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N O . 04 =0A3@D/B7= B63A6/@3@A=4A6=@/ BVSe]`ZR^OW\bSRPg8]O\AZ]\QhSeaYWW\VS`aQWS\QS¿QbW]\\]dSZ /2]]`W\b]=QSO\WaQ]Z]`TcZOaeSZZOabV]cUVb^`]d]YW\U 7\bVS 38 Tcbc`WabWQbOZSO\ObW]\]Te][S\QOZZSRAVO`S`aZWdSO^SOQSTcZQ]]^ The intricacies of a hyaluronic acid (HA) microparticle become S`ObWdSSfWabS\QS]\AV]`OO\]QSO\¿ZZSR[]]\W\ORWabO\bUOZOfg a work of art in this high-magnifi cation image from a scanning AVO`S`aO`SOPZSb]a^S\RSfbS\RSR^S`W]Rac\RS`eObS`bVO\Yab] electron microscope. This particle, produced in the laboratory Oag[PW]bWQ`SZObW]\aVW^eWbV^c`^ZS]fgUS\ab]`W\UPOQbS`WO´]\S of Kristi Anseth, resulted from treating HA with hyaluronidase ]TbVSOcbV]`¸a[O\g\]Rab]aQWS\QSTOQbe]dS\W\b]bVSab]`g to decrease its molecular weight, followed by aqueous, nontoxic EVS\O\SWUVP]`W\UQWdWZWhObW]\ObbOQYabVSAVO`S`aVO`\SaabVSW` chemical crosslinking. Because HA is a natural component of ORdO\QSRPW]Z]UWQOZY\]eV]eb]RSTS\RbVSW`V][SZO\R joint-lubricating synovial fl uid, this engineered particle, which does not trigger an immune response, is ideal for delivering ;S`eS\ aeO[ R]e\eO`R O[]\U bVS RSS^S` P`O\QVSa UZWRW\U drugs and genes to the joint area. eWbVO\STT]`bZSaaU`OQSVS`TSSbPSObW\Ua[]]bVZgOa¿aVbOWZa BVS W\\S`ZWRa]T;S`eS\¸aSgSaUZSO[SRZWYSV]]RSR^SO`Za)bVSgeS`S \Obc`OZU]UUZSaeVWQV`Sb`OQbSReVS\VS`VSORac`TOQSR /_cO`bS` ]TO\V]c`^OaaSRPST]`SVS`aYW\bc`\SRZOdS\RS`bVS\eVWbSOa VS`[WQ`]aQ]^WQag[PW]\baUOdSc^]fgUS\O\RaVSac`TOQSROUOW\ T]`ORSS^Zc\UTcZ]TOW` 0S`S\WQSObbVObbW[SeOa\SO`ZgOadW]ZSb OaO\ObWdSAVO`S`PcbSdS\a]aVS\SSRSRbV`SSP`SObVaT]`SOQV ]\S;S`eS\b]]Y 4`][bVSP]]Y/2]]`W\b]=QSO\Pg8]O\AZ]\QhSeaYW '&$8]O\ AZ]\QhSeaYW @S^`W\bSReWbV^S`[WaaW]\T`][B]`0]]YaORWdWaW]\]T B][2]VS`bg/aa]QWObSa::1 8]O\: AZ]\QhSeaYWWaOPW]Z]Ug^`]TSaa]`O\RO\66;7c\RS`U`ORcObS ^`]U`O[RW`SQb]`Ob9S\g]\1]ZZSUSW\5O[PWS`=VW] 4]`[]`SOP]cb VS`aQWS\QS¿QbW]\e`WbW\UaSSµAb`O\US`bVO\4WQbW]\¶^OUS# Frank Stockton Frank Melinda Cushing / Anseth lab vol. 2o november ’o7 no. o4 23>/@B;3 >@3A723 13 C>4@= >3@A>31B7D3A/<2=>7<7= 16@=<71:3 AQWS\QS3RcQObW]\ "" An Even Broader Reach "# Smart Young Minds 7\abWbcbS =0A3@D/B7= 43/BC@3A 14 2o 26 32 6 5 < / 3= < Going the Distance Small Talk The Changing Face Deciding Factors How far will Scott Strobel Studying how marine bacteria of DNA Forage or mate? Stay or run? take his students to fire their light up when ready, a scientist Each individual’s genome Innocent or guilty? Deal or interest in science? To the known for her communication is its own unique landscape. no deal? Each is a job for the Amazon and back. skills revealed the purposeful And variations much larger brain’s “jury room.” chitchat used by these tiny than slight misspellings in organisms. our DNA base pairs may explain our looks as well as our susceptibility to disease. VISIT THE BULLETIN ONLINE FOR ADDITIONAL CONTENT AND ADDED FEATURES: www.hhmi.org/bulletin COVER IMAGE: PIETARI POSTI HHMI contributers Fiduciary Trust CompanyInternational Director, RetiredChairman&CEO /\\S; BObZ]QY Law Dean /HowardUniversitySchoolof 9c`b: AQV[]YS3a_ President /TheRockefellerUniversity >OcZ | November 2007 PSUO\R`OeW\U]PaSaaWdSZgW\ ''' 7\ !VS`\]\ab]^R`OeW\U PSUO\R`OeW\U]PaSaaWdSZgW\ ''' 7\ 1VWQOU]Ac\BW[Sa eOaP]`\W\6SZaW\YW4W\ZO\RW\bVSZObS '% a EVS\]bVS`YW WaOT`SSZO\QSe`WbS`eV]aS[S[]W` BVSEOaVW\Ub]\>]ab 1VOW`[O\ 6SOZbVQO`S=\ZW\ST]`2c[[WSa 6Wa¿`abOaaWU\[S\bbVS`SeOabVSOaaOaaW\ObW]\ObbS[^b]\ CA/B]ROg 6=E/@2E=:7 Howard Wolinsky, Moran: James Kegley, Pietari Posti, Charmaine Wheatley Bruce Weller 39 reviewers—brought totheJaneliaFarm ResearchCampusfor Why? To uselingoborrowed fromtheworldofdiplomacy, our participated inthedeliberationsfound processelectrifying. guided andinformedbytheadviceofdozensscientists outside about investigatorappointment andrenewal,butourdecisions are review oftheir work,whichcustomarilyoccursatthefive-yearmark. nations frominvitedinstitutions.We makeasimilar investmentinthe HHMI HHMI PEOPLE NOTPROJECTS—THAT’S ASHORTHANDDESCRIPTION On Review thought, andenergyinidentifyingpromising scientists tojoin the researchplansorannualdo notsubmit detailed progressreports. considerable latitudetodecide how besttousetheir resources.They their workintounexpecteddirections andfieldsofinquiry. Theyhave questions. Theydon’tneedanyone’s permission ifthatsearchmoves identify creativescientists andsetthemfreetoexplorechallenging submit applicationsdirectly to interesting andchallengingsinceweswitchedtolettingcandidates from thesameinstitution. reviewed byanyonewhoisadirect competitororcollaborator that some“ingredients” areofflimits since investigatorscan’tbe just right—complicatedbythefact and aspoonfulofthattotaste dients a pinchofthis forabatchofminestrone soupthat takes emerging field. aninvestigator’sbasis toensurethatwefullyunderstand workinan more specialized expertise,andothersmayparticipate onanadhoc perspective. Scientific ReviewBoardmembersarechosenfortheir Advisory Board( hold acompetition.OurreviewersincludemembersofourMedical work ofourcurrentinvestigators;thisnumber increaseswhenwe it withoutthem. our investigatorprogram,itispeopleintensiveandwecouldn’tdo a processthatisessentialtothecontinuedofoureffort.Like vitality siasm—as wellasahighdegreeofthoughtfulnessandfairness—to even thoseoutsidetheir specific field,the tunities ininternationalresearch.Byparticipating inmostreviews, everything fromourundergraduateeducationprogramstooppor- for February 2008issueofthe tion forinvestigatorsengaged in patient-orientedresearchthe ical distribution, andgender. have tosay. We’re alsolookingfordiversity ofexpertise,geograph- tive process,andwhodemonstrateanabilitytohearwhatothers inacollegial,interac- skill, andtemperament,whoarecomfortable withtherightmixforaging forfreshtalent—scientists ofknowledge, The Institute’s scientific leadershipmakesthefinaldecisions Given ourapproach,weinvestaconsiderableamountoftime, Assembling areviewpanelisanalogoustofinding theingre- Each year,upwardof60scientists participate inreviewingthe You willbeabletoreadmoreabout theresultsofourcompeti- HHMI whoserveonourreviewpanels.Theybringvigorandenthu- investigatorcommunity. thathasbecomemore Itisatask ’s approachtosupporting scientific research.We striveto MAB ), whoalsoadvisemeandmycolleagueson HHMI HHMI HHMI ’s isconstantly scientific staff Bulletin , ratherthanrequesting nomi- MAB . Manyofthosewho providesaconsistent Fifteen willbenamed selected from242applicationsthroughpreviousroundsofreview. merits ofeachcandidate. The discussions focusedon40finalists, what constitutestruepatient-orientedresearchandthescientific a two-daymeeting—engagedinfullandfrankdiscussion about that contributetoscientific discovery. abroadviewof the varietyofstylesandapproaches reviewers take answer questions abouttheir work.Onesize doesn’tfitall,andour but alsomakea35-minute andhaveanopportunity to presentation role.Investigators submit materialsinadvance reviewers playavital great promise ofinnovativeandoriginalcontributions. forge linksbetweenbasicbiologyandmedicine, anddemonstrate approachestobiologicalresearch, that enablecreativeexperimental their chosenfieldinnewdirections, developnewtoolsandmethods significant biologicalquestions inadeepandrigorousmanner,push one ormoreofthefollowing attributes:thattheyidentifyand pursue through their insightandjudicious advice,helpguideourchoices. But thatacclaimneedstobesharedwiththoseotherscientists who, determine whethertheir five-year markforahighlyfocuseddiscussion abouttheir workto ask that “ Assembling areviewpanelis B6=;/A1316 of thattotastejustright. takes apinchofthisandspoonful for abatchofminestronesoupthat analogous tofindingtheingredients We delightingivingourinvestigatorsthespotlightat The assessmentsarechallengingallaroundand,onceagain,our We meetindividually with eachofourinvestigatorsatthe HHMI investigatorsdemonstrate—atasuperlativelevel— HHMI HHMI investigators. appointment willberenewed.We November 2007 president ” | ’ s letter HHMI BULLETIN HHMI . ! 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I’dstayfora up thepoopand I wouldn’tjustpick 16//:;3@ =\S]TbVS[]`S[c\RO\SSgS ;]bVS`a^`]dWRSRaO[^ZSa]TbVSW` 7\RSSR>OZ[S`^O`bWQW^ObSRW\a][S µESPSQO[SQZ]aS¶aVSaOga]TbVS ” :W\RaOg;]`O\ Illustration: Peter Arkle Photo: Chana Palmer upfront & 3f^Z]`W\U!2A^OQS After a 20-year wait, a team of scientists is building an atlas to map individual brain neurons the way astronomers identify stars in the sky. @Sb`WSdW\U:]ab;S[]`WSa Scientists have found that certain substances, at least in the lab, prevent neurodegeneration from Alzheimer’s disease and restore what was seemingly forgotten. BVSAc[]T7ba>O`ba Many of the brain’s sophisticated functions may ultimately arise from the straightforward process of addition. Our most complex of organs, the brain, takes center stage. HHMI scientists are mapping the signals that direct its development, revealing the logic of the surprisingly simple algorithms it uses to process information, and are even exploring ways to reverse the mind-robbing effects of Alzheimer’s disease. One researcher kept a project on the back burner for 20 years until technology caught up with his dream to build a 3-D atlas of the developing nervous system. Never doubt the power of a doggedly curious mind. November 2oo7 | HHMI BULLETIN % upfront Exploring 3-D Space After a 20-year wait, a team of scientists is building an atlas to map individual brain neurons the way astronomers identify stars in the sky. TREATING GENE EXPRESSION PATTERNS AS A SEARCHABLE CONSTELLATION of stars. The idea was too far-fetched to tackle two decades ago, when Easier said than done. “I remember Chris Q. Doe was a postdoctoral fellow. He wanted to build an atlas thinking it would be impossible—and that showing the three-dimensional location of transcription factors involved was with only a handful of CNS genes identified,” says Doe. He dropped the idea in generating the fruit fly’s central nervous system (CNS). Other as technologically unfeasible. The seed, atlases, however, covered simpler one- and two-dimensional patterns. however, was planted. Now, 20 years and more than 200 tran- As proteins responsible for initiating gene scription-factor genes later, Doe and his expression, the many transcription factors in postdoc Michael Layden are on the verge a fruit fly CNS correspond to different types of seeing such an atlas become a reality, of neurons. Making sense of these patterns thanks to a collaboration with computer could help scientists discover how brain cells scientist Eugene W. Myers, a group leader develop and go on to form complex circuits. at HHMI’s Janelia Farm Research Campus. What we want to Doe, now an HHMI investigator at the Doe and Myers met at a neuroscience “ University of Oregon, gives credit for the idea conference held at the Ashburn, Virginia, do would be like of creating an atlas to his former postdoctoral campus in March. “We’ve been working searching Google adviser, HHMI investigator Matthew P. Scott, hard at this ever since,” says Doe. “The for the shape of a who is now at Stanford University. Scott had methods of computational biology are now developed an atlas of Hox gene expression for so advanced that it’s conceivable to make a person’s head. Drosophila. He and his colleagues discovered computer atlas of the nervous system and that Hox genes, which determine where limbs map the expression of hundreds of genes.” 16@7A2=3” and segments will form in the developing And if that atlas were searchable, he notes, embryo, are expressed in a one-dimensional it would potentially allow scientists to solve pattern. When Doe struggled to make sense two important mysteries in neurobiology: of his three-dimensional data, he recalls Scott how a stem cell becomes a particular type of saying: “Just build an atlas.” neuron, and how neurons come together to Illustration: Jon Han Photo: John Clark Han Photo: John Illustration: Jon form circuits that allow for all the complex neuron-specific transcription factors in late- processes governed by the brain. “Our best developmental Drosophila embryos. Then, hypothesis is that neurons that make up a using confocal microscopy, they produced two- circuit share a transcription-factor code,” dimensional images—optical “slices”—of the says Doe. “Many labs are looking to identify resulting three-dimensional patterns of fluo- these circuits. We’re hoping our atlas will rescence. Doe and Layden are creating stacks help them determine which transcription of these slices for each of the more than 200 We are creating stacks factors those neurons have in common.” transcription-factor genes identified to date. “ Then researchers could work backward Myers and his team take these stacks and of these slices for to figure out which genes direct progenitor produce a computer-generated model for each each of the more than cells to differentiate into particular types of gene that resembles a constellation—glowing neurons, says Stephen Crews at the University points of color in a black three-dimensional 200 transcription-factor of North Carolina at Chapel Hill. Crews space. The last step in building the atlas genes we know. has created a two-dimensional atlas of gene involves overlaying these patterns on one expression for more than a hundred genes another. To do this, Myers’ team is writing soft- ;716/3::/G23< ” involved in the development of Drosophila ware that aids in the recognition of the patterns midline CNS. Because transcription factors created by the glowing nuclei of each neuron. “We can easily do a Google search using are largely conserved throughout evolution, “We’re learning to identify these nuclei the the name of a person,” says Doe. “What we Crews expects the three-dimensional fly atlas way astronomers identify stars in the sky,” want to do would be like searching Google will help in understanding development Myers says. “How do you find the North Star? for the shape of a person’s head.” According of the nervous systems of higher animals. You look for the pattern created by the stars to Myers, no one has yet accomplished this “Having a searchable atlas of hundreds of that make up the Big Dipper. In the same next-level search technology. “We’ll learn a genes that all labs could have access to would way, we are looking for invariant patterns.” lot of biology by doing this,” he says, “but really be a huge step forward,” he says. Making the atlas a searchable one will we will also learn a lot about exploring and To create the first draft of the atlas, Doe and be the next challenge, as current search understanding three-dimensional space.” . Layden used fluorescent antibodies to label technology is limited to one dimension. – CAMILLE MOJICA REY John Clark John upfront Retrieving Lost Memories Scientists have found that certain substances, at least in the lab, prevent neurodegeneration from Alzheimer’s disease and restore what was seemingly forgotten. LI-HUEI TSAI RECALLS A LIFE-SHAPING EVENT WHEN SHE WAS A TODDLER living with her grandmother in Taiwan. “Every morning we took a short walk to the local market for groceries. One day, on the way back, there was a thunderstorm, so we took shelter in a little shed. After the rain, I seemingly long-gone remembrances. said, ‘Let’s go home now.’ I looked at my grandmother’s face and it was Caretakers have noted that immersing completely without expression. ‘Home?’ she asked. ‘Where is home?’” Alzheimer’s patients in intellectually stim- ulating environments tends to evoke these Mystified and frightened at the time, Her recent studies focus on a class lucid moments. Tsai came to understand that her grand- of enzymes called histone deacetylases Remarkably, Tsai and her colleagues mother, then in her 50s, probably had (HDACs), which perform many func- observed the same phenomenon in the early-onset Alzheimer’s disease, a heritable tions in cells and derive their name from lab. After inducing Alzheimer’s disease form of the mind-robbing illness that strikes their ability to remove small chemical in mice that had been taught a battery of victims in the prime of life. Now an HHMI tags, called acetyl groups, from histone learning and memory tasks, they found investigator at the Massachusetts Institute proteins—key components of chro- that those housed in cages with toys and of Technology (MIT), Tsai’s mission is to mosomes. Because histone acetylation other intellectual stimulation regained end Alzheimer’s disease. “That memory patterns can influence gene expression, “lost” memories of their acquired skills, and others like it,” she says, “are a big HDACs have widespread physiological but the lessons learned by those kept in source of my inspiration to carry out this consequences, including in Alzheimer’s spartan cages remained forgotten. line of research.” disease, as Tsai’s team first reported in When they examined the acetylation Four years ago, her research team the online version of Nature last April. patterns of brain histones in these two created a powerful mouse model that, They were investigating a well-described groups of mice, researchers discovered unlike most previous models, shows the but poorly understood phenomenon that the patterns differed dramatically. hallmarks of human Alzheimer’s disease: called “fluctuating memory,” in which With that finding, complemented by massive loss of neurons, the presence of even advanced-stage Alzheimer’s patients prior reports of the beneficial effect neurofibrillary tangles, and accumulation suddenly regain, at least for a short while, of HDAC inhibitors on learning and of amyloid peptides in the brain, accompa- nied by severe memory loss. What’s more, the extensive and rapid brain deterioration “It seemed that the existing neurons were in the mice can be quickly turned on and more active in communicating with each off. “These two characteristics render the other and making more synapses. mice ideal for looking for potential thera- peutics,” Tsai says. :76C37BA/7” HHMI BULLETIN | November 2007 memory, the Tsai team was motivated to test such agents on its mouse model. They discovered that administering an HDAC inhibitor—sodium butyrate or trichostatin A—to the mice instead of environmental enrichment was enough to restore lost memories. “The brains of the treated mice didn’t look any bigger and the number of cells in the brain didn’t look significantly different from those of untreated mice,” says Tsai. “But it seemed that the existing neurons were more active in communicating with each other and making more synapses.” @SacZbaT`][abcRWSaW\bVSZOP]T:W6cSWBaOWacUUSabbVObµ[S[]`gZ]aa¶[OgPSO\W\OQQc`ObS Tsai cites recent studies on an HDAC RSaQ`W^bW]\]TQS`bOW\[S\bOZRSTWQWbaOaa]QWObSReWbV\Sc`]RSU\S`ObWdSRWaSOaSa called SIR2, which shows anti-aging prop- erties in many organisms. “Alzheimer’s disease is a typical product of aging,” she neurodegeneration but preserved their Tsai, since the enzyme targets many other says. “So to me, it’s quite logical that the cognitive and memory functions as well. protein substrates besides histones, but her next question was whether SIR2 might The scientists also tested the neuro- team is trying to pin down its biochemical also be beneficial in treating this illness.” protective effects of resveratrol, the role in the brain. With her colleague David Sinclair’s compound in red wine that has attracted Given these experimental results, Tsai research team at Harvard Medical School, considerable scientific and media atten- is “cautiously optimistic” that new drugs Tsai’s group tested that notion using the tion for its possible anti-aging properties. for preventing, even reversing, the effects MIT mice and then reported their find- They found that resveratrol, an activator of Alzheimer’s disease may become reali- ings last June in the online version of The of SIRT1, offered the mice substantial ties in the not-too-distant future. “I can’t EMBO Journal. The overexpression of protection from neurodegeneration and tell you it’s a year or two from now,” she SIRT1—the human version of SIR2—in preserved their learning ability. Just how says, “but I don’t think it will be as long Matt Kalinowski the mice not only protected them from SIRT1 protects the brain is unclear to as 10 years.” . – PAUL MUHLRAD November 2007 | HHMI BULLETIN upfront The Sum of Its Parts Many of the brain’s sophisticated functions may ultimately arise from the straightforward process of addition. WHEN NEUROSCIENTIST RAFAEL look at the wires and transistors, and try to work revealed that spines are containers Yuste likens the human brain to identify the logic of its circuitry.” for calcium, which controls the strength of The potential of this reverse-engineering the neuron-to-neuron connection. But in a a computer, he is zeroing in on approach is evident in Yuste’s recent inves- series of papers published over the last two its breathtaking simplicity, a cir- tigation of an item in the cortical “parts list” years in Proceedings of the National Academy cuitry whose logic, he postulates, called the dendritic spine. of Sciences, Yuste provides evidence, using In most cortical neurons, these tiny slices of mouse brains, that spines also serve is the stuff of first-grade math. ¶ knob-like features are liberally scattered an electrical function, perhaps even more Yuste, an HHMI investigator at over the surface of dendrites—the projections important in the neuron’s processing of Columbia University, studies emanating from neuronal cell bodies. When incoming nerve signals. one neuron sends a signal to another, the Working with Roberto Araya, a postdoc- the cortex, the seat of per- impulse moves from its cell body, through toral associate in Yuste’s lab, and Kenneth ception, memory, and language. its axon, to its axon terminals, across a gap, Eisenthal from Columbia’s chemistry or synapse, to the head of a spine on the department, Yuste started with evidence He and his colleagues treat receiving dendrite and then to the cell body that nerve signals can be transmitted the cortex in the same way engi- of the neuron. between neurons that lack spines. While neering students are taught to The fact that most cortical neurons are such neurons are comparatively rare in covered with as many as 20,000 dendritic the cortex, their ability to function without treat a device of unknown func- spines suggests the spines’ importance in the help of spines—still able to marshal the tion: “We take apart the box, processing impulses. Yuste’s postdoctoral calcium associated with nerve transmission— “We take apart the box, look at the wires and transistors, and try to identify the logic of its circuitry. @/4/3:GCAB3 ” BVSaSZWdSRS\R`WbSaW\bVSP`OW\O`SQ]dS`SReWbVaZS\RS`\SQYSRa^W\Sa bVObVSZ^b]OQQc`ObSZgac[OZZW\Q][W\U\S`dSaWU\OZa ©HHMI / AP, lab Photo: Clark Jones Science Image courtesy of Yuste HHMI BULLETIN | November 2007 suggested that “nature doesn’t need spines received? It occurred to them that “maybe to work in a linear fashion and serve as to accomplish this.” the logic of the design is to enable the nerve adding machines. In a brain marked by a Unable to believe that ubiquitous spines cell to add arithmetically, just as you would “distributed” circuitry, in which neurons were superfluous, the researchers pursued teach a child to do,” Yuste explains. “The sample incoming information over the a hunch that spines had an undiscovered spine neck could serve to electrically isolate widest possible area, a mechanism that electrical role. Using lasers, they “turned inputs, thus enabling the soma to add every accurately sums many signals would gather on” individual spines to mimic the arrival input without interference.” all possible information. of an incoming nerve input. Then they They then found that, when two spines Yuste’s speculation goes further. Perhaps, measured the voltage generated in the cell on the same dendrite were simultaneously based on simple addition, nature found body of the same nerve cell, finding that the stimulated, the voltage they conveyed to the algorithms that could be used to build amount of current delivered through the soma was precisely the sum of their signals. a diverse set of mental functions. Yuste spine to the soma was inversely proportional At the same time, when two regions devoid aims to demonstrate this notion in human to the length of the slender neck supporting of spines were stimulated, they interfered tissue. If he succeeds, linear summation the head of the spine. with each other, and the resulting voltage was would be shown to be the elegant operation Now it was time to do some reverse much smaller than the sum of the two inputs. that renders the cortex a kind of universal engineering to find out why spines were Thus, not only do spines compartmentalize computer, able to mobilize elementary “filtering,” or impeding, incoming nerve calcium to regulate synaptic strength, but they math to accomplish such complex (and, signals. Why, after all, would evolution select also help the neuron accurately add inputs. paradoxically, nonlinear) ends as thinking, an architecture that diminished incoming The implication, Yuste hypothesizes, is remembering, and imagining. . signals at the very point where they were that dendritic spines enable cortical neurons – PETER TARR <3C@=/B@=: HHMI INVESTIGATOR RAFAEL YUSTEWaR`WdS\Pg[]`SbVO\ObVS]`SbWQOZ SOQV `Sa^]\aWPZS T]` O ·\SWUVP]`V]]R¸ ]T Q]`bWQOZ \Sc`]\a ¶ BV`SS W\bS`Sab W\ bVS ab`cQbc`S O\R Tc\QbW]\ ]T bVS QS`SP`OZ Q]`bSf /a O ]` T]c` ]TTWQS`a [WUVb ^Ob`]Z O PSOb S\Q][^OaaW\U a][S ^VgaWQWO\aQWS\bWabVSOZa]eO\bab]aSSeVObVO^^S\aeVS\Q]`bWQOZ \Sc`]\a EVS\bVSgRSbSQbO\O^^`]OQVW\US^WZS^bWT]`[eOdSbVS QW`QcWba [OZTc\QbW]\ O\R eVOb QZW\WQWO\a QO\ R] OP]cb Wb ,, WHEN W\VWPWb]`g \Sc`]\a TW`S RWaQVO`UW\U GO[W\]Pcbg`WQ OQWR 5/0/ HE STARTED HIS LAB AT COLUMBIA,GcabSb]]YO\W\bS`SabW\S^WZS^agO O \Sc`]b`O\a[WbbS` RW`SQbZg W\b] bVS QSZZ P]RWSa ]T \SWUVP]`V]]R [OX]`RWaSOaSW\d]ZdW\UbVSQ]`bSf BVSTW`abb]caSQOZQWc[W[OUW\U \Sc`]\a ,, SO LONG AS THEY HAVE A RESERVE ]T5/0/bVS\Sc`]\OZ b] dWacOZWhS O QW`QcWb GcabS O\R U`ORcObS abcRS\b BcR]` 0ORSO ^]ZWQSQO\ab]^bVSeOdS /^S`a]\eWbVS^WZS^ag[WUVbSf^S`WS\QS µeS`S OPZS b] W[OUS bVS a^`SOR ]T O\ S^WZS^bWQ aSWhc`S \Sc`]\ Pg bVWa Oa O aSWhc`S eV]aS STTSQba O`S Z]QOZWhSR 0cb WT bVS 5/0/ \Sc`]\ T]` bVS dS`g TW`ab bW[S¶ GcabS aOga ;]`S `SQS\bZg GcabS `SZSOaW\U \Sc`]\a SfVOcab bVSW` ac^^Zg bVS eOdS ^OaaSa bV`]cUV O\R ^]abR]Q /\R`Se B`SdSZgO\ OZa] O ^VgaWQWO\aQWS\bWab QO``WSR `SQ`cWba\SO`Pg\Sc`]\aO\R^`S^O`Sab]W\dORSbVS\SfbbS``Wb]`g´ ]cbSf^S`W[S\baOW[SRObRWaQ]dS`W\UV]eS^WZS^bWQaSWhc`Sa´]`Ob ZSORW\Ub]OTcZZPZ]e\aSWhc`S ,,WHILE CAUTIONING THAT THE WORK ZSOabbVSW`O\OZ]UaW\[WQS´a^`SORbV`]cUVQ]`bWQOZbS``Wb]`g BVSW` b]RObSW\d]ZdSa[]caSQSZZaGcabSPSZWSdSaWbQ]cZRSdS\bcOZZgZSOR TW\RW\Ua`S^]`bSR]dS`bVS^OabgSO`W\bVS8]c`\OZ]T November 2007 | HHMI BULLETIN ! HOW BY Marc FAR Wortman WILL G T D SCOTT ILLUSTRATION STROBEL BY Pietari TAKE Posti HIS O H I STUDENTS TO FIRE I E S THEIR INTEREST IN SCIENCE? N T TO THE AMAZON AND G A BACK. N C E “Ain’t no mountain high enough, ain’t no watching, the 20-year-old slung his collec- because they have not experienced enough valley low enough” could be Scott A. tion bag over his shoulders, took off his of science’s excitement or opportunities,” Strobel’s theme when it comes to turning boots and socks, grabbed a dangling vine, Strobel says. He asserts that some of the his students into scientists. There is almost and began his ascent. blame rests with the types of projects no limit to how far he will go, even accom- Vekhter’s and his fellow students’ offered to undergrads. “It’s the problem of panying his undergraduates from New Amazon adventure was a bioprospecting ownership,” he says. “All too often, we give England to the heart of a South American trip, the first offering of an experimental undergraduates too small or too technical jungle. But don’t ask him to climb a tree. discovery-based science education a piece of the scientific question to figure A recent journey took Strobel, an HHMI program Strobel created for Yale under- out how it fits into the equation.” Instead professor at Yale University, and 15 under- graduates. The concept for the course won of firing the student’s imagination, such graduates from a New York City airport to Strobel an HHMI professor’s award, which experiences often extinguish the desire to Lima, Peru, followed by a two-hour flight provides him and Yale with $1 million in pursue science as a career. to Puerto Maldonado, a town in the Upper support over four years. Few undergradu- Strobel wanted to see what he could do Amazon rainforest. Then they motored ates ever get the opportunity to learn by to change that outcome at Yale. “The idea six hours by boat down the Madre de Dios doing like Strobel’s students. When they is to give students control of scientific deci- River. A final two-mile slog through knee- applied for the course, they knew they’d sions,” he says. “That’s critical to the success deep mud, swarming insects, and pouring be trekking far from home, but they may not of any research experience, regardless of rain brought them to the base of an iboga have realized just how far—as scientists— the student’s academic level.” He devised tree (Tabernanthe iboga), an immense the experience would take them. an experiment in undergraduate scientific succulent whose upper branches disap- research for which, as he explained in peared in the dense canopy overhead. FIRING the course description, “There is no lab Once there, student Daniel Vekhter, a IMAGINATION manual.” Students choose plants and wiry Yale junior from Buffalo, was near his According to Strobel, most scientists can microbes that interest them, pluck small prize. But it was up to him to do the trace their professional start to a rewarding samples from an untouched part of nature, climbing—more than 30 feet overhead college research experience. But too many and then bring them back to a campus and out on a limb stretching from the undergraduates who take on research laboratory for analysis using a variety of iboga’s thick vine-draped trunk. He was projects abandon science after getting available techniques—many of which