriendsat theCalvert nd somethinglike that just lying f - be nds, includingtheskull and f n - ds, ds, visit identi O f To hear and see sborne alsodonates nds to museums—he www.hhmi.org/bulletin/may2010 f May 2o1o May ed porpoisespecies f

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f bulletin at, rst . 5 6 hhmi in front ofher. With hertoes onthe reaches for the trapeze bardangling climbs to a23 When it’s herturnto jump, Wagers She becamearegular at theschool. trapeze class andabsolutely loved it.” pretty fun,” says Wagers. “Iwent to a of Circus Arts.“Ithoughtthat sounded mentioned theSanFrancisco School grueling week oflabwork, andafriend mind offscience after aparticularly at Stanford f soaring through midair. Shetook upthe is aonce inalifetime experience. to join her, plummetingthrough thesky research articles.For most whoagree f has atradition ofskydiving withthe scientist at Harvard MedicalSchool, airplane. Wagers, anHHMIearlycareer comes next: a 10,000 lication isnothingcompared to what of gettingapaperaccepted for pub­ For Amy Wagers, theadrenaline rush Through the Air She Floats ying trapeze whenshewas apostdoc rst authorofeachherlab’s major centrifuge “It’s really pretty thrilling,” shesays. She wanted ahobby to take her Wagers, however, isnostranger to bulletin U niversity.

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foot May 2o1o May - high platform and - foot fall from an sky peze madehercuriousto tryother but herspontaneousforay into tra­ it everyone claps.” everyone goes ‘Aaah’ and if you make sayscatch Wagers. a you miss “If you,”watching and cream ice eating San Francisco. ferent feel from thecircus schoolin Jordan’s Furniture store, ithasadif­ above thefood court ofamassive hour driv Reading, Massachusetts, just ahalf School ofNew York hasabranch in discovered, however, that theTrapeze days of stem cells andaging,shethoughther at Harvard MedicalSchoolstudying about timing.” and you have to nothesitate. It’s all it’s very focusing. You have to listen Wagers. “Then whenyou actuallyjump, there’s that rushofintimidation,” says glimpse thenetbelow. very edgeoftheplatform, shecan Newport, Rhode Island. Though her and Wagers booked asky dive in skydiving.” The paper was accepted, she told hercollaborator, “we’re going very Wagers cameupwithaplan:“If this got positive comments from Nature, their on laborated junior faculty memberat Harvard col­ Wagers hadalways loved heights, there, sitting “Therearefamilies When Wagers landed a faculty spot “At that moment,standing upthere, - h f igh stunts. When she and another rst paperfor bothofusgetsin,” f e from Harvard. Located ying trapeze were over. She f r st paper and and paper st - TION: N O I AT M R O F N I E R O M R O F de very muchanovice,” shesays. “I’m seconds upontheplatform. “I’mstill science for just thosefew terrifying though—a way to clearhermindof f only herknees.Shesays herlove of herself upsidedown from thebarby the kneehang,inwhichshesuspends several basicmaneuvers, including paper published,Iwould goskydiving.” whenever my labhadanimportant ahead andjumped.“Then Idecided date ofthebooking,Wagers went ­collaborator conveniently forgot the circus.” —Sarah C.P. Williams Wagers’“Young see 42. research, page on Again” ying trapeze isgoingto stay ahobby, f O nitely notleaving science for the n thetrapeze, Wagers haslearned To Amy about more learn

Peter Arkle upfront

08Sr c atc h i n g t h e S u r fac e T here’s nothing funny about an itch that drives you mad.

0 1 L ive Long a n d P r o s p e r Mix amyloid plaques with longevity and you get mice that not only live longer, but healthier too.

web only content With different approaches and on different continents, Dan Goldberg and Alan Cowman land on an enzyme critical to the malaria parasite’s destructive ways. Read the story at www.hhmi.org/bulletin/may2010.

Why bother trying to extend life if those added years aren’t healthy ones? Disease and disability ruin countless retirement plans. For some people, the discomfort from a skin disease or an allergic reaction can make life miserable. For others, a life-saving medication becomes impossible to take because it causes an unbearable itch. Researchers are thinking hard about quality of life. Some are trying to figure out how to add years while bypassing the neurological diseases of aging. Others are dissecting the pathways involved in itch—which can spill over into pain—so it no longer drives people to distraction.

May 2o1o | hhmi bulletin 7 upfront

Scratching the Surface There’s nothing funny about an itch that drives you mad.

I f t h e s u b j e c t o f i t c h s e em s f r i v o lo u s c om pa r e d t o o t h e r medical matters, consider this: in regions where the drug chloroquine is used to treat malaria, patients often discontinue treatment rather

than endure the excruciating itch that comes as a side effect. And case of these receptors was found almost exclu- studies tell of itch sufferers who injure themselves in search of relief; in sively on a class of sensory neurons thought to be involved in the sensing of pain. one well-documented case, a woman scratched through her skull and Dong and Anderson first presumed that into her brain tissue in her sleep. ¶ Still, the subject of itch was ignored the Mrgprs, too, were related to pain. “At in favor of pain studies for decades, says HHMI early career scientist the time, we had no inkling of itch,” he says. To determine the role of the receptors, Xinzhong Dong, a at the histamine receptors on the surface of sen- the scientists engineered a line of what Johns Hopkins ­University School of Medi- sory neurons. But allergic itch accounts for Anderson calls “super-knockout” mice lack- cine. Attention to the field is increasing only one-third of all types of itch. ing 12 genes coding for receptors in the now, thanks in part to Dong’s work unravel- Other forms of itch—including the Mrgpr family. ing the puzzling pathways that carry certain kind caused by chloroquine—don’t work They expected the mice to be less sensi- itch sensations from the skin to the brain. through histamine receptors, so antihis- tive to pain than normal mice, but the mice In collaboration with HHMI investiga- tamines are ineffective. Lacking a better lacking the Mrgpr genes appeared suspi- tor David Anderson, a neuroscientist at the option, physicians usually treat non­ ciously normal. “What was striking was that California Institute of Technology, Dong allergic itch with steroids, which, if used there was very little wrong with these mice,” identified a protein that functions as an itch for long, can have dangerous side effects, recalls Anderson. They showed virtually no receptor in a small subset of nerve cells. including eye disease, osteoporosis, and difference in their response to pain, com- The scientists reported the research in the gastrointestinal illness. The search for alter- pared with normal mice. December 25, 2009, issue of Cell. native treatments has been complicated by Years later, Dong was inspired by stud- Allergic itch happens when cells in the absence of a known receptor. ies conducted by Zhou-Feng Chen, another the immune system release the chemical Nearly a decade ago, when Dong was a former postdoc from Anderson’s lab who is histamine. It is easily treated with antihis- postdoc in Anderson’s lab, he stumbled on now at the Washington University School tamines, which lessen itch by binding to a class of receptors called Mrgprs. A subset of Medicine, on how neurons deliver itch

8 hhmi bulletin | May 2o1o VSA Partners poison ivy; Dong’s lab is testing that ques- that testing is lab Dong’s ivy; poison or psoriasis with associated that like itch, nonallergic of forms other to respond tors receptor,” saysDong. histamine the like receptors, itch novel as three timeslessoftenthannormalmice. lacking mice the chloroquine, injected researchers similarly, scratching furiously. behaved But when the mice knockout and normal Both the mice. the into histamine inducing itch responses? their in deficits any show they would tion: the to returned Dong brain. the to sensations It can’t be said yet whether the recep- the whether yet said be can’t It “Now, we think these receptors function itch- injected first researchers The -knockout mice with a new ques-new a with mice Mrgpr-knockout genes scratched less—nearly scratched genes Mrgpr specifically yougetitchsensation,” hesays. them activate you if and neurons, sensing neu itch-sensing The pain. get you neurons, ing you activate a large population of pain-sens- rate, but the pain circuitry is much larger. If that these two circuitries are not really sepa- different ones for pain, and others for ordinary touch. itch, to dedicated cells—those nerve distinct are there that is possibility itch, if you get a lot, you feel pain.” Another the get you sensation, the of bit little a get you “If Dong. pain,”explains to brother tle debate, saysDong. of a a of root the to get discoveryhelps the But tion. Dong proposes a third view. “We think “Wethink view. third a proposes Dong “Some people propose that itch is the lit- ­r ­s n rsd wti a ust f pain- of subset a within reside ons ensation about which there’s heated heated there’s which about ensation has a huge impact on the quality of life.”qualityof the on impact huge a has it But disease. Alzheimer’s or cancer like conditionlife-threatening a it’snot because have under “People animal. the for issues health own its create could exposure steroid continued that warned has veterinarian and Anderson’s steroids, is treatment only The says. he neck,” her and head her off fur of acres tears just she problem; itch chronic a has “She cat. his bring: could drug a such that cells down,” saysAnderson. compounds and find a drug that shuts those itch-inducing nonhistaminergic, multiple to respond that neurons of population the A – S And he has a daily reminder of the relief find to be would here prize big “The r a h G o f ­e o stimated the importance of itch r h t May 2o1o May

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May 2o1o May Mix amyloid plaques with longevity and you get mice that not not that mice get you and longevity with plaques amyloid Mix Live Long and Prosper and Long Live only live longer, but healthier too. too. healthier but longer, live only Andrew Dillin has found a way to manipulate the the manipulate to way a found has Dillin Andrew IGF pathway to sequester misfolded proteins. misfolded sequester to pathway IGF

