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10 ’ . EB F bel Prizesbel Steitz for Tom Szostak. Jack and o N The China ConnectionMembrane· EquilibriumDigital· AtlasWorm Years of workYears scores and of colleagues are behind thebehind in this issue a common good common a

HHMI BULLETIN • Howard Hughes Medical Institute • www.hhmi.org vol. 23 / no. 01 Grant Jensen and Dianne Newman labs / Caltech / labs Newman Dianne and Jensen Grant Magnetic Charm can read about their work in the online Bulletin. work can read about their themselves along the lines of Earth’s magnetic field. Scientists magnetic field. Scientists themselves along the lines of Earth’s into chains, as seen in this view from inside the cell. This kind into chains, as seen in this view from inside of surprising architectural complexity is seen more and more by of surprising architectural complexity is seen believe these magnetotactic called organelles bacteria use special Some of the more curious organisms in the bacterial world orient in the bacterial organisms Some of the more curious electron cryotomography, Grant Jensen and colleagues discovered Grant Jensen and colleagues discovered electron cryotomography, researchers like HHMI’s Jensen and Christine Jacobs-Wagner. You You Jensen and Christine Jacobs-Wagner. researchers like HHMI’s magnetosomes, filled with magnetite crystals, to find oxygen. Using of cytoskeletal filaments. The filaments help position the organelles that magnetosomes are membranous structures flanked by a network that magnetosomes are membranous structures 4000 Jones Bridge Road Chevy Chase, Maryland 20815-6789 www.hhmi.org O b s e r v a t i o n s

pioneer experimentalist

Commonly known as the “father of microscopy,” Antony van Leeuwenhoek should also be given his due as one of the first true biological experimental- ists. Modern-day counterparts Grant Jensen and Christine Jacobs-Wagner, whose examinations of bacterial architecture are described in the online version of this magazine, count themselves among his admirers.

Antony van Leeuwenhoek (1632–1723) remains one of the most imperfectly understood figures in the origins of experimental biology. The popular view is that Leeuwenhoek worked in a manner that was essentially crude and undisciplined, using untried methods of investigation that were lacking in refinement and objectivity. He has often been designated as a “dilettante.” His microscopes, furthermore, have been described as primitive and doubt has been expressed over his ability to have made many of the observations attributed to him. … Research shows these views to be erro- neous. His work was carried out conscientiously, and the observations were recorded with pains- taking diligence. Though we may see evidence of his globulist understanding of organic matter (and indeed, this view has frequently been cited as evidence of his observational inadequacies), this minor preoccupation cannot detract from two firm principles that underlie his work: (a) a clear ability to construct experimental procedures which were, for their time, rational and repeat- able, and (b) a willingness both to fly in the face of received opinion—for example, over the question of spontaneous generation—and to abandon a previously held belief in the light of new evidence.

In his method of analysing a problem, Leeuwen- hoek was able to lay many of the ground rules of experimentation and did much to found, not only the science of microscopy, but also the phi- losophy of biological experimentation. … Within a short time, Leeuwenhoek was beginning—not merely to observe—but to experiment. His earli- est examples of specimen preparation date from the letter of 1 June 1674. Here he prepared fine sections of elder pith, and cork, and enclosed these in a folded envelope for the Secretary of the Society, Henry Oldenburg, and his ‘curious friends’ to observe. By 7 September 1674 he 42 was working on the anatomy of the eye through This two-tailed worm won’t get very dissection, and on 4 December of that year he far without a brain. Planaria have an described work on the optic nerve. unmatched ability to regrow body parts, but when scientists muddled a signaling Ford, Brian J., 1992, From Dilettante to Diligent pathway in this planarian, strange things Experimenter, a Reappraisal of Leeuwenhoek as happened. The animal grew another tail microscopist and investigator, Biology History, 5 (3), December. in place of the head that had been pared away. The altered signaling left it with two digestive systems (green) and an extended central nervous system (red). Rink, Gurley, Elliot & Sánchez Alvarado Eduardo Recife february ’1o vol. 23 · no. o1

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web only content Listen to Jim Collins talk about one of today’s hot fields: synthetic biology. / See photos from Dan Bolnick’s lab group trips to glacial lakes in British Columbia to collect stickleback fish. / Read how Christine Jacobs-Wagner and Grant Jensen are discovering detailed information about bacterial architecture. Join us at www.hhmi.org/bulletin/feb2010. 24 30

Features Departments cover story p r e s i d e n t ’ S L e t t e r l A b B o ok A h e a d o f t h e C u r v e 03 Beyond Our Borders 40 Histones Wreaking Havoc 12 Jack Szostak is drawn to uncharted 4 1 c e n t r i f u G E Righty, Lefty territory. His curiosity and big thinking 42 Viral Takeover 04 No Dozing Off have earned him a Nobel Prize. 05 Through Stickleback Eyes A s k a S c i e n t i s t cover story 06 Kiddie Chemistry 43 Could transplanting part of an V i e w F r o m t h e To p u p f r o n t animal’s eye into a human improve 18 An uncanny way with crystals led Tom the human’s night vision? Steitz to a clear view of the ribosome’s 08 Restoration Hardware structure—and to the Nobel Prize. 01 GPS for the Nematode U p C lose 44 PERSPECTIVES A N D O p i n i o n s Nano-Motion Pictures T h e C h in a C o n n e c t i o n 34 Nt o a B e n e 24 China-born, U.S.-trained scientists Ann Stock are helping foster innovation and 36 Q&A—What’s the best science talk 46 News of recent awards and other revitalize research in their native land. you’ve ever attended? notable achievements c h r o n i c l e o b s e r vAT i o n s Aa M t ter of E q u i l i b r i u m S c i e n c e E d u c at i o n 30 Researchers are getting at the cell’s Pioneer Experimentalist 38 SMART in More Ways Than One busy internal membranes by studying 39 2009 Holiday Lectures on Science: human diseases. Exploring Biodiversity

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: C h risto p h er S i las N e al 2 i m h h 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 The PrudentialInsuranceCompanyofAmerica Former Vice Chairman&ChiefInvestmentOfficer Chairman /SeaBridgeInvestmentAdvisors,L.L.C. Keit L. Garnett The UniversityofChicago Distinguished ServiceProfessorofHistory Chairma President Emeritus&HarryPrattJ Ph.D., Gray, H. Hanna University ofT M.D Regental Professor&Chairman,DepartmentofMolecularGenetics Goldstein, L. Joseph WilmerHale Barshefsky Senior InternationalP Charlene Ambassador S Esq Senior P E III, E T Baker, S A. U James R T I M H H

prri ad ietl poorpe bsd n a Deo California, Diego, San in based photographer lifestyle and portrait A other publications. (2) in appeared has writing Her parrot. journalist, she spends more time than she’d sciencelike freelance trying a to Now wrest journalism. controlin degreeof her a keyboardwith direction from changed her 10) Hardware,”page After a decade of working at the lab bench, Los Angeles-based fancy. (1) E originality, humor, and beauty, whether the work is a commissioned piece or a with each new illustration. She prides herself on approaching all projects with creative thought, times surreal, Emily Forgot’s playful visual some- language continues tothe everyday,innovate,and the evolve, odd, and surprise the Embracing Alston. Emily artist graphic London-based When he washe When 20, walks onthebeach.(3) loves10) page loveshe creatingas picturesmuch as sur He lives in Portland, Maine, where he also enjoys performing with his band, The Joint Chiefs. (4) then, he’s written for Since 33. of age old ripe the at writing freelance into fell he health, public in degree master’s After world. the travelto school fromaway n i t e l l u b ice-Chancellor nne M. Tatloc M. nne Ph.D Richard, F. lison mily artner /BakerBottsL.L.P. F or

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Emily Alston, Lauren Gravitz, Lou Mora, Charlie Schmidt Barbara Ries two of whom trained in the United because States of Wu’s program. the and lively scientific culture. A part of that story is told incomplex, this issue of rich, a by connected now are China and States United scholarly research. China’sfor commitmentscientificseeds sowedrenewed to and the they where home, returned Others here. researchers academic as success great achieved them of Many school. graduate for country this to students Chinese 400 some brought program the years nine Biology Examination and Administration program. Over a period of entists through the China–United States Bio rice crop. Wu began cultivating an entire generation of Chinese sci- passion in the 1980s—one just as as ensuring important a bountiful descendent of a long line of scientists and scholars developed a new This China. and States United the in reverberate continuesto and Wu’s impact on Ray science went But beyond those conventional oneself. aspirations than success greater even achieve who students around us, discoveries that make a difference to society, and talented world the of aspect new a illuminates that work meaningful aspire: continues toinformhisown work. research—which to approach HHMI’s of hallmark a remains that culture independence—a and creativity prized that environment scientific a credits creating with Szostak Wu issue.) this in profiled fellow Nobelist and Tom Szostak Steitz, (Both who Medicine. shared or the 2009Physiology Chemistryin Prize Prize, Nobel are 2009 the share at to on went and student graduate 19-year-old a arrived as Cornell who Szostak, Jack HHMI’s was years early the during Wu lab the through passed who scientists many the of One pests. of variety a and salt, drought, withstand better could that rice vated culti- of strains engineering of challenge difficult the and genome rice the on attention his focused Wu Later, genomes. whole ing sequenc- for the stage the set to simplified helping sequencing, DNA that of process discoveries major made laboratory His cist. help youngercolleagues.Myselfincluded. to way his of out went who school old the of scientist a gentleman, true a was He visit. my of highlight the be Wuhimself—would by straight was visit my forward. about much that and University Cornell at talk a Wugive Wuown.Ray to my a me of asked encounter had the of issue University this biochemistrythe California,at of faculty Berkeley, had I in stories the of member newish a disparate as Indeed, China. and onnects States United the was all of these and more to several generations of researchers across m Bulletin: Ray Wu. Gifted scientist, mentor, advocate, and friend, he person c A Beyond Our Borders Thanks in great measure to the efforts of Wu and others, the the others, and Wu of efforts the to measure great in Thanks would scientists most which to one is trajectory career Wu’s Wu made his scientific mark as a molecular biologist and geneti- o Bulletin m — What I didn’t expect was that a home-cooked meal—made o c n

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n i t e l l u b 3 4 i m h h he admits.Heneedn’thave worried. in themiddleofaseriousresearch lab,” a disaster to plophigh schoolstudents f place first iGEM competitors to a stellar 6th Francisco, hadcoached Lincoln High’s at the Wendell A.Lim,amolecularbiologist precedent. In2007, HHMIinvestigator from around theworld. chances against 112elite college teams lagged butfeeling goodabouttheir school inSanFrancisco, were jet- Lincoln HighSchool,anurbanpublic merger ofbiologyandengineering. enthusiasm insynthetic biology—a competition (iGEM),designedto fuel Genetically Engineered Machine top scores inthe2009International go for thegold. Technology inCambridge, ready to hall at theMassachusetts Institute of laughter andthen their armsskyward, they dissolved into chanted “1,2,3,CELLB a circle, leanedinto touch hands,and California highschoolstudents formed carrying backpacks,adozen orso Clad inmatching team T-shirts and No Dozing Off light ofLim’s initialreservations. “My prestigious colleges anduniversities. rst reaction was to thinkitwould be centrifuge There was, after all,astirring The teenagers from Abraham Gold meantearningoneofthe This was atriumph,especiallyin

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February 2o1o February f led into alecture O T S!!” Flinging ­speci ­pr promoters, ribosomebindingsites, logical parts”—includingbitsofDNA, “standard, interchangeable bio- built aproject usingatoolbox of our media. but we forgot to add antibioticsto to dominipreps anddigests today, cultures overnight yesterday hoping team memberinhisblog.“We grew error. “Iambehinddd!”wailed one learning by doing—andby trialand students willinglyworked longhours, their “cellbots” to deliver drugsto and former Genen They could imaginepro them to carrymolecularpayloads. steer and neutrophils called cells the navigational ability of white blood George Cachianes,triedto harness and otherr spiel whenwe were practicing our says. “Whenever I’d go off onalong Lim’s mantra—“keep itsimple,” she Jacqueline Tam. Wendell if wasthere,” one recalls meetings that itwas gonnabealong lab before joked “We sometimes humor. good with all totakeit and style demanding and serious toLim’s otein-coding sequences, O Each iGEMteam conceived and The students learned to adapt toadapt learned students The The Lincoln team, withteacher And they learned theworth of ver thesummer, thecharged-up f c targets. aw materials. O h, boy.” ­ t ech scientist ­ gr amming ­ plasmids, f Jenny Cutraro the-box ideas.” —Richard Saltusand incredible source ofcreative, out-of- what’s possible andnot.They are an have the biasesofexperience about year’s team. He’s already signedupto coach next accomplished.” our team, ourproject, andwhat we says, “we are de disappointment at the outcome but medal butdidn’tplace amongthe the Cellbots team earnedasilver our ideas.” this slide?’ This really helpedsimplify off. What were you tryingto convey on presen nalists. Tam acknowledged theteam’s “These young, smartpeopledon’t Lim isfar from disappointed. At theNovember competition, ta ­ tions, he’d say, ‘Sorry—I dozed f nitely very proud of