after microorganisms that he planned to their diplomas. “Students grow discouraged Strobel uses in his own research program, spend the coming summer and next which focuses on basic biological processes school year studying, and that, he hoped, including how RNA catalyzes protein would form the beginnings of his career. synthesis and RNA splicing in the genome. With a wary Strobel and his classmates He drew inspiration from a program launched in 2002 by HHMI professor Graham F. Hatfull at the University of “THESE STUDENTS’ PROJECTS GIVE THEM A SENSE OF INTELLECTUAL OWNERSHIP $ HHMI BULLETIN | November 2007 Pittsburgh. After collecting local soil experiments never require him to leave the The senior Strobel has identified scores samples, Hatfull’s undergraduates and laboratory, Gary’s ventures into the bio- of previously unknown endophytes. Several high school students isolate, sequence, and chemistry of natural products regularly have proven valuable, among them a annotate mycobacteriophages—viruses take him to distant places. Several times fungus that produces the anti-cancer drug that infect bacteria and are used by each year, he travels to rainforests and paclitaxel, more popularly known by its researchers to learn about the genetics of other biologically diverse locations across brand name Taxol, and a fungus that numerous diseases. “These students’ proj- the planet in search of endophytes— generates volatile chemicals that have ects give them a sense of intellectual bacteria and fungi that live symbiotically proven useful for treating human waste. ownership and project control,” says on plants. The fascinating biology of these Scott has accompanied his father on a Strobel. “It inspires them to see science as organisms led Scott to build his Yale few rainforest trips over the years, but those something they can do.” course around them, and to persuade his were nearly always family vacations, not father to lead the Amazon expedition. bioprospecting trips. “That’s my dad’s type COMPLEMENTARY Many endophytes produce natural of science,” he says. Sitting on a stool in a STRENGTHS chemicals that inhibit the growth of organ- Yale laboratory sporting overalls and a wide Scott Strobel had an inspiring teacher from isms potentially toxic to the plant host or grin, Gary looks like he would happily very early on—his own father, Gary Strobel, provide it with some other evolutionary sleep in a tent in the wild. His son, wearing a renowned plant pathologist at Montana advantage. Endophytes’ biological activity shirtsleeves, slacks, and a more serious State University. From age 2, Scott would has also served human ends, providing a demeanor, acknowledges, “I want to be in spend days with his father in the biology source of chemicals for pest control prod- a comfortable bed at night.” Yet for this laboratory. After majoring in biochemistry ucts, for example, and for many medicines. HHMI research course, Scott says “trying at Brigham Young University, Scott earned From cancer therapies to antibiotics, to combine his brand of science with mine” his doctorate at the California Institute of about 40 percent of all prescription drugs made sense. Technology studying site-specific cleavage derive from natural compounds. Yet, very Cong Ma, now a Yale College senior of genomic DNA. His current interest in few endophytes on the Earth’s 300,000 from Williamsport, Pennsylvania, who the biochemistry of RNA gelled during post- plant species have ever been characterized, participated in the HHMI research course, doctoral work in the University of Colorado even though nearly all plants serve as host says that the two Strobels’ different natures at Boulder laboratory of Thomas R. Cech, to one or more bioactive microbes. make them complementary, and highly now president of HHMI. effective, team leaders. “Gary is really Though their styles differ, his father encouraging and outgoing. Scott is a little continues to inspire. Now 69 years old, Gary Strobel is lean and weathered with close-cropped hair. Unlike Scott, 43, whose AND PROJECT CONTROL.” —SCOTT STROBEL Scott Strobel (right) and his father, Gary Strobel, joined forces to bring their complementary styles and expertise to a discovery-based science course for Lisa Kereszi undergraduates. November 2007 | HHMI BULLETIN % more reserved. But both are fun-loving and one of the most remote places you can Tiny Plant, Grand Adventure great characters. I wouldn’t have picked get to,” says Ma. They hiked into an anyone else to lead us.” undisturbed, primeval forest with plenty to 9Oc`g3WaS\[O\T]QcaSRVS` All students participating in the keep them on their toes: along with the Vc\b]\QO`\Wd]`]ca^ZO\ba AVS program took a special spring-semester biting bugs, he recalls walking past Vg^]bVSaWhSRbVSge]cZRPS course, taught by Scott and visiting experts. a small but potentially deadly pit viper, a W\VOPWbSRPg[]`SS\R]^VgbSa It combined microbiology, pharmacology, venomous snake known as a fer-de-lance. bVO\]bVS`^ZO\baPSQOcaSbVSg SObW\aSQbabVObVOdSb`OdSZSR plant science, ethnobotany (the study of He also witnessed a giant otter snagging T`][^ZO\bb]^ZO\b BVS]\Zg plants in human culture), conservation, and and making a meal of a piranha. “It was QO`\Wd]`]ca^ZO\bbVSU`ORcObS intellectual-property law. After researching amazing,” he says. bSOQVW\UOaaWabO\bQ]cZRTW\R the indigenous plants and the culture of Gary knows many of the world’s rainfor- Rc`W\UbVS/[Oh]\Sf^SRWbW]\ the Amazon, each student—and two ests intimately, yet even his knowledge V]eSdS`eOabVSbW\g2`]aS`O graduate student teaching assistants— counted as cursory within the over- []\bO\O /ZbV]cUVbVS[Obc`S ^ZO\bQ]cZRTWb]\bVSTOQS]T defined a theme that would guide his or whelming natural diversity and dense O_cO`bS`SOQVZSOTbVSaWhS]TO her plant collection during the expedition. growth the group encountered. “It’s not ^S\QWZbW^3WaS\[O\¸aRWaQ]dS`g One student collected plants native like going to a garden and picking flowers,” Wa^`]dWRW\UTWdSabcRS\baW\bVS peoples use to treat tuberculosis infections; he says. To scout out their plants within the QZOaaOdS`WbOPZSTc\UOZb`SOac`S another opted for plants likely to produce seemingly impenetrable tangle, they relied QVSabb]Sf^Z]`S antioxidants. One aspiring scientist on a guide, Percy Núñez, an Amazon- targeted carnivorous plants, while another basin native and professional field biologist 6S`Vg^]bVSaWaaSS[ab]VOdS PSS\P]`\S]cbOaaVSWa]ZObSR sought plants used to treat wounds. from Peru’s National University of San bV`SSTc\UWbVObYWZZSRSdS`g Vekhter’s iboga-tree extracts appealed to Antonio Abad in Cusco with an encyclo- bSab]`UO\Wa[aVSSf^]aSRb] him because of their reputed properties for pedic knowledge of tropical botany. bVS[ AVST]c\RbVSQ]Z]`SR battling opioid addiction. “From a societal Shouts of “I found my plant!” or calls Q][^]c\RabVSTc\UW^`]RcQSR point of view,” he says, “it would be great over the walkie-talkie of “We found your W\QcZbc`S[SRWOµab`WYW\UO\R if one of our plants had value. That’s some- plant!” came frequently as the students OeSW\a^W`W\U ¶Be]]TbVSTc\UW `SZSOaSORO`Y`SRacPabO\QS thing everyone in the class cares about.” spied their prey, recalls Strobel. They used eVWZSObVW`RTc\Uca^`]RcQSaO machetes and plastic bags to cut and dS`gP`WUVbgSZZ]eQ][^]c\R A collect small stems and leaves. ]`[Wf]TQ][^]c\Ra DIFFERENT Most specimens had to be collected PLANET from upper portions of plants, where endo- C\RS`U`ORcObSabcRS\baVOdS While many of their friends headed for phytes are more likely to be found in \]ebOYS\]dS`VS`^]bS\bTc\UW BVSgRSdSZ]^SRbe]PW]OaaOga spring-break beaches or home, the Yale abundance and less likely to be contami- W\eVWQVSfb`OQbaT`][P]bV`SR undergraduates left their world behind. nated by soil microbes. Hence, Vekhter’s Tc\UWQ]\bW\cSb]^`]dSVWUVZg They voyaged to a place in the upper high climb up the iboga tree—where he did OQbWdS /abcRS\b\]bWQSRbVOb Amazon basin still largely free from the find the endophytes he was after. Other bVS\SO`ZgW\dWaWPZSbW^a]TbVS developed world’s intervention. “It was students collected samples from high 2`]aS`O[]\bO\O¸aW\aSQbQObQVW\U branches using clippers attached to long O^^S\ROUSaO`S`SR^]aaWPZg poles. “The way Scott is making us get our RcSb]bVS^`SaS\QS]TbVS`SR ^`]RcQW\UTc\UW scientific chops is really unique for under- graduates,” Vekhter says of their adventures. EVWZS3WaS\[O\Wa`Sbc`\W\Ub] By the end of the two weeks, the VS`U`ORcObSabcRWSaaVSaOga students had found more than half the µ7Q]c\b[gaSZTdS`gT]`bc\ObS plants on their lists. For Gary Strobel, it b]VOdSPSS\O^O`b]TeVObVOa was his most fruitful bioprospecting trip bc`\SR]cbb]PSOU`O\RORdS\ bc`SabO`bb]TW\WaV ¶´; E ever. The group returned to Yale with & HHMI BULLETIN | November 2007 SHOUTS OF “I FOUND MY PLANT!” those crystals as 2,4-diacetylphloroglucinol (DAPG), a broad-scale antibiotic produced OR CALLS OVER THE WALKIE-TALKIE by some strains of Pseudomonas fluorescens OF “WE FOUND YOUR PLANT!” bacteria. Fenn’s preliminary analysis shows that the bacterial strain she isolated CAME FREQUENTLY AS THE STUDENTS produces DAPG on a scale several times SPIED THEIR PREY. greater than any previously reported. She plans to continue her research in hopes of demonstrating that this strain exhibits samples of around 300 plant species, many compounds are in it. Having a publication unprecedented efficiency in antibiotic of which he had never seen before. All would be really exciting.” production—and to learn more about became reference species in the Yale The students probed their microbes its properties. University Herbarium, one of the nation’s further. They grew them in liquid culture Fenn, like several other students in the oldest and most extensive plant-specimen and extracted metabolites to look for the class, intends to collaborate with various collections, and in Núñez’s herbarium at biologically active components. The crude Yale laboratories to see if her molecules the university in Cusco. extracts were also screened using a variety have any promising disease-modulating of biochemical assays. Those steps might properties. In fact, a Yale School of Medicine GETTING include separating out individual molecules scientist has already invited Schorn to screen DOWN using chromatography, studying structure the extracts she found using his cellular TO IT through crystallography, and applying other assay for potential Alzheimer’s disease Upon returning to Yale, the young laboratory techniques to look for interesting treatments. The undergraduates, most of researchers prepared their specimens for and potentially beneficial properties. whom expect to continue working on their bioactivity screening. They dissected them, As the students dug into their projects, projects during the current school year, are culturing minute bits in plates containing Scott challenged them, “Anything your already thinking like advanced medical growth medium as well as test organisms mind can imagine, go for it. Figure out investigators, says Strobel. placed a couple of inches away. The the taxonomy and what is known. Look For him, the results prove something students then waited to see what activity beyond that and see what’s new. Then you he was unsure of at the start. “We’re seeing might emerge when the endophytes and have to decide what you’re going for.” that undergraduate students can go from a their bioactive products proliferated and Kathleen Fenn may have already jungle trail to complete chemical charac- encountered the test organisms, which discovered something truly new—and terization of a natural product in less than included a variety of plant pathogens as potentially medically beneficial—in the four months,” he says. “That’s astounding.” well as human-infecting bacteria and rainforest. She collected a stem sample But much more important to him is the fungi. Among them were Candida albicans from a Capirona decorticans tree. She hope that the course has “inspired the (a cause of many fungal infections, some hypothesized that it might prove useful scientific imagination” of his students, now resistant to treatment), Escherichia after she learned that Amazonian native giving them a “feeling of empowerment to coli (responsible for many types of infec- tribes apply capirona-based concoctions control the direction of an inquiry.” tion), and Bacillus subtilis (widely used by for a variety of medicinal purposes With the HHMI grant, Strobel will researchers as a model organism). including treating fungal infections, repeat the Yale course three times, taking When an endophyte or its products diabetes, and wounds. Back in New Haven, his classes to new locations in search of showed visible activity, the students put Fenn isolated a strain of pink-colored endophytes. The final outcome of Strobel’s them through a battery of tests to isolate the bacteria from it, which when cultured experiment in science education may not source of their bioactivity. DNA samples formed pink crystals on top of the test be known for years to come. For Vekhter, from several microbes were sent to a Yale colonies. A Yale crystallographer identified who plans to study his iboga endophyte laboratory for sequencing. In several cases, extracts through his senior year at Yale and the resulting data revealed bacteria and intends to “stay in science,” the results are fungi whose genomes differ significantly already clear. As an undergraduate, he from any known organism in GenBank, says, “Usually you get plugged in” on a the annotated online collection of all professor’s research project, “but here we publicly available DNA sequences main- get to do our own thing.” . tained by the National Institutes of Health. Michelle Schorn, a junior from San Diego, is one of the students who found a novel bacterium. As a result, she says she expects, “to write a paper identifying it and what November 2007 | HHMI BULLETIN ' small talk Studying how marine bacteria light up when ready, a scientist known for her communication skills revealed the purposeful chitchat used by these tiny organisms. by Paul Raeburn photographs by Greg Miller HHMI BULLETIN | November 2007 November 2007 | HHMI BULLETIN known for Her graduate adviser had funding from the type of antibiotic based on interrupting her full- U.S. Navy to study how certain bacteria bacterial communication—one that might provide footing for the barnacles, which work against all kinds of bacteria, not just steam-ahead cling to hulls and rudders with epoxy-like one or a few species. approach strength, causing an enormous drag on a to life and ship’s progress. the communicator Bassler has picked up speed since then, Bassler, often described as a force of nature, work, hhmi becoming what one colleague calls a “rock is known not only for her research achieve- investigator star” of microbiology and earning a 2002 ments. She is a distinguished speaker, a MacArthur Foundation Fellowship, popu- gifted teacher, and having a conversation bonnie l. larly known as a “genius” award. “Bonnie with her is like taking a drink of water from bassler began