Lou Mora Arwn d e D illin wan t s t o i nc r e a s e t h e h u m an h e alt h s pa n — no t just years, but healthy years. He believes the secret to preventing many age-related neurotoxic diseases—including Alzheimer’s, Parkinson’s, so clear that it wasn’t just time—there was something inherent about remaining youth- and Lou Gehrig’s diseases—lies in the body’s ability to recognize and ful,” Dillin says. sequester improperly folded proteins. ¶ Dillin, an HHMI investigator When they moved the Alzheimer’s at the Salk Institute for Biological Studies, has been building a strong research to mice, Dillin and Cohen, now at the Hebrew University Medical School in case for his misfolded-­protein theory. A down too far, it kills the animal, but at a cer- Jerusalem, found even more striking results. few years ago, he showed that there are tain level you get a positive response.” In his In research published in Cell on Decem- mechanisms in immature worms that can own lab, Dillin discovered the genetic deter- ber 11, 2009, they created an Alzheimer’s inactivate misfolded, toxic proteins; as the minant responsible for longevity induced mouse model with downregulated IGF animals age, however, that surveillance sys- by caloric restriction—another long-known signaling and compared those animals tem degrades until the aggregation of those but little-understood cause of increased with mice engineered to have Alzheimer’s proteins leads to disease. Now, he and his lifespan—and found that a different signal- with a normal lifespan. Just like the worms, colleagues have linked that finding to mice ing pathway, acting on the roundworm gene mice with downregulated IGF still had Aβ engineered to exhibit Alzheimer’s disease. pha-4 (FoxA in ), was responsible. aggregating in their brains—with as many [Prions are a different set of proteins that Dillin contends these three distinct path- plaques as their Alzheimer’s addled coun- misfold with different results—see “A Silver ways have at least one thing in common: terparts—but they were almost completely Lining,” page 22.] “We think that all these pathways, when asymptomatic. Amyloid beta, or Aβ, is a misfolded they are downregulated, trick the system to The results confounded the group for protein that accumulates in the brains of turn on the protein surveillance machinery the better part of a year. But they eventu- Alzheimer’s patients and creates dense much more highly, to really take care of the ally found that the longer-lived mice had plaques that are a hallmark of the disease. proteome,” he says. plaques that were far denser and in a con- When Dillin genetically reprograms mice Using Kenyon’s discovery of the IGF formation that likely eliminated much of to have a longer lifespan, they seem to retain pathway as his springboard, Dillin has the misfolded proteins’ toxicity. Rather than the youthful ability to isolate, compartmen- talize, and pack away Aβ proteins. The “This is the first study to show that you’ve result: plaques that appear similar to those of Alzheimer’s but are denser and seemingly not only extended an animal’s lifespan but also benign. Somehow, the surveillance mecha- actually improved its quality of life. nism identifies and secludes the dangerous proteins in a way that older brains cannot. Adrewn D i llin ” He began to take a hard look at aging during his postdoc at the University of Cali- begun investigating whether downregulat- destructive, the plaques in these mice were fornia, San Francisco. From 1999 to 2002, ing the IGF pathway can keep an animal actually protective, amassing the danger- he studied the genetics of aging in the lab healthy as it lives longer. A postdoc in his ous protein in such a way as to inactivate it. of Cynthia Kenyon, who in 1993 discovered lab, Ehud Cohen, combined a worm model Something about muting the IGF pathway, that changing a single gene could double a of Alzheimer’s—in which Aβ proteins accu- Dillin believes, allows for continued protein roundworm’s lifespan. Changing the gene, mulate in the roundworm’s body wall— surveillance and protection from mecha- called daf-2, downregulated the insulin/ with the long-lived, IGF-downregulated nisms that have gone awry. insulin growth factor (IGF) pathway, which worms. The onset of toxicity was delayed in “This is the first study to show that you’ve is found in organisms from the tiny worm to the worms. “I thought the protected worms not only extended an animal’s lifespan but the largest mammals. would actually have fewer plaques than the also actually improved its quality of life,” The IGF pathway is one of three genetic unprotected worms. That’s what any neurol- Dillin says. The transgenic mice were liv- pathways known to affect aging. Dillin had ogist would tell you,” Dillin says. “But they ing longer, and they were eluding a disease a hand in discovering the other two. One, actually had more.” they had been genetically programmed to involved in mitochondrial signaling, he dis- The longer-lived worms accumulated develop. Dillin is investigating the mecha- covered in 2002 during his time in Kenyon’s plaques, but the plaques seemed far less nisms involved and is looking at other neural lab. “If you reduce mitochondrial function toxic than those in the regular IGF worms. conditions as well, including Parkinson’s and you can increase lifespan,” he says. “If you go “It was a really striking result, because it was Lou Gehrig’s diseases. W r – L a u e n G r av i t z

May 2o1o | hhmi bulletin 11

Light is becoming the tool of choice for researchers who want to precisely manipulate neurons and other cells. by Ivan Amato / photography by Jessica Haye and Clark Hsiao here’s a reason neuroscientist and Fixing brains is quite an ambition for a field that comman- bioengineer Karl Deisseroth shows the same video at most of deered its core technology from single-celled organisms. his talks. The movements of the gray mouse with the long tail offer a striking illustration of the power of light to manipulate Borrowing from Nature Tspecific cells. Bacteria, fungi, plants, and other organisms use a repertoire of Barely visible in the overhead view of the mouse is a -thin molecular switches that respond to light. Spanning the mem- optical fiber that feeds through the animal’s skull into the right branes of many of these microbial species are light-activated gates motor cortex of its brain. As the mouse casually sniffs around and and pumps that control the passage of positively charged sodium, explores its white basin, a cool blue glow appears at the fiber’s potassium, calcium, and hydrogen ions or negatively charged point of entry. At that instant, the mouse starts circling leftward chloride ions. around the basin, swiftly and deliberately, as though it just Those ancient, light-activated membrane gates and pumps received marching orders. A few moments later in the video, the can be transferred into other cells of the living kingdom, includ- blue glow disappears. The mouse suddenly stops marching and ing mammalian brain and muscle cells, with genetic engineering reverts to its lazy meandering, eventually sitting on its haunches. techniques. Once transferred, those mobile modules become con- Deisseroth, an HHMI early career scientist at Stanford Uni- trollable with light. “If you can do that,” says synthetic biologist versity, is part of a growing community of researchers, including and HHMI investigator Wendell Lim at the University of Califor- several HHMI investigators, who draw upon genomics, genetic nia, San Francisco (UCSF), “you have an extraordinarily powerful engineering, biochemistry, , microbiology, bio- tool. You can use light to perturb systems and modify them. We physics, bioengineering, and optics to tease out the complexities can get a kind of systematic control that we have not had before.” of brain circuitry and to manipulate researcher-specified cells The handiest light-activated molecule so far is channelrho- (such as the motor cortex cells of the marching mouse) among dopsin-2 (ChR2), which was originally found in the light-sensitive thickets of diverse cell types. “eye spot” of Chlamydomonas reinhardtii, a type of green algae. Patients with optical fibers inserted into their brains are not on In Chlamydomonas, upon exposure to blue light, ChR2 opens the agenda, says Deisseroth, a psychiatrist who sees patients one and allows positively charged ions into the cell. That triggers a day a week. But the laboratory approaches he and others have sequence of changes that influence the cell’s cilia-based pro- been developing could reveal telling details about healthy and pulsion and, thereby, its motion and feeding behavior. When dysfunctional brains that point the way to improved treatments transferred into neurons, ChR2 becomes a light-activated trigger for people. Today’s therapies—drugs, electroshock, surgery— that makes the modified neurons fire more easily. Deisseroth’s sometimes work. But “they are crude and have side effects,” he group used motor neurons that they genetically modified to bear says, because they are not very selective about the cells and tissues ChR2 receptors to make the mouse march in response to light. they affect. “My patients have motivated me to find elegant tools If ChR2 is a blue activator, halorhodopsin (NpHR) is a yellow that speak the language of the brain.” silencer. It was discovered in Natronobacterium pharaonis, a bac- Edward Boyden, a former postdoctoral of Deisseroth terium isolated from a high-alkaline, high-salt lake in Egypt. In who now runs the Synthetic Neurobiology Group at the Mas- the bacterium, the light-driven NpHR channels pump chloride sachusetts Institute of Technology, has taken early steps in the ions into the cell, a flow that ultimately helps drive the synthe- direction of human applications. In April 2009, he and col- sis of ATP, the cell’s biochemical fuel. Transferred into neurons, leagues published a paper in Neuron reporting that the same kind however, these channels respond to yellow light by hyperpolar- of protocol underlying the marching mouse can work, apparently izing the cells, effectively silencing them. safely, in macaque monkeys. And in 2008, he and two colleagues ChR2 and NpHR make for a powerful duo. They enable launched the start-up Eos Neuroscience in San Francisco, whose researchers to rig neurons and other cell types, including mission, according to its website, is to “develop treatments for muscle cells and perhaps even insulin-making pancreas cells chronic neurological disorders.” and immune system cells (see Web Extra, “No Neuron Left

14 hhmi bulletin | May 2o1o Unturned,” www.hhmi.org/bulletin/may2010), with light-­ HHMI investigator at Duke University Medical Center, where he controlled on and off switches. From a third light-activated gate, studies the structure and dynamics of the synapses through which VChR1, Deisseroth’s group developed a tool that responds to neurons communicate with one another. Deisseroth’s group, for light on the red side of the spectrum. VChR1, a channelrhodop- one, continues to stock the shelves with more and more optoge- sin in Volvox algae, is a cell excitor like ChR2. netic switches. For like HHMI investigator Massimo Scanziani Their newest category of switches, the optoXRs, enable of the University of California, San Diego, the real experimental researchers to modify cells to respond to light as though they power of these switches becomes clear when they are inserted were being stimulated by neurotransmitters, such as adrenaline into specific types of neurons. and dopamine. These switches combine a light-sensing rhodop- To achieve this, Scanziani appends the gene for, say, ChR2 or sin component with the internal parts of a G protein-coupled NpHR, to stretches of DNA known as “cell selective promoters,” receptor. That’s a large family of receptors that trigger internal each of which becomes operative in only one neuron type. So, even cellular responses to sensory, hormonal, neurochemical, and though the gene-insertion step might occur in all neuron types, only other ­stimuli arriving at the outside of the cell. For neuroscien- one of those types will actually express the ChR2 or NpHR switches. tists, optoXRs open entirely new research approaches for studying “This gives you immense sensitivity,” says Scanziani, who Parkinson’s disease, schizophrenia, addiction, and other severe uses the technique to probe the function of specific cells in the neurological problems, Deisseroth says. cortex of animal brains, the region associated with sensation and Boyden and his colleagues are trolling the ever-enlarging thought. In mice and rats, for example, Scanziani studies how library of genomic databases to diversify the optogenetic tool set. sensory inputs, such as the contrast between different elements of That’s how he and his coworkers found Arch and Mac, two light- a visual scene, are processed by neuronal circuitry in the visual driven proton pumps (the first from a bacterium, the second from cortex. “You now can manipulate a circuit and understand what a fungus) that silence cells into which the researchers insert them the heck it does in the brain,” Scanziani says. when the switches are exposed to yellow and blue light, respec- The repertoire of light-switchable modules available for tively. The scientists reported their initial work with them in a ­optogenetics studies is growing. “There’s a Home Depot of dif- Nature paper on January 7, 2010. ferent kinds of switches out there,” says Michael Ehlers, an (continued on page 48)

Karl Deisseroth, Wendell Lim, and Massimo Scanziani are using light as a type of remote control to manipulate cells and tease out the daunting complexity of muscle,

Deisseroth: Darcy Padilla Lim: George Nikitin / AP, ©HHMI Scanziani: Denis Poroy / AP, ©HHMI heart tissue, and particularly brain tissue.