Peter Arkle Matthew Rainwaters VancouverIsland. Columbia’s British on estuaries and patchwork a is case, lakes, of streams, research Thethis assistants. lab,in his and Bolnick for Dan lab the at rainyday a it’s justanother morning: face-down Floating Through Stickleback Eyes local parasites. local tinytapeworms, other and nematodes, of assortment an with relationships developeddistinctive, coevolutionary populations says,stickleback individual water, of spacedbodies closely of he “dozens in dozens and dozens” and evolutionarySequestered dynamics. investigatingsardine-sized the he’s prowledsummers, 10 island, the pastFor the sticklebacks. three-spined works with Bolnick Galapagos, the of stantly shifting dynamicinvolves Like Darwin studying the the Likestudying Darwin U nderstanding whetherthiscon- in a cold a lake in on f n ches ches f s h’s bears, and leeches. Field work here mountain backdrop, home to cougars, swath of rain forest with a spectacular ise. Bolnick’s summertime range is a students.” their excitement that to of some spread theycan about, really is research what see theycan If 12. through K teachers, science future torecruit try I assistants, research for look I “When scientists. next-generation formative research. chosen for their bold, potentially trans- scientist, he’s one of 50 academics recently appointed HHMI early career at the parasitic diseasesinhumans. systems, he says, could help us combat genetic changes in stickleback immune That excitement is no empty prom- training interested in He’salso Bolnick is an evolutionary biologist U n iversity of Texas at Austin. A the world through stickleback eyes.” one one lake to another, andeven between kel, you seehow behavior differs from next lake,” he says. “But when you snor- water, catch the waterobservation. under- close-up and wading,canoeing, camping, of challenges stoutlythe met says,season’s researcherseach have happens. what watch new and in up habitats, them water, of body to another them pen preservetruck tothem, or tag them to trap members hundreds of Eagle Scouts than education majors. involves skills more common among the wild.” the variation in personality of kind this says.was “She the bottom,” the approaching Bolnick only grabbing only alwaysanother mud, the in pecking different wayschoose one feeding; of place consistently same the in living discovery. individuals that found “She water, the in signi a made Kim Texas hours long During school. high todayrural a at who biology teaches for research mer Hendrix, assistantKim —George Heidekat there front you.”in right of spectacular suddenly, times, there’s something you’re what to going You really is science about: know don’t what students Now tell her can she science.before, seen serious doing snorkeled,watching ress.“Here who’d was somebody never there’s meantime, prog- already been says. the Bolnick in determined, But parasite–hostyet is puzzle to be That point of view paid off lastsum- view off of That paid point “You could just toss traps into the kids,” city “mostly Bolnick Although Projectsvary often require but team Howbehaviors those : A R T X E B E W bulletin/feb2010 at trips collection stickleback f sh andanother. You start to see February 2o1o February See photos from Bolnick’s Bolnick’s from photos See f . o f ating food and never foodand ating sh, andgoonto the f r f st to document stto document f s n h she’d h never d. But some- But d.

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c s n i t e l l u b h and and h ant ant 5 6 i m h h really quickly,” hesays. of softballs,getbiggerthan the kids gift: “The models,withballsthesize he’d landedontheperfect Christmas model setfor saleonlineandknew narrow, Burke found agiantmolecular son’s jobasachemist. one to teach herstudents abouther her preschoolers love. Soshepocketed They reminded heroftheTinkertoys use to build3-Dmolecularstructures. the ball-and-stick modelschemists at a visitto hislabat missing proteins indiseasedcells. ics—molecules engineered to replace scientist, designsmolecularprosthet- the toddler set. to make chemistry larger thanlife for caps, thetwo Burkes have collaborated County don’thave to resort to bottle called LittlePeople’s Place. Mary EllenBurke, whorunsapreschool models for molecules,” says hismother, were bent. caps according to whetherornotthey ings by liningupMooseheadandPabst and heful store inrural Carroll County, Maryland, lived across thestreet from aliquor Burke collected bottlecaps.Hisfamily When hewas four years old,Marty Kiddie Chemistry centrifuge U To setherbackonthestraight and Burke, anHHMIearlycareer So that otherchildren inCarroll “I realize now that they were his rbana–Champaign, hismothersaw

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February 2o1o February U niversity ofIllinois O n the scienti sign language, socialawareness, and curriculum has always included Spanish, tion to reading, writing,andmath, her chance, canoutlearnany adult.Inaddi- children are littlepeoplewho, given the school for 34years onthepremise that aka Mrs.Mary, hasbeenoperating her schooler really learn? MaryEllenBurke, called hersonfor more ideas.Claiming like water and carbondioxide, she bored withbuildingsimplemolecules and blackbecamecarbon. beled crayons, sored becameoxygen of colored cookie dough.Shealsorela- well asfashioning ediblemoleculesout of molecules,usingthegiantmodelsas entire curriculumaround thesynthesis Mrs.Marybuiltan can learnbigones.’” said, ‘Ifthey canlearnbadwords, they thing,” shesays, adding,“I’ve always make itinteresting, they canlearnany- were trendy in child development circles. But how muchchemistry canapre- When Mrs.Maryandthekids got “Kids are like giantsponges—ifyou f c method—long before they —Kendall Powell and gotdown to some seriousplay. giant stick and brightlycolored balls page for building urea, grabbed the K.C. Nicolaou. The bookstarts withthe That ChangedtheWorld by chemist ing proteins, MartysentherMolecules to be busy saving theworld from miss- f f Nicolaou book,he fell out!”But whenshepulledoutthe this stuff inmy head,andyour stuff to kindergarten they mademeputall sons, hesaid,“Mrs.Mary, whenIwent remembered aboutthechemistry les- later inlife. Whensherecently asked through onaninterest inscience the stage for herstudents to follow at LittlePeople’s Place. grew upinandworked asateenager with preschoolers,” says Marty, who the conversation, that’s instant success an immediate hit. ve-year-old BenWeller what he rst moleculeever synthesized: urea, His momhopesherefforts willset “If you cansomehow work ‘pee’into f ipped to theright

Peter Arkle upfront

08S G P f o r t h e N e m ato d e Janelia scientists have made it easier to navigate C. elegans territory.

0R 1 e stor at i o n H a r dwa r e A signaling molecule important during neuron development is critical to adult neuron repair as well.

web only content HHM I investigators Christine Jacobs-Wagner of Yale University and Grant Jensen of the California Institute of Technology have revealed that bacteria are surprisingly sophisticated and well organized. Read the story at www.hhmi.org/bulletin/feb2010.

Tiny, transparent C. elegans is a dream organism for many scientists. Its developmental cycle is short—it can reproduce just days after birth. No need to invest in cages or tanks; a Petri dish will do. Its relatively small genome has been sequenced, and the developmental patterns of every one of its 900-plus cells have been traced. It’s the perfect organism for researchers impatient for answers about how animals develop and function—and how to trigger tissue repair in humans. A new digital atlas will make studies of this diminutive creature even easier.

February 2o1o | h h m i b u l l e t i n 7 upfront

GPS for the Nematode Janelia scientists have made it easier to navigate C. elegans territory.

Yu o ’ d th i n k t h e g ene t i c s o f a c r e at u r e a s s m a ll a s t h e e yela s h -

sized roundworm Caenorhabditis elegans would be simple. But scientists are finding surprising complexity: they now know that more gene expression as animals develop and than one genetic pathway can drive the worm’s cells to a single devel- age. They wanted to measure gene activity opmental fate. The large-scale studies needed to yield this kind of cell by cell to learn how each cell’s genes result are possible for two reasons: in C. elegans, the name and fate of control its fate. They needed an efficient way to iden- each cell on the pathway from egg to adult Thanks to Janelia Farm scientists Eugene tify a worm’s cells and then match up gene are well known, and now there’s a powerful Myers, Hanchuan Peng, and Fuhui Long, expression profiles to each cell’s develop- tool for analyzing this treasure trove of data. the tedious task can now be turned over mental path. More specifically, they needed Large collections of drawings and micro- to a computer. Using a new “digital atlas,” a computer program that could discern scope images have been compiled into print researchers can prepare a worm for micros- individual cells in a digital image and then and online worm atlases that offer research- copy, snap a digital image, and in a few hours correlate them to the identities documented ers abundant anatomical information. But retrieve a navigational map of its cells— in the worm atlas. navigating their pages and relating them kind of a WPS, or worm positioning system. Image interpretation doesn’t come as to the cells in an image of an actual, indi- The idea for the digital atlas grew from easily to a computer as it does to a human, vidual lab worm can take days for a skilled a conversation between Myers and Stanford Myers says. Variations in an object’s shape, worm researcher and, in some cases, yield University developmental biologist Stuart inconsistencies in the staining of a sample, ambiguous results. Kim. Kim’s lab group studies changes in and blurry edges contribute to a computer’s

brea k i t d o wn

To capture data for the digital worm atlas, the computer worm’s body visibly outlines the worm and provides the first first has to mathematically straighten out kinks and contor- clues; the computer calculates the identity of the remaining tions from the worm’s body so that it is shaped like every other cells based on their size, proximity to their neighbors, and posi- worm, says Hanchuan Peng. Then it must sort out where one tion relative to the fluorescently labeled body-wall cells. ¶ The cell ends and another begins. ¶ Before imaging, researchers end result is a three-dimensional digital atlas—described in the stain the worm’s DNA blue, so the computer can recognize September 2009 issue of Nature Methods. The atlas is freely each cluster of blue as an individual cell nucleus. The digital available online, and it can identify 357 cells in the larval L1 image is then stretched and rotated so that its size and orienta- worm with about 86 percent accuracy. The remaining cells are tion match that of the computer’s “reference” worm. ¶ Finally, so tightly packed in the worm that even the human eye can’t the computer must identify and name each cell. A genetically sort them out. “We’ve reached a performance level that’s encoded fluorescent label in the muscle cells that line the usable for a high-throughput study,” says Eugene Myers. —J.M.

8 h h m i b u l l e t i n | February 2o1o Siggi Eggertsson ber 31, 2009, the Janelia Farm scientists scientists Farm Janelia the 2009, 31, ber in reported atlas, digital the steps (seesidebar,“BreakItDown”). of series a into it divided they computer, the for accessible and logical processing visual the Tomake egg. the that from emerges form larval 1/4-millimeter-long development— the of stage L1 in worm’s cells the 558 the recognize to computer you do teach acomputertodothat?” how says—“but he represent, to likely is image an what to as clues for edge it is “seeing.” Humans draw on prior knowl- what understand to tries it when confusion In the first high-throughput study using using study high-throughput first the In the teaching by started team Myers’ Cell on Octo- on to guide a laser as it destroys or activates activates or destroys it as laser a guide to for functional studies, as well—for example, tool a as used atlas the see to hopes Peng is a triumph for the field of computer vision. fates. tical developmental patterns varied, even among cells with iden- expression that found researchers The cell. individualeach in gene’sactivity the giving identificationtable rapidly generated a data cell automated This cell. by cell rescence fluo- the measure to computer a used then and fluorescence to linked was gene cific created worms in which the activity of a spe- the expression of 93 genes to cell fate. They correlate to team Kim’s with collaborated For the Janelia team, the new worm atlas says, “butthisisamilestone.” he days,” early still it’s and problems hard very are “These fly. fruit the as such isms, organ- well-studied of forms embryonic of atlases digital see eventually to expects He development. during plans body out laid carefully through pass organisms most that ­s out its life as that of cellular anatomy is as well defined through- animal’s other no While cycle. life worm’s to atlas tal or genetic backgrounds. conditions different many under role NNI N N J – pecific cells in studies comparing a cell’s cell’s a comparing studies in cells pecific e The researchers plan to expand the digi-the expand to plan researchers The f e r

­r M epresent the later stages in the the in stages later the epresent i c February 2o1o February h a W O L C. elegans, Myers notes s k i

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February 2o1o February A signaling molecule important during neuron development development neuron during important molecule signaling A Restoration Hardware Restoration is critical to adult neuron repair as well. as repair neuron adult to critical is To rescue injured nerves, Yishi Jin is studying studying is Jin Yishi nerves, injured Torescue fast-growing fast-growing C. elegans C. .