stuck to her guns and knew what she was a fire hose. Ask her why she became a doing,” says Richard M. Losick, an HHMI scientist, for example. “I had this wonderful her career professor at Harvard University with whom experience in graduate school, where I pondering Bassler has collaborated and published. loved doing experiments. I really liked ocean- “She is quite extraordinary in her energy being at the bench, and I really wanted to and breadth of interests.” keep being in school, because Heaven dwelling It comes as no surprise to people who’ve forbid I should actually have to get a real barnacles worked with her that Bassler’s unglamorous job, I mean, I wasn’t going to do that … experiments with barnacle-involved and so anyway …” that foul bacteria led to the puzzle of how and when Or ask her about teaching an introduc- ships and a little-known ocean-dwelling bacterium tory biology class to non-science majors. becomes luminescent. And in solving that “We use the word ‘evolution’ in every slow them puzzle, she moved from an obscure area of lecture. We use it to explain how every down. research to a central unsolved problem in protein folds to make its binding site, how microbiology: How do bacteria communi- the cell membrane and the proteins in it cate with each other? function. We don’t use the word to imply The answers she found have transformed anything about monkeys but, rather, to thinking about bacterial communities. explain every single reaction in one’s body She has shown that bacteria, far from being that has been optimized to make us alive, opportunistic loners, are highly social or how things have gone wrong to, say, give creatures that incessantly chatter among you cancer. We try to convey to the students themselves, with the hosts they infect, and that evolution underpins every single, beau- even with other species of bacteria by tiful, magical biological thing that happens.” means of a common “language” that no Where she finds time to take a breath is one thought existed. That signaling system itself a kind of magical biological thing. has been dubbed “quorum sensing” and Five days a week, Bassler begins her Bassler is poised to devise a radically new day with a 5:42 alarm, giving her just HHMI BULLETIN | November 2007 enough time to get to the YMCA to teach a 6:15 a.m. aerobics class. She met her husband, actor/dancer Todd Reichart, shortly after she moved to Princeton, when she signed up for a swing dance class; he was the teacher. They still dance off and on. “We look really good at weddings, but that’s it,” she jokes. Her dual interests in dance and biology led to a friendship with choreographer Liz Lerman, who received a MacArthur Fellowship the same year that Bassler did. Bassler participated with other researchers in the development of a Lerman dance piece called Ferocious Beauty: Genome. Bassler and Reichart (who refers to his Bonnie Bassler sensed that a tiny, light-emitting organism wife as “hyperkinetic”) also canoe and could reveal big things about bacterial communications. hike whenever they get the opportunity, often taking an extra week after one of Bassler’s far-flung scientific meetings to climb the nearest 14,000-foot peak. “I don’t “For many of these kids, it’s the first class geneticist at the Agouron Institute, a do anything where I have to be attached to they’ve taken that isn’t subjective,” she nonprofit research organization in La Jolla, a rope and could fall off and die,” she says. says. Unlike literature classes or creative California, presented his research. “But I will walk forever.” writing workshops, in science—she teaches Silverman’s focus was a marine bacte- With all that exercise, Bassler is athlete them—“there’s a right answer and a wrong rium called Vibrio fischeri, which has the trim. She curls her legs up under her on answer.” Without a class like hers, she ability to light up, or bioluminesce. It is the chair when she talks, and when she says, many of them may graduate from found, among other places, in the “light wants to make an important point she college without understanding that or organ” on the underside of the bobtail leans in and whispers, as if confiding a anything about science. And that, in squid, with which the bacteria live symbi- secret. Or she stands up and shouts, if turn, will make it more difficult for them otically. The squid hunts at night in shallow that’s what it takes. to address scientific debates as adults, water, and when moonlight threatens to Her communication skills serve and as citizens. make it visible to predators by virtue of its Bassler well in her teaching, something shadow on the sand below, the bacteria she considers an essential part of her follow the light bioluminesce and the light organ glows. work. She is director of graduate studies Back when Bassler was working on barna- Goodbye shadow. in the molecular biology department at cles, while at Johns Hopkins University, This clever masquerade depends on an Princeton and also teaches the molecular she attended a meeting of Navy-sponsored unusual property of V. fischeri, discovered in biology course for non-science majors. researchers where Mike Silverman, a the 1970s. When grown in the laboratory, November 2007 | HHMI BULLETIN ! A Different Approach for Cholera ;]abPOQbS`WOeO\bb]USbW\b]bVSP]Rg`S^`]RcQSO\RabOgT]`SdS` BVSg [cZbW^Zgc\bWZbVSgVOdS`SOQVSRacTTWQWS\b\c[PS`ab]ObbOQYO\RbVS\ aS\aW\UbVObbVSgVOdSO_c]`c[ZOc\QVbVSObbOQY But Vibrio cholerae, bVSQOcaS]TbVSRSdOabObW\UW\TSQbW]\Y\]e\OaQV]ZS`OWaRWTTS`S\b 7bZWdSa W\Q]\bO[W\ObSRR`W\YW\UeObS`eVWQVWaV]eWbbg^WQOZZgS\bS`abVSP]Rg =\QSbVS`SWbObbOQVSaWbaSZTb]bVSW\bSabW\SO\RPSUW\ab][O\cTOQbc`S bVSb]fW\abVObQOcaSbVSWZZ\SaaSdS\PST]`SWba\c[PS`aVOdSaWU\WTWQO\bZg `WaS\ 7b Wa dW`cZS\b T`][ bVS abO`b /\R eVS\ Wb `SOQVSa O ^O`bWQcZO` ^]^cZObW]\ bV`SaV]ZR´eVWQV Wb [SOac`Sa bV`]cUV _c]`c[ aS\aW\U´Wb aeWbQVSa]TTWbadW`cZS\QSUS\Sa Then V. cholerae produces O\S\hg[S do we have a quorum? bVObQZW^a[O\g]TWba\c[PS`]TTbVSW\bSabW\OZeOZZa 0gbVObbW[SS\]cUV Silverman, now retired in Jackson Hole, b]fW\VOaPSS\^`]RcQSRb]QOcaSRWO``VSOeVWQVeOaVSabVS\SeZgT`SSR Wyoming, remembers it differently. “She POQbS`WO]cb]TbVSP]Rg A][S]TbVS[eW\Rc^W\^cRRZSaO\R`WdS`aO\R SdS\bcOZZg W\ R`W\YW\U eObS` D QV]ZS`OS¸a PSVOdW]` QZSO`Zg RWTTS`a T`][ came from a good lab, and I ran a small bVOb]T[]ab]bVS`^ObV]US\WQPOQbS`WO 7beO\bab]abOgW\bVSP]RgT]` operation and I needed her,” he says. ]\Zg O aV]`b bW[S´b] `S^`]RcQS TO` TOabS` O\R []`S STTWQWS\bZg bVO\ Wb “From the time she arrived, she worked Q]cZRW\O^]]Z]TabO\RW\UeObS`´O\RbVS\SaQO^SW\ZO`US\c[PS`ab] hard. I would come into the lab at night, W\TSQb[]`SV]aba Although with other infections bVSWRSOWab]RSdSZ]^ and there she was. And she would be there OR`cUbVObRWa`c^ba_c]`c[aS\aW\U´a]bVObbVSPOQbS`WOR]\¸bW\WbWObS dW`cZS\QS´eWbV D QV]ZS`OS bVS ]^^]aWbS ab`ObSUg O^^ZWSa aOga 0OaaZS` again in the morning.” She soon asked for µ6S`SbVSR`cUWabVSOcb]W\RcQS`WbaSZT]`OaW[WZO`[]ZSQcZSbVObe]cZR more responsibility, and he gave it to her. VOabS\_c]`c[aS\aW\U´O\RbS`[W\ObSdW`cZS\QS^`S[Obc`SZg ESeO\b “In Wyoming, they say give a horse its bVSDWP`W]QV]ZS`OSb]ZSbU]PST]`SbVSg¸dSW\Q`SOaSRbVSW`\c[PS`aO\R head—let it run,” he says. In some of their most recent ^`]RcQSROZ]b]Tb]fW\ ¶ `SaSO`QVSTT]`ba In Silverman’s lab, she began working 0OaaZS`O\RVS`Q]ZZSOUcSaVOdS^c`WTWSRWRS\bWTWSRO\Rag\bVSaWhSRbVS on Vibrio harveyi, a species closely related D QV]ZS`OSOcb]W\RcQS` /\RbVSg¸dSaV]e\bVObWTbVSgORRbVSag\bVSbWQ []ZSQcZSb]D QV]ZS`OSWbbc`\a]TTdW`cZS\QS BVS\SfbabS^Wab]b`gbVOb to V. fischeri and also bioluminescent— Sf^S`W[S\b W\ [WQS 7T bVS aQWS\bWaba QO\ Qc`bOWZ dW`cZS\QS W\ [WQS bVSg again, as long as its population is large Q]cZRVOdSbVS[OYW\Ua]TO^]eS`TcZ\SeQV]ZS`OR`cU ´> @ enough. Bassler’s job was to learn how the bacteria produce and monitor the popula- tion-indicating chemical signal. She started making mutants of the the bacteria don’t glow until their popula- certain peak. When the level gets high bacteria—to try to knock out the signal so tion passes a critical threshold. Then they enough, the lights go on. that they wouldn’t illuminate. But she light up simultaneously. The general reaction at that Navy couldn’t get them to go dark. Sometimes But if bacteria are loners, seeking research meeting, Bassler recalls, was “So they were dim, but they always lit up. That nothing more than nutrients and an oppor- what?” His findings were seen as an oddity led to the first of a series of discoveries tunity to reproduce, how do they know in an odd organism, nothing more. But that, she says, were then difficult to their population has exceeded the threshold Bassler was fascinated. “I was a biochemist, imagine—but seem perfectly obvious in to light up and then do so in concert? Silverman was a geneticist. I didn’t know hindsight. V. harveyi, it turned out, has Silverman figured out that this light- any molecular biology or genetics. I didn’t not one chemical signal but two. “You emitting behavior represents an amazing really know what a gene or a transcription knock one out and the other one works, feat of self-recognition on the part of the factor was—nothing! But I knew I wanted and they still light up,” she says. bacteria. He discovered the mechanism to work on these Vibrios. I ran up to Another surprise was that the two Vibrio underlying how the bacteria produce him—literally ran—after his talk, and species use different molecules for signaling and release a chemical signal that their said, ‘You have to take me on as your and different mechanisms for detecting fellows can detect. As the population postdoc.’” Despite her lack of experience, those signals. Because they are so closely grows, this chemical accumulates, and he did take her on. “I still don’t understand related, Bassler and everyone else had the bacteria detect it when it reaches a that,” she says, laughing. guessed they would use the same signaling " HHMI BULLETIN | November 2007 machinery. It was interesting work but still communication, likely with multiple acted as individuals,” explains Bassler. considered at that time to be an anomaly of signals,” Bassler says. “They have incredibly Thus, long before the appearance of multi- these two bizarre bacteria. complicated chemical lives, of which we cellular organisms, bacteria had devised a “Everybody kept asking me ‘Why do so far understand almost nothing.” way to act together, as if they were a multi- you want to study bioluminescence?’ and I Bacterial chemical communication is cellular organism. kept trying to explain that I wasn’t studying now referred to as “quorum sensing.” That Bassler’s work gave bacteria a central bioluminescence,” says Bassler. “I was is, the bacteria determine when their role in the development of higher forms of trying to study cell-to-cell communication. population has attained a quorum, so to life on earth. They have survived for Bioluminescence was the thing we could speak, and that tells them they can go into billions of years not only because they are see in the lab—a remarkably easy way to action in unison—doing whatever they tough but also because they are far more detect when cells ‘talked to each other’ need to do. Not only do they converse with sophisticated than anyone had realized. with the aid of these chemical words.” one another and then act simultaneously, These big-picture observations attracted In the early 1990s, other scientists began they also divide up chores and specialize. other scientists’ attention. Princeton to investigate chemical signaling in terres- “They’re recognizing that if they have professor Thomas J. Silhavy, who helped trial bacteria as well, finding that it was not the right number—and they synchronize bring Bassler to Princeton, says he saw that limited to marine oddities. “Now we under- their behavior—they can carry out tasks her work on Vibrio “could lead to some Charmaine Wheatley stand that probably all bacteria use chemical that they could never accomplish if they (continued on page 56) November 2007 | HHMI BULLETIN # B 631 6 3 1 631 631 6 /<5 6 /<5 6 /<5 6 /< 5 7<54 7 < 54 7<5 7<5 ////13= 13= 1 3= 13= 4 2 631 6 3 1 631 631 6 /< 5 6 <5 <5 <5 < 5 < 5 < 5 < 5 ////13= 13= 13= 3= 4 2< 4 2< 4 2< 4 2< 631 631 61 6 <5 5 5 5 < 5 < 5 < 5 < 5 ////3= 3= 3= 3= 2< 2< 2< 2< 6 6 6 6 5 5 5 5 < < < < ////3 = 3= = 2< < < < 6 < < /// < < < < $ HHMI BULLETIN | November 2007 B63 16/<5M<5 4/ 1 3 =42 0GAB 3 D3=:A=< 3OQVW\RWdWRcOZ¸aUS\][SWaWba]e\c\W_cSZO\RaQO^S /\RdO`WObW]\a[cQVZO`US`bVO\aZWUVb[Waa^SZZW\Ua W\]c`2 November 2007 | HHMI BULLETIN % regions rich with genes, so that some people had more copies of particular genes than other people. “We were finding a huge amount of copy number variation— that was the message,” says another pioneer in the study of structural variation, Stephen W. Scherer, a former HHMI n the basement of the Foege Building on the campus of the international research scholar who directs the Centre for University of Washington, the DNA of a woman known only as Applied Genomics at the Hospital for Sick Children in G248 lies in thousands of tiny wells inside a freezer cooled to Toronto, Canada. –84˚C. Five floors above, HHMI investigator Evan E. Eichler The discovery has been a revelation for many geneticists. “A points to her DNA as the harbinger of a new way of thinking lot of the more complex disorders are not explained by coding about human genetics. variation, which is what people were looking for,” says HHMI “The human genome” is a misnomer, according to Eichler. investigator Val C. Sheffield, who for years has suspected that G248 has big sections of DNA that other people don’t have, structural variation might play a prominent role in the eye and she’s missing DNA that most people do have. “In the last diseases he studies in his University of Iowa lab. “But until few years, it’s been shown that big changes in DNA—insertions recently we haven’t had the technologies to look at variation and duplications and deletions and inversions—are extremely on a genome-wide scale.” common in the population,” Eichler says. “That’s the first The new picture that Eichler, Scherer, and a handful of important point. The second important point is that these other geneticists have been painting differs radically from the changes play a role in human disease—everything from HIV traditional view of our genome. Instead of the book of life, susceptibility to autism to mental retardation to epilepsy.” DNA is more like the scrapbook of life. Sentences, paragraphs, A few years ago, most human geneticists would have been or entire chapters are copied and haphazardly inserted into very skeptical about such a statement. At that time, geneticists various parts of our genome. In some people, the same page focused almost exclusively on spelling differences in the repeats over and over, while other people don’t have that human genome—places where the chemical bases that make page at all. And geneticists have been tying this structural up DNA, represented by the letters A, T, C, and G, differ from variation to an increasing number of diseases. “It’s amazing,” one person to another. According to the thinking of the day, says Scherer. “At human genetics meetings, 30 to 40 percent these individual changes in DNA codes largely accounted for of the talks have a direct focus on copy number variation.” differences in our genetic susceptibility to disease and in our physical appearance. But in the first half of this decade, a handful of geneticists, working independently at labo- ratories scattered across the United States and µE3¸@347<2M<5 Canada, began to notice something strange. As they looked more carefully at human DNA, <3E>/@B A =4B63 they found that some people had multiple 6C;/<53<=;3 copies of big sections of DNA, hundreds or thousands of base pairs long. Sometimes these /<2B6/B¸A/ structural variants, as they came to be known, were in DNA regions that didn’t seem to be >=E3 @ 4C:B67<5 ¶ doing anything. But sometimes they were in 3D/<3716:3@ & HHMI BULLETIN | November 2007 /B@C37<27D72C/: B]PSQ][^ZSbSZgOQQc`ObSbVS6c[O\5S\][S>`]XSQbaV]cZR VOdSPSS\QOZZSRbVSµ6OZT]TO1][^]aWbS6c[O\5S\][S The discovery of structural variation was >`]XSQb ¶PSQOcaSbVS2 November 2007 | HHMI BULLETIN ' disease all the time,” says Scherer. But he and his team were finding big differences that didn’t seem to have an obvious effect on health—including million-base-pair insertions or deletions, “which was really unbelievable.” Many geneticists were skeptical. At that time, the technologies they were using were so new that the differences might have come from experimental design or malfunctioning equip- ment. “We were criticized a lot,” Scherer says. “My first grant application [to study structural variation] was rejected, because people said it couldn’t possibly be true.” But as analytic techniques improved, so did the evidence for substantial structural variation. Charles Lee of Brigham and Women’s Hospital in Boston had found similar DNA differences, as had a group at Cold Spring Harbor Laboratory led by Michael H. Wigler. By about 2003, the case for widespread structural variation in the human genome was becoming unassailable. 