May 2o1o | hhmi bulletin 15

Elaine Fuchs brings an eye for the creative to the many-colored facets of her life and work. by robin marantz henig | photography by peter ross

May 2o1o | hhmi bulletin 17 devised a method to test the hypothesis. They attached green fluorescent markers to infrequently dividing cells from adult mouse tissue, which they thought might be stem cells, and then purified, cultured, and grafted the cells onto hairless mice. When the mice grew green fluorescent hair and skin, the scientists knew the tagged cells were in fact stem cells. With her colleague Peter Mombaerts, Fuchs later cloned healthy mice from these stem cells using a technique known as nuclear transfer. They removed the nucleus of a mouse oocyte and replaced it with the nucleus of a hair follicle . They then grew the hybrid cell in vitro to the blastocyst stage and implanted those cells into the uterus of a mouse. While only a few percent of the clones survived to become healthy mice, the experiment arm-in-arm, Elaine Fuchs and her hus- Fuchs sees in the paintings that inspire demonstrated that skin stem cells can be band, David Hansen, look like any other her carries back to biology. successfully reprogrammed to a pluripo- New York couple: slim, elegant, dressed Hansen, a professor of philosophy tent state with the capacity to generate all in black. But listen in on their conver- and education at ’s 220 different cell types in the body. sation as they pause before a Picasso, as Teachers College, has a different interpre- The reports of these experiments— I was able to do one afternoon last win- tation, focusing instead on geometry, on published in 2007 in Cell, Science, and ter, and you can hear something more: the flatness of Picasso’s figures. the Proceedings of the National Academy two fiercely intellectual people who look Trailing the couple on this museum of Sciences—led to a flurry of media atten- for inspiration for their creative work outing is a film crew making a documen- tion. Such attention, however, is not really in almost everything they do, including tary on women in science. The crew is what Fuchs is interested in. To her, the real museum-going. supported by L’Oréal, the French cos- questions about stem cells are much more This trait might be one reason that metics company that partners with the basic than creating hair or cloned animals. Fuchs, head of the Laboratory of Mam- UNESCO Foundation to fund the pres- “What I really want to know is why malian and Development at tigious L’Oréal-UNESCO Awards in the embryonic stem cells can choose any tis- in New York, has Life Sciences, given every other year to five sue pathway, while adult stem cells are managed, in her nearly 30-year career, outstanding women scientists, one from much more restricted in their options,” to pioneer new ways of studying skin and each continent. Vignettes from this docu- she says. Yes, she has shown that skin stem hair and to manipulate stem cell differen- mentary will be presented at a ceremony cells can be reprogrammed to generate a tiation so deftly that she was able to turn a in Paris in early March, celebrating Fuchs whole mouse. But more important is what skin stem cell into a cloned adult mouse. and the four other 2010 award recipients. happens in nature, when skin stem cells “I look immediately at the central fig- It is the latest in a string of accolades for turn into skin, hair, or sebaceous glands, ure,” Fuchs says to her husband as they Fuchs, an HHMI investigator since 1988. but never—without laboratory manipula- gaze at Picasso’s Three Women at the She also received the National Medal of tion—a neuron or a kidney cell. Spring, “and I follow her hair.” Eventually, Science from President in she tells him, she follows the folds of the a 2009 White House ceremony. Seeing Opportunity woman’s robe and the stream of water she Fuchs’s stem cell work is among the This kind of lifelong questioning began, in directs into a brown pitcher. “I get a sense discoveries that led to these honors. In the a way, with a butterfly net in a field behind of the river here, with the river as a part late 1990s, she and her students and post- Fuchs’s childhood home in Illinois. of the flow of life.” And over on the left docs generated mice with thick fur coats, “Early on, my mother made a but- side of the canvas, she says, “the exposed suggesting that they might have stumbled terfly net for my sister and me,” recalls features of the women are tantalizing, in a on a clue about how hair follicle stem Fuchs. Her sister Jannon is four years way that suggests fertility.” Much of what cells work. Several years later, her team older, and the two girls spent long after-

18 hhmi bulletin | May 2o1o in Denton, Texas, where she is a professor of neuroscience at the University of North Texas, “I would have preferred to be the social one!” Fuchs’s father assumed Elaine would become a teacher—it was Jannon whom he urged to go into science—and so Elaine headed down that path. When she entered the University of Illinois in 1968, she enrolled in chemistry, physics, and mathematics classes, but she still didn’t think of herself as an especially good stu- dent—until she looked around her. In her science classes, Fuchs was one of just three women of some 200 students. She knew that meant a particular kind of scrutiny. “I remember being in the physics class thinking, ‘If I were to get an A, the pro- fessor would think I cheated. But if I get the best grade in the class, the professor couldn’t think I cheated, since I would be doing better than everyone else.’ Boy, that really motivated me.” She made straight As in college, often at the top of her class. But Fuchs wasn’t a total grind. She joked around with the science geeks, hung out with the graduate students, and in one class asked the TA to teach her how to ­juggle tennis balls. She intended to join the Peace Corps after graduation—a plan that changed when she was assigned to work in Uganda, then under the bloody rule of Idi Amin. She chose graduate school at ­ instead. At Princeton, in 1972, Fuchs again E laine Fuchs’s studies of skin and hair cells may eventually lead to a cure for felt the sting of being a woman in a man’s baldness, but she manipulates stem cells to address larger health questions. world. Fuchs recalls her advisor, Charles Gilvarg, saying on more than one occasion noons in the fields behind their house in no concept of nanomolar concentration,” that he didn’t think there was a place for Downers Grove. Soon they were catch- she says with a smile. “I just wanted to speed women in science. Fuchs took his dismis- ing butterflies, insects, pollywogs, and the things up. So I dumped the entire contents sive attitude as a challenge. She worked occasional crayfish from a nearby swamp. into the water—and killed all of my tad- hard, often staying in the lab until 10 p.m., “We had butterfly nets and strainers and poles. That was my first real science experi- studying spore formation in bacteria as old kitchen utensils, and we started to ask ment”—pretty much a complete failure. she sought to acquire the skills of a bench for science books for Christmas,” she says. It was Jannon who seemed destined to scientist. But she also played hard, begin- When she was about eight years old, be a scientist, she says; Jannon was “the ning what would become a lifelong love Fuchs read about using thyroid hormone smart one” and Elaine was “the fun one.” affair with travel. Even on a paltry $3,000 to accelerate metamorphosis in pollywogs. Elaine admired her big sister, but Jannon a year ­stipend, Fuchs managed to travel She pleaded with her father, a geochemist Fuchs remembers it from a slightly differ- to India, Nepal, Guatemala, Mexico, Peru, at Argonne National Laboratory, to get her ent vantage point. “If given the choice,” Bolivia, Ecuador, Turkey, Greece, and some so she could try it for herself. “I had Jannon told me by phone from her home Egypt during her five years at Princeton.

May 2o1o | hhmi bulletin 19 Eager to tackle human biological C reating New Dynamics They were neighbors in Hyde Park, and problems, Fuchs pursued a postdoc in In 1980, Fuchs became an assistant pro- their husbands were also good friends— the Massachusetts Institute of Technology fessor of biochemistry at the University in fact, Lindquist introduced Fuchs and (MIT) lab of Howard Green, a pioneer in of Chicago and once again found her- ­Hansen—so the two couples got together culturing human cells—specifically, skin self in a man’s world. As she was setting often for dinner and conversation. cells derived from newborn foreskins. “I up equipment on the first day in her lab, “Every New Year’s Eve we would go learned cell culture from a master,” she the department chairman’s lab technician out together to a restaurant, and then to a says. “Howard really paid attention to the dropped by. “Are you Dr. Fuchs’s new lab dance party sponsored by the Chicago kind of detail that, even now, very few technician?” he asked. Symphony,” says Lindquist. Getting to people have the capacity to do.” He rec- “Umm … I am Dr. Fuchs,” she replied. know her professionally and socially, ognized, for instance, that to grow human Things got better a few years later Lindquist says, showed her that Fuchs is epidermal cells, you have to co-culture when a departmental reorganization “both a phenomenally good scientist and a them with fibroblast cells from the der- brought a cohort of three strong female phenomenally good human being.” mis, located just beneath the epidermis, biologists together into the new Depart- One of Fuchs’s goals when she got thus reproducing the “cross talk” between ment of Molecular Genetics and Cell to Chicago was to make a cDNA library cell types that occurs in nature. Biology: Fuchs; , already (a collection of DNA fragments used to At MIT, Fuchs started wearing make­up a member of the National Academy of help identify genes and the proteins they and nice clothes, partly to annoy a female Sciences; and another assistant professor, produce) of the major structural pro- colleague who said women scientists should Susan Lindquist, now a lifelong friend teins she’d been characterizing at MIT. avoid looking too feminine. Today she still and fellow HHMI investigator. Fuchs and In those early days of recombinant DNA dresses carefully and elegantly, and her long Lindquist designed and co-taught a course technology, such a goal was ambitious. blonde hair is always permed. With bright called Gene Expression in Cell Biology, Eventually, Fuchs and her colleagues blue eyes, a long oval-shaped face, and a which they continued until Lindquist not only determined the DNA sequences dazzling smile, she has skin so wrinkle-free left for MIT and the Whitehead Insti- encoding these proteins but also defined that it makes you wonder whether studying tute for Biomedical Research. And their the two basic subunits required for the skin cells is its own fountain of youth. friendship went beyond the classroom. most important structural protein, ­,

20 hhmi bulletin | May 2o1o to self-assemble into filaments. And they After a few litters of K14 mutants were keratin genes, K5 and K14, and switch on discovered that the filaments, in turn, born with no apparent defects, Fuchs’s lab two others, K1 and K10. were essential for the skin’s protective and manager, Linda Degenstein, noticed a These studies established a paradigm hydrating functions, forming an elabo- mother mouse eating a newborn pup with for what are now 89 distinct genetic dis- rate cytoskeletal network that provides an apparent skin defect. Might Degen- orders of intermediate filament proteins. mechanical integrity to the cells at the stein have stumbled on nature’s way of This work also led to a greater under- skin surface. taking care of deformed offspring—and standing of normal skin. When Fuchs By the mid-1980s, Fuchs moved on also an explanation for why all the trans- moved her lab to Rockefeller in 2002, to investigate what happens when the genic pups in the litter appeared normal? she continued to focus on skin stem cell genes involved in making keratin pro- Clearly, they thought, close observation differentiation. teins are damaged. At the time, geneti- of the mice in the immediate hours after Fuchs’s research today looks at the cists approached such a question using a delivery was needed. signaling pathways that help a skin stem technique known as positional cloning. “We essentially had a stakeout all night cell decide whether to become an epi- An investigator would choose a disease long,” recalls Vassar, now a professor of dermal cell or a hair follicle. For a stem of interest and then find a large family cell and molecular biology at Northwest- cell to become a hair follicle, at the with affected members. Then the scientist ern University in Chicago. “We would right moment, the pathway known as would collect DNA samples from every- bring the mice into the lab, and then Wnt must be turned on, and another, one in the family and study the differences camp out the entire evening waiting for known as BMP, must be switched off. In in DNA sequences between the affected them to give birth.” The stakeout revealed the absence of these opposing signals, and the unaffected, hoping to find the rel- that some of the K14 mutations were so the stem cell becomes skin. While such evant mutation. severe that the very act of birthing stripped research at some point could lead to the “This strategy did not divulge how or the epidermis off the newborn. The mouse elusive cure for baldness, Fuchs is focused why the defect in the protein caused the pups were unlikely to survive in this way, on its less commercial, more profound tissue abnormality, which was what I was so the mother was instinctively cutting implications for human health. She and interested in,” Fuchs says. “So we started at her losses, eating the doomed mutants so her colleagues are now investigating the the reverse end and worked our way back.” she didn’t have to waste energy caring for relationship between the process of stem This process involved a relatively new them. A less attentive team would have cell activation and defects that cause cell kind of laboratory model, developed in the missed it altogether. proliferation and cancer. early 1980s: the transgenic mouse. It was a Vassar and a postdoc, Pierre ­Coulombe, backward approach, since the idea was first now chairman of biochemistry and molec- M aintaining Focus to create a mouse with a specific mutation ular biology at the Bloomberg School of Fuchs and Hansen spend most weekends of interest, then analyze the pathology of Public Health at Johns Hopkins Univer- exploring New York, often ending up the tissue defects, and finally find a resem- sity in Baltimore, managed to remove the at one of the city’s many art museums, blance to a human genetic disorder. mutant newborns from the cage in time standing for long stretches at a time in Not many scientists were making trans- to assess the damage. “The severe blis- front of their favorite paintings. A few in genic mice in 1986. Fuchs contacted one tering was due to mechanical fragility in particular at the Metropolitan Museum of the few in the Midwest—Susan Ross these mice,” Vassar says. Without a proper of Art—Virgin and Child by Murillo, at the University of Illinois—and asked keratin network, the skin cells were as frag- Vermeer’s Young Woman with a Water about sending a graduate student, Robert ile as eggshells, ready to break under the Pitcher—really hold their attention, as Vassar, to train in the Ross lab. mildest strain. well as several Picassos at the Museum of With this training, Vassar created a After a trip to the medical library, Fuchs Modern Art. “We can stand in front of a transgenic mouse expressing a mutation and Vassar uncovered two rare human painting for an hour,” Hansen told me, in the K14 gene, which is responsible diseases that looked much like the mouse “and even though we’ve seen it dozens of for building a keratin network in the disease: epidermolysis bullosa simplex times before, we see something new in it.” innermost layer of the epidermis. But (EBS), which involves blistering of the The same is true, it seems, of the way the transgenic mouse with the K14 muta- inner epidermal layer, and epidermolytic Fuchs looks at a skin cell—like a work of tion seemed to be normal in appearance, hyperkeratosis (EH), which manifests in art that reveals new insights every time she health, and behavior—in other words, the outer layers. Within a year, they had studies it, no matter how many times she’s the mutation showed no distinct pheno- worked out the genetic basis for both EBS looked at it before. Like Picasso in his type. “We were very disappointed,” Fuchs and EH, building on a discovery Fuchs cubist period, she continues to focus her recalls. “We thought it was a complete fail- had made as a postdoc, that as epidermal kaleidoscopic view on familiar questions ure, a good idea but bad luck.” stem cells differentiate, they switch off two in search of surprising answers. W