Lou Mora stng I t i i n h e r s u nli t o f f i c e at t h e U n i v e r s i t y o f C ali f o r n ia , San Diego, Yishi Jin laughs as she describes herself as an impatient person, ill-suited to waiting for an animal to progress through its life span. Her model organism of choice, one that can reproduce just three days after birth, reflects her need for fast answers. ¶ And yet, as the Long-distance control didn’t make sense. HHMI investigator describes the 15 years of research leading to her Using a second fluorescent marker, they found mRNA molecules were present both most recent discovery—a potential way to enzyme appeared to be controlling the in the cell body and at the synapse. force injured adult neurons to regrow— activity of a signaling molecule called MAP To confirm that mRNA regulation was impatience isn’t exactly the word that comes kinase—which she later showed was impor- happening at the synapse, they turned to to mind. Tenacity seems more suitable. tant in synapse development. But Jin had the femtosecond laser. But when Jin and Jin grew up in a small village outside yet to figure out why it was involved in deg- her colleagues severed an axon in a MAP- Beijing during China’s Cultural Revolu- radation, too. kinase-deficient worm, they were startled tion. She came to the United States in 1985 In a second line of research Jin began to to see that the neuron couldn’t regenerate. to earn her Ph.D. and was lured by the pure explore adult nerves and their regenerative The MAP kinase molecule that is so impor- logic of genetics. In her postdoc, she chose ability. Using a blazingly fast, precise laser, tant in creating synapses also appears to play to study neural development. She became called a femtosecond laser, Jin and her col- a vital role in rescuing injured neurons. enamored with the tiny, short-lived round- leagues found that when they sliced through “The entire MAP kinase pathway is reused worm Caenorhabditis elegans. With only axons in live C. elegans, the neurons could in adult neurons,” Jin says. When neurons are 302 neurons, all meticulously mapped, the regenerate, navigating around the injury site injured, it’s devastating. “They need to trans- worm was an attractive subject. Its rapid development was a big plus: Jin could cre- “I would be totally thrilled if one day, even in ate mutants and knock-out animals almost faster than it took most postdocs to get their C. elegans, an injured axon could completely go mice to breed. back to its normal position. Synapses are the site of communication between the axon, or sending end, of one yishiin j ” neuron and the receiving end of another. Using green fluorescent protein, Jin could and sometimes even restoring the nerve’s mit an injury response: regrow your axon, visualize details of the synapses. She could original function (see “Nerve Verve,” HHMI and grow it quickly.” And it happens locally. also perturb them—creating mutants with Bulletin, Winter 2005). Jin is now anxious to manipulate the visible changes to their synapse structure— Jin’s two lines of research came together kinase activity to promote faster injury and then track those changes into the worms’ late last year, in work published in the response, to push the regrowth of injured genomes, determining which genetic muta- ­September 4, 2009, issue of Cell. She knew nerves and guide them to their original tions caused the altered synapses. that MAP kinase had to be controlling target—something essential to restoring Jin began by trying to understand the something else at the synapse, and she and function in humans and other species that molecular signals underlying synapse devel- her colleagues found a likely target: it was have much more complex neural systems opment in C. elegans. One of the very first regulating the speed of messenger RNA than worms. mutants her lab produced had fewer total (mRNA) decay, which occurs to signal the She calls herself impatient, but Jin’s per- synapses, which looked abnormal in shape synapse to reset itself to prepare for the next sistence and drive are pushing her to solve and size. To figure out why, Jin and her col- stimulus. But as far as anyone knew, mRNA the ultimate neural puzzle, even if it helps leagues cloned the responsible genes and was produced in the neuron’s main cell only the worms at first: “I would be totally discovered that the mutant worms lacked a body, far from MAP kinase at the synapse. thrilled if one day, even in C. elegans, an never-before-described enzyme that seemed They predicted that the mRNA existed injured axon could completely go back to to be involved in protein degradation. The and was being regulated at the synapse. its normal position.” W u – L a r e n G r av i t z

February 2o1o | h h m i b u l l e t i n 11 Ahead of the

Curve Jack Szostak is drawn to uncharted territory. His curiosity and big thinking have earned him a Nobel Prize. by Dan Ferber photography by Leah Fasten

12 h h m i b u l l e t i n | February 2o1o February 2o1o | h h m i b u l l e t i n 13 It was not the first time Jack Szostak gambled on an experiment, nor would it be the last.

Risky, big-payoff experiments like these kept science exciting. organism contains thousands of very short chromosomes that are Sure, bread-and-butter studies that would inform no matter how linear yet remain stable inside the cell. Blackburn had used these they turned out were always going to be necessary, he knew. But minichromosomes to get a large enough quantity of chromosome it was experiments like these that Szostak liked best—far-fetched, tips to study, and at the conference she described how the unusual, perhaps, but potentially groundbreaking. repetitive DNA sequence of those tips seemed to confer stability. What if he took chromosome tips from a single-celled pond “It was a surprise, a shock almost,” Szostak recalls. “Here I was creature called Tetrahymena and transplanted them into baker’s working on all these reactions that DNA ends engage in. Then yeast, an organism evolutionarily miles away. In Tetrahymena, here’s Liz talking about some little piece of DNA that just makes those tips, called telomeres, functioned like the tips of shoelaces, a stable end. It was completely the opposite behavior.” He button- protecting the DNA in chromosomes from damage. Would they holed her, and the two had an intense conversation about protect yeast DNA in the same way? chromosome tips. Szostak floated his wild idea about a telomere “We thought it was a long shot because yeast and Tetrahymena transplant experiment, and the two agreed to try it. are so distantly related,” recalls Szostak, now an HHMI investiga- Blackburn sent Szostak some DNA from Tetrahymena’s chro- tor at Massachusetts General Hospital, whose early work on mosome tips. Szostak attached it to a piece of linear yeast DNA telomeres won him a share, with Elizabeth Blackburn and Carol and then introduced the hybrid into yeast cells. Once the yeast Greider, of the 2009 Nobel Prize in Physiology or Medicine. “Yet had multiplied in culture, he ran their DNA on a gel, transferred it was a very easy experiment to do. If it worked it would tell us a it to a special paper, treated the paper with a radioactive probe lot, and it would open up the field.” that would bind to Tetrahymena DNA, and exposed it to a sheet of x-ray film. If the yeast maintained the hybrid DNA as a linear Mysterious Ends chromosome, Szostak would see a single band on the film. It was the autumn of 1980 and Szostak, then 27 and a new faculty In the darkroom, with gloved hands, he separated the x-ray member at Harvard Medical School, had been excited about film from the paper and inserted the film into an automated trying the experiment ever since he’d returned from a Gordon processor. In a matter of minutes, the machine would spit out the Research Conference on nucleic acids a few months earlier. At developed film outside the darkroom. Szostak walked to the Harvard, he had focused the efforts of his small team on under- hallway and waited. standing the molecular nature of recombination—the process by which higher organisms shuffle the genetic deck, exchanging An Early Passion pieces of DNA between chromosomes before reproducing. Szostak’s headlong dive into science started early. As a preco- Szostak was particularly interested in what happens to the cious 14-year-old high school student, he got a summer job in ends of DNA molecules. DNA exists as a double helix that can be a lab at a Montreal chemical company, where his mother also extended like a long piece of rope. Just as the ends of a rope tend worked, testing the ability of fabric dyes to withstand light and to fray, the ends of a DNA molecule are less stable than the rest detergent. Later, as a teenaged cell biology major at McGill of the molecule: enzymes inside the cell can chew them back, University, he bounced around a few chemistry labs before attach them to other DNA ends, or recombine them with other launching his first true research project: he showed that a simple DNA molecules. species of algae called Eudorina released hormones that triggered But the DNA at the tips of chromosomes is not degraded, and sexual development. biologists had long wondered why. Science classes of all sorts engaged the talented student; in At the Gordon Conference, Elizabeth Blackburn, of the one memorable lecture, a professor named John Southin University of California, Berkeley, presented her results on described how scientists had deduced the mechanism of DNA Tetrahymena’s curious chromosomes. The unicellular freshwater replication from test tube observations. “It was so amazing—this

14 h h m i b u l l e t i n | February 2o1o long chain of logical deduction between the actual experimental Orr-Weaver remembers a crowded laboratory, with graduate observations,” Szostak recalls. Far ahead of his classmates, Szostak students and postdocs sharing lab benches and squeezed into just graduated from McGill at the age of 19 in 1972 and headed to two bays. Szostak would often head to the same lab benches to do Cornell University for graduate school. his experiments. The lab “smelled great, like a bakery” from the He worked with molecular biologist Ray Wu at Cornell, devel- yeast they all worked on, and there was tremendous intellectual oping a way to make a small snippet of DNA and use it to detect ferment as well. “He had all these great ideas. There was this kind the messenger RNA encoding a specific protein—routine now, of buzz about the place,” Orr-Weaver recalls. but pioneering in the mid-1970s. Szostak’s telomere transplant experiment contributed to that As an advisor, Wu was relatively hands off. He let Szostak buzz. As he stood waiting in the hallway outside the darkroom pursue experiments that interested him. But, “he was always that day, the x-ray film emerged, dropping from the developer there to talk about things when I needed someone to talk to,” into his hands. “All the DNA was in a single band, which meant Szostak recalls. After a postdoctoral fellowship in Wu’s lab, that it had to be replicating as a linear piece of DNA,” Szostak Szostak landed a faculty job at Harvard Medical School in 1979, recalls. He showed the film to everyone in the lab, including at the relatively young age of 26. Orr-Weaver. In those days, Szostak was very slender, with a long There, Szostak adopted a management style similar to Wu’s. ponytail and a scraggly beard, and quiet, Orr-Weaver recalls. “I He assigned each graduate student and postdoc a project in a can’t imagine him ever raising his voice. But when something distinct area of biology. “He had people spread out so they really worked, his face beamed with excitement.” enjoyed their creativity,” says Terry Orr-Weaver, Szostak’s first Once Szostak knew that Tetrahymena telomeres functioned graduate student at Harvard, now at the Massachusetts Institute of in yeast, there were loads of experiments to do. He excised one of Technology (MIT). But that also meant they were solely respon- the two Tetrahymena tips from the linear DNA, for example, and sible for whether a project succeeded or failed. “It’s really tough then fished for pieces of yeast DNA that stabilized it—and isolated training, but it’s the best kind,” she says. yeast telomeres. Janis Shampay, a graduate student in Blackburn’s

Today, Jack Szostak is focused on creating a cell from scratch. His lab team is working to build a self-replicating nucleic acid genome and put it into a fatty acid vesicle, something he calls a “protocell.”

February 2o1o | h h m i b u l l e t i n 15 lab compared the sequences of Tetrahymena and yeast telomeres place,” with Szostak “spending a lot of time sitting on the couch that had been maintained in yeast and learned that yeast cells in his office reading papers and thinking great thoughts.” were adding a characteristic DNA sequence of their own to the Lorsch himself took lab-evolved RNAs that bound ATP (the transplanted Tetrahymena telomeres. This finding suggested an cell’s energy-supplying molecule) and evolved them further in test enzyme existed in the cell that built up telomeres—an enzyme tube experiments into RNAs that actually catalyzed chemical reac- that Carol Greider, as a graduate student in Blackburn’s labora- tions on ATP. “Even though everyone else said it was crazy, Jack tory, would later isolate and name telomerase. Greider is now at knew it was going to work.” Szostak’s decade of work on RNA evolu- the Johns Hopkins University School of Medicine. tion shed light on how RNA molecules might have evolved and how A graduate student in Szostak’s lab, Andrew Murray, now a early cells could have evolved increasing metabolic complexity. professor at Harvard University, combined yeast telomeres with Shortly after being named an HHMI investigator in 1998, several other essential pieces of chromosomes, thereby creating however, Szostak began contemplating an even more fundamen- yeast artificial chromosomes, which would be used to map and tal problem. How did the earth’s first cells form from a brew of clone human genes for the human genome project. organic chemicals? For about a year, beginning in 2000, Szostak, Vicki Lundblad, then a postdoc in Szostak’s lab and now a David Bartel, a former student of Szostak’s and an HHMI investi- professor at the Salk Institute, identified a yeast mutant in which gator at MIT, and Pier Luigi Luisi of the Swiss Federal Institute telomeres grew shorter with each generation. After more than 50 of Technology in Zurich brainstormed, discussed, and debated generations, the cells sickened, lost chromosomes, and died. this question. In an important theoretical paper published in “That made us think that perhaps what happened in aging was Nature in 2001, the three argued that membrane biophysics and that the telomeres were getting too short,” Szostak says. This test tube evolution of RNA and DNA had advanced enough to turned out to be true in cultured human cells, though the jury’s envision creating cells from scratch in the laboratory. The title of still out about the role telomere shortening plays in human aging. the paper was “Synthesizing Life.” Other intriguing results followed. In cells from normal adult “Having put all those ideas down on paper, I thought that it tissues, telomerase is repressed. A therapeutic door opened when was incumbent on us to actually explore them experimentally Bill Hahn’s team at the Dana-Farber Cancer Institute showed and see where it led,” Szostak says. that expressing telomerase can help make normal adult cells cancerous, and drug companies have pursued telomerase inhibi- Building the Protocell tors for use in cancer chemotherapy. “Jack didn’t work on Today, Szostak’s 18-member team operates from an airy, sunlit telomeres all that long,” says Hahn. But his ideas about telomeres laboratory at Massachusetts General Hospital, a far cry from the “were the seminal ideas, at the beginning of the field.” cramped space of his first years at Harvard Medical School. At his lab bench, Itay Budin, an easy-going graduate student, uses Life’s Murky Beginning a syringe to draw a volume of cloudy lime-green solution from a Although important questions remained about telomeres in the flask, inserts its needle into a small, stainless steel contraption late 1980s, Szostak was ready to move on. He knew that scientists containing a paper filter, and inserts a second glass syringe into streaming into the telomere field would follow up. Says Szostak: its other side. Then, he pushes hard on the plunger of the “My approach is to find something off the beaten path.” full syringe with the heel of his right hand, forcing the liquid In the mid-1980s, that meant RNA. Tom Cech, who later through the filter. The plunger on the other side slowly fills with became president of HHMI, and Sidney Altman had just discov- liquid, which is now clear. Budin is preparing microscopic sacs of ered that RNA could catalyze chemical reactions inside cells, lipids called vesicles—as small as one-thousandth the width of a just like today’s protein-based enzymes. Biologists proposed that human hair—that can serve as membranes for the simple model the earth’s earliest life forms lived in a so-called “RNA world,” in cells that Szostak hopes to synthesize. which RNA was both a carrier of hereditary information—a role After contemplating the basic properties of life, Szostak, played today by DNA—and a ribozyme, or catalyst of chemical Bartel, and Luisi had realized that the simplest possible living reactions. “What made the whole ribozyme field so exciting is cells—which they dubbed “protocells”—required just two that it provided a new model of the origin of life,” Szostak recalls. components: a nucleic acid genome to transmit genetic informa- Over the next decade, Szostak’s team worked out methods to tion encapsulated by a lipid sac that could itself grow and divide. evolve new and useful RNAs, and later DNAs, from scratch. Jon Szostak set out to build a protocell in the laboratory. Lorsch, then a grad student in the lab and now a professor of Budin is part of a contingent of Szostak’s team that is building biophysics and biophysical chemistry at the Johns Hopkins the protocell’s lipid sac. Modern cell membranes are relatively School of Medicine, recalls “an interestingly laid-back and fun impermeable and require an array of protein pumps and channels