5S\SbWQWabaZWYS3dO\3WQVZS`b]^O\RAbS^VS\AQVS`S`O`SbgW\Uab`cQbc`OZ Furthermore, evidence was accumulating dO`WObW]\aSS\W\]c`US\][Sab]O\W\Q`SOaW\U\c[PS`]TRWaSOaSa that some of these variants influence health. The human genome regulates itself through a His team continued to study duplications after the release of process still largely unknown. But variable numbers of a gene can the draft human genome in 2000, and they discovered that many produce a greater or smaller amount of a protein important to the were occurring in particular “bad neighborhoods” of the genome. body, and a duplicated section of DNA can disrupt the function There, multiple copies of DNA sequences made the genome of an important gene. susceptible to further rearrangements through a process known As Scherer and others investigated the genomes of people as nonallelic homologous recombination (see sidebar, page 31). with genetic disorders, they found that structural variation often The DNA in those regions seemed to be “churning,” continually seemed a more likely contributor to the disorder than DNA rearranging itself from one generation to the next. Eichler was spelling differences. Schizophrenia, Alzheimer’s, Parkinson’s, sure those rearrangements had consequences for human evolu- autism, kidney disease, and many other diseases were linked to tion and health. But what were they? structural variation. “We’ve been shocked to see how quickly the idea has been adopted and how many diseases are being associ- B637;>/ 1 B=<6 3 /:B6 ated with large structural variants,” Scherer says. about this same time, at toronto’s hospital for In the past couple of years, Scherer has focused on structural Sick Children, Scherer was equally puzzled by what he was seeing variants in patients with birth defects and neurological disorders. in the genome. He and his colleagues were searching chromo- For example, at the Hospital for Sick Children screens of chil- some 7 to uncover genes involved in disease. In the process, dren with unexplained genetic disorders have shown that some they were uncovering massive and unexpected differences in the 20 percent have structural changes in their DNA that may chromosomes of different people. “Most geneticists thought that contribute to their conditions. He also has been participating in if you had a large genetic change, it would be associated with studies to identify and characterize structural variation in the Dion Evan ©HHMI Scherer: / AP, Ron Wurzer Eichler: ! HHMI BULLETIN | November 2007 genome, including differences between chromosomes in the genetic basis of diseases like diabetes, hypertension, and high choles- same cell (see sidebar, page 29). “It’s incredible how many people terol levels?” he says. “We know there is a genetic factor, but what are using these data, from commercial companies to clinical is the role of single base pair changes versus structural changes?” geneticists to everyone in between,” he says. To answer that question, Eichler and a group of colleagues known as the Human Genome Structural Variation Working E6GD/ @ 7/B7=<- Group have decided to get a better fi x on where the structural at the university of washington, where he moved variation in our genome occurs. The freezer in the basement of in 2004, Eichler and his colleagues also have been delving into Eichler’s laboratory containing the DNA of G248 is one of 62 the link between structural variation and disease. In one particu- freezers scattered around the United States, each containing the larly intriguing study, they examined the DNA of 290 British DNA of a single individual. The working group will compare children with neurological disabilities. “We were looking for each donor’s DNA with the reference sequence from the recurrent deletions in regions of the genome that are highly Human Genome Project, looking for locations where the DNA dynamic,” says Andrew Sharp, the postdoctoral fellow in Eichler’s doesn’t line up. Wherever they find a discrepancy, they’ll lab who headed the project. sequence the DNA to identify the differences. Of the 290 children, 16 had deletions or duplications that are Understanding human disease is the main objective, but “likely to be pathogenic,” according to the group’s September Eichler wants to know something else. Why did variable regions 2006 paper in Nature Genetics. Remarkably, four had very similar of our genome evolve, and what purpose do they serve? but not identical deletions on the long arm of chromosome 17. Eichler’s hypothesis is that structural variation is a way for All four, though unrelated, had very similar features, including our genomes to remain fl uid and adaptable. As our ancestors silvery hair, blue eyes, and a bulbous nose—“they could be encountered new environments and new circumstances, brothers and sisters,” says Sharp—but their shared characteristics continual rearrangement of their DNA would have generated hadn’t been noticed before. And the region of their deletions lots of evolutionary experiments. In fact, initial comparisons included several genes implicated previously in neurological and have shown that humans and other primates have much more behavioral conditions. structural variation than do other mammals. Eichler speculates that Building on that success, Eichler’s group has begun examining the unique abilities of primates—our elaborate social structures the connection between structural variation and a range of more and communication abilities—may be related to the amount of common diseases. “The million dollar question is: What is the structural variation in our genomes. “Maybe the cost of having these new abilities is the possibility of disease caused by genes that allow us to adapt to the right environments at the right time,” he says. AE/>>7<5A35;3 November 2007 | HHMI BULLETIN ! DEC IDI NGF ACT ORS Forage or mate? Stay or run? Innocent or guilty? Deal or no deal? Each is a job for the brain’s “jury room.” by Richard Saltus / illustration by Barry Falls November 2007 | HHMI BULLETIN !! Whether you’re a FRUI T FLY or a FINANCIER, life is an endless series Bargmann and HHMI investigator Michael Shadlen, among of decisions. others, want to uncover the critical cells and circuits that complete the chain from input to output—the bridge between sensation and action. Exploring this arena provides “a window on higher brain function,” says Shadlen, a neurobiologist at the University of Washington. He’s especially interested in “how humans and other complex animals take a bit of evidence from the world and hold onto it for later use, or combine it with other information.” With new tools and experimental designs that range from straightforward to elaborate, HHMI researchers are devising the means to observe and map decision making in simple organisms The world is an uncertain and changing place, to which humans and complex primates. They are observing risk assessment and and animals respond by considering the potential reward and cost survival choices made by worms and flies—for themselves as well of different options and estimating the odds of success before as for their offspring. Studies of monkeys are revealing circuitry committing to a choice. involved in more sophisticated learning and keeping track, or Neuroscientists have set their sights on identifying the network playing the odds. Ultimately, they hope to understand higher of cells, circuits, and chemicals—the brain’s “jury room,” so to cognitive abilities such as reasoning and deliberation. One thing speak—where the evidence is weighed and verdicts decided. made clear by these early studies: “thinking” like a statistician is “There are extremely few examples where we really know what not exclusive to humans. the nervous system is doing from sensory input to a behavior,” says Cornelia Bargmann, an HHMI investigator at Rockefeller Single-Neuron DETAILS University. “We can map them out in simple reflexes, like an Human studies in psychology explain human choice behavior in animal’s escape response, but what we’d really like to understand economic, medical, ethical, and crisis situations, among others. is the steps by which information is transformed and integrated Peering into the brain itself, functional MRI devices can locate all the way through.” activity in the cortex as people perform decision-related tasks. Researchers, including HHMI scientists, have already done Such experiments have identified particular brain areas and prodigious work over several decades to piece together how structures that appear to be crucial, but the methods do not have animal and human nervous systems detect sensory information— sufficient resolution to tease out the exact neural wiring involved. especially sights, odors, and tastes—and encode it in electrical For this reason, among others, experimental animals of several signals in the brain. For example, HHMI investigator William types offer numerous advantages. Newsome, at Stanford University, identified specific neurons in Scientists like Shadlen want the details. He is seeking answers monkeys that detect the direction in which an object is moving. “at the level where single neurons are discharging and making On the output side, Newsome and others have mapped circuits decisions,” he says. “You can’t study that with functional imaging.” that direct motor activity, such as a monkey’s eye movements in As monkeys play visual discrimination games that require a response to a stimulus. correct choice to win a reward, Shadlen records activity in groups !" HHMI BULLETIN | November 2007 of single brain neurons. He varies the rules of the games to test different components of the decision process and determine how they are represented in the ebb and flow of neural activity. When Shadlen was a postdoc in William Newsome’s lab, the two researchers identified nerve circuits in the cerebral cortex of monkeys that became more active when the animals made a decision about visual information with which they were presented. These neurons were located in the lateral intraparietal (LIP) area of the cortex. More recently, Shadlen designed a set of experiments to test the monkeys’ ability to make a correct choice when they had to sum up statistical clues presented in a short series. People do this all the time: think of a poker player calculating the changing odds of winning a pot as she draws additional cards into her hand. The research, published by Shadlen and Tianming Yang in the June 28, 2007, issue of Nature, found that the monkeys became quite adept at the task, showing that they were capable of probabilistic reasoning. “No one had ever tried to train a monkey to do this kind of thing,” says Shadlen. “We had no idea if the monkey could.” He and his colleagues trained two monkeys to stare at a point on a screen for several seconds, then shift their gaze to either a red spot or a green spot; if they picked the better target, they improved the chances of getting a reward. Sometimes the red spot brought the reward and sometimes the green, but even the better choice did not always pay off—it’s a matter of playing the odds. In each trial, the monkeys were shown four different shapes on the screen, one after another, every half-second. Each shape signified a different probability value of success, alone and in combination with the other shapes. If the monkey correctly combined the probabilities, he was likely to move his eyes to the correct target and improve the odds of winning a reward. While the monkeys were playing this game, the researchers recorded electrical activity from 64 individual nerve cells in the LIP areas. The rate of firing in the nerve cells increased or decreased whenever the animals saw a new shape on the screen that altered the probability of a particular target being the correct choice. As the subject became more convinced of the right choice, the LIP neurons increased their firing rates. Shadlen and Yang showed that the quantity computed by the monkey’s neurons could be described by a mathematical term, the “log likelihood ratio”; in other words, the logarithm of probabilities. “It was enormously satisfying to watch a monkey add and subtract in his head and to keep a running tally of the state of odds in favor of one proposition and against another,” Shadlen says. “To see these operations carried out by neurons in the brain ;WQVOSZAVORZS\b]^O\R1]`\SZWO0O`U[O\\abcRgRSQWaW]\a Shadlen: Charles Peterson Bargmann: Matthew Septimus Shadlen: Charles Peterson was breathtaking.” W\O\W[OZab]UOW\W\aWUVbaW\b]VWUVS`Q]U\WbW]\ November 2007 | HHMI BULLETIN !