May 2o1o | hhmi bulletin 21 AlrL Si ve ining Sure, some prions can cause diseases, but others are turning out to be beneficial.

by Richard Saltus illustration by Deth P. Sun

22 hhmi bulletin | May 2o1o

Evn e tHE worstgang of rogues Research at the Massachusetts Institute of Technology. “Prions may reveal surprising qualities that cast them in a more favorable are a really deeply rooted part of normal biology.” light. In fact, evidence is mounting that a class of proteins called She developed this silver-lining view of prions back when prions—despite the fact that their best-known member causes a most scientists saw nothing but their destructive side. In a review rare, deadly brain-wasting scourge in humans—can also be good written in 1997, Lindquist wrote: “My contention is that yeast and citizens in the life of a cell. mammalian prions are not oddities in a biological freak show, but In 1982, Stanley Prusiner, a biochemist at the University of actors in a larger production now playing in a theater near you.” California, San Francisco (UCSF), isolated the first prion as That prediction is being borne out by a stream of discoveries the cause of lethal scrapie in sheep. In 1997, he won a Nobel from her Whitehead laboratory and others in the United States Prize for the achievement and for characterizing a mechanism and abroad. “The real excitement now is to determine how wide- for ­protein aggregation and self-perpetuation, or as the Nobel spread this biology is,” Lindquist says. committee wrote, “for his discovery of prions, a new biological principle of infection.” The good guys In the intervening years, a variety of proteins with primi- The first hint that prions might be advantageous in multicellular­ tive self-sustaining properties have been found in yeast, fungi organisms came in 2003 in a series of studies in the giant marine and bacteria, snails, flies, turtles, frogs, birds, mice, and other snail Aplysia californica. A major question in brain research is mammals, including cattle, sheep, deer, elk, and people. The how memories are stored. Research in Aplysia had shown that functions of these prions are far more diverse and complex than memories are stored at specific nerve synapses that undergo long- anyone imagined. term strengthening that lasts as long as the memory lasts. In the Prions are proteins that have converted from a normal config- first of two papers published in Cell in 2003, HHMI investiga- uration to a “misfolded,” self-perpetuating form that reproduces tor and neuroscientist at Columbia University, and even though it lacks a genetic blueprint like DNA or RNA. Like his former postdoc, Kausik Si, now at the Stowers Institute for one bad apple spoiling the barrel, the prion sets off a cascade, Medical Research, found that the long-term maintenance of converting other proteins of the same kind from which it was this process at nerve synapses requires continuous production formed into prions as well. of prote­ ins, which is regulated by a protein called CPEB. To be sure, some prions are nothing but bad news. That first But how did CPEB keep this process going? Si noticed that one, termed PrPSc by Prusiner, forms toxic amyloids, abnormal one end of CPEB resembles the prion domain found in yeast proteins that aggregate to form tough, fibrous deposits in cells. prions. He suggested that the protein could convert to a self-­ Amyloids spread through the brain and spinal cord, decimating perpetuating form that was distinctively prion-like. He and nerve cells in animals and humans. Kandel wondered if, when stimulated repeatedly (as in learning), A string of recent findings, however, shows that some prions can the CPEB in synapses could become a self-sustaining protein serve beneficial functions—among them: helping maintain long- that spurs the ongoing translation of messenger RNA (mRNA) term memories in snails, mice, and fruit flies; fast-forwarding into memory. evolution in yeast to equip them with survival traits; aiding syn- “In principle, this could be how you remember things for the thesis of the pigment melanin in mammals; forming biofilms that rest of your life,” says Kandel. give adhesive properties to bacteria; and storing hormones inside To test this idea Kandel and Si joined forces with Lindquist. endocrine cells. In the second 2003 Cell paper, they observed that CPEB “The disease prions are just a minor idiosyncrasy,” says HHMI proteins from the Aplysia, when inserted into yeast, formed self-­ investigator Susan Lindquist, a leading researcher on protein perpetuating units. In a follow-up paper in Cell in February 2010, folding and prions at the Whitehead Institute for Biomedical Si and Kandel showed the same in Aplysia’s own sensory ­neurons:

24 hhmi bulletin | May 2o1o Lenny Gonzalez that had a beneficial effect in allowing cells to try out genetic variation hiddenintheir genome,”genetic Lindquist says. out try to cells allowing in effect beneficial a had that an essentialroleinthemaintenance ofyeastprions. plays Hsp104 that observed others and She proteins. aggregated 1998 a dissolving by temperature in in changes to adapt yeast helps showed paper, she which, a Hsp104, on protein, working was “heat-shock” She observations. landmark his published self-replicating andformsfibrousamyloids, justasinmammals. is form PSI+ The psi–. and version—PSI+ prion a and normal a between forth and back switch can Sup35p as known protein in a normal form and a misfolded prion form. A case in point, the Institutes of Health reported that certain yeast proteins could exist tial benefits of some prions. In 1994, Reed Wickner of the National ­S also existsinhumans. of homolog prion-like of role ­features the probe to system model the using is and a memory. forms that is strengthening form synaptic the prion maintaining the for essential and prion self-sustaining a like acts CPEB accharomyces cerevisiae “Later, my lab reported that PSI+ was an ‘evolvability factor’ factor’ ‘evolvability an was PSI+ that reported lab my “Later, Wickner that time the around field the entered Lindquist yeast fast-growing the in been have studies prion Most the on working is Si in learning and memory. Kandel’s lab group has found a Aplysia and fly CPEB in mice. A homolog of CPEB of homolog A in mice. CPEB fly and , which yielded the first clues to the poten- Aplysia Aplysia CPEB homolog in the fruit fly fly fruit the in homolog CPEB prion phenomenonisanalternate evolutionarypathway. the that argument convincing a building with Lindquist credits who Switzerland, in Zurich of Hospital University the at expert prion a Aguzzi, way,”Adriano non-genetic says a in information have evolvedthroughtheselectivepressureofstress. stress, andchangesincarbonsources. oxidative concentration, salt as such variables environmental to adapt yeast the helps potentially switching prion can by selected that be phenotypes new of collection The states. prion have that proteins 19 uncovered and genome yeast the surveyed had can form beneficialprions. Weissman that someproteins of timesuggests to Jonathan conserved over longperiods Evidence that prionshave been o ncie t esr ta sm o te el srie under survive cells the of some that ensure to inactive, to active or active, to inactive from switch will cells yeast logged water- the in Various prions environment. different drastically a in now is yeast the puddle, a into and vine the from falls yeast more numbers onaroulettewheel.” on money put who gamblers prions—“like become and misfold The more stress the yeast is under, the more likely its proteins will “Westrategy,”speak. ‘bet-hedging’ a as this of explains. think she to so waters, the test to genes silent previously on sion—turning conver- the make cells of number small a Just prions. to colony whole the switch doesn’t organism the Lindquist, says ditions, and couldhelptheorganism toevolvemorequickly.” beneficial potentially are that states biological new immediate provides this that think we and cell, the in expression gene of pattern the change “They explains. Lindquist switched,” is tion ­hundreds ofthousandsyears. for microorganisms in conserved been have they shown, has he as because, beneficial,”—especially are that prions form can’t proteins other that mean doesn’t “that toxic, certainly almost is PrPSc the while that, agrees Lindquist.He with collaboration in also and independently prion PSI+ the of functions survival ied some donot. w ater. Some of those activation switches help the yeast, but but yeast, the help switches activation those of Some ater. “I think the prion principle is a wonderful way to distribute distribute to way wonderful a is principle prion the think “I may prions that suggestion Lindquist’s reinforce results The For example, Lindquist explains, if a grape dusted with with dusted grape a if explains, Lindquist example, For con- changing with confronted suddenly is yeast the When func- their state, prion the into switch proteins the “When L Jonathan Weissman, an HHMI investigator at UCSF, has stud- indquist and colleagues reported in in reported colleagues and indquist Cell Cell May 2o1o May in 2009 that they they that 2009 in

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bulletin ­ 25 Susan Lindquist, Eric Kandel, and colleagues have ­collaborated to show that proteins involved in normal cell processes can convert to a self-perpetuating, prion-like form to maintain memory, for example.

A killer introduction The 1982 discovery of prions by Stanley Prusiner, a biochemist at UCSF, was a stunning answer to a longstanding and stubborn problem: what was the mysterious agent responsible for trans- missible spongiform encephalopathies (TSEs)—progressive, incurable, and lethal diseases that destroy nerve cells and leave a sponge-like trail of destruction? The earliest known TSE was scrapie, an affliction of sheep. Other TSEs now known to be prion diseases are bovine spongi- form encephalopathy (BSE, or mad cow disease) and some very rare but lethal neurodegenerative diseases in humans, including Creutzfeldt–Jakob disease (CJD), variant CJD, kuru, and familial fatal insomnia. These diseases have incubation periods measured in years. The BSE epidemic of the 1980s and early 1990s killed 170,000 head of cattle and led to the slaughter of more than If for any reason the protein fails to fold correctly, it may not work 4 million cows, mostly in England, before it subsided. During this at all, or its function may be different from what was specified. epidemic, a form of BSE called variant CJD spread to humans PrPSc, the scrapie prion isolated by Prusiner, is a misfolded who ate meat products from the infected herds. Mad cow disease form of a naturally occurring cell-membrane protein, PrP, which killed about 200 people. is expressed in nerve tissue and elsewhere in healthy people and Scientists had determined that the agent carrying scrapie was many animals. very small and extremely hardy: it couldn’t be inactivated by heat, ultraviolet radiation, or denaturing, which would destroy Reason for being any genetic material used in reproduction. Researchers have spent many years in a frustrating hunt for the Prusiner reported that the cause of scrapie was a novel infec- function of the normal PrP protein. Surely this protein must have tious particle, which he dubbed a “prion,” consisting solely of some other reason for being than to form lethal prions. Studies misfolded proteins, devoid of genetic material. This was hard showed that mice in which the PrP protein was “knocked out” to swallow for many scientists, since even the smallest bacte- were resistant to infection with the misfolded PrPSc prions. ria and viruses have some genetically encoded instructions Otherwise,­ lacking the PrP protein seemed to have little effect. for replication. A piece of the puzzle seems to have fallen into place. Aguzzi For years afterward, some skeptics rejected the “protein-only” and other scientists reported in January 2010 in Nature Neuro- model of prions, arguing that they must contain some genetic science that the protein helps maintain the myelin sheaths that material that had escaped detection. A strong refutation of that surround and protect neurons in the peripheral nervous system. view came in 2000 when Weissman at UCSF reported that he In mice engineered to lack PrP, peripheral nerves suffered pro- had created synthetic prions in a test tube directly from a pure gressive damage as a result of demyelination. Aguzzi said in an yeast protein, Sup35. interview in the journal that he suspects PrP plays a similar role To understand what makes a prion, recall that cells manufac- in higher mammals. ture proteins by assembling chains of amino acids according to a The finding may also bear on another longstanding enigma: “recipe” contained in a specific gene. Then the protein folds into a are prion diseases caused by a “gain-of-function” process—the mis-

three-dimensional configuration like a complex piece of origami. folded protein itself damages nerve cells—or a “loss-of-function”­ Lindquist: Cheryl Senter / AP, ©HHMI Kandel: Matthew Septimus