16 h h m i b u l l e t i n | February 2o1o “I can’t imagine him ever raising his voice. But when something worked, his face beamed with excitement.” Terry Orr-Weaver

to transport molecules from one side to the other. But Szostak’s RNA grow bigger faster—and steal lipids from adjacent vesicles team has developed sacs for their protocells that are composed of with less RNA. The results suggested that early cells that repro- fatty acids—simple precursors of today’s membrane components duced their RNA faster would have had a competitive advantage, that are far more permeable and would have allowed primitive and early cells with just a single gene—perhaps an RNA gene that cells to “feed” on simple molecules. could copy itself—could have undergone Darwinian evolution. Fatty acid vesicles can also divide into daughter cells, as any They also suggest that if Szostak can succeed in building a cell must. In March 2009, Szostak and graduate student Ting self-replicating nucleic acid and put it into a fatty acid vesicle, Zhu reported in the Journal of the American Chemical Society he’ll have a living, self-replicating protocell. that adding fatty acids to vesicles caused them to morph into long filaments. But, remarkably, gentle shaking severs these filaments, Life with Nobel and the pieces become daughter vesicles. Szostak calls the work At 4:45 in the morning on October 5, the phone rang at Jack a “breakthrough” because it provides a plausible mechanism by Szostak’s house, waking Szostak and his wife, Tel McCormick. It which a small force—say, the force of wind moving water in a was Göran Hansson of Sweden’s Karolinska Institute, who told pond—would cause the membranes of primitive cells to reproduce. Szostak that he, Carol Greider, and Elizabeth Blackburn had won A second contingent of Szostak’s lab is working on the proto- the Nobel Prize for their groundbreaking early work on telomeres. cell genome. For a protocell to evolve in a Darwinian fashion its Szostak had little time to react. At 5 a.m., there was an inter- genome must replicate accurately, yet occasionally make mistakes. view with someone from the Nobel Foundation’s website. By Bartel’s team at MIT has evolved a replicase—an RNA molecule 6 a.m., a photographer from Harvard arrived, who shot photos of that begins to catalyze its own replication in test tubes—though Szostak as he fielded call after call. When he finally made it to better replicases are needed. In contrast, postdoc Alonso Ricardo the lab, he saw balloons, streamers, and high-spirited lab and other Szostak lab members are devising protocells that need members. There was a 10 a.m. party in the conference room with no replicases. They’re fine-tuning chemical cousins of RNA and champagne, cheese, and crackers; lunch with the hospital’s presi- DNA that assemble spontaneously when provided with their dent; a visit to the statehouse to meet the governor, and nonstop respective building blocks, called nucleotides. interviews with newspaper and television reporters. It was enough In 2008, Szostak’s team reported in Nature that they created to make anyone’s head spin. protocells that combine two of the essential properties of life. But not Szostak’s. The next morning, Szostak rushed into his Fatty acid vesicles containing DNA could “feed” on nucleotides group’s weekly lab meeting, where graduate student Ting Zhu outside them, and then the ingested nucleotides could chemi- would present his recent findings on lipid vesicles. An animated cally replicate the DNA fragment inside. The findings are crucial, discussion followed, in which young chemists, biophysicists, and Szostak says, because researchers had thought that nucleotides Szostak himself interrupted with questions and made theoretical were too bulky to make it through a cell membrane unaided. and technical suggestions. It was a typical lab meeting. To be truly alive, according to the accepted scientific defini- Still, for weeks reporters and dignitaries remained in hot tion, protocells would also need to evolve via Darwinian natural pursuit. There was a documentary for the BBC, a thick stack of selection. To do that, they’d need at least one trait specified by requests for autographs, even a congratulatory note from President their genome that would let one protocell outcompete another. In Obama, followed by an invitation to the White House. Nearly a 2004, Szostak and graduate student Irene Chen provided a proof month after the event, a reporter asked Szostak about his post- of principle that such test tube evolution was possible. Physical Nobel life. Was he eager to get back to science after the Nobel and chemical forces alone, they found, make vesicles with more hullabaloo? Replied Szostak: “I definitely am.”W

February 2o1o | h h m i b u l l e t i n 17 18 h h m i b u l l e t i n | February 2o1o View from the Top

An uncanny way with crystals led Tom Steitz to a clear view of the ribosome’s structure—and to the Nobel Prize. by Brian Vastag photography by Paul Fetters

February 2o1o | h h m i b u l l e t i n 19 Tom Steitz likes to tell a story about the day that The trio, working independently, used the same basic tech- launched him toward a Nobel Prize. It was spring 1963, and he niques as Perutz to scale the Mount Everest of biological mol- was a graduate student at Harvard University. A buzz ran through ecules—the ribosome. Weighing in at more than 150,000 atoms, the medical campus: Austrian-born chemist Max Perutz of the the ribosome is the engine of life, a delightfully intricate cellular Cambridge Laboratory of Molecular Biology was lecturing about gizmo that churns out countless billions of proteins that brick by how he and John Kendrew had unraveled the shapes of the oxy- biological brick build bacteria, birds, and biochemists. As Steitz’s gen-toting blood protein hemoglobin and the muscle protein map of the large subunit of the ribosome helped show, the struc- myoglobin. The two were the first to reveal the atomic structure ture reaches back to the very beginning of cellular life on Earth, of a protein, and they did it with the powerful yet fussy technique some two billion years ago. of x-ray crystallography. The work earned them the 1962 Nobel Decoding its structure afforded a glimpse into that almost Prize in Chemistry. unknowable past—and offered a roadmap to the future of anti- In front of a capacity crowd, Perutz turned on a stereoscopic biotics. “I’ve hiked up a lot of mountains,” says Steitz, speaking projector and told the audience to don their 3-D glasses. An assis- literally and metaphorically, “and when we got that first glimpse tant twiddled some projector knobs. “Out popped this gargantuan of the ribosome, well, that was the view from the top.” molecule over Max’s head,” Steitz recalls. “And the whole audi- ence went, ‘Whoa!’ Everybody was stunned. None of us had seen Mapping the Machine the atomic structure of a protein—ever.” It’s Thanksgiving week; the Yale University campus is half empty. As Perutz stood under the molecule pointing out features now But Steitz’s lab hums with a dozen workers mapping the mol- familiar to any freshman biochemistry student, Steitz remembers ecules of life. Steitz arrives at 10:30 a.m., fresh from the gym and thinking, “‘Wow. This is the way to understand biological mol- relaxed in a fleece pullover—a hale, white-topped, and bearded ecules.’ And I wanted to do it.” 69-year-old still feeling a “subdued glow,” as his wife Joan puts it, So he did. And 47 years later, Steitz, an HHMI investigator from the Nobel announcement six weeks prior. since 1986, joined Venkatraman Ramakrishnan of the MRC As Steitz chats, laughing easily, he remembers things to do— Laboratory of Molecular Biology in England and Ada Yonath of come up with a title for his upcoming Nobel speech, send an the Weizmann Institute of Science in Israel in winning the 2009 artifact to the Nobel museum, revisit a manuscript with a postdoc. Nobel Prize in Chemistry. He grabs a colorful plastic model of a ribosome—a grapefruit-

20 h h m i b u l l e t i n | February 2o1o The deep structural understanding of the ribosome offered by Tom Steitz’s team is enabling Rib-X, the company he cofounded, to invent new antibiotics.

sized riot of blue, red, yellow, green, and purple whorls—and saxophone. In the fleeting summers he bunched radishes at his mutters, “Maybe I’ll send them this.” grandfather’s truck farm outside of town, the dirt imbuing a love Steitz returns the model to a low cabinet packed with a dozen of green things that has carried to his ever-expanding garden on more, all molecules he has mapped over four decades. the Connecticut coast. “A lot of scientists would consider their careers a success if Steitz headed to Harvard for graduate school, where he hung they’d done just one of them,” says Peter Moore, Steitz’s long- around the laboratory of James Watson who was poking into ribo- time friend and Yale colleague who also played a key role in somes. While Steitz developed an interest in cellular structures, determining the structure of the large ribosomal subunit. he also grew interested in one of Watson’s students, a Minnesotan Later, Joan Steitz—herself a Yale professor and HHMI inves- named Joan Argetsinger. Joan and Tom soon married, and, in tigator—lists the structures her husband solved before the ribo- 1969, Joan became the first in the family to publish key discover- some. “A lot of regulatory proteins, polymerases, transposases, all ies about the ribosome, figuring out how the molecular machine these different kinds of proteins. And the ultimate peak on the initiates its protein-making cycle. (Joan Steitz was profiled in the horizon was the ribosome. It was a very logical progression of his February 2006 HHMI Bulletin.) life’s work,” she says. The new couple moved to the other Cambridge, in England, There’s a theme to all those molecules. Each is a cog in the in 1967 and began work in the same institution where Watson central dogma put forth by Francis Crick in 1958 that explains and Crick had puzzled out the structure of DNA. Steitz thrived how information flows in organisms: from DNA to RNA to in the all-science-all-the-time environment, where the lunchtime proteins. Early in Steitz’s career, exposure to some of the great conversation rarely strayed from the laboratory business of the minds in biology helped trigger the notion of mapping every cog day. Here an idea seeded at Harvard germinated: Steitz wanted to in the machine. take apart the central dogma, piece by piece, like a clock. An audacious goal, but one Steitz has largely fulfilled, says He set to the task soon after the couple both landed faculty Moore. “When you look at what he’s contributed to fundamental slots at Yale in 1970. In 1980, he tackled one of the enzymes aspects of information transfer in organisms, it’s just enormous. that copies DNA, a polymerase, and solved it, the first polymerase The ribosome is the capstone, but it’s by no means his only big structure published. Then “he marched through,” as he puts it. contribution.” Over the next 25 years, he published a staggering number of structures. Crystal Wrangling Revealing these hidden shapes has always been a means to Steitz was born in Milwaukee and through high school con- understanding how the machines work, what they do. So Steitz sidered a career in music, earning gold medals playing his dogs after a target for years, decades, capturing snapshots in the “I’ve hiked up a lot of mountains and when we got that first glimpse of the ribosome, well, that was the view from the top.” Tom Steitz

February 2o1o | h h m i b u l l e t i n 21 life of a protein. Frame by hard-earned frame, a movie appears. But the years ticked by, and Steitz grew antsy. He began plan- Molecular behaviors emerge. Actions make sense. ning to use Yonath’s recipe as a jumping off point. “I’ve gotten Early on, Steitz discovered he had a knack for making crys- some heat about that,” says Steitz. “In the crystallography field, tals—the fickle first step in the process of figuring out a mol- they say, ‘Oh, those are Yonath’s, right?’ But after 10 years, good ecule’s shape. “Crystallography is a little bit of witchcraft—or grief.” There was no reason for Steitz to start from nothing— maybe it’s a lot of witchcraft,” says François Franceschi, a crystal- Yonath had published her work. lographer at Rib-X Pharmaceuticals, the New Haven, Connecti- Franceschi, who collaborated with Yonath’s lab for 12 years, cut, company Steitz cofounded in 2001. When starting with an says, “It was clear that at some point other people were going to unmapped protein, a scientist doesn’t know the conditions under jump on the train. But, I think at the end of the day, competition which the particles will line up and solidify. The scientist doesn’t is what fuels progress.” even know if any given protein can make a crystal. The protein The Yale ribosome project launched in 1995 when an incom- might be too floppy, too fragile, too this, too that. Superstitions ing postdoc named Nenad Ban agreed to take on the challenge. abound: Maybe this lucky lab jacket will do it; maybe if I hop on After a lot of noggin-scratching, Steitz, Ban, and Moore found a one foot while stirring; maybe if I turn around three times and say couple of possible reasons why Yonath was not succeeding: First, a Hail Mary while tossing salt over my shoulder. the crystals were hypersensitive to salt. A drop in salinity caused Though Steitz stopped his direct crystal wrangling in the late them to “twin.” The ribosome particles aligned in two distinct 1980s, he still takes pride in the skill. He recalls a Christmas patterns instead of one. That slowed progress for a year or so until break—he often works during breaks—late in his hands-on career, it was solved. The more challenging problem, however, was how when a lab member was stymied. Steitz crystallized the stubborn to make a heavy atom derivative of these crystals and correctly protein and at the end of the week had “one and two millimeter locate the positions of the bound heavy atoms in the crystal. It monsters.” He left them in the lab with a note saying, “There it is.” required new approaches. At 10 times the size of the biggest molecule anyone had ever RNA at the Core solved, the ribosome crystals demanded a stronger heavy atom Around that time Steitz began eyeing the looming peak, the last signal than is provided by simple heavy atoms. As the team in the line, the reason all those other shapes existed. There was a worked through the twinning problem, they made a derivative problem, though: Someone else, his Nobel co-laureate, Yonath, using a super heavy atom cluster containing 18 tungsten atoms had staked out the turf. In 1980, she made the first ribosome crys- bound very tightly to each other. “At low resolution they scatter tals. Among crystallographers, says Moore, there is a “courtesy essentially as one atom containing 2,000 electrons,” explains convention that says you don’t jump in on top of somebody who Steitz. “That gave a strong signal, which got us started.” Ban did had crystallized something. You give them the opportunity” to much of the heavy lifting, with Steitz offering a stream of ideas. use the pretty, hard-won specks to solve the structure themselves. Two more postdocs signed on, Poul Nissen and Jeff Hansen, and “When you look at what he’s contributed to fundamental aspects of information transfer in organisms, it’s just enormous.” Peter Moore