# another, or whether they somehow all work on the information simultaneously, controlled by some “master” controller. Worms Make CHOICES Although monkeys do not approach the sophisticated brain function of humans, they can be trained in tasks that illuminate different aspects of human decision making. Other animal models have other advantages: they are inexpensive, reproduce quickly, and large numbers of them can be used in studies. Decision behavior has been identified, for example, in the roundworm Caenorhabditis elegans and the common fruit fly Drosophila, which also lend themselves to genetic manipulation as a means of singling out nerve circuits of interest. >]abR]Q@SPSQQOGO\U`WUVbO\R[S\b]`aGcV mine whether the signals are processed by one brain area after Drosophila food, a video camera, and her own ingenuity. Andrew Nagata !$ HHMI BULLETIN | November 2007 “No one had ever tried to train a MONKEY to do this kind of thing. We had no idea 4:G/1@=0/B71A 2Oc\bW\UTSOba]T[W\WObc`WhObW]\abO\RPSbeSS\DWdSY if the monkey 8OgO`O[O\O\RbVSQ]\b`O^bW]\VSWaPcWZRW\Ub]`SOR bVS[W\Ra]T2`]a]^VWZOW\`SOZbW[S µ=c`U]OZWab] c\RS`abO\RbVS\Sc`OZQ][^cbObW]\ac\RS`ZgW\URSQWaW]\ could.” [OYW\UW\`Sa^]\aSb]aS\a]`gW\^cb¶aOga8OgO`O[O\O 8O\SZWO4O`[TSZZ]e µEScaSbVSTZgPSQOcaSWba\S`d]ca agabS[WaaW[^ZS`O\ReSQO\caSUS\SbWQb]]Zab]abcRg MICHAEL SHADLEN QW`QcWbQ][^cbObW]\ObOZSdSZ]TRSbOWZ\]b^]aaWPZSW\ZO`US` agabS[a ¶CaW\U[WQ`]ac`UWQOZb]]ZaO\RabSORgVO\Ra´ 8OgO`O[O\aOgaVSVOaae]`\]TTQ]TTSSb]R]bVWae]`Y´bVS Yang, a postdoc in the laboratory of HHMI investigators Lily `SaSO`QVS`aQO\Sf^]aSbVSP`OW\]TbVSTZgeVWZSWbaP]Rg and Yuh Nung Jan at the University of California, San Francisco, O\RVSORO`SbSbVS`SRW\^ZOQSeWbVeOf]`UZcSZSOdW\UWba studies the genetic basis of choice behaviors. While observing ZSUaT`SSb][]dS 6OW`ZWYS[WQ`]SZSQb`]RSaO`SW\aS`bSR pregnant fruit flies in miniature plastic chambers she designed, W\b]bVSP`OW\]TbVS]\SSWUVbVW\QVZ]\UW\aSQbb]`SQ]`R OQbWdWbgW\W\RWdWRcOZ\Sc`]\aeVWZSObe]^V]b]\[WQ`]aQ]^S Yang noticed that the females spent considerable time searching ]PbOW\adWacOZW[OUS`g]TZO`US`P`OW\`SUW]\aO\R^]^cZObW]\a their environment for a suitable spot to lay their eggs. ]T\Sc`]\a 8OgO`O[O\O\RVWa^]abR]Qa3cUS\WO1VWO^^S She concluded that the Drosophila females considered both O\R8]VO\\SaASSZWUO`S\Sfb^ZO\\W\UOQS\bS`abOUS the consistency and taste of the medium on which they walked XcUUZW\UOQb(bVSgO`SRSdSZ]^W\UOagabS[W\eVWQVObW\g before committing their future offspring to a specific site. “After POZZZSaabVO\]\S_cO`bS`W\QVW\RWO[SbS`Waac^^]`bSR all, selecting an appropriate site to lay its eggs is presumably the ]\O\OW`Q]Zc[\ZWYSO^W\U^]\UPOZZ]dS`Oab`SO[]TOW` T`][O[W\WZSOTPZ]eS` BVSTZgbSbVS`SRb]Wba`SQ]`RW\U ultimate decision a fly mother has to make, as the consequences RSdWQSeWZZPSZ]eS`SRc\bWZWbaTSSbb]cQVbVSPOZZ µ/abVS of such decisions are likely to have a significant impact on the TZg[]dSaWbaZSUaW\`Sa^]\aSb]dWacOZW\^cba¶aOga8OgO`O[O\ reproductive success of the species,” says Yang. µeS¸ZZ`SQ]`RbVS[]dS[S\ba]TbVSPOZZO\RW\TS`eVObbVSTZg In one experiment, she placed pregnant fruit flies in a small eO\bab]R] ESV]^SbVWaaSbc^eWZZOZZ]ecab]ZW\Y\Sc`OZ plastic chamber with a sweet substance on one half of the floor ^`]QSaaW\Ub]RSQWaW]\[OYW\UPSVOdW]` ¶´@ A and a bitter compound on the other. Would the flies choose one side over the other for egg laying? Surprisingly, the mothers-to-be shunned the good-tasting medium and favored the bad-tasting “Her work really opens up a whole area,” comments Yuh side to deposit their eggs. Nung Jan, Yang’s mentor. “Because once we know there is this “Initially, I assumed that maybe I had accidentally switched robust behavior for decision making, we can bring in all our the flavors,” recalls Yang. “So I checked by licking them!” techniques, already developed as well as new, to follow up and After further trials, Yang concluded that a pregnant fly will lay get at what might be components of the circuit.” eggs on a sugary medium if that’s the only choice, but if there is Behavioral choices are the nitty-gritty of sheer animal survival as a non-sweet alternative, it will opt for that side. Why? Yang can’t well as the engine of advanced human culture. HHMI scientists are say for sure, but she speculates that perhaps the bitter location is betting that understanding these decision-making circuits in rela- less likely to attract predators that could jeopardize the offspring. tively simple settings will ultimately expose the brain mechanisms “The fly’s response to the sucrose medium isn’t automatic,” the responsible for higher cognitive capacities in humans. As Shadlen researcher notes. “Its decision to accept or reject the sweet medium argues, “even human consciousness is mediated by relatively as an egg-laying site appears to depend on the availability of simple, unconscious decisions to engage the environment.” . ‘better’ options.” Yang has identified some of the nerve pathways that control egg laying, and she plans to use genetic tools to FOR MORE INFORMATION and to see reproductions of experimental trials from Michael further analyze simple decision making in animals. Shadlen’s study, visit www.shadlen.org/mike/movies/ProbClass/Abstract.html. November 2007 | HHMI BULLETIN !% >3@A>31B7D3A=>7<7= Kristi S. Anseth BODY, HEAL THYSELF ENGINEERED GELS MAY PROMPT THE BODY TO REPAIR ITSELF AS NEVER BEFORE. John Johnston John !& HHMI BULLETIN | November 2oo7 Kristi S. Anseth, the first engineer to become an HHMI investigator, has invented new classes of hydrogels—synthetic bioinspired micro- environments that support and interact with living cells. Working with clinicians, chemists, and biologists, the University of Colorado at Boulder researcher and her colleagues are developing a form of tissue engineering to coax the body to heal itself. Imagine that a soldier could quickly regrow the bones of and the artificial scaffolding begins to dissolve. Meanwhile, his shattered leg, that a skier could donate a bit of her own the skier exercises her knee, and mechanical forces refine cartilage to rebuild the protective cushion in her damaged the shape. Instead of a titanium joint replacement, she knee, or that an implant of tailor-made brain cells could cure has regrown a natural cushion of her own cartilage to the shaking of Parkinson’s disease. support her knee. That is the promise of tissue engineering, a field often In nature, the extracellular matrix provides not only called regeneration medicine. Clinicians, engineers, biolo- support but also a location for molecular signals that are gists, chemists, and materials scientists are joining forces to traded back and forth as the cells build a specific structure marshal the body’s developmental and repair mechanisms or organ. Taking advantage of this cell-gel crosstalk, Jeffrey to heal wounds, rebuild damaged tissues, and replace A. Hubbell and his group at the École Polytechnique essential cells. Fédérale de Lausanne (Switzerland) have shown in In my laboratory, our challenge is to design customized animal studies that a synthetic gel can provide a matrix biomimetic gels, also called hydrogels, that imitate some that stimulates the animal’s bone marrow to fill the gaps aspects of the extracellular matrix—the natural three- between fragments with strong bone cells. The matrix is dimensional microenvironment that encourages cell growth laced with encapsulated doses of a growth-promoting during development and wound healing and during normal protein that are only released, dose by dose, when growing tissue homeostasis. These artificial matrices already are bone-marrow cells send an activating signal to a cache of being tested as structural supports for cell-built treatments the protein within the gel. such as joint repair. The next generation of gels will support With further advances, artificial gels may also be tailored cells’ metabolic functions, such as insulin regulation for to support stem cells—an important requirement for any diabetes, and encourage cell-to-cell connections, as with cell-based treatments of Parkinson’s disease or type 1 diabetes, neurons in the brain. which so far do not provide lasting benefits in the body. A A second challenge is to learn the biomimetic cues that customized gel could guide the process of coaxing precur- cells require to perform a desired repair. We may discover sors to become the desired cell type. The gel would then that our task is less to control natural processes than to trigger protect the therapeutic cells with molecular barriers. And the right conditions so that the cells themselves can take on it would be embedded with further instructions for cell the job of building and organizing tissue. therapy—signals to be activated once the cells were implanted A treatment now in clinical trials to repair the cartilage in the body. Brain cells, for example, could be encouraged worn away from a skier’s painfully damaged knee offers a to send out axons and perhaps be guided to connect with simple example of the way a biomimetic gel works. Injected specific types of neurons. into the space within the joint, the hydrogel—which The technical advances needed to take advantage of combines water with large macromolecules—is activated these opportunities will require synergistic efforts across by beams of light to form a molecular mesh. This mesh disciplines. Scientists and engineers working together will forms a firm but flexible scaffold, rather like organized advance gel niches from their infancy to mature, sophisti- Jell-O, built in the presence of the patient’s own cartilage- cated environments, illuminating the possibilities for forming cells, which secrete tissue components that cell-based strategies to repair tissues. decorate the lattices of macromolecules like vines on a trellis. Stimulated by cues from the three-dimensional INTERVIEW BY JANET BASU. Kristi Anseth does research and scaffolding, the cartilage-built structure gains strength teaches at the University of Colorado at Boulder. November 2oo7 | HHMI BULLETIN !' >3@A>31B7D3A=>7<7= Jack E. Dixon SCIENCE TRENDS SCIENCE TODAY REQUIRES A BROADER SET OF TOOLS. Paul Fetters Paul " HHMI BULLETIN | November 2oo7 The life of a researcher is not what it used to be, according to Jack E. Dixon. HHMI’s vice president and chief scientific officer thinks scientists today face a more complex, more interesting venture than when he first set up his laboratory 30 years ago. At the same time, he says, young investigators must contend with a funding system that rewards “safe science” and saps creativity. How has science changed? thinking creatively about solving biological problems. When I first started in science it was possible to be at the Without reliable funding, that lab is unstable. We have top of your game by focusing intently on one narrow area. people with a tremendous amount of training—under- Today, we have new fields of study—molecular biology, graduate, graduate, and postdoctoral training—who have genomics, stem cell biology—that pull so many scientific become faculty members and they can’t get a shot at using specialties together. Now scientists have to be willing that training because they spend a large chunk of time to move into areas where they are less knowledgeable. applying for funding or having their grants turned down Science today requires a broader range of skills than in by funding agencies. the past, which is what makes it more complex and also I would argue that isn’t a good use of time for people more interesting. to repeatedly rewrite a grant rather than conduct the This new complexity requires scientists to collaborate and research proposed in it, especially when one considers be much more interactive to address scientific questions. that extraordinary breakthroughs are often reported by The very best people must be better at communicating not younger scientists. only with researchers in their fields, but also with scien- tists in a broad range of fields. That is exciting because it Are you seeing a different impact on young investigators and means you are constantly challenging yourself. Research seasoned investigators? also appears to be moving at a faster pace. The grant situation affects both groups. When I was chair of the biological chemistry department at the University of Is anything important lost when scientists do less Michigan Medical School, I used to say there were two themselves and do more with reagent kits and other times in a scientist’s career when he or she needed special prepackaged tools? attention: at the beginning and near the end. Young scien- Sure. I don’t know of any lab director or principal inves- tists are full of energy and ideas they want to try out. Yet, tigator who is not concerned about this. Those who use the percentage of grants going to investigators under age kits know how to mix things together to get results, but 40 has dropped from 27 percent in 1995 to 17 percent in they often don’t know the biochemistry or the molecular 2005. This bleak funding outlook has a devastating effect biology that went into putting that kit together. If the on a young person’s morale, confidence, and productivity. experiment doesn’t work, they don’t really understand Looked at another way, the average age for a scientist why. The kits are a blessing and a curse. However, it’s a with a Ph.D. to get a first research project grant from the genie that’s out of the bottle and it’s clearly not going back National Institutes of Health (the RO1 grant) is 42. To put in—kits are here to stay. that into perspective, HHMI President Tom Cech would have been awarded his Nobel Prize before he received his What is the short-term—and long-term—impact of the first RO1. My mother had a saying: pennywise and pound slowdown in federal funding for biomedical research? foolish. I think that applies to this situation where you Scientists spend a lot of time writing and rewriting grant effectively take away the 10 most productive years in a applications—time better spent working in their labs or scientist’s career. INTERVIEW BY LISA SEACHRIST CHIU. Jack Dixon, a chemist by training, maintains an active research program at the University of California, San Diego. November 2oo7 | HHMI BULLETIN " ?