26 hhmi bulletin | May 2o1o change, in which conversion of the normal protein to prions robs a prion determines its configuration and how the resulting struc- the nerves of something they need to stay healthy? tures differ at the atomic level. Outside the nervous system, another hint of PrP’s normal func- HHMI investigator David Eisenberg, a protein structure spe- tion came in a 2006 report from the Lindquist lab. The scientists cialist at the University of California, Los Angeles, uses various found that expression of the protein in stem cells is necessary for types of x-ray crystallography techniques to study the structure of the self-renewal of blood-manufacturing tissues in bone marrow. the amyloid proteins produced by prions. The study showed that all long-term hematopoietic stem cells In 2005, Eisenberg showed that when a protein converts to a express PrP on their surfaces and that blood-forming tissues lacking prion, it polymerizes into an aggregate made up of tightly packed PrP in stem cells exhibited increased sensitivity to cell depletion. layers known as beta sheets (as opposed to the coiled alpha heli- ces that dominate in the normal protein structure). The firmly Structure as blueprint bound beta sheets, held together by an interlocking of their HHMI scientists have begun to another prion riddle— side chains that Eisenberg has termed a “steric zipper,” give the the existence of distinct “strains” of prions that produce different prion its stable, tough properties. In fact, the sheets are so closely phenotypes. For example, the PrPSc prion causes several distinct packed that they exclude water, making prions insoluble. neurological diseases in animals and humans. Each disease is In a 2009 paper in Nature Structural & Molecular Biology, slightly different in the length of its incubation period, the typical Eisenberg proposed an explanation of how a single protein gives symptoms, and the areas of the brain that are damaged. rise to varying shapes of amyloids that specify different strains. “This was one of the most intriguing and challenging questions,” Instead of DNA alterations, as in living organisms, prion strains explains Weissman. In viruses or bacteria, strain differences are speci- are specified by structural changes that are sufficiently stable to fied by instructions in their genetic code. If prions lacked any genetic perpetuate the strain identity in successive prions—and when material at all, where were the blueprints that determine strains? they jump from cell to cell and animal to animal. Weissman carried out a series of experiments demonstrating In one type of strain-determining mechanism, the same seg- that prions could propagate as distinct strains, each specified by ment of a protein’s amino acid sequence can specify different different arrangements of atoms in the protein’s structure. The “packing” arrangements of the beta sheets. In an alternative structural configuration of a prion strain was the blueprint for mechanism, distinctive beta sheets are produced by different making more copies—no DNA required. ­segments of the protein. Using the powerful yeast system, Weissman and colleagues “Our hypothesis is that the differences in packing produce created synthetic prions with different configurations that gener- diverse amyloid fibrils, and these fibers cause different disease ated phenotypically diverse strains. In another experiment, they types,” says Eisenberg. analyzed two distinct strains of the yeast protein Sup35, one of In fact, these variations that Eisenberg is finding at the most which was strongly infectious and the other weakly infectious. fundamental, atomic level may come full circle to explain the The analysis required a special application of nuclear magnetic array of functions—some harmful, some helpful—found in resonance spectroscopy, which enabled him to identify structural ­prions ranging from yeast to humans. differences at the atomic level underlying these ­different pheno- Meanwhile, he and other scientists, including Si, Kandel, types. The results, published in Nature in 2007, confirmed that and Lindquist, are searching for evidence of the positive side the same protein can misfold into dramatically different prion of prions. conformations—which is why the phenotypes they produce can If that search is fruitful, Si has a radical proposal: “Prions have vary so significantly. been so tightly linked to the diseases that if we find more of these Some of the newest prion work takes a deeper look at multiple positive functions, I think eventually we might have to come up strains. The goal is to figure out how the amino acid sequence of with a new name for them.” W

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b ny Ra dy Barrett illustration by Mike Perry

Teewh n Janelia computing cluster puts a premium on expandability and speed. ple—it’s pretty obvious to anyone which words are basically the same. That would be like two genes from humans and apes.” But in organisms that are more diver- gent, Eddy needs to understand how DNA sequences tend to change over time. “And it becomes a difficult specialty, with seri- ous statistical analysis,” he says. From a computational standpoint, that means churning through a lot of opera- tions. Comparing two typical-sized protein sequences, to take a simple example, would require a whopping 10200 opera- Computational biologists have a need for to help investigators conduct genome tions. Classic algorithms, available since speed. The computing cluster at HHMI’s searches and catalog the inner workings the 1960s, can trim that search to 160,000 Janelia Farm Research Campus delivers and structures of the brain. computations—a task that would take the performance they require—at a mind- only a millisecond or so on any modern boggling 36 trillion operations per second. F aSTER Answers processor. But in the genome business, In the course of their work, Janelia A group leader at Janelia Farm, Eddy deals people routinely do enormous numbers researchers generate millions of digitized in the realm of millions of computations of these sequence comparisons—trillions images and gigabytes of data files, and they daily as he compares sequences of DNA. and trillions of them. These “routine” cal- run algorithms daily that demand robust He is a rare breed, both biologist and code culations could take years if they had to be computational horsepower. Geneticists, jockey. “I’m asking biological questions, done on a single computer. molecular biologists, biophysicists, physi- and designing technologies for other peo- That’s where the Janelia cluster comes ologists, and even electrical engineers ple to ask biological questions,” he says. in. Because a different part of the work- pursue some of the most challenging Eddy writes algorithms to help re- load can easily be doled out to each of problems in neuroscience, chief among searchers extract information from DNA its 4,000 processors, researchers can get them how individual neuronal circuits sequences. It’s a gargantuan matching their answers 4,000 times faster—in hours process information. Their discoveries game where a biological sequence— instead of years. The solutions don’t depend, now more than ever, on the seam- DNA, RNA, or protein—is treated as a tend to lead to eureka moments; rather, less interplay of scientists and computers. string of letters and compared with other they provide reference data for genome Humming nonstop in Janelia’s compact ­sequences. “From a computer science researchers as they delve into the com- computing center are 4,000 processors, standpoint, it’s similar to voice recognition plexities of different organisms. “These 500 servers, and storage machines holding and data mining,” he says. “You’re compar- computational tools are infrastructural, a half a petabyte of data—about 50 Libraries ing one piece against another. We look for foundation for many things,” Eddy says. of Congress worth of information. a signal in what looks like random noise.” While that may not sound dramatic, Though there are many larger clus- Eddy looks for the hand of evolution in Eddy’s protein-matching algorithms are ters around the world, this particular DNA by comparing different organisms’ an industry standard, used by researchers one is just right for Janelia Farm. “Beau- genomes. He’s searching for strings of as the search tool for a reference library tifully conceived, ruthlessly efficient, DNA sequences that match—more than called the Protein Families database, and extraordinarily well run by the high-­ random chance would dictate. or . There are roughly 10 million performance computing team,” according “It’s a lot like recognizing words from proteins in the database. Luckily about to Janelia researcher Sean Eddy, the sys- different languages that have a common 80 percent of those sequences fall into tem is designed to make digital images ancestry, thus probably the same mean- a much smaller set of families and Eddy available lightning fast while muscling ing,” he explains. “In two closely related has designed the analysis software to query through the monster calculations required languages—Italian and Spanish, for exam- for matches in this data set. “When a new

30 hhmi bulletin | May 2o1o Paul Fetters ra te otae n ps te enve- lope,” hesays. the push and software the break improve them. his analysis tools to the failure point so he can stressing means which users, his of ahead step one keep to has Eddy bilities. have software design and upkeep responsi- for which Eddy and his Janelia team 12,000 protein families. identifies currently database The says. he to,” added being always tionary—it’s dic- a like is [Pfam] in, comes sequence BOTTO M TO accom- togrowneasily be can andsystem previous the than responsive more nitude mag- of order an is that platform a vides six timesmorememory. has and one old the than faster times 10 to up is system new The them. built who engineers the by signed are and 2 or 1 ber num-serial have components the of some fact, design—in particular this for tomer cus- first the is Janelia class supercomputer.” “working a system the calls Eddy Networks, Arista and Dell, Intel, by built com- of components hardware available mercially up Made refresh. technology four-year regular a of part as upgraded tific needs may change and evolve rapidly. scien- the since particularly response, fast premium on expandability, flexibility, and a puts design Its it. demand requirements if more many serve to up scale can and staff support and researchers cluster 350 The serves users. its and both by overseers its processors of “cluster” a as to referred is system computing Janelia The A M I DDLE: P: to try and experiments up set “We called database RNA an also is There “Janelia’s new computing cluster pro- cluster computing new “Janelia’s recently was cluster computer The osaic R oian Egnor M: Sean Eddy Elena