22 h h m i b u l l e t i n | February 2o1o the quintet decided to inch their way up the mountain instead proteins, building life. Fortunately, there exist minute differences of racing to the top. That is, they collected low-resolution data between bacterial and human ribosomes. That’s good news for producing fuzzy, low-resolution images, double-checked against Rib-X, and bad news for bacteria. all available data, and then gradually sharpened the picture. They developed new techniques at low resolution without investing the Approach to Antibiotics huge resources needed to obtain high-resolution data. On a computer screen, Rib-X scientist Brian Wimberly rotates While mapping their first low-resolution images, the team a bacterial ribosome, a tangled, multihued mass. He zooms in, double-checked their data against ribosome images made by flying through the green and yellow outer shell, deep into the red HHMI investigator Joachim Frank of Columbia University and purple heart. He points to a hexagon jutting into a vast black College of Physicians and Surgeons. Though fuzzy by crystal- hole. The hexagon is a single base of RNA, an adenine labeled lography standards, Frank’s electron microscopy images offered A2058. Wimberly clicks his mouse and a blue filament appears proof that the new techniques developed by the Yale team were, next to it, an antibiotic of the macrolide class. This drug binds to in fact, working. They drove on. A2058 deep inside the ribosome, blocking protein production. In 1998, the Yale team published their first paper on the ribo- No protein means no life for the bacteria. some, a low-resolution map of the large subunit—the factory Human ribosomes, in contrast, display a different base at that component of the machine, the part that actually builds proteins. location, a guanine. The substitution subtly alters the shape of (The other part, the small subunit, is the foreman—it receives the protein-making center of the ribosome, rendering our cells messenger RNA and tells the large subunit what to do. Co-laure- impervious to macrolides. In the never-ending evolutionary arms ate Ramakrishnan mapped it.) The team revealed their methods, race, though, bacteria exposed to macrolides learn this trick, too. and the race was on. “Everybody changed course,” says Steitz, They change adenine to guanine, and bing: antibiotic resistance. adopting the new methods his team had developed. Such miniscule alterations, along with other types of antibiotic Within a year, the Yale team sharpened the image threefold. resistance, account for some 99,000 deaths in the United States It was time for the push to the summit—a trip to the powerful each year. About half of antibiotics work by interfering with bacte- beam at Argonne National Laboratory in Illinois. Data poured in. rial ribosomes, and the scientists at Rib-X exploit the deep struc- Moore remembers seeing it and thinking, “Oh my god. We went tural knowledge Steitz’s team provided to invent better ones. The out and caught the whale. Now what are we going to do with it? 40-person company has two new antibiotics poised for pivotal How are we ever going to figure out what all that stuff means?” phase three studies, with two more ready for human safety tests. Raw crystallography data resemble blobs on a gray field. Rib-X CEO Susan Froshauer says there’s been but a trickle “There’s nothing that says, ‘I am a carbon, I am a nitrogen,’” says of new antibiotics from big pharma, hampering efforts to treat, Moore. The team spent months interpreting the blobs, nearly for example, drug-resistant tuberculosis and nasty hospital-borne hand-placing each atom—all 100,000 of them. In early 2000, the bacteria like Staphylococcus aureus. “These are serious, serious team completed a finely wrought 2.4-angstrom-resolution struc- infections,” says Froshauer. ture. “It was extraordinary,” says Steitz. “We had no idea what the Steitz didn’t tackle the ribosome to make new drugs, but once ribosome was going to look like.” he did, he understood the opportunity. In eight years, Rib-X scien- Some 31 proteins glued together the outer shell and helped tists have determined the structures of some 400 ribosome–anti- with housekeeping. But deep inside, where the protein-making biotic complexes. It took the Yale team five tough years to solve magic happened, there was nothing but coiled RNA, 3,000 bases just one of them. of it. Here, laid bare, was the secret of life, or at least one of them: Steitz talks about the company as a parent might talk about Proteins were not built by other proteins, as biologists had once a child. “I’ve been so pleased,” he beams. During the Yale press assumed. RNA did the job. For several decades, starting with conference announcing his prize, Steitz repeatedly bent ques- Francis Crick in 1968, some ribosome researchers had theorized tions about himself into praise for Rib-X. that to be the case, but the Yale structure proved it. Maybe his Midwestern roots are responsible for that self- The implications were profound: The ribosome structure pro- effacing manner. In any case, Steitz is right at home in Con- vided deep support for the theory that the first organisms on Earth necticut now, with a house on the coast, the sailboat he enjoys were built from RNA. “The ribosome is a prime basis for the with Joan and their son Jon, the roses, the 600-bottle wine cellar, ‘RNA world’ hypothesis” of how life began, says former HHMI the gourmet-chemist meals, a warm coterie of life-long friends president Thomas Cech. and colleagues, a view from the top. Taking a rare moment to And while the shell differs from organism to organism, the survey his career and the ever-expanding knowledge of the ribo- business end, the RNA center, is nearly identical across every some pouring in—his original publication has been cited 1,500 species on the planet. For some two billion years of cellular evo- times—Steitz knows his work isn’t done, saying, “There’s always lution, the same heart of machine has been there churning out just one more step.” W

February 2o1o | h h m i b u l l e t i n 23

THE

CHINAE

NNChina-born, CT U.S.-trained scientists O are helping foster ONby Robert Koenig innovation sillu tration by Mike Perry and revitalize research in theirI C native land.

February 2o1o | hhmi bulletin 25 26 i m h h

four weeks teaching and researching in in researching and teaching weeks four under which Xu spends about one of every underpinnings ofmanyhumandiseases. genetic the reveal valuable help to tools research scientists give to aims apart, work at those two laboratories, half a world Xu’suniversities. research biomedical ing lead- China’s of one Fudan, at Medicine Molecular and Biology Developmental of Institute the of cofounder a is he ics, HHMI an Yale’sin investigator as genet- of department duties his to addition In person. in and virtually Shanghai—both like I’msittinginShanghai.” “It’s teleconference. a for prepares he as level sound the testing Xu, bespectacled the says fantastic,” is “This Shanghai. in University Fudan at researcher mouse a Wu, Xiaohui collaborator, scientific a of face the on focus and webcam distant in China. miles7,400 away,is scene the that Except cubicle. scientist’s any be grams—could dia- half-finished and files with stacked image that flickers on—showing a desktop Medicine.The of YaleSchool the at wall office his on screen 4-foot-wide the at up looks and control remote his on button a

n i t e l l u b The around-the-world arrangement— around-the-world The in be to Xu for reason good There’s a swivel to control the at pokes Xu

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February 2o1o February i an Xu taps taps Xu an ern model of research with a Chinese cost cially inthefieldofmedicine.” to other places, it can only be good—espe- disseminated be can science of style can Ameri- the “If States. United the in lived since has America, South in time brief a as a young child with his parents and, after Kong Hong left who biochemist a Tjian, Robert President HHMI says enterprise,” ical researchersinthetwocountries. potential for more synergy among biomed- the see experts many Westernscience, of templates successful adopt to begins and research. As China expands its laboratories a biomedical in become player international major to poised stagnation—is of theirto decades which—after land, native back” “give to time is it that feeling the Their personal stories vary, but many share research. Chinese of quality the improve help to time part least at work to willing are who Xu like expatriates attracting by researchers totheWest. young talented its of many lost cen- and tury 20th the of most for research can Ameri- North behind lagged that nation a in scientists with collaboration closer toward step innovative an also China—is The Fudan institute combines a West-a combines institute Fudan The global a much very as science see “I part in up, catching is China Today, F window totheWest. a become has citythat Chinese a in dents stu- science young bright of generation new a for has mentor American school an become high Jiaxing his of sheep” “black former The years. 30 last the over scientists Chinese expatriate of spectives model is emblematic of the changing per- who firststudied underXuin Shanghai. Ding, Sheng postdoc Yale says great mentor,” a and focused, highly creative, is New in “He model. a such as Xu describe and Haven, China in both him, with models ininnovativescience.” role are now needs China “What says. he research,” technology and science in ily growth has made it possible to invest heav- pursuing science, and its recent economic in interested are who people young smart spur innovationinChina’s research. help to needed is says Xu that template 29)—a page Move,” “Bold (see structure tegic board game. “I liked the game game the liked “I game. board stra- tegic Chinese “Go”—a playing Jiaxing in years school high unhappy his spent he that admits Xu grin, impish an With o ll The story of how Xu became a role role a became Xu how of story The work who students and Researchers of number tremendous a has “China o w in g Opp o r t u nitie s Abr oa d

Dustin Aksland Xu: Chris Jones Wang: Matt Rainwaters Han: Carmel Zucker tainted family.tainted politically a from came he because cipal And Xu was mistreated by his school prin- cal views who bows to bourgeois pressures. roader”—someone with left-leaning politi- “capitalist a as punished was mother his camp; labor a to demoted was teacher, a father, His Xu’s. like families intellectual on hard was which 1976, to Revolution, 1966 from Cultural the during kid” leged family history made him “a targeted came from.” ancestors your where matter doesn’t “It good,”are you if win you because says. he Min Han,University California, Berkeley University ofTexas Unlike the Go meritocracy,Xu’sprivi- Go the Unlike Xiaodong Wang, Medical Center Mu-ming Poo, of Coloradoat (top) Tian Xu, Yang Danand Southwestern of Medicine; University of (bottom, l-r) Yale School right page: at Dallas; left page: Boulder transplanted urban “young intellectuals” intellectuals” “young urban transplanted campaign Countryside” the to “Down Zedong’s Mao Chairman 1960s, late the and in seniority.dominationby starting Then, corruption, favoritism, political to vulnerable universities—became at than rather institutes Science of Academy in place took research most which under system— ossified That 1949. in communist takeover the after model Soviet the along restructured then and 1940s and upheavals, and social turmoil of the 1930s political wars, the by damaged which been had science, Chinese to blow latest The Cultural Revolution was only the only was Revolution Cultural The ­C tion to Fudan University coincided with with coincided University Fudan to tion applica- his But college. attended have never might Xu 1978, beyond continued pursued science. mighthave who promisingscholars many of careers the destroying areas, rural to Texas Southwestern Medical Center at at Center Medical Southwestern Texas of University the at investigator an HHMI now Wang, Xiaodong was program same the in recruited Another scientist talented 1990s. and 1980s the during universities U.S. to students Chinese ing recruit- in role key a played who biologist University Cornell Wu, a Ray late the by Los Angeles—as part of a program created California, of University the from Ph.D. his States—getting United the in study to recruited was and University (Peking) olution, Han majored in biology at Beijing at Fudan. institute new the establishing in laborator col- main Xu’s been has who Boulder, at Colorado of University the at investigator HHMI a Han, Min biologist molecular recalls sciences,” life study to place good a not was China time, that “At stories. lar of $1,500. stipend a on year school a for York New in living of challenge the and pocket his in $50 with Harlem in house ramshackle a at English—arrived no virtually spoke student—who young the 1983, In ogy. biol- in program graduate college’s the in accepted was Xu York, New of City College the from official visiting a met he After abroad. Ph.D.s their pursue to had they science, first-rate do to that, covered Xu and other Chinese undergraduates dis- tremendous.” the but Xu. then, high not was says research of level “The me,” changed really “Fudan universities. to admissions merit-based hina’s reform movement that restored restored that movement reform hina’s If the severe academic disruption had had disruption academic severe the If Sent to a farm during the Cultural Rev- simi- share expatriates Chinese Many That spirit may have been uplifting, but spirit spirit of scientific exploration was was exploration scientific of February 2o1o February