/ What was your very first job? As with many of life’s firsts—first bike ride, first kiss, first car— one’s first job is hard to forget (and sometimes hard to believe). Four HHMI researchers reminisce with the Bulletin on their earliest working days. — EDITED BY JACQUELINE RUTTIMANN Ellen Fanning Eric Gouaux Charles Boone Mark F. Bear SOCIETY OF HHMI HHMI INVESTIGATOR, HHMI INTERNATIONAL HHMI INVESTIGATOR, PROFESSORS, OREGON HEALTH & SCIENCE RESEARCH SCHOLAR, MASSACHUSETTS INSTITUTE VANDERBILT UNIVERSITY UNIVERSITY UNIVERSITY OF TORONTO, OF TECHNOLOGY TORONTO, CANADA “As a freshman at UW- “The summer after my “My first job was to wash Madison, I set bowling pins freshman year in college I “My first summer job, at the sailboats for $1 an hour at a at the college bowling alley. hitch-hiked to a salmon prime age of 15, was as the local boat dealer. My friend Behind the pins there was processing plant in Kenai, right-hand-man for a dairy and I were the dealer’s first a pit with a platform high Alaska, every morning and farmer. Waking up to milk two employees; I think we enough for me to stay out spent the day loading cows at 5 a.m. while the were 12 years old.” of the way of speeding bowl- cleaned salmon onto huge stars twinkled and the sum- ing balls and flying pins. stainless carts and wheeling mer dew was heavy on the After each player’s turn, I the carts into cavernous cold grass, delivering calves, would jump down into the boxes for flash-freezing. I stacking thousands of bales pit, roll the ball back to later quit the salmon plant to of hay, and working in the the player, retrieve the pins, join a small mining group barn became a normal way place them in the triangu- that would helicopter into of life. The sheer volume lar pin-setting cage, and a claim west of Denali of manure was memorable. hop back up on the plat- National Park and had to I spent days moving vast form. I can’t remember carry a .44 to protect myself amounts of excrement from how many lanes I took care from brown bears. I only the barn back to the field.” of, but it was strenuous.” encountered one bear—I looked at him, he at me, and, after a few moments, I turned and walked back to camp.” Fanning: Daniel Dubois / Vanderbilt University Gouaux: Paul Fetters Boone: David Rolls Bear: Betsy Cullen Fetters University Gouaux: Paul Daniel Dubois / Vanderbilt Fanning: " HHMI BULLETIN | November 2oo7 chronicle "" AQWS\QS3RcQObW]\ An Even Broader Reach / Smart Young Minds "$ 7\abWbcbS "& :OP0]]Y Baby’s First Bacteria / Gender Switch? / A Noisy Brain Is a Normal Brain # /aYOAQWS\bWab Can inflammation of a nerve cause inflammation of the tissue it serves? # C^1Z]aS , 30 August 2007, 448:1009-1015. © 2007. Hackathon Nature #" <]bO0S\S Celebrating 60 Years of Cech Inspirations / Druker Wins Keio Medical Science Prize / HHMI Researchers Receive Paul Marks Prize BVSP`OW\¸aOQQSaa]`g]ZTOQb]`gPcZPabOW\SR PZcSW\bVWabWaacSaSQbW]\`SQSWdSaaWU\OZa T`][bVSd][S`]\OaOZ]`UO\O\R[Og^ZOgO Q`WbWQOZ`]ZSW\^`]QSaaW\U^VS`][]\SaWU\OZa aSSµ5S\RS`AeWbQV-¶^OUS"' Adapted by permission from Macmillan Publishers Ltd: November 2oo7 | HHMI BULLETIN "! science education An Even Broader Reach B638/19A=<:/0¸AAC;;3@>@=5@/;7AA3@D7<5;=@36756 A16==:/<21=::353ABC23 the program has already paid handsome dividends, attracting more women and minority students to the program each year. Since 2003—the year the lab began receiving HHMI support for the program— the program has enrolled about 72 percent women and 29 percent minority students annually. And the number of high school students applying has increased dramatically. From 1989 to 2003, an average of 56 high school students 0cWZbPgO>`W\QSb]\C\WdS`aWbg^`]TSaa]`W\ ' 6WUVaSOa[O\aW]\WaOaV]`beOZY applied each year. From 2004 to 2007, that number T`][8OQYa]\:OP]`Ob]`gO\RbS[^]`O`gV][ST]`abcRS\baW\bVSZOP¸aAc[[S` jumped to an average of 131 high school applicants. AbcRS\b>`]U`O[ Geiger recruits through former students as well as a national network of contacts among scientists LYNN M. RIDDIFORD CREDITS SEVENTEEN MAGAZINE—AND THE and high school and college teachers. “My recruiting is aimed at Jackson Laboratory—for launching her career in science. The then- attracting applications from underrepresented students—minorities, 16-year-old found an article about the summer research program at the first-generation college or college-bound, those from working class venerable institution in Bar Harbor, Maine, tucked amid pages of 1950s backgrounds, and inner-city students,” he says. “I want to be sure that fashion layouts and dating advice. Intrigued, she wrote to the laboratory, more kids from those backgrounds hear about us.” requested an application, and set about convincing her parents to let her One of Geiger’s pupils this summer was high school senior Seanna spend her summer 1,500 miles away from the family farm in Illinois. Pieper-Jordan, who is of Native Hawaiian and Native American “It would have been the first year that I could have worked in the descent. Just like Lynn Riddiford, Pieper-Jordan traveled thousands of summer and it was going to cost them $15 a week,” Riddiford remem- miles—in this case, from Honolulu to Bar Harbor—to pursue her bers. Her parents agreed to let her go, and her experiences at The dream of becoming a scientist. She spent her summer doing research on Jackson Lab sparked a lifelong love of science. Riddiford, recently muscular dystrophy in Gregory Cox’s lab at The Jackson Laboratory. appointed a senior fellow at the Janelia Farm Research Campus after A student at the Kamehameha Schools in Honolulu, Pieper- 34 years on the faculty at the University of Washington, studies the Jordan credits two teachers “who cared and encouraged me to look hormonal control of insect growth, molting, and metamorphosis. further into science,” she says. “I applied to The Jackson Laboratory Since 1929, The Jackson Lab, known for its genetics research, has Summer Student Program with a small hope that I would be nurtured the scientific imaginations of thousands of students—many given the chance to show the abilities of a student from an often of whom have made names for themselves in the world of science. overlooked minority.” Clearly inspired by her summer in the lab, Earlier this year, The Jackson Lab was one of 20 research institu- Pieper-Jordan says she is now setting her sights on college and a tions that received HHMI grants to reach out to their local communities career in the biological sciences. . – JIM KEELEY to stimulate interest in science, particularly among young students. The Jax, as scientists worldwide call it, received $749,000 from HHMI, which will “It would have been the be distributed over five years. Some of that money first year that I could have will support the Summer Student Program for high school and undergraduate students, where students worked in the summer come from around the country to conduct original and it was going to cost research as part of a team. them $15 a week. According to Jon R. Geiger, who directs the Summer Student Program, HHMI’s investment in :G<<@72274=@2 ” Fetters Paul Riddiford: Highseas mansion: Jim Keeley "" HHMI BULLETIN | November 2oo7 Smart Young Minds /AC;;3@B@/7<7<5>@=5@/;7<7B7/B320G/ 6/<24C:=4;=B7D/B32C<23@5@/2C/B3A7A ;/97<5/6=;3/B8/<3:7/4/@; NINETEEN-YEAR-OLD JONATHAN YOKE, SURROUNDED BY PLIERS, resistors, and small vials teeming with flies, proudly showed off the machine he was building to determine how flies respond to gravity. actually deflected by a puff of air—that would confirm an impor- The device encloses them in a tube mounted on a wheel that will tant role for the targeted neural circuitry. turn—effectively changing which way is “up”—according to a Bharioke says one of the best aspects of working at Janelia computer’s instructions. A camera will spin with the wheel to record was access to the scientists. Livia Zarnescu, a math major at the the flies’ reactions. University of Arizona, agrees. “Everybody is so smart and enthu- Yoke’s creation is the brainchild of Janelia Farm fellow Michael siastic about what they do. Most hours of the day, you’ll find Reiser, who studies how fruit flies gather multisensory informa- someone here working. You can go in and ask someone about tion and make choices as they interpret the world. Yoke is one of their work and they’ll be happy to show you.” She worked with four undergraduates who conducted research at HHMI’s northern group leaders Julie Simpson and Eugene Myers, who have taken Virginia research campus during summer 2007, finding their way on the ambitious task of mapping the fruit fly’s neural circuitry to Janelia Farm on their own initiative. Each contacted Janelia’s for motor activity. associate director for science and training to inquire about opportunities. Reiser says he appreciates the contributions of undergraduates like Yoke because, “many of them possess impressive courage—a certain fearless- ness—that allows them to tackle a challenging project.” A computer-engineering major at the University of Virginia, Yoke has more experience in building robots than in biology. But his technical skills combined with his interest in neuroscience make him a good fit for Janelia, where interdis- ciplinary approaches are especially valued in addressing difficult questions about the brain. Yoke became interested in signals in the brain as a Boy Scout participating in an annual wheel- chair walk with paralyzed veterans. “Their brains worked fine, but they couldn’t control their C\WdS`aWbg]T1]Z]`OR]abcRS\b1VSZaSOB`S\U`]dSe]`YSReWbV:]`S\:]]US`b] limbs,” he recalls. “It seemed like there should be W[^`]dSW[OUW\U]T\Sc`OZOQbWdWbgW\bVSP`OW\ some way to fix that.” On the same floor as Yoke and his machine-in-progress, Zarnescu’s work covered a wide scope—from dissection and University of Toronto student Arjun Bharioke worked in the lab staining with fluorescent antibodies to programming the computer of Janelia group leader Karel Svoboda. Though only 20 years algorithm needed to overlay images from thousands of samples. old, Bharioke speaks about neuroscience like an old pro. His Simpson was glad to have Zarnescu there for the summer. “She project aimed to understand how the brain gets rewired during could speak computer [with the programmers] and then come learning. He used a new technique for activating specific back and speak English to us.” neurons: injecting a light-sensitive protein into the brains of Chelsea Trengrove switched majors several times in her first year mice, followed by a pulse of light. First, he trained the mice at University of Colorado at Boulder, yet her pull toward neurosci- to push a lever in response to a puff of air on their whiskers in ence remains strong. “When I was five years old, I would read about exchange for a drink of water. Then, he aimed the light pulse the brain. All I want to do is research the brain,” she says. “Since at neurons believed to be involved in whisker movement. If the being at Janelia, I’ve thought that maybe I should get my Ph.D.” Paul Fetters Paul mice went for the water—even though the whiskers were not 1= November 2oo7 | HHMI BULLETIN "# institute news 1= HHMI Expands Support of New Physician-Scientists 7 ONLY A SMALL FRACTION OF THE PHYSICIANS says William Galey, program director for who graduate from U.S. medical schools HHMI’s graduate education and medical each year pursue a career in academic research training programs. research. The reasons vary, but graduates When the awards were created last often cite two in particular: insufficient time year, 13 grantees received $150,000 over a for research and lack of financial support. three-year period. This year, the 20 awardees To minimize those hurdles for a small will receive $375,000 over five years. “It’s not easy to go back cadre of physicians, HHMI has named 20 Each year, HHMI invites alumni of new recipients of its Physician-Scientist the HHMI–National Institutes of Health and do science once Early Career Award. Now entering its second Research Scholars Program and the you’ve started down the year, the awards program is part of the HHMI Research Training Fellowships Institute’s commitment to help promising for Medical Students who are starting clinical path, so it’s really physician-scientists launch their careers in up their labs with full-time, tenure-track important to get a good academic research. positions to apply. The funding must be solid footing early in your “It’s not easy to go back and do science used for direct research expenses, and the once you’ve started down the clinical awardees’ institutions must allow them career. path, so it’s really important to get a to spend at least 70 percent of their time E7::7/;5/:3G good solid footing early in your career,” conducting research. . ” Kochel Tom "$ HHMI BULLETIN | November 2oo7 Connecting Research Institutions with Local Communities 66;77<7B7/B7D3AC>>=@BA=CB@3/16>@=5@/;AB= /2D/<13>C0:71C<23@AB/<27<5=4A173<13 TO BRIDGE RESEARCH INSTITUTIONS WITH 6756:756BA=4A3:31B32>@=5@/;A their local communities and to spark the public’s interest in science, particu- Virginia Commonwealth University W\@WQV[]\RDW`UW\WOeWZZcaSWba larly among young students, HHMI has %# U`O\bb]SRcQObS9 aQWS\QSbSOQVS`aOP]cbagabS[aPW]Z]UgO\ awarded $22.5 million for educational O^^`]OQVW\eVWQVOQSZZ]`]`UO\Wa[WaabcRWSROaOeV]ZS E]`YaV]^aeWZZ programs at 31 institutions around the P`W\Ub]USbVS`aQWS\QSbSOQVS`aeWbVagabS[aPW]Z]UgU`ORcObSabcRS\baO\R country. The grants are going to medical ^]abR]Qb]`OZTSZZ]ea BVWab`OW\W\UeWZZVSZ^bSOQVS`aQ`SObSOQbWdWbWSabVOb schools, hospitals, research institutions, a S\Q]c`OUSabcRS\bab]RSaWU\O\RQ]\RcQbbVSW`]e\aQWS\bWTWQW\_cW`WSa BVSaQV]]ZOZa]^ZO\ab]Q`SObSR]e\Z]OROPZSdWRS]abSOQVS`ZSaa]\^ZO\a school of dentistry, and a school of veteri- O\ROQbWdWbWSa nary medicine. Ranging from $529,308 to $750,000 to be distributed over a five- Baylor College of Medicine W\6]cab]\BSfOaeWZZcaSWba%"'$ %U`O\b year period, the grants will support new b]P]ZabS`WbaA3:4AQWS\QS3RcQObW]\:SORS`aVW^4SZZ]ea^`]U`O[W\ outreach programs or ongoing activities eVWQVSf^S`WS\QSRaQWS\QSbSOQVS`a´[O\gT`][aQV]]ZaW\SQ]\][WQOZZg with a demonstrated record of success RWaORdO\bOUSRO`SOa´^OW`c^eWbV0OgZ]`^]abR]Qb]`OZ`SaSO`QVS`aO\R in broadening access to science across U`ORcObSabcRS\bab]T]`[aQWS\QSSRcQObW]\W[^`]dS[S\bbSO[a BVSbSOQVS`a diverse populations. O\RaQWS\bWabaZSO`\T`][]\SO\]bVS`Pgb`ORW\U^ZOQSa(bSOQVS`ae]`YW\O ZOPT]`bV`SSeSSYaO\RaQWS\bWabaP`WSÀgbSOQVW\OQZOaa`]][ A3:4bSOQVS`a “Many of these institutions are [OYSbVSY\]eZSRUSbVSg¸dSUOW\SROdOWZOPZSb]OZZ6]cab]\bSOQVS`adWO reaching out to traditionally underserved ]\ZW\SdW`bcOZe]`YaV]^aO\RR]hS\a]T^`]U`O[OZc[\WO`S\]eZSORW\U populations,” says Jill Conley, director bSOQVS`^`]TSaaW]\OZRSdSZ]^[S\bOQ`]aabVS\ObW]\ BVS^`]U`O[VOa of HHMI’s precollege science education RS[]\ab`ObSR`S[O`YOPZSacQQSaa 4]`SfO[^ZS]\SA3:4aQV]]ZaOeWba program. “They are also engaging girls in abcRS\ba¸acQQSaa]\bVSaQWS\QS^]`bW]\]TbVSBSfOa/aaSaa[S\b]T science at a particularly critical time in 9\]eZSRUSO\RAYWZZa`WaST`][ &^S`QS\bb]& ^S`QS\bOTbS`^O`bWQW^ObW\U their educational development.” W\bVS^`]U`O[T]`Xcab]\SgSO` A number of the grantees aim to improve Purdue University School of Veterinary Medicine W\:OTOgSbbS7\RWO\OeWZZ science education by enhancing teachers’ caSWba%"'%##U`O\bb]Q`SObSQ][^cbS`POaSRµ¿SZR¶b`W^ab]UWdS[WRRZS knowledge of scientific concepts and how aQV]]ZabcRS\baW\`c`OZ7\RWO\OaQV]]ZaeWbVZW[WbSR`Sa]c`QSabVS]^^]`bc\Wbg science is done. Their programs will help b]ZSO`\OP]cbbVSZOP]`Ob]`gS\dW`]\[S\b >c`RcSWabO`USbW\UabcRS\ba teachers develop hands-on, inquiry-based W\U`ORSa$bV`]cUV&PSQOcaS[WRRZSaQV]]ZWaQ]\aWRS`SRO\Sa^SQWOZZg activities for the classroom. Other projects Q`cQWOZbW[Sb]\c`bc`SQVWZR`S\¸aW\bS`SabW\aQWS\QS AbcRS\baeWZZPSOPZS will target students directly, teaching them b]dWSe]\ZW\SO\W[ObW]\aZWdSRS[]\ab`ObW]\aO\RSf^S`W[S\baOaeSZZOa W\bS`OQbeWbVe]`YW\UaQWS\bWaba how to think like scientists. And some will strengthen parents’ and other commu- The Queen’s Medical Center W\6]\]ZcZc6OeOWWeWZZcaSWba%"%$"" nity members’ understanding of scientific U`O\bb]Q`SObSOaS`WSa]TVSOZbVaQWS\QSSdS\W\U^`]U`O[aOW[SROb concepts, thereby enriching the network W[^`]dW\UVSOZbVZWbS`OQgO\RW\Q`SOaW\UbVSS\`]ZZ[S\b]T