of R F ivas, Lou Sheffer l y N May 2o1o May eurons

| hhmi bulletin 31 modate changing requirements,” says Vijay But Scheffer’s matching is just the first processors. Those familiar with office net- Samalam, Janelia’s director of information step in the image-manipulation process. works know it well: ­Ethernet, the popular technology and scientific computing. Janelia software engineer Philip Winston standard for moving electronic data from That expanded capacity is a big help to takes the processed pictures and does the point A to B. While it has been a long- Janelia fellow Louis Scheffer, an electrical unthinkable—he chops them up again. standing protocol for slower connections, engineer and chip designer by training. He creates smaller “tiles” of the photos, 10-gigabit Ethernet has not traditionally He uses the cluster to help researchers which can be more easily added and been the choice of makers and engineers map the brain wiring of the common fruit subtracted from a computer screen as a of top supercomputers who until recently, fly Drosophila melanogaster. Essentially, researcher pans across an image. “To open when best performance was a must, used it’s a massive three-dimensional image- a single image would take five minutes if specialized networking technology called manipulation challenge. First, slices of you didn’t tile them,” says Winston. Only InfiniBand. brain 1/1,000th the thickness of a human 20 tiles are required on the screen at any “Now Ethernet switches are as effi- hair are digitally photographed with an one time. Currently, Winston is working cient as, or very close to, InfiniBand and electron microscope and stored. In each with four million tiles as part of the Janelia you don’t need a different [networking] layer, the computer assigns colors to the Fly Electron Microscope project to map skill set,” says Spartaco Cicerchia, man- neurons so researchers can trace their the entire brain of the fruit fly. ager of network infrastructure at Janelia path. As an example, the medulla of the Humans proofread the final fly-brain Farm. The bottom-line advantage is that fly, part of the brain responsible for vision, image for accuracy, to trace the neural Ethernet is easier to work with, familiar requires more than 150,000 individual paths and make sure the computer has to more networking engineers, and tends images to create the full mosaic, which is identified structures correctly. “[People] to be cheaper to use. 1,700 layers (slices) deep. are an important step,” says Winston. Lower latency—the time it takes to But all these pictures must be knitted “Without them, the computer segmen- move data across a network connection— together so scientists can follow neural tation would be 95 percent right and we is now possible via Ethernet due to a paths and see where they lead. Think wouldn’t know about the other 5 percent.” relatively new networking standard called Google Earth. As you pan across the Scheffer and Winston’s ultimate goal iWarp. Traditionally, computers’ proces- globe, data are fed onto the screen so you is to completely automate the mapping sors must manage the flow of information can “fly” from one location to another, process and to teach the computer to packets as they pass between them. In the and more images are required as you drill identify the inner structures of the fruit new systems, those packets are handled by down to examine surface topography. fly brain, in particular the different types a separate piece of hardware made by the Making the transitions smooth in between of neurons, and the axons and dendrites chip manufacturer Intel. images requires fine-tuned alignment. “It’s branching out from them. “To do the “Traditionally, [central processing units not completely simple—there are a whole whole fly brain we have to improve the handle] network packets. However, when bunch of distortions to deal with,” says automated segmentation,” says Winston. network interface speeds went from 1 to Scheffer. Some are caused by the electron Scheffer hopes to achieve the computer- 10 gigabits per second, the load on CPUs microscope itself as it dries out the target generated—and accurate—mapping of increased by an order of magnitude,” says specimen during imaging. the brain within the next five years as Goran Ceric, Janelia’s manager of scien- To align one image to its neighbor more pieces are imaged and processed. tific computing systems. takes about one minute of computer time. The creation of iWarp helped alle- But once matched, the resulting checker- Easier Communications viate this issue and reduce latency and board must be stacked and aligned with The increased speed of the new computing overhead. iWarp helps in three ways, the mosaic of images above and below. system will make that effort easier going according to Ceric: by processing net- “You need to make about one million forward. The cluster is faster than its pre- work packets using specialized hardware comparisons,” Scheffer says. “It would decessor for two reasons: it has more than instead of CPUs; by placing data directly take [a personal] computer four years.” four times as many individual processors, into application buffers, thus eliminat- With Janelia’s parallel processors on the and it’s using a networking technology that ing intermediate packet copies; and by task, the job is done in a few hours. speeds up the communication between reducing a need for “context switching,”

32 hhmi bulletin | May 2o1o Janelia’s IT team—Vijay Samalam, Spartaco Cicerchia, and Goran Ceric—recently updated its computing cluster, building it from ­commercially available hardware components by Intel, Dell, and Arista Networks, and using popular and now faster Ethernet networking.

in which a processor must pass commands daily. “If you take those vocalizations and programs is identical,” Rivas says. “We’re back and forth between an application computationally lower frequencies, they going to try to determine the types of and an operating system. “For many paral- sound remarkably like bird songs.” [mouse] vocalizations and try to model lel applications,” he says, “if you can lower Egnor is trying to better understand each one.” communications time between processors the elements of these mouse whispers. Once those models, or “families,” are in different systems over the network, the “When you look at mouse vocalizations, delineated, researchers can then test new better your performance is.” there appears to be some acoustic struc- mouse vocalizations against these tem- The new network infrastructure has ture to them. What is it for?” she says. plates. “Then we’ll try to catalog every- dropped the communications lag inside To find out, she is collaborating with thing the mouse says,” Rivas explains. The the Janelia cluster from 60 to 10 micro­ another Janelia fellow, Elena Rivas, who analysis takes the computing cluster only seconds—a sixfold improvement. is starting to process the communications a few moments to run. using a statistical analysis tool called a “The beautiful thing about Janelia Mouse Talk hidden Markov model. The software is is that I stream that [information] to the Janelia Farm fellow Roian Egnor isn’t a similar to that which Sean Eddy uses to data share, and Elena picks it up and starts computer scientist or network engineer, compare millions of DNA strands. working on it,” Egnor says. but her research on the vocalizations of “The cool thing about hidden Markov Making that transfer possible is mice (and the neural pathways required) models is, you can tell them ‘Look, here’s another hidden attribute of the Janelia depends partly on heavy computation what I think are good examples of what research complex—its internal network. power. Though famed for their quiet I want you to characterize. Learn them, It’s the pipeline that carries huge image or ways, it turns out mice are chatterboxes. and then I’m going to give you unlabeled auditory files without clogging or slowing All their communications, unfortunately, vocalizations and I want you to see which down the system. In the startup phase, that happen at frequencies between 30 and match and which don’t,’” Egnor says. meant overbuilding the fiber infrastruc- 100 kilohertz, far above the range of Rivas has reworked a standard pro- ture as much as possible and designing human hearing. tein analysis program called HMMER3 it to handle unpredictable loads through “There’s a secret world up there,” says to handle Egnor’s data, which comes in 10-gigabit ports. Janelia’s network is fully

Paul Fetters Egnor, who records hours of mouse talk one-terabyte chunks. “The core of the (continued on page 48)

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May 2o1o May S E V I T C E P S R E P

o & p I N I o n s ern Peering in Time in ak Back Joseph P. Noel Noel P. Joseph

John Dole Joseph P. Noel wants to use paleontology to learn how plants endured history’s harsh climates—and how to ready crops to face severe conditions in the future. Protecting the world’s food supply by borrowing from plants of the past is a natural solution that should appeal to the public, says the HHMI investigator at the Salk Institute for Biological Studies.

Most people are familiar with biodiversity. But “chemodiver- Some plants have evolved those enzymes further to make sity”—the tapestry of natural chemicals found in plants—is a flavonoid-like molecule called resveratrol. This molecule, just as important for life, the appearance of new species, and found in red wine, has received plenty of positive public- the survival of many different ecosystems. More than any ity over its anti-aging and cholesterol-lowering properties in other organism, plants produce hundreds of thousands of animals. The grapevine makes resveratrol to defend against different kinds of chemicals. They use unique chemical fungal infections. After generations of breeding for grape cocktails to protect themselves from the elements, battle quality, however, some modern grapevines have lost the abil- infections, and attract pollinators, among many other things. ity to make resveratrol as efficiently as their ancestors. To get People have long exploited plant chemicals—as medicines, the same level of protection that resveratrol could provide, for example. With modern tools to compare genes and enzymes wineries have to use artificial fungicides, which can damage from diverse organisms, we are now in a position to under- the environment. stand the natural history of plant chemical systems—much To make the grapevines naturally fungus resistant like a paleontologist but at a molecular level. Evolution teaches again, growers could try to restore resveratrol biosynthesis us how plants responded to threats such as climate change in through breeding, a slow process. I suggest, instead, that the past and how we can speed up their adaptation today. scientists could use genetic engineering to quickly and pre- The importance of plant chemicals to animals, and cisely return the right enzyme to the grapevine. This kind ultimately people, goes all the way back to the Cambrian of pinpoint ­engineering, based on what nature has already explosion. Approximately 500 million years ago, animal life explored, would allow scientists to take a shortcut to engineer underwent a large evolutionary expansion. That event was crop plants. very likely predated by plants moving from water to land. We could also use this technique to engineer plants to Plants provided food for the newly arriving animals. If plants withstand climate change. History repeats itself: in past eras, hadn’t migrated onto land, you and I wouldn’t be here. carbon dioxide concentrations on Earth were 10 times higher These early land plants needed protection from the sun’s than they are now, and most of the planet was a hot, wet envi- damaging UV rays. When ancestors of these early plants lived ronment. With collaborators, I hope to re-create ancestor in water, the water absorbed most of the UV rays. To live on enzymes from these time periods and discover what kinds of dry land, however, plants needed sunscreens. The sunscreen chemicals helped them thrive in high temperatures. We can molecules they likely used looked much like modern plant apply the same genetic changes to speed up plant adaptation chemicals called flavonoids. In today’s plants, flavonoids play to climate change today. a number of roles: they are very effective at absorbing UV Genetic manipulation of plants remains controversial; radiation, and they are responsible for the colors of flowers. people worry about unintended consequences of moving a Different species of plants make unique, but similar, chem- gene from one organism into another. But that’s not what icals using similar enzymes. By comparing the few genetic we’re doing here. We want to restore an ability—thriving differences between closely related enzymes, we can envi- in a warmer, carbon-dioxide-rich climate—that the ances- sion the “ancestor enzyme” that these cousins evolved from. tors of modern plants once had. While the plants would be Studying this “old” enzyme in the lab, we learn what chemi- transgenic, we would use the plants’ own genes, not genes cals it likely made. In essence, we reanimate these molecular borrowed from other organisms. I think the public will likely fossils to peer back in time. approve of this more natural approach. In my lab, we have used this technique to discover that the enzymes that make flavonoids are very similar to the enzymes that make fatty acids in all organisms. Modern plant ances- tors, by a fluke of evolution, coopted the enzymes that make Ivn t e r i ew b y A m b e r D ance. Joe Noel is the director of the fatty acids, changed them incrementally, and began mak- Jack H. Skirball Center for Chemical Biology and Proteomics ing sunscreens. at the Salk Institute.

May 2o1o | hhmi bulletin 35 Q & A I f you were to take a year off to “change the world,” what would you aim to do? Great scientists possess creativity and analytic skills that can be applied to problems outside their laboratories. In the online edition of this Bulletin, Patrick O. Brown explains why he’s trimming back his academic responsibilities for a year so he can make a difference for the planet. Here, other scientists ponder what they might do with a free year.