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n i t e l l u b 27 Dallas. Wang recalls the “incredible cul- a world power, its universities and bio­ One of the most influential U.S.-trained ture shock” of his move from Beijing to medical research lagged behind Europe. scientists who has announced plans to Texas in 1985. Thousands of young Americans went to return permanently to China is Wang, Even if they were not directly affected Britain, Germany, and France for their who plans to move to Beijing this summer by the Cultural Revolution, many younger graduate or medical studies and to learn as he begins his second stint—after 5 years Chinese science students also headed the research techniques of the great Euro- in a part-time, long-distance capacity—as to the United States because “you didn’t pean masters. the director of China’s National Insti- stay in China if you wanted a career in Eventually, American university inno- tute of Biological Sciences. The institute research,” says neuroscientist Yang Dan, vators—including pathologist William H. started from scratch a few years ago under an HHMI investigator at the University Welch, who built the Johns Hopkins Uni- a mostly Western model and now boasts of California, Berkeley. After she’d earned versity School of Medicine into a research 23 labs and 500 scientists—nearly all its her initial degree in physics at Beijing powerhouse, and Abraham Flexner, whose principal investigators did their Ph.D. (Peking) University, Dan was restricted 1910 report led to fundamental reforms of and/or postdoc work in the United States. by the rigid Chinese system from doing U.S. medical schools—combined lessons Wang says he has reached a point in graduate studies in another field, so she from Europe with their own ideas to cre- his life “when it’s time to give back” to his decided to pursue a life sciences Ph.D. ate what has become the world’s leading native country. “And there are great oppor- program at Columbia University in New biomedical research complex. tunities in China today.” Xu expresses York, where she had to work hard to catch “Like America in those years, China is similar sentiments about his inner need to up on basic biology and related courses on the cusp of great advances in ­science help young scientists in China—­especially that she had missed in Beijing. and technology,” says Xu. “One of my out of gratitude to his early inspiration to Despite the sometimes difficult transi- dreams is to set up a new university in professors at Fudan, who “opened up a tions, many of those students succeeded China that would teach innovation and new world of science for me.” with the help of talent, hard work, and would be modeled on some of the most For her part, Dan has become involved American mentors. “We were nurtured effective research institutions in the West.” in the past 5 years in research collabora- and cultivated by our professors,” recalls Before that happens in China, however, tions with neuroscientists in Shanghai Xu, who landed a fellowship at Yale within plenty of work needs to be done. In the and has been mentoring young scientists a year of his arrival in New York and was meantime, numerous initiatives are under there and at Berkeley. “A lot of really good soon using fruit flies as a model organism way to deepen scientific ties between expatriate scientists are trying to revamp to decipher the roles of genes in neural China and America. After China began the research structure at Chinese uni- development. to reform its economy, the nation stepped versities,” she says. “The idea is to more Excited by his early success, Xu called up its efforts to convince top expatriate strongly link teaching and research.” his mother in China and explained that scientists to return home. In 1998, the In addition to university reforms, similar he was making a name for himself in education ministry’s Changjiang ­Scholars efforts are being made to bolster ­Chinese America by studying flies. After a long Program started offering incentives for Academy research, including an inno­ pause, she said: “Son, we have lots of flies expatriates to do research and to teach at vative initiative led by Dan’s husband, right here in our hometown.” universities in China. After many targeted ­neuroscientist Mu-ming Poo, who is also researchers in the United States said they based at University of California, Berkeley. Emulating the West had little interest in returning to China Born in China, Poo began his university On the corner of Xu’s desk sits a stack full time, the program was altered in 2006 studies in Taiwan and later excelled in the of books about famous American medi- to include some senior scientists on a part- United States. Asked by Academy officials cal innovators. “I want to see how this time basis. to assess neuroscience research in China, country built up biomedical research,” he In 2009, China’s central government he advised them in 1999 to create an says, looking for a template for potential started an ambitious program called entirely new institute to avoid “the flawed reforms in China. ­Qianren Jihua, or the Thousand-Person mechanism of managing China’s estab- In the field of medical research, Xu Plan. The goal is to recruit as many as lished scientific institutions … [which] left sees parallels between pre-World War I 2,000 top Chinese-born scientists, finan- little room for innovation.” Poo became America and today’s China. A century ago, cial experts, and entrepreneurs back to the founding director of the Chinese Acad- while the United States was becoming China over the next decade. emy’s Institute of Neurosciences, which

28 h h m i b u l l e t i n | February 2o1o Bo o ld M ve

It took a leap of faith for Tian Xu to move from gene per mouse and creating an efficient way to create Shanghai to Harlem in 1983, but he says the biggest knockout mutants. ¶ “Geneticists had been searching risk he has taken during his career was switching a for decades to find a system like this for mammals—an decade ago from fruit flies to mice as model organisms efficient tool for transgenesis and mutagenesis,” says Xu, to study gene functions. ¶ Xu had made his name at who displays a framed cover of the August 2005 issue of Yale and later as a postdoc at HHMI Vice President the journal Cell that featured his piggyBac report. “Now Gerald M. (Gerry) Rubin’s lab at the University of we have the tool and we need to produce the mutant California, Berkeley, for his Drosophila research— mice strains for scientists to use in their research.” conducting large-scale analyses of mutant flies to ¶ With the new technique, scientists can produce decipher the roles of key genes and the biochemical the mutant mouse strains about 100 times faster and pathways related to cancer cell growth and metastasis. cheaper than they could with previous methods. And ¶ But when Xu applied for an HHMI investigator Xu says the Institute of Developmental Biology and position in 1996, he made a bold proposal: he would Molecular Medicine at Fudan University in Shanghai, discover a way to create mutant mouse strains as easily which he coestablished at the urging of Chinese as developing mutant flies. That would represent a ­officials, is able to produce such strains at a lower cost big step forward in genetic screening of mice, about than a similar facility in the United States. ¶ At the 99 percent of whose genes have direct equivalents in Fudan institute, which already houses 25,000 mouse the human genome. ¶ “It was risky because I had a lot cages, Xu and his researchers so far have produced to learn about mouse genetics,” Xu recalls, describing about 5,000 strains of knockout mice. The goal is to the years of complex and often frustrating research that produce 100,000 mutant strains by the end of 2010, it took for him to come up with the deceptively simple among which scientists hope to eventually identify breakthrough: using a moth transposon (“jumping knockout equivalents for nearly all of the 25,000 or so gene”) called piggyBac. Inserted into the mouse genes in the mouse genome. ¶ “I wanted to accomplish genome, the tiny segment of DNA causes random things with a real impact on society,” says Xu. “To do mutations when the animal breeds, disabling one that, you need to take some risks along the way.” —R.K.

is producing high-quality research. He Xu says he didn’t really want to start a number of Chinese science students are receives no salary and “works only on new institute at Fudan but was convinced placing heavy burdens on faculty. “Every scientific aspects” of the institute, while to proceed because “it was a priority for lab tends to have way too many students. retaining his faculty and research position the Chinese. I like it because the research And there are serious ethics problems that at Berkeley. is connected with a university, which is result from the pressure to produce lots “I think it’s a very positive trend,” says unusual for China.” With the advent of of papers.” HHMI’s Tjian. “These scientists have a teleconferencing and high-speed Internet Wang is optimistic as he prepares for sense of responsibility to their native coun- in China, he finds that he can “accom- his move to Beijing, saying that China’s try and it’s clear that China is progressively plish our goals with fewer trips back and economic success is freeing up tremen- expanding its scientific presence.” forth” between New Haven and Shanghai. dous resources for research. “Young Like his Fudan institute colleague, people have an easier time getting grants Engaging a Common Goal Han opted—for family as well as profes- in China today than in the U.S.,” he While the current trends in Chinese sional reasons—to limit his China com- says. Also, those students “treat scientific science are mostly headed in the right mitment, despite entreaties from Chinese research as a privilege. If a merit-based direction, expats say it will take time—as officials to move back. “I regard the U.S. ­system takes root, these young people will well as a continued government commit- as my main base for research,” he says, get great opportunities and excel.” ment to reform the research system—to “but that doesn’t mean that you can’t Poo agrees that, “as more scientists reach the nation’s potential. In the mean- make contributions to Chinese science.” return to China after successful post- time, many of the older generation of Han says, “I see changes in both direc- docs in the U.S., the quality of Chinese China-born scientists prefer to keep their tions—good and bad” in Chinese science. research will continue to improve.” But research bases in the United States. For example, the dramatic increases in the (continued on page 48)

February 2o1o | h h m i b u l l e t i n 29 A Matter of Equilibrium by sarah c.p. williams Researchers are getting at the cell’s busy internal membranes by studying human diseases. illustration by emily forgot Emily Forgot / agencyrush.com

On a computer screen, two empty bubbles float toward one another. They’re made of membranes, like those in a vesicle, a membrane-enclosed sac. of sec24 and each recognizes different in living cells. When the digitized mem- Randy Schekman, an HHMI investigator proteins. If no sec24 variant recognizes a branes touch, molecules in each begin at the University of California, Berkeley, protein, that protein remains in the ER. bobbing and shifting. Soon, the mem- focuses on vesicles that transport newly That can cause a problem during branes merge, forming one larger sphere made proteins out of the endoplasmic organism development, according to a where once there were two. It’s a slow- reticulum (ER), which is itself a maze of recent collaboration between Schekman motion computer simulation of one of membranes. The ER is involved in synthe- and David Ginty at the Johns Hopkins the most hard-to-visualize processes inside sizing, folding, and transporting proteins University School of Medicine. ­living cells: membrane fusion. produced by the ribosome. But not all In 2008, Schekman got a call from In a living organism, the fusion—as well proteins are destined to leave the organ- Ginty, an HHMI investigator who studies, as the separation, or fission—of mem- elle. The ­vesicle-creation machinery is among other things, the development of branes happens constantly: when a sperm selective, picking off the ER assembly line the neural system. A graduate student in fertilizes an egg, when HIV enters an only proteins that display certain chemi- Ginty’s lab had been studying an extreme immune cell, when neurons release neu- cal signals—like the zip codes a post office form of spina bifida, in which the neural rotransmitter. Yet the molecular details of needs to ship packages. tube fails to close during fetal development. this vital process are hard to nail down. “There has to be a way of ensuring In his search for gene mutations leading Membrane fusion is fast, and scientists that only a restricted set of proteins are to this birth defect, the student turned up can’t freeze membranes in the act of merg- transported from one place to the next,” he sec24b—one of the four sec24 variants. ing. They can, however, take a step back says. “Otherwise everything would blend.” Neural tube closure during develop- and look at links between membrane traf- [Cells have a system for sending way- ment relies on a precise gradient of mole­ fic and human diseases. ward proteins from the Golgi back to the cules to distinguish areas of the fetus. From birth defects to neural degenera- ER. See Web Extra “Return to Sender” Together, Ginty and Schekman’s labs tion, when a cell can’t control its mem- at www.hhmi.org/bulletin/feb2010.] revealed that without sec24, one of these branes, the effects are severe. Studying The vesicles that transport proteins molecules, vangl2, remains stuck in the the diseases that result from disorganized from the ER to their next destination— ER and never establishes the gradient membranes has illuminated basic bio- the Golgi apparatus, a stack of membranes the cell banks on. Though earlier fetal chemical processes that keep membranes where proteins are further processed—are development can progress with a, c, and at equilibrium. called COPII vesicles. A specific set of d variants of sec24, neural tube closure proteins coat their surface. Schekman has stalls without sec24b. The results were Moving Parts characterized these COPII coat proteins, published online in Nature Cell Biology The outer surface of a cell is a membrane, showing that one of them, called sec24, on December 6, 2009. and membranes also divide a cell’s con- decides whether proteins leave the ER in Schekman’s group is also exploring ER tents into discrete areas. Like a house with vesicles. Human cells have four variations management of a macromolecule that is rooms dedicated to different purposes— eating, sleeping, cooking—a cell has p art 2 of 2 compartments for different processes— In Part 1 of this two-part series, readers learned building proteins, storing chemical mes- about the action-packed outer membrane of the cell sengers, generating energy. The walls of the cell’s rooms are membranes. (see HHMI Bulletin, November 2009). When material in a cell needs to move from one spot to another, it moves

32 h h m i b u l l e t i n | February 2o1o Tom Rapoport, Randy Schekman, and David Chan have opened a new window into the membranes within the cell—including vesicles, endoplasmic reticulum, and energy-generating mitochondria—by studying diseases of the metabolic and neural systems.

important to human health: cholesterol. transport by vesicles. Sometimes an entire between tubules. This mechanism could When a cell doesn’t need cholesterol, it organelle needs to move or change shape be responsible for generating a tubular stores SREBP, a protein involved in cho- or size. Unlike most houses, designed with network and may well be what the cell lesterol production, in the ER. When the immovable walls, cells can rearrange their uses to shift its balance of tubules and cell requires cholesterol, vesicles trans- insides as needed. sheets, says Rapoport. port SREBP out of the ER, allowing it to Tom Rapoport, an HHMI investigator Scientists have linked a mutation in turn on cholesterol-producing machin- at Harvard Medical School, wants to know atlastin with a neurological disease: hered- ery. Current cholesterol-lowering drugs how cells achieve this fluidity. His team itary spastic paraplegia, characterized by block that final production machinery, has probed the biochemistry of various progressive weakness and stiffness of the but ­Schekman would like to see drugs membrane channels; now they’re dabbling legs. The disease is caused by shortening of that block the creation of the vesicles that in questions of membrane architecture— axons, the long slender fingers that project carry SREBP out of the ER in the first and are seeing connections to disease. outward from neurons to relay messages place. His lab is collaborating with HHMI The lab group specifically studies how from the body’s extremities to the brain. investigator David Ginsberg at the Univer- the cell generates the elaborate network Rapoport’s study linking atlastin to sity of Michigan to identify which sec24 of interconnected sheets and tubules that tubule fusion—and more specifically, ER variant wraps SREBP in membranes and make up the ER. The ER is sheet-like fusion—offers an explanation for spastic to determine how to block the interaction nearest the nucleus of the cell and con- paraplegia. Without ER fusion, it’s likely between SREBP and that variant. sists of more tubules near the periphery of that the ER network in long neuron cells “There is really an increasing overlap the cell. In different stages of the cell’s life can’t extend far. “If the ER network is between trafficking in the cell and human cycle, the balance of sheets and tubules not extending all the way,” says Rapoport, metabolic diseases,” says Schekman. All changes. Scientists are only beginning to “that’s causing problems at the ends of forms of hyperlipidemia—including high understand how it happens. the axons.” cholesterol in the blood—relate to how In 2006, Rapoport identified two fami- Interestingly, an analogous problem membranes move lipid molecules around, lies of proteins—reticulons and DP1s— in plants has been linked to defects in ER he says. Brain disorders may also involve that shape the lipids of the ER into morphology. Plants with a mutation in a cell membranes (see Web Extra “Dropping tubules. In a test tube, lipids mixed with protein that functions like atlastins have the Payload” at www.hhmi.org/bulletin). these proteins spontaneously arrange short wavy root hairs in places where the themselves into tubules. More recently, in roots should be long. In both cases, the Shape Shifting an August 2009 paper in the journal Cell, ER’s inability to mold its membranes has At times, the cell requires a more monu- Rapoport and his collaborators pinpointed tremendous consequences.