— E D I T E D B Y S a r a h C . P. W i lliam s

Richard H. Ebright Maria Spies L. René García Susana López HHMI Invest i g at o r H H M I E a rly Career HHMI Invest i g at o r HHMI Internat i o n a l R u t g e r s , T h e S tat e S ci e n t i s t T e x a s A & M U n i v e r s i ty R e s e a r c h S ch o l a r U n i v e r s i ty o f N e w J e r s e y U n i v e r s i ty o f I l l i n o i s at I n s t i t u t e o f “I would spend the year U r b a n a – C h a m pa i g n B i o t e c h n o l o g y, “I would run for the traveling areas of the world N at i o n a l A u t o n o m o u s “I would most certainly United States Senate. that are experiencing social U n i v e r s i ty o f M e x i c o pass up this opportunity— Our country faces edu- and educational problems, “I would invest that year a year is too short to ‘change cational, economic, and both to share my own in convincing people who the world’ for better, even environmental crises that expertise with the people make enormous amounts if the offer comes with a threaten its preeminence there and to learn from of money (TV and movie superhero cape. People in and possibly even its sur- them. I would coordinate stars, singers, athletes, my line of work are already vival. There is a dearth the trip with a traveling etc.) to donate just a small in a privileged position to of persons in the Senate hands-on science exhibi- part of their earnings to make a positive impact. with the ability to process tion, so people could play make a well-administered With every scientific mys- and interpret the quantita- with simple microscopes, foundation, with the sole tery we solve, with every tive information needed telescopes, and other scien- purpose of ensuring that young researcher trained, to recognize and address tific tools to explore their every child in underdevel- with every student taking these crises. environment. Through my oped countries has access something away from Alternatively, I would travels, my goal would be to all available vaccines, our lectures, we make restore coral reefs by to observe the differences independent of their cost, the world, if not a better transplanting artificially and similarities between and to guarantee that these place, at least a more propagated corals. Over a the various regions’ trou- ­children are nourished enlightened one. I believe one-year period, I would be bles. At the end, I would properly during the first I am in exactly the right able to plant 5,000–10,000 contemplate what I had five years of their lives. This place to make incremental coral plugs and cover an learned and then decide would help give a fair start but lasting contributions acre of seabed. This would future activities to promote in life to the people born in to the world.” be a small part of the world, more lasting changes.” underdeveloped nations.” but it would be a start.” Ebright: Jennifer Altman Spies: L. Brian Stauffer / UIUC News Bureau García: Michael Stravato / AP, ©HHMI López: David Rolls

36 hhmi bulletin | May 2o1o chronicle

38 s cience education 46 n ota bene T he Heart of a Snake / 2010 Gilliam Fellows Lee Wins National Academy Award / HHMI Early Career Scientists Named Vilcek Finalists 40I n stitute N e w s Lummis Elected HHMI Trustee / Jibrell Selected Specific areas of a mouse brain are visible with a as Vice President of Information Technology / new molecular tool developed by HHMI scientists. HHMI Investigator Sean Carroll Named Vice Here, fluorescence reveals which neurons in a President for Science Education mouse’s brain are involved in whisker movement and tactile sensation. Visit www.hhmi.org/bulletin/ 42 l ab book may2010 to read about the brain-illuminating tool. Y oung Again / Lab-Grown Liver / Going Solo

45 a sk a scientist H ow do scientists learn about plants that are extinct? Looger Lab

May 2o1o | hhmi bulletin 37 38 hhmi the wild through these year-long fasts. Their heart and liver balloon mals withmore“extreme”physiology. organismsmodel typical beyond think to researchers ani-study and exhorting Diamond Jared physiologist reptile by article an came across she 2006, In turn. unexpected an took research her when studying heart biology in mammals, including humans, for 15 years and disease. the of ­m landscape genetic the how understanding in who interested Leinwand, is for organism study ideal an make they feeding, to be a great way to lure upper class students into hands-on biology. HHMI Leinwand’sLeslie professor animal choicesize. of model out turned has in double nearly liver and heart their meal, a do score they once AN and, food, without year full a go can snakes These Yo u A The HeartofaSnake a  n nd ammalian heart shifts during feeding, exercise, pregnancy, pregnancy, exercise, feeding, during shifts heart ammalian science education science u Diamond was studying Burmese pythons, which can survive in survive can which pythons, Burmese studying was Diamond been had Boulder, Colorado, of University the at Leinwand, to response dramatic a such undergo organs python Because

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Brett Ryder Because of the novelty of working with snakes, and the fact that takingly inspecting agarose gels containing amplified DNA samples almost nothing is known about the genetics and molecular biology of from polymerase chain reactions they performed earlier that week. pythons, she thought it would create an ideal learning opportunity. The gels separate DNA fragments by size, allowing the students to The snakes are housed in a balmy room in the basement of the compare their amplified product against a standard of known size psychology department. Leinwand’s laboratory assistant, Chris Wall, and identity. Next they will work with RNA derived directly from reaches into one of the bins with a gloved hand and deftly retrieves a the python’s liver tissue. dappled chocolate brown and tan Burmese python and drops it onto Several groups exclaim that they have successfully obtained a scale. This 210-gram snake is nowhere near as intimidating as the the DNA product they were after. Kaisa Wallace-Moyer, a junior 20-foot-long, 200-pound specimens that grow in the wild. Burmese majoring in chemical and biological engineering, says she enjoys pythons are really quite docile, Wall explains, though they can be the ownership that comes with running experiments that don’t have testy when hungry. a predictable outcome. “It’s just really cool knowing I get to come Back in the classroom laboratory, 16 students look on as Wall in here and do my own experiment,” she says. makes a smooth incision along the length of the euthanized snake’s Senior Ashley Crary agrees that the hands-on experience is glossy, muscular underbelly, explaining that snake organs are quite ­critical to learning the techniques. “It’s scary but also exciting that similar to humans’, only greatly elongated. The young snake hasn’t we’re actually practicing what we say we want to grow up and do.” eaten in a month, so the tissues the class collects today will yield Leinwand compares the python’s dramatic heart enlargement genetic information about its fasting condition. “So, pythons have after a meal to the beneficial heart enlargement that occurs in highly no venom sac?” one student asks. “Nope, they just kill by constric- trained athletes. “If we can understand how the python does this tion,” says Wall. “They’re actually really strong, and you’ll see that over and over again throughout its life, it could lead to therapeutics the entire body, outside of the internal cavity here, is solid muscle.” that could promote improved cardiovascular health,” she says. Wall took Leinwand’s course in the spring of 2008 and joined She hopes the students’ work will help paint a complete pic- her research group immediately afterward. He has been accepted ture of the expression patterns of these python genes during the into a Ph.D. program in biomedical sciences at the University of extreme metabolic shifts before and after feeding. But it’s not just California, San Diego, and says that Leinwand’s course cemented the ­experimental results that Leinwand is after. “My main goal is his interest in becoming a researcher. not the outcomes from the students’ experiments,” she says. “If they This semester, the students in Leinwand’s lab are analyzing gene learn to be excited about research and to think scientifically, that expression in a set of python genes that control liver proliferation. would be a success. If great results are a by-product, all the better.” W ­ They huddle in small groups around their lab benches, pains­ – A m an d a M a s c a r e lli

2010l Gil iam Fellows

After his grandmother died of liver cancer, Flavian D. Brown decided to devote his career to cancer research. Rachel A. Johnston’s childhood obsession with breeding guppies started her down the path to becoming a population geneticist. They are just two of the fve exceptional students who received HHMI’s 2010 Gilliam Fellowships for Advanced Study. Since 2005, Gilliam fellowships have helped 30 students go to graduate school. Gilliam fellows come from groups tradi­ tionally underrepresented in the sciences and are former participants in the Institute’s Exceptional Research Opportunities Program. Each fellow receives $44,000 in graduate school support annually for up to fve years. The 2010 fellows are (from left) Brown, Mariam El-Ashmawy, Johnston, Silvia N. Kariuki, and Lisandro Maya-Ramos. Brown: Tom Roster El-Ashmawy: Amy Gutierrez Johnston: Ken Stinnett Kariuki: Mark Segal Maya-Ramos: Mark Harmel

May 2o1o | hhmi bulletin 39 institute news

Lummis Elected HHMI Trustee

F r e d R . Lu m mi s , a H o u s t o n bu s i ne s s m an a n d e n t r e p r e ne u r , Landmark FBO, TRE Finan- has been elected a Trustee of HHMI. He becomes one of 11 ­Trustees cial Services, Avalon Advisors, of the Institute. and Amegy Bancorporation. Lummis, 56, is Chairman and Chief Executive Officer of Plat- He is a cum laude graduate form Partners LLC, a Houston, Texas-based investment company of Vanderbilt University, in that he cofounded in 2006. Before founding Platform Partners, he Nashville, Tennessee, where managed private equity investments for two successor firms, The he captained the men’s tennis CapStreet Group and Summit Capital. team. He received his M.B.A. Lummis began his business career at Texas Commerce Bank in from the University of Texas 1978 and ultimately managed a venture capital portfolio for the bank at Austin. He and Claudia, his before becoming senior vice president of the private investment firm wife of 33 years, have three of Duncan, Cook & Co. in 1986. From 1994 to 1998, Lummis served grown sons. as Chairman, President, Chief Executive Officer, and a director, Lummis and his family until 2008, for American Tower Corporation—today the largest inde- have a long association with pendent operator and owner of telecommunications towers in the HHMI. His father, William R. Lummis, served as a charter Trustee world. In 1998, he took over Advantage Outdoor Co. and managed of the Institute for more than two decades, until he retired in 2007. its operations until it merged with Lamar Advertising Co. in 2000. The elder Lummis played a critical role in reorganizing the Insti- A trustee of Baylor College of Medicine in Houston since 1996, tute following the death of Howard R. Hughes, Jr., the Institute’s Lummis also serves as Chairman of Cardtronics and a director of founder and Lummis’s cousin. W

Jibrell Selected as Vice President of Information Technology

Mmoo h a u d J i b r e ll , a n As chief information officer and director of information tech- expert in global information nology for the Washington, D.C.-based American Psychiatric technology (IT), has been Association (APA) from 2001 to 2002, Jibrell led a major realign- named HHMI’s next Vice ment of the systems that support the APA’s publishing and other President of Information activities. He also has extensive experience in the manufacturing Technology. Jibrell joined sector and held positions in IT and product management with the the Institute in March 2010, Thermo King Corp., a division of the Ingersoll-Rand Co. that man- after a seven-year tenure at the ufactures heating and cooling systems, from 1992 to 2001. From Ford Foundation. 1998 to 2001, he was a global product manager responsible for a “Mohamoud brings a line of bus air conditioning systems manufactured in the United wealth of experience to States, the Czech Republic, China, and Brazil. HHMI as a leader in infor- Trained as a mechanical engineer, Jibrell received his bachelor’s mation technology within degree from Trinity College in Hartford, Connecticut, and began the nonprofit sector,” says his career as an engineer with the Otis Elevator Co., a subsidiary of Robert Tjian, president of HHMI. “He brings vision, as well as United Technologies Corp. in Farmington, Connecticut. He was a demonstrated ability to collaborate effectively across a distrib- born in Somalia and moved to the United States as a teenager. He uted organization.” lives in Vienna, Virginia, with his wife Teha and their three children. At the Ford Foundation in New York, Jibrell served as chief Jibrell serves on the board of Samasource, a nonprofit organi- technology officer, overseeing IT operations in 13 locations. He led zation that leverages the power of the Internet to provide paying major initiatives to streamline the foundation’s IT operations and was work to marginalized people, including refugees and disadvantaged involved in developing and implementing new enterprise-wide sys- women around the world. He is also a board member of XBRL tems to support its worldwide grant-making activities. These efforts US, Inc., a nonprofit consortium that supports business report- included implementing a strategic plan, integrating global IT infra- ing standards in the United States through the adoption of XBRL

structure, and consolidating application systems into a single facility. (extensible business reporting language). W Jibrell: Paul Fetters Lummis: Courtesy of Fred Lummis

40 hhmi bulletin | May 2o1o HHMI Investigator Sean Carroll Named Vice President for Science Education

h h M I a nno u n ce d i n A p r i l t h at S ean C a r r o ll , a n awa r d - among young people? These winning scientist, author, and educator, will become the Institute’s are crucial challenges and vice president for science education. I hope to promote the very Carroll will be responsible for directing HHMI’s portfolio of positive role that science can science education activities when he succeeds Peter J. Bruns in play in our culture.” September. Bruns, a geneticist and former Cornell University fac- Carroll traces his own ulty member, announced his retirement last year after nine years fascination with science to in the post. a childhood interest in col- “Sean is a gifted scientist who also displays an extraordinary lecting snakes, noting in an talent for translating complicated scientific ideas in compelling, interview with the journal understandable ways to members of the public of all ages,” says Nature that they inspired both HHMI president Robert Tjian. “He is in a unique position to con- his first experiments (their nect our scientific and educational programs.” choice of food) and sense of Carroll, an HHMI investigator at the University of Wisconsin– beauty (the patterns of their Madison since 1990, studies the development and evolution of skin). Today, Carroll’s laboratory uses fruit flies—Drosophila mela- animal form. He is considered a leader in the field of evolutionary nogaster and its relatives—as models for understanding how new developmental biology, or evo-devo. Carroll and his colleagues have body patterns evolve over time. used the tools of modern molecular biology and genetics to reveal In a series of studies published over the last several years, Carroll how genetic changes during an organism’s development shape the and his colleagues have traced the origins of complex body-color evolution of body parts and body patterns. patterns. They’ve pinpointed mutations in gene regulatory elements The 49-year-old Carroll is also widely known as a speaker and responsible for when and where in the body those genes are used. writer about science for the general public. He is the author of six “We are now able to trace the genetic steps of evolution in unprec- books, including Remarkable Creatures: Epic Adventures in the edented detail. What our work has revealed is that, in general, body Origins of Species, a finalist for the 2009 National Book Award in parts and body patterns evolve through ‘teaching old genes new nonfiction. He writes a monthly column (also called “Remarkable tricks’—that is, using very old genes in new ways,” he says. Creatures”) for the science section of The New York Times and has Carroll is recognized as an exemplary teacher and last year served as a consulting producer for the public television program received the Outstanding Educator Prize from NOVA distributed by WGBH in Boston. In March, Carroll received the Society for Developmental Biology. The prize, established in the 2010 Stephen Jay Gould Prize in recognition of his efforts to 2002 in honor of a major figure in embryology, honored Carroll’s advance public understanding of evolutionary science. contributions to the field and singled out his leadership as a mentor “HHMI has had a big impact in shaping how science is taught, and educator. He is also a recipient of the Distinguished Service particularly at the undergraduate level. Colleges and universities are Award from the National Association of Biology Teachers. Along shaking up what they teach and HHMI has been a catalyst for that with David Kingsley, a fellow HHMI investigator, Carroll delivered change. That’s a great legacy to join,” says Carroll. the Institute’s 2005 Holiday Lectures on Science, “Evolution: Con- HHMI is the nation’s largest private supporter of science educa- stant Change and Common Threads.” tion. It has invested more than $1.6 billion in grants to reinvigorate A member of both the National Academy of Sciences and the life science education at research universities, liberal arts colleges, and American Academy of Arts and Sciences, Carroll graduated summa undergraduate-focused institutions as well as to engage the nation’s cum laude from the Washington University in St. Louis, , leading scientists in teaching through the HHMI program. and received a Ph.D. in immunology from Tufts University, where Other notable initiatives include the Science Education Alliance, he worked in David Stollar’s laboratory. Carroll did his postdoctoral launched in 2007 as a national resource for the development and dis- research at the University of Colorado, Boulder, in the laboratory of tribution of innovative science education materials and methods, and Matt Scott (now an HHMI investigator at the Stanford University the Exceptional Research Opportunities Program (EXROP), which School of Medicine), where he began his explorations in embryol- offers mentored research experiences to select undergraduates. ogy and the study of genes that control body organization in the “I want to help other people have as much fun as I have,” says developing fruit fly. Carroll in describing his decision to take on the new role at HHMI. Carroll joined the faculty of the University of Wisconsin in 1987 “That requires thinking about how to foster creativity and inno- and became a full professor in 1995. He is the Allan Wilson Profes- vation on a larger scale. We all need inspiration, but how do we sor of Molecular Biology, Genetics, and Medical Genetics. Carroll

Jeff Miller nourish curiosity and inspire an interest in science, particularly plans to maintain his laboratory at the University of Wisconsin. W

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q A How do The fossil record is the primary way study petrified wood to learn about that scientists learn about extinct plants. extinct trees. scientists Scientists in the field of paleobotany Using the physical characteristics (paleo means ancient, botany is the study they observe in all these types of fossils, learn about of plants) study fossils to learn about the paleobotanists can gain information plants that evolution of plants that are alive today about how plants in the past survived. and to discover clues about what the By matching fossils to living species, are extinct? Earth was like in the past. they can hypothesize about the cli- Unfortunately for researchers, not all mates in which extinct plants lived. For asked by Latrice, an elementary school plants leave fossils behind. For a plant to example, if the fossil shows a leaf with student from Maryland become fossilized, mud or sediment has a thick, waxy structure, the plant prob- to bury it quickly but gently, so it doesn’t ably lived in a dry environment where it fall apart. As the sediment around the had to conserve water, similar to many plant gradually forms rock over time, the modern-day cactuses. By comparing shape of the plant is preserved. Depend- fossilized plants with related plants of ing on the speed of the process and the today, scientists can also identify when surrounding environment, different types different traits first appeared, telling us of fossils can form. In some fossils, called how plants have evolved over time. impressions or compressions, a flattened With the advent of DNA technol- section of the plant is pressed into sedi- ogy, paleobotanists have also been able ment. In fossils like this, scientists can to study plants and their evolution using use high-powered microscopes to observe genetic techniques. Although fossils details of the plant’s overall shape and preserved in rocks don’t contain DNA, the organization of its parts, but they researchers sometimes luck out and can’t usually identify individual cells. discover actual plant material—such as Other times, a three-dimensional spores, pollen, leaves, or pine cones— plant is fossilized. This happens when that’s been preserved in very cold or dry undamaged plant material is sur- climates or inside hardened tree resin rounded by minerals as it decays. As (called amber once it’s fossilized). Ana- with an impression fossil, scientists can lyzing these preserved plant bits and the usually observe only the external struc- DNA inside them is one more way that ture, but they can learn more than if the scientists can learn about ancient plants. plant had been flattened. In rare cases, f u r t h E R R E A D I N G minerals penetrate the plant tissue and Aen s w r b y J ayat r i D a s , a senior exhibit & Museum Victoria in Australia http://museumvictoria.com.au/prehistoric/time/plant.html preserve the cells in great detail. This program developer at The Franklin Institute in Philadelphia and a former HHMI The Paleobotany Project at the Denver Museum of process, called permineralization, is also Nature & Science www.paleobotanyproject.org/ how petrified wood is formed. ­Scientists predoctoral fellow.

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

May 2o1o | hhmi bulletin 45 46 is a practicing pediatric oncologist and his his and oncologist pediatric practicing a Butte is Research. Pediatric for Society from the Award Investigator Young 2010 the Physician-ScientistAward,Career Early won HHMI an of recipient Medicine, of School HHMI investigator HHMI rejection. transplant in implications has which gens, patho- from cells own body’s the distinguish cells T how on research his for plantation Transplant of Surgeons and the American Society Society of Trans- American the by g the of ­A recipient 2010 the is Medicine, of School Washington of University the at tor ­Ba hhmi L At Mich to went America, of Society ics Genet- the by given and professor HHMI for Award late the for named Education, in Excellence Jones W. Elizabeth 2010 The of microarrays. development the in work pioneering his of recognition in Award Facilities Resource Biomolecular of Association 2010 the won Medicine of School University Stanford the versity ofCalifornia, LosAngeles. uished Career Award. Bevan was chosen chosen was Bevan Award. Career uished eia Tasln Cnrs Distin Congress Transplant merican nota bene nota TLI L T s u n ANNIE I N N A J Lee Wins NationalAcademy Award erjee p

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l bulletin y L a b , 47 continued from page 15 a minuscule “game of life” movie onto mammalian cells con­ (ightl moves) taining the phytochrome module. Each movie frame displays a Cell Sculpting pattern of dark and light boxes. The pattern evolves in a systematic way Lim, at UCSF, is applying optogenetic methods to illuminate the from frame to frame—dark boxes become light and vice versa, localized, protein–protein interactions that underlie everything according to simple mathematical rules. By projecting these from turning genes on and off, to making cells more or less sensitive changing patterns of light and dark boxes (pixels) onto a cell, the to stimuli, to cytoskeletal remodeling that alters a cell’s shape or researchers induced the cell surface to embody the same morph- influences its movements. ing patterns. Phytochrome B is a light-sensitive receptor in the mustard plant In a paper in the September 13, 2009, issue of Nature, Lim and Arabidopsis thaliana that Lim is developing as a versatile molecu- several UCSF colleagues at the Cell Propulsion Lab say they should lar tool. In its normal role, the phytochrome enables the plants to be able to link the phytochrome light switch to many other cell respond to shade. When bathed in red light, for example, the phy- signaling pathways that involve the recruitment of protein players. tochrome undergoes a shape change that leads to the alteration of Lim refers to the system as a “universal remote control” for experi- gene expression in ways that cause the plant to grow toward sunnier mentally dictating when and where in a cell to activate a pathway of patches of space. interest. He can also imagine expanding the toolkit (see Web Extra, In one audacious show of experimental control, Lim and his col- “Beyond Light,” www.hhmi.org/bulletin/may2010). leagues combine the phytochrome with an enzymatic component “We are learning how to dissect biological systems the way into modules so they can use light to trigger the polymerization of electronics engineers dissect circuits,” Lim says. Elegant, pre- actin protein molecules in a cell. This results in localized changes cise interventions in neural circuitry, the kind that optogenetics in the cell’s cytoskeletal framework, which determines the cell’s researchers are exploring, stand a chance of eventually taking the shape. Using precision optics, the researchers can induce localized place of blunt instruments like surgery, electrodes, and the present shape changes with enough finesse that Lim refers to the process generation of pharmaceuticals. W as cell sculpting. Lim can imagine using light to orchestrate new organizations of we b e x t r a : To learn about specific studies using optogenetics and how researchers are

cells, perhaps even for making neuron-based logic components for looking beyond light to manipulate neurons, go to www.hhmi.org/bulletin/may2010. biological computers or to help reconstruct damaged nerve tissue. To demonstrate the utility of the approach in fine cell sculpt- we b e x t r a : Listen to Karl Deisseroth talk about the clinical potential of optogenetics.

ing, Lim’s group used a digital micromirror array device to project www.hhmi.org/bulletin/may2010

continued from page 33 the global standard, called the Linpack must be air conditioned away. “It takes less (heilict s on marvel) Benchmark, traditionally used to measure power and we produce fewer BTUs,” says meshed and runs at “line rate”—meaning performance and rank top supercomputers. Cicerchia. that the 40-gigabit/second data-center back- Right now, the Janelia system would rank As Janelia researchers go about their bone is available to every user at all times, roughly in the top 200 of existing comput- day thinking up novel ways to explore rather than being designed to serve only ing clusters, says Ceric. Janelia plans to neural networks, few contemplate the a small percentage of researchers as they enter its cluster in the next edition of the silicon ­marvel that quietly makes much of need it while the rest ponder their research Linpack ranking system this summer. their work possible. But ask any of them to or go to lunch. The installation’s increased efficiency consider their research without the clus- The computing cluster communicates is also better for the planet, since it gob- ter and you quickly enter the realm of the with the rest of the campus through 450 bles less electricity. The old cluster ran at unthinkable. miles of fiber optic cable, operating at 1 25 million operations per second per watt. “In a single day at Janelia we can do gigabit/second to users’ desktops. Now it can produce 200 million operations something that would take 11 years on a The updated cluster also runs at an per second on the same amount of power. single-processor workstation,” says Eddy. impressive 84 percent efficiency, based on And it throws off less heat that ultimately “We breathe CPU cycles like air.” W

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

48 hhmi bulletin | May 2o1o