Rapoport: Leah Fasten Schekman: Mark Richards Chan: Jill Connelly/AP, ©HHMI mental shift in membranes than protein a protein—atlastin—that causes fusion (continued on page 48)

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Paul Fetters Ann Stock knew that high school students would enjoy getting their hands on molecular models. But the HHMI investigator and structural biologist at the University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School had no idea how much she’d get out of it as well.

Through inquiry-based education, students learn the process with computers, others had deeper understanding of biology, of science rather than just the facts about science. Structural some picked up structure quickly. biology is a wonderful way to do that; it’s something that For me, there were expected and unexpected benefits. For students latch onto very quickly. With a structure in hand one, we received a set of these expensive models, which are you can start to understand a protein’s function. wonderful tools for our lab. And it took surprisingly little work. That’s the underlying basis of the SMART Team Program. The SMART team setup allows for interaction between high SMART stands for “students modeling a research topic.” school students, their teacher, and their university mentor, Teams of high school students and their teacher work with but with a minimal time commitment from the mentor. The a local research lab to design and build a physical model students visited three times during the year, and I went to of a protein being studied by the lab. I had my first chance their school once. I wanted to see them in their environment to mentor a team of students in 2008 – 09. and listen to their rehearsal for the ASBMB meeting. My team from Pingry School in Martinsville, New Jersey, In addition, the program gave my lab members great modeled a family of response regulators involved in bacterial training to create a culture where education matters. Today’s signaling pathways. We used the models to explore different graduate students and postdocs pursuing a career in academ- protein domain interactions and conformational changes ics have an interest in teaching, especially inquiry-based induced by phosphorylation. Mentors try to choose projects teaching. Many didn’t have exposure to experimental science relevant to current issues in science and health. In our case, early in their careers, and they realize its import. bacterial signaling relates to antibiotic development. The SMART teams rotate to different mentors each year, but students begin to see the molecular details in the broader I had such a good time I’ve found a way to stay involved. context. They’ve all heard about MRSA and Staphylococ- At the ASBMB meeting, Pingry teacher Deirdre O’Mara cus aureus. and I attended a workshop by biochemist J. Ellis Bell from The students—just sophomores—got an incredible intro- University of Richmond. Bell’s freshman biology students duction to science and molecular biology. By the end of the spend the entire semester exploring a protein, making muta- project, the kids had a visceral understanding of their mol- tions, then analyzing the effects. Impressed, Deirdre and I ecule, what it is, how it functions, and its dynamics. They decided we could build a class around the models we worked also gained enormous confidence that they can do science, on last year. She spent a month in our lab over the summer explore, and ask questions. When the students presented learning the techniques needed to have the students construct their work at the national American Society for Biochemistry mutants and run assays. This spring, we will ask her students and Molecular Biology (ASBMB) meeting, they walked away to read two conflicting papers, evaluate the conclusions, and with a prize. then, based on what we’ve seen in crystal structures, create I was amazed by how much a sophomore in high school a hypothesis that updates the story or overturns previous can understand and appreciate. They gain real intuition and conclusions. I anticipate that they’ll end up with a publica- insight into a protein structure after an experience like this. tion out of this work that will contribute to the field. During the program, the students used small magnets It’s an interesting experiment to see how far one can take to simulate electrostatic interactions. The weak magnets high school lab science. Unfortunately, it requires resources required very specific positioning, but the team became and motivated teachers. Pingry is a private school with beauti- remarkably good at aligning the molecular components. We ful lab facilities. It would be wonderful to be able to extend split the eight students into teams of two to develop models this program to public school systems. HHMI is funding to explain particular features of the proteins. It was fantastic to centers to train high school teachers to become leaders of watch them work: Their different skills showed through just SMART teams. The limiting factor is teacher training; finding like one sees in laboratory research teams. Some were facile mentors won’t be difficult.

Ivn t e r i ew b y C o r i Van c h i e r i . Ann Stock is associate director of the Center for Advanced Biotechnology and Medicine, a research institute at Rutgers University and UMDNJ–Robert Wood Johnson Medical School. See page 38 for a science education story on the SMART teams.

February 2o1o | h h m i b u l l e t i n 35 Q & A What’s the best science talk you’ve ever attended? It takes a bold, fascinating presentation to stand out from the talk after talk that researchers sit through at a typical scientific meeting. Here, four HHMI scientists describe lectures that have lingered with them for years—because of their topic, eloquence, or abrasiveness.

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

Robert B. Darnell A. Belén Elgoyhen Daniel I. Bolnick Nancy Bonini HHMI Invest i g at o r HHMI Internat i o n a l H H M I E a rly C a r e e r HHMI Invest i g at o r T h e R o c k e f e l l e r R e s e a r c h S c h o l a r S c i e n t i s t U n i v e r s i ty o f U n i v e r s i ty I n s t i t u t e f o r R e s e a r c h U n i v e r s i ty o f T e x a s P e n n s y lva n i a o n G e n e t i c E n g i n e e r i n g at A u s t i n “Francis Crick at a Cold “To me, best talk means a n d M o l e c u l a r B i o l o g y, “At the 2003 Society for the Spring Harbor meeting C o n I C e t most exciting. One related Study of Evolution annual on neurobiology in 1990. “The talk I attended that to my own research I heard meeting, I attended a talk by Crick spoke at the end of I liked the most was as a grad student. Allen a graduate student describ- the meeting and berated the 2005 Presidential Laughon gave a thrilling ing his analysis of how the entire neuroscience Lecture of The Society of talk on fly development Drosophila genes respond community for their presen- Neuroscience by Ranulfo that opened my mind to to selective breeding. On tations. He told them they Romo from the UNAM, the realm of possibilities opening his PowerP­ oint file, scrupulously avoided the México. He elegantly and for Drosophila, a concept I the computer crashed and big question that they all very clearly showed how eventually incorporated into would not restart. He took wanted answered but were sensory information is my work by developing the a deep breath and delivered afraid to ask: how does the processed in different parts fly as a model for human one of the clearest and most brain think? He went on of the brain. His findings disease. A second spectacu- engaging talks I have ever to lay out a blueprint for have several implications. lar talk was one I heard as seen, without any visual finding a mechanism for One of them is how a phan- a postdoc: Patricia Kuhl backup or notes, and with- consciousness, based upon tom perception like tinnitus gave a seminar on language out complaint. His grace his own thinking and his (the perception of a noise and the amazing ways we under pressure and obvious work with Christoph Koch in the brain in the absence integrate facial cues into mastery of the material on how to approach such of an external source) might what we hear people say. earned him the only stand- a difficult question: make be generated in the central Although unrelated to my ing ovation I have seen at reasonable assumptions, nervous system.” own research, it highlighted establish a model system, a meeting.” truly fascinating aspects of and test assumptions quanti- cognition and I remember tatively. It was brilliant.” it vividly to this day.” Darnell: Rockefeller University Elgoyhen: David Rolls Bolnick: Sasha Haagensen Bonini: Paul Fetters

36 h h m i b u l l e t i n | February 2o1o chronicle

38 s cience educ at i o n 46 n ota b e n e SMART in More Ways Than One / 2009 Holiday Eight Elected to Institute of Medicine / Lectures on Science: Exploring Biodiversity Fuchs Wins L’Oréal-UNESCO Award

40 l a b book A DNA molecule’s intricate twists and turns provide Histones Wreaking Havoc / Righty, Lefty / unique spots for proteins to bind. New research has Viral Takeover shown that proteins (blue- and red-knobbed structures) prefer binding to areas with negative electrical poten- 43a s k a s c i e n t i s t tials (red), most often found in the narrow groove Could transplanting part of an animal’s eye into between turns of the DNA helix (see page 40). a human improve the human’s night vision?

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February 2o1o | h h m i b u l l e t i n 37 38 i m h h N I CH P GH H SMART inMoreWays thanOne the protein, known asLuxP. of model three-dimensional sophisticated a him built students the exchange for a few In hourswell. as of biology, mentoring,molecular of spreadprofessor a out Hughson, for over winner several months, a was team the with Working team. Topic) Research a Modeling were inluck. Jersey, New Martinsville, in School, Pingry nearby the from mates class- his and Horlbeck But reaction. that in involved protein one had the opportunity to spend months exploring the structure of just have not might students visiting these sophomores, As other. each with communicate dish the in bacteria marine the when happens Princeton University. Petria of dishFredat contents in Hughson’slaboratory ing biology glimmer- the at stared he as 2004, fall in student school high a as the dark, and wow! That’s what Max Horlbeck remembers thinking r i science education science o They were members of Pingry School’s SMART (Students (Students SMART School’s Pingry of members were They told, were classmates his and Horlbeck luminescence, That t

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t you engage students in building protein models, you grab their their grab you models, protein building in students engage you “When Modeling. BioMolecular for Center MSOE’s at biologist molecular and biochemist a Herman, Tim SMARTdeveloper says significant research,”a in allowingplay role to peripheral them but Eighty percentoftheSMART teamsareinpublicschools. grant from HHMI. The National Institutes of Health funds the rest. education science precollege a by funded them of 18 country, the Todayschools. 7 throughout teams 50 than more runs program the at based teams 10 Milwaukee with started It the (MSOE). Engineering at of School 2001 in launch its since considerably grown cial innearly everylabI’veworkedinsince.” University. “What I learned during that experience has been benefi- Columbia at science computer and biochemistry studying junior a manipulate protein structure is a valuable skill,” says Horlbeck, now to how“Knowing science works. high-level how to introduction an hr “Our main goal is to introduce kids to professional science by by science professional to kids introduce to is goal main “Our has program team SMART the feedback, positive by Sustained got classmates his and Horlbeck and model, his got Hughson o u g h

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Maxwell Loren Holyoke-Hirsch attention and focus it in a magical way. They begin to wonder, and “backwards” approach to education. Instead of working forward then ask questions, about how a protein’s function and structure from genes to proteins, she explains, the students backtrack from a depend on each other.” protein to its genetic origins, which dictate structure. “These models The SMART team experience typically begins with high school help to make that whole process real and understandable,” she says. teacher training at MSOE. Over two weeks in the summer, teachers Deirdre O’Mara, a biology teacher at Pingry School, says the learn how to design proteins using molecular visualization software. SMART team program provides professors a way to give something They take those skills back to their classrooms, where they teach back. “They tend to be thrilled that the students get so interested,” students how to design protein models, which are then physically she says. “Soon they’re having fantastic conversations about theory, created at MSOE with automated, rapid-prototyping equipment. structure, and why a particular protein residue is important. You get “We use a modified inkjet printing technology that builds them this high-level conversation that goes on as the relationship develops.” up layer by layer,” Herman explains. “We just replace ink in the More than 90 percent of students who participate in SMART printheads with pigmented glue, and then glue together successive report a positive impact on career choices, Herman says. And 85 layers of plaster powder to build up the final physical model.” Two percent of teachers involved in the SMART program return year models are made; university mentors keep one, the students keep after year. the other. Meanwhile Horlbeck—like many of the 1,300 students who “The models make incredible tools,” says Ann Stock, an HHMI have gone through the SMART team program so far—is eyeing a investigator and biochemist at University of Medicine and Dentistry career in research. And he credits the SMART team experience for of New Jersey–Robert Wood Johnson Medical School. “We use them teaching him how to make sense of biological structures. “When for explanatory purposes and also to explore how different domains you first look at a protein, it’s hard to see why it performs its specific in a family of proteins can be arranged.” Stock mentored one of function,” he says. “But through this experience, we learned how to Pingry School’s SMART teams during the 2008 – 2009 school year connect structure and function, which makes proteins much more (see Perspective, page 34). She lauds what she says is the program’s meaningful.” W ­– C h a r l e s S c h m i d t

2009 Holiday Lectures on science E xploring Biodiversity: The Search for New Medicines

Glow-in-the-dark bacteria and poisonous sea snails took center stage at the 2009 Holiday Lectures. HHMI investigator Bonnie Bassler (bottom left) and HHMI professor Baldomero Olivera (top right) introduced 180 D.C.-area high school ­students to the creatures through lectures and hands-on projects that explained how the organisms are helping identify potential medicines. The two researchers were joined in a panel discussion about biodiversity by (top left, l–r) HHMI President Robert Tjian, biologist E.O. Wilson, and physician-environmentalist Eric Chivian. Paul Fetters

February 2o1o | h h m i b u l l e t i n 39 40 i m h h related to sepsis, the researchers exposed blood vessel cells—normally caused by sepsis. No one ever guessed they had a more central role.” assumed they leaked out of cells as a side effect of the major damage inflamed andcleavedtheir toxicactivitiesneutralizedbyAPC. in cultures where macrophages—a type of immune cell—had becometously. Jun Xu,postdoctorala fellow inEsmon’s labnoticed was determined tofurtherunravelthemolecularbasisofsepsis. mechanism remained unclear, and it didn’t work in all cases. Esmon its APC, from developed was Xigris, drug, commercial a Although sepsis. block could (APC) C a protein that activated called showed compound previously Foundation Research Medical homa the spiralofeventsthatmakesepsislethal. to severe system infection. histones Destabilizing that escape the immune cell can halt the of response deadly potentially the sepsis, encourage they bloodstream, the in research land they New when that cell. suggests the outside place no histones—have called The proteins that keep E DNA wound tightly inside a cell’s nucleus— L h A Histones Wreaking Havoc o lab book lab c F E I R B N I To determine whether the chopped up histones were more directly “People had seen histones in the blood before,” says Esmon, “but Theidea that histones might play arole in sepsis came serendipi- Okla- the at group lab Esmon’s T. Charles investigator HHMI w U side were in areas known to be linked to to linked be to known areas in were side greater showed activity. side which measured jobs—and complementary they or that matching doing were time—indicating same the at spontaneously that brain the of sides both on areas tracked scientists The ter. chat- constant brain’s the monitored while they ahead straight stare and still lie to participant each asked they So task. any to unrelated activity, baseline its divides brain area becomes active. what observe then list—and a memorizing toperform task—likea watching or images participant a ask researchers experiment, fMRI typical a In activity. neuron indicates regions to certain tasks. fMRI measures measures blood fMRI tasks. brain certain to link to regions (fMRI) imaging resonance Buckner reveals just L. how complex thisdivisionis. Randy investigator HHMI developed by technique imaging An sides. true that the brain divvies up jobs between “right- is “left-brained,”it others but brained”and are people some that myth a It’s T

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q A Could The ability of many animals to see clearly be immense given the complex struc- at night is enviable, and there are a num- ture of the tapetum and the unsuitable transplanting ber of anatomical differences between anatomy of the human eye for accepting these animals and humans that explain the transplant. part of an their superior visual acuity in low-light In some animals, like alligators and animal’s eye settings. The most noticeable difference fruit bats, the tapetum is integrated is the presence of the tapetum lucidum, into the retina and would be next to into a human which creates the “eye shine” in species impossible to remove. In dogs, cats, and improve the ranging from household pets to livestock sheep, the tapetum is located between to nocturnal predators. The tapetum the retina and the choroid, which is the human’s night lucidum bounces incoming light back ­vascular layer just behind the retina. through the photoreceptors of the retina, Even though these tissues might be vision? giving these light-sensing cells a second ­dissectible from the animal, it would opportunity to be stimulated by the light. be unsafe to separate the human’s ret- A high school biology student In low-light settings, these animals gain ina from the choroid in order to insert better image resolution. the animal’s tapetum. Much of the The tapetum may not be an advan- human retina depends on blood flow tage in all settings, however, as it appears from the ­choroid for its survival, and the to limit the crispness of central vision transplanted tapetum would interrupt when levels of ambient light are high. this flow. While the tapetum reflects dim light The better course of action is to con- to make objects more visible in the sider external aids to night vision. There dark, it also reflects bright light, causing are two basic approaches. The first is glare and image distortion. So its util- to make use of a greater spectral range ity in humans would be limited, given than the visible light spectrum. The our preference for daytime activity and most commonly used technology in bright indoor lighting. A better approach this regard is an active infrared night would be to understand the science vision system, in which the device of the tapetum lucidum and then use shines infrared light (unseen by the that knowledge to design technological normal observer) and then detects infra- adaptations for low-light settings. red reflections with a special viewer. Of course, it is interesting to consider The second approach is to expand the the feasibility of tapetum lucidum trans- human’s ability to see very low levels of plantation. The first, and probably most light through the use of image intensi- important, limitation would be rapid fiers. This technology is applied in night rejection of the animal tissue by the vision goggles. human immune system. The immune system would recognize the transplanted tapetum as “foreign” and therefore would Aen s w r r e s e a r c h e d b y J e r e m y B . F U R th E R R E A D I N G fight to reject and ­destroy the trans- W i nga r d, a resident in ophthalmology at Ollivier, F.J. et al. Comparative morphology of the the University of Pittsburgh Medical Center tapetum lucidum (among selected species). planted tissue. Moreover, the technical Veterinary Ophthalmology 7(1): 11–22. 2004. difficulties for this type of surgery would and former HHMI medical student 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?

February 2o1o | h h m i b u l l e t i n 43 up close

Nano-Motion Pictures Scientists are now able to track the movements of single proteins as they shuttle along a DNA strand.

sty W I f l , s m o o t h ly, a d o u b l e - h e li x o f D NA u nwin d s a nd October 22, 2009, Ha’s team used FRET to investigate single- parts, exposing two complementary strands. Somehow each of stranded DNA binding (SSB) protein, a key player in DNA these strands, without getting a molecule out of place, gathers replication. Whenever DNA unwinds and separates itself into the nucleotide building blocks it needs to become whole again. two single strands of nucleotides, each of these strands swiftly One double-helix thus becomes two; a cell divides; and life wraps around SSB proteins. It had been thought that SSB goes on. ­proteins help to protect these naked DNA single strands from HHMI investigator Taekjip Ha would love to see how this the ravages of enzymes and oxidants and that they might also fundamental molecular act unfolds in real time. He disarmingly coordinate the work of other repair and maintenance proteins. calls his goal a “pie in the sky dream,” since there are no micro- “But the binding of SSB proteins to DNA is so tight,” says Ha. scopic techniques that can produce moving images at such fine “We wondered how they are removed when they need to be.” resolution. But he has just taken a big step toward realizing his Using FRET with two fluorescent-dye tags, plus a more dream, with a landmark study that reveals the detailed motions advanced tri-dye version that tagged three points, Ha’s group of a key protein involved in DNA replication. was able to “watch” an SSB protein as it was wrapped by a single In the study, Ha and his colleagues at the Urbana–­Champaign DNA strand. To their surprise, the protein shuttled back and campus of the University of Illinois used a relatively new molecu­ forth, fixing small strand defects, known as hairpins, as it went. lar imaging technique known as fluorescence resonance energy No one had ever observed a protein moving like that on single- transfer, or FRET. This obscure quirk of quantum physics stranded DNA. occurs when a certain kind of light-absorbing molecule invis- The team then added another DNA repair and maintenance ibly donates its absorbed energy to another that lies close by. protein, RecA, which is known to bind along the length of The efficiency of this energy transfer depends precisely on the single-stranded DNA, somehow displacing SSB. The resulting distance between the donor and acceptor molecules; if both FRET data strongly suggested that as RecA extended along the are fluorescing, then by measuring their respective luminosities single-stranded DNA, it prodded SSB and turned its “random one can determine the tiny distance between them with great walk” into a one-way move, at about three nucleotide base pairs accuracy—even as it changes rapidly. per step. SSB’s removal of the hairpins in turn allowed RecA to Physicists had known about FRET for 50 years when, in continue extending itself. 1996, a young graduate student at the University of California, In follow-up work, Ha and his team brought out another tool, Berkeley, first used it to track the distance between donor and a nano-sized “tweezer,” based on the phenomenon of optical acceptor fluorescent tags on a single biological molecule, a trapping, in which a beam of bright light effectively sucks a tiny short stretch of DNA. That student was Ha, and since then he object toward its center. Using a laser, they optically trapped and his associates have developed the ability to deploy multiple a microsphere that was already linked to FRET-tagged DNA; fluorescent tags to track the motions of even complex molecu- the DNA’s other end was bound to a molecular anchor. One lar shapes. of Ha’s grad students, Ruobo Zhou, used the technique to In work led by then biophysics graduate student Rahul Roy gradually pull the single-stranded DNA away from SSB while (now a postdoc at Harvard University), published in Nature on recording the applied tension as well as FRET signals. The SSB

44 h h m i b u l l e t i n | February 2o1o Adapted from Nature, Vol. 461, 22 Oct. 2009, p. 1096. ­d for mechanism general “a him to suggests also direction single a in moving keeps it that so SSB of prodding apparent thought. RecA’s been had than robustly and easily more struc- much ture nucleotide single-stranded a along move can proteins partly unwrapped. when even forth, and back move to able seemed still protein isplacement ofSSB.” To Ha, these findings indicate that repair and maintenance maintenance and repair that indicate findings these To Ha, repair work and then move off the DNA at the right time. second protein, RecA, appears to prod SSB to keep moving in one direction to do its FRET to measure energy transfer among multiple small defects (red DNA hairpin) on single-stranded DNA during replication. They used Taekjip Ha’s group watched a single-stranded DNA binding (SSB) protein as it RecA filamentgrowth RecA filamentelongation onhairpinDNA RecA bindspartiallydisrupted hairpin RecA filamentextension Hairpin disruptionby SSB SSB diffusion DNA hairpin h J – these techniques want tobeusedbyeverybiologist.” I “Eventually tools. research arcane somewhat still and new these disseminating and systematizing of job the with up taken also is days these Ha’smuchtime of But for,” says. ask he can you resolution ultimate nucleotide.the “That’sDNA really single a than smaller dimensions track to able be techniquesto f i m u Ha and his lab group are trying to refine theirmeasurement refine to trying are group lab his and Ha orescent tags and found that a S c n a b e l f x ed February 2o1o February W

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of of F ­ . 47 continued from page 29 tists rarely happens, and the outcome of the live connection to his colleague in Shang- (Tehinah c connection) reviews, if they were carried out, rarely has hai. They are discussing how to expand he cautions that “the new traditions of any consequence.” the Fudan institute’s research and offer its high-quality ­science have yet to become While Xu believes that far more progress unique mouse mutants to scientists world- established at most of the Chinese research needs to be made, he is generally optimis- wide who are trying to understand and find institutes. My concern is that most institu- tic about China’s “tremendous potential” cures for diseases. tions need to move more quickly in the in science. “Scientific interaction is one of “This is a site where East meets West,” he direction of merit-based resource alloca- the best ways to deepen the understanding says. “We are engaged in a common goal: to tion and promotion. Rigorous review of the between China and America,” he says, look- develop knowledge as a way to improve the research performance of individual scien- ing up at his teleconference screen with its well-being of humankind.” W

continued from page 33 that branch off them. With crippled mito- since mtDNA defects are associated with (Atter Ma of Equilibrium) chondrial fusion machinery, the arbor of additional pathological conditions. For other diseases, though, the ­culprit fibers was reduced to short stumps. On a computer screen, when membrane is the equilibrium between the fission Looking closer at the mitochondrial fission and fusion are slowed down, they and fusion of a different organelle: the membranes, Chan saw fragmented organ- appear to be straightforward processes. Press mitochondrion. elles, not the interconnected network that play and the membranes move. The merging Mitochondria, energy-generating organ- ought to be there. Furthermore, mitochon- of membranes looks fluid and natural, like it elles, snake throughout the insides of cells dria usually contain their own DNA— requires no molecular machinery at all. After in an interconnected network. “People often mtDNA. “But in this fragmented mutant, all, two soap bubbles can join together without think of mitochondria as static organelles only a fraction of them have mtDNA,” the help of proteins. But inside the cell, as that work alone,” says HHMI investiga- Chan says. The observation of missing DNA these researchers have shown, taking away a tor David Chan, “but they constantly fuse explains why fragmented mitochondria piece of the membrane’s control mechanisms and divide. No one really understood why can’t produce energy—they lack the DNA leads to a messy jumble of membranes, or a these events happen, or how, until the last that encodes proteins controlling energy stand-still in vesicle creation—and both prob- 10 years.” generation. Neurons may be particularly lems have unmistakable links to disease. W Chan, at the California Institute of sensitive to these defects, because the cells

Technology, studies how the cell achieves are among the most energy demanding. we b e x t r a : To learn what happens when vesicles arrive a balance in its mitochondria network. His lab is pursuing the link between mito- at their targets and how structural biology is illuminating If fusion overwhelms fission, the mito- chondrial fission and fusion and mtDNA, the biology of vesicles, visit www.hhmi.org/bulletin/feb2010. chondria become excessively long and connected, eventually “collapsing into a messy jumble,” says Chan. And if fission Subscribe! overwhelms fusion, the organelles are dra- Knowledge Discovery Research Education matically fragmented and less efficient at producing energy. It’s a delicate balance. These four key components of HHMI’s work also guide and defne the mission When geneticists at Duke University of the Institute’s quarterly magazine, linked a mitochondrial fusion gene to a the HHMI Bulletin. neurological disease, Chan wondered how Subscribing is fast, easy and free. Visit a defect in mitochondrial fusion might lead www.hhmi.org/bulletin and follow the to peripheral neuropathy, which causes instructions there to subscribe online. numbness and weakness in the hands and While you’re online, read the Web edition of the Bulletin. feet. Chan engineered mice that lacked the implicated fusion gene, mitofusin2. He found defects in the mitochondria of HHMI BULLETIN the Purkinje cells, a class of neurons in the brain known for the dramatic fan of fibers

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48 h h m i b u l l e t i n | February 2o1o