November 2oo7 | HHMI BULLETIN "% lab book Baby’s First Bacteria @3A3/@163@A23:D37 A baby may get her eyes from mom and her hair from dad, but Hundreds of different where does the bacteria in her gut come from? To answer this species of bacteria were question, HHMI investigator Patrick O. Brown at Stanford found to inhabit an University School of Medicine and colleagues found themselves infant’s gastrointestinal up to their ears in diapers—about a year’s worth—to analyze the tract, and each baby had microbial contents of newborns’ bowels. a different mix. The Babies are born with a sterile intestinal tract, but within a fraternal twins in the matter of days bacterial colonies establish themselves in the gut, study showed the most eventually (by adulthood) outnumbering human cells 10 to 1. similarity, suggesting that AQWS\bWabaVOdST]c\RbVObbVS[Wf]T These multiplying microbes serve numerous purposes, including genetics and environment POQbS`WOW\OPOPg¸aUcbWaaVO^SR]dS`bW[S protecting against harmful pathogens and aiding digestion. work together to shape “The tricky thing is that we don’t really know what the ideal the gut population in a reproducible way. By year one, all the population looks like,” says Chana Palmer, Brown’s former infants had a generalized profile close to that of an adult. graduate student and first author of their July 2007 PLoS “It almost doesn’t matter where you start off because we all Biology report. end up in the same place,” says Palmer. “There are some bacteria To get a view of the bacteria found in the gut, Palmer collected that are really well suited for your gut and they’re going to win stool samples from 14 babies and their parents at several intervals no matter what.” over each baby’s first year (see “Baby Biology,” page 6). She spread Whether bacterial flora are a function of genetics or the envi- fluorescently labeled DNA from the samples on a microarray ronment or both remains to be tested, says Brown, who likens the glass chip dotted with known bacterial DNA. Samples whose process to gardening. “What comes up depends both on what DNA sequence matched any bacterial sequence on the chip seeds were sown and which are best suited to the particular soil latched onto those spots and were tallied by a computer. and climate.” . – JACQUELINE RUTTIMANN 7<0@734 :7B67C;3/A3AAG;>B=;A=4 3f^Z]`W\UZWbVWc[OaO^]bS\bWOZaOZdS UZOaabVS\OZZbVSbOUaO`SaS_cS\QSRaW[cZ <3C@=:=571/:27A=@23@7<;713 T]`\Sc`]RSUS\S`ObWdSRWa]`RS`a[OYSa bO\S]caZg /Q][^cbS`^`]U`O[[ObQVSa 66;7W\dSabWUOb]`6cROG H]UVPWObbVS aS\aSOQQ]`RW\Ub]H]UVPWPSQOcaSW\ bVSbOUab]Y\]e\US\Sa(bVS[]`SbOUa 0OgZ]`1]ZZSUS]T;SRWQW\SO\R]bVS`aVOdS ^OababcRWSaZWbVWc[VOaPSS\aV]e\b] Oaa]QWObSR eWbV O US\S bVS VWUVS` bVS aV]e\W\[WQSbVObZWbVWc[O^agQVWOb`WQ ^`]dWRSa][S^`]bSQbW]\T]`bVSP`OW\W\O Sf^`SaaW]\]TbVObUS\S R`cUcaSRb]abOPWZWhS[]]RaVWTbaSOaSa dO`WSbg]TQ]\RWbW]\a CaW\U>;/53bVS`SaSO`QVS`aQ][^O`SR bVSag[^b][a]Ta^W\]QS`SPSZZO`ObOfWO OU`]c^]TVSOZbVg[WQSeWbVOU`]c^bVOb bg^S O\W\VS`WbSR\Sc`]RSUS\S`ObWdS <3E53<3A/AA=17/B32E7B6 VOROUS\SbWQ[cbObW]\bVObQOcaSa61; RWa]`RS` BVSW`O`bWQZSeOa^cPZWaVSR;Og ' 6G>3@B@=>6711/@27=;G=>/B6G OTbS`OP]cb #eSSYa]TOUS ASWR[O\¸a %W\>:]A;SRWQW\S /aS_cS\QW\UbSQV\W_cSRSdSZ]^SRPgO U`]c^T]c\R% $US\SabVObeS`S]dS`OQ BVS¿\RW\UaacUUSabWb[OgPS^]aaWPZS bSO[ZSRPg66;7W\dSabWUOb]`1V`WabW\S bWdS]`c\RS`OQbWdSW\61;[WQSQ][^O`SR b]caSbVSR`cUb]OZZSdWObSRSbS`W]`ObW]\W\ 3 ASWR[O\Ob0`WUVO[O\RE][S\¸a eWbV\]`[OZ[WQS A][S]TbVSaSUS\SaO`S []b]`Q]]`RW\ObW]\ZSO`\W\UO\R[S[]`g 6]a^WbOZO\RVS`VcaPO\R8]\ObVO\5 \SeZgZW\YSReWbVbVSRWaSOaS [O\WTSabSRPga^W\]QS`SPSZZO`ObOfWObg^S ASWR[O\Ob6O`dO`R;SRWQOZAQV]]ZVOa BVS abcRg^cPZWaVSR 8c\S & % W\ >`SaS\bb`SOb[S\baT]`bVSQ]\RWbW]\O`S WRS\bWTWSRVc\R`SRa]TUS\SaeWbVOZbS`SR AQWS\QSQ]cZRVSZ^aQWS\bWabaRS¿\SbVS^ObV ZW[WbSR >ObWS\bacacOZZgRWOU\]aSRW\bVSW` Sf^`SaaW]\W\bVSVSO`bQ]\RWbW]\Y\]e\ eOgabVObZSORb]bVSRWaSOaSO\RcZbW[ObSZg bVW`bWSa ]` T]`bWSa U`ORcOZZg Z]aS []b]` Oa^`SQZW\WQOZVg^S`b`]^VWQQO`RW][g]^ b]bO`USbaT]`^`SdS\bW]\O\Rb`SOb[S\b O\R[S[]`gTc\QbW]\O\RRWSeWbVW\OTSe ObVg61; 7\^S]^ZSeWbV61;bVSVSO`b gSO`a]T]\aSb]TbVSRWaSOaS [caQZSbVWQYS\aO\RTOWZab]`SZOf\]`[OZZg ;71@=@ "& HHMI BULLETIN | November 2oo7 Gender Switch? ;713B6/B1/<<=:=<53@23B31B>63@=;=<3A031/CA3=4/A7<5:353<3 23:3B7=<1@=AAB630=C<2/@73A=4BG>71/:53<23@036/D7=@ Female mice do not usually initiate sex or mount their partners. Yet male and female components controlled by a switch. That switch a subset of mutant females, studied by HHMI investigator is sexually dimorphic and modulated by pheromones.” Catherine Dulac and her Harvard research team, has upended the Dulac is careful to clarify that olfactory cues impact sexual world of lab mouse intercourse. behavior in mice much more than in humans. Like other primates, Dulac’s study suggests that sexual behavior in mice is not exclu- people lack vomeronasal organs and perceive the world mostly sively connected to inherent differences in the male and female through vision. But Dulac insists that focusing on the fact that her brain. Instead, she found that gender roles become strikingly fluid study pertains to olfaction is missing the point. It is the switch mech- when the mice are unable to detect pheromones. anism, independent of the sensory modality, that could apply to Mice detect pheromones through a chemosensory organ called several other species, she says. “We are shattering the dogma on the the vomeronasal organ (VNO), located in the nasal cavity. The male and female brain and the major importance of testosterone.” VNO requires a specific ion channel called TRPC2 to function. Dulac hopes that her findings will provide a fresh outlook for When Dulac and colleagues Dr. Tali Kimchi and Jennings Xu everybody in her field. Next, she plans to focus on whether the bred TRPC2 knockout male and female mice, the mutant mice male knockout mice ignored chemical cues that generally produce gendered behavior. demonstrate typically Male knockouts showed a lack of aggression toward other males, female behavior. “There and mounted male and female mice indiscriminately. Female are some species of knockouts exhibited typical male behavior, such as attacking rodents in which the intruding males, pelvic thrusting, and soliciting sex by using their father exhibits parental noses to poke other mice in the rear. behavior,” she explains. “There’s a major finding here,” says Dulac. “Sex-specific “Maybe there’s some- behaviors were assumed to be controlled by sex-specific neurons. thing there.” . /TS[OZS[]caSaV]eaac`^`WaW\U PSVOdW]`Pg^c`acW\UO\]bVS`TS[OZS We found that the brains of animals in a given species may have – SHELLEY DUBOIS 7<0@734 ]T]bVS`US\SaO\Rb`WUUS`aQSZZacWQWRS Q]\b`]Z´SfbS\RZWTSPg`SRcQW\UaWU\OZW\U ^`SRWa^]aSRb]bVSaSRWaSOaSab]][cQV QOZZSRO^]^b]aWaW\RO[OUSRQSZZa bV`]cUVOa^SQW¿Q^ObVeOgW\bVSP`OW\ W\acZW\]dS`OQbWdObSa7`a W\bVSP`OW\O\R ;WQ`]@
November 2007 | HHMI BULLETIN "' lab book
A Noisy Brain Is a Normal Brain
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New research from H. noise, were distributed randomly. The changes were seen during Sebastian Seung’s the learning tasks as well and could represent the existence of an laboratory at the unstable neural network in the motor cortex. For decades, scien- Massachusetts Institute tists have thought that the process of learning can be detected as of Technology (MIT) changes in a stable neural network: when there is no learning, suggests that scientists there are no changes in firing rates. According to Seung, the still have quite a bit to background noise was surprising. “Then the question became learn about learning. how to interpret [it],” he says. The researchers One idea is that there are two components in the brain—a
7<0@734 BVS¿\RW\UaW\[WQSO`SZWYSZg`SZSdO\b U`]e\ W\ QcZbc`S 7\ US\S`OZ W\Q`SOaSR W\ÀcS\QSbVSRSdSZ]^[S\bOZ^`]^S`bWSa b]Vc[O\^`]abObSQO\QS`aaOga6g\Sa O^]^b]aWaOQbWdObSaQgb]b]fWQBZg[^V] ]TbVSQSZZa PSQOcaS ]bVS` `SaSO`QVS`a VOR T]c\R QgbSaeVWQVObbOQYbVS^ObV]US\ 66;7W\dSabWUOb]`BV][Oa1 ARV]T >`]bSW\" 0b]PS`SRcQSRW\[SbOabObWQ EVS\aQWS\bWabaW\TSQbSR[WQSeWbVbVS ObbVSC\WdS`aWbg]TBSfOaA]cbVeSabS`\ ^`]abObSQO\QS`aQ][^O`SReWbV\]`[OZ be] ab`OW\a ]T POQbS`WO bVSg ]PaS`dSR ;SRWQOZ1S\bS`Ob2OZZOaO\RQ]ZZSOUcSa ^`]abObSbWaacS bVObQgb]b]fWQBZg[^V]QgbSa^`]ZWTS`ObSR ^cPZWaVSRbVSW`¿\RW\UaW\bVS/cUcab [cQV []`S W\ [WQS W\TSQbSR eWbV bVS %WaacS]TbVS>`]QSSRW\Ua]TbVS 6/<271/>>7<5BC03@1C:=A7A O^]^b]aWaW\RcQW\U ab`OW\ BVWa [SO\a # HHMI BULLETIN | November 2oo7 ask a scientist ? / Can Inflammation is caused by the body’s of cells due to injury or infection—are response to a perceived threat. When found even in neighboring cells. inflammation the body senses a disturbance, such The resulting symptoms are quite of a nerve as an insect bite, wound, infection, or different from chickenpox. Shingles allergen, immune system cells swarm to starts with sensations of pain or tingling cause the affected area. The physical presence of the skin that the infected nerve serves. of the immune cells and the chemi- A few days later, painful lesions appear inflammation of cals they release for communication on the skin. While chickenpox appears the tissue and action, known as cytokines, cause all over the body, shingles is restricted to the four classic signs of inflammation: a dermatome, an area of skin served by it serves? redness, swelling, heat, and pain. a specific nerve, producing a localized In at least one instance, inflamma- rash, usually on one side of the face or Philip, a curious adult from Virginia tion of a nerve causes inflammation in trunk. The immune system responds the tissue it innervates, albeit indirectly. accordingly and the area becomes This case involves reactivation of the inflamed. During the next five weeks, varicella zoster virus (VZV), the virus the rash turns into blisters that break responsible for chickenpox, which open, crust over, and then disappear. many people contract as children. A Most patients feel relief from pain vaccine is now available that protects when the rash disappears, but some against VZV. Initial VZV infection, experience pain for weeks, months, characterized by an extensive itchy or even years. This condition, known rash, rarely results in anything that as post-herpetic neuralgia, is the most cannot be taken care of by an oatmeal common serious complication from bath. However, even after symptoms VZV reactivation. It results from disappear, the virus remains in the damage to pain-sensing neurons, body, traveling up the spinal cord to causing them to misinterpret harmless nest in the dorsal root ganglia (clusters signals as painful ones. Problems may of sensory neurons that lie along the also arise depending on which nerves spine), where it becomes dormant and are infected. Infected facial nerves just quietly inhabits nerve cells. can cause facial weakness, such as in For about 1 million Americans each Ramsay Hunt syndrome and Bell’s year, that dormancy ends and VZV reac- palsy; infected nerves serving the eye tivates and causes shingles. Reactivation or ear can cause disabling pain and usually occurs when the immune system loss of vision or hearing. becomes suppressed and can no longer keep the virus at bay. VZV actively ANSWER RESEARCHED BY LINDSEY replicates and travels down the infected PUJANAUSKI, a graduate student in nerve, causing havoc along the way. immunology at the University of Colorado Inflammation and necrosis—the death Health Sciences Center. FOR MORE INFORMATION on shingles, visit www.cdc.gov/vaccines/vpd-vac/shingles/dis-faqs.htm. BVSaQWS\bW¿Q^`]QSaaabO`baeWbVO_cSabW]\ EVS\OaQWS\bW¿QW\_cW`g^W_cSabVSW\bS`Sab]TOVWUV aQV]]Z]`Q]ZZSUSabcRS\bO\RO\aeS`aQO\¸bPST]c\RW\QZOaa]`W\ObSfbP]]YabcRS\baQO\bc`\b] 66;7¸a/aYOAQWS\bWabESPaWbS BVS`Se]`YW\UaQWS\bWaba¿SZROeWRS`O\US]TPW][SRWQOZ_cSabW]\a November 2007 | HHMI BULLETIN # up close Hackathon It takes a dedicated chunk of time to agree on a system for making sense of everybody’s fruit fly brain images. Mark Longair Stephan Saalfeld Stephan Preibisch Arnim Jenett University of Edinburgh, Max Planck Institute, Max Planck Institute, Janelia Farm Research Scotland Dresden, Germany Dresden, Germany Campus, Ashburn, Virginia /\Sc`]W\T]`[ObWQWab /Q][^cbS`aQWS\QS >`SWPWaQVWaOQ][^cbS` 8S\SbbWaO\Sc`] :]\UOW`RSdSZ]^ab]]Za abcRS\beWbV aQWS\bWabT]QcaSR]\ PW]Z]UWabW\bS`SabSR b]Sfb`OQb\Sc`OZ Sf^S`bWaSW\W[OUS W[OUS^`]QSaaW\U W\c\RS`abO\RW\U Q]\\SQbWdWbgW\T]`[O ^`]QSaaW\UdWacOZWhO abObWabWQaO\R^ObbS`\ µeVS`STc\QbW]\aO`S bW]\T`][abOQYa]T bW]\O\RbVSQ`SObW]\ `SQ]U\WbW]\ 6SaOgaO Z]QObSRW\bVS bV`SSRW[S\aW]\OZ ]TESPO^^ZWQObW]\a ^S`a]\OZVWUVZWUVb 2`]a]^VWZOP`OW\¶ W[OUSa]TbVSÀgP`OW\ AOOZTSZRWaQc``S\bZg T`][bVSe]`YaV]^ O\RV]eWb^`]QSaaSa ^`]RcQSRPgQ]\T]QOZ W\bS`SabSRW\OZWU\W\U eOaµbVSQ][^ZSbW]\]T W\T]`[ObW]\ 6SWa [WQ`]aQ]^g Q]\aSQcbWdS[WQ`]a [gTOab 2O\R!2 Q]\ab`cQbW\UO\ObZOa Q]^gaZWQSaW\bV`SS abWbQVW\UOZU]`WbV[ ¶ ]TbVSÀgP`OW\ Fetters Paul RW[S\aW]\a Q]``SZObW\UTc\QbW]\ O\RO\Ob][g # HHMI BULLETIN | November 2oo7 lock them in a room, give them plenty of caffeine, and the variety of scientific approaches, each covering different and let them have at it. Well, it wasn’t that draconian, but an degrees of detail, the prospect was fairly daunting. Yet, the international group of “hackers”—so named for their ability to group devised the basis for a file-sharing system for importing find their way through a morass of code—did put in an energetic and exporting digital images across microscope platforms. two weeks this summer at Janelia Farm Research Campus to Ultimately, the goal is a “brain morphing” software program hash out a way to compare anatomic images of the Drosophila that lets researchers orient themselves within the fly brain brain. It sounds simple enough, but considering the variety of and reliably compare measurements. Plans for Hackathon II microscopes in use, each run by its own particular software, are in the works. . Benjamin Schmid Albert Cardona Yuriy Mishchenko Wuerzburg, Germany University of California, Janelia Farm Research /PW]W\T]`[ObWQWO\ Los Angeles Campus, Ashburn, Virginia W\bS`SabSRW\OZZ¿SZRa 1O`R]\OWaOPW]Z]UWab ;WaVQVS\Y]WaO bVObP`W\Ub]USbVS` abcRgW\UV]ebVSP`OW\ Q][^cbObW]\PW]Z]UWab [ObVS[ObWQa e]`Ya ;]ab`SQS\bZg eWbVO\W\bS`SabW\ Q][^cbS`aO\R VSWaT]QcaSR]\bVS W[OUS^`]QSaaW\U 6S >O`bWQW^O\ba\]b^WQbc`SR( PW]Z]UgAQV[WR [WQ`]O`QVWbSQbc`S]T WaO\Oaa]QWObSW\bVS 8cZWSAW[^a]\8O\SZWO4O`[) Qc``S\bZgT]QcaSa]\ bVS2`]a]^VWZOP`OW\ ZOP]T8O\SZWOU`]c^ EOg\S@OaPO\R November 2oo7 | HHMI BULLETIN #! nota bene A>=B:756B Celebrating 60 Years of Cech Inspirations 4`WS\Ra TO[WZgO\R Q]ZZSOUcSa ]T 66;7 >`SaWRS\b BV][Oa@ 1SQVUObVS`SRW\0]cZRS`1]Z]`OR]8cZg ³ !T]`Oag[^]aWc[W\1SQV¸aV]\]` BVSSdS\bQ][ [S[]`ObSRaSdS`OZ[WZSab]\Sa(bVS #bVO\\WdS`aO`g ]T1SQV¸a<]PSZ>`WhS³eW\\W\URWaQ]dS`g]TQObOZgbWQ @ A13<3A4@=;B631316µ@=/AB¶1:=19E7A34@=;B=>:34BB=;1316)67AE7431/@=:1316)/5@=C>13:30@/B7=<17@1/ '%' A==</4B3@13168=7<32B63C<7D3@A7BG=41=:=@/2=4/1C:BG7<1:C27<51:=19E7A34@=;:=E3@:34B1/@=:1316B=;1316 /<243::=EA173 HHMI investigator 4@323@719E /:B by the American Chemical Society (ACS) Award for Computers in Chemical and at Children’s Hospital Boston received for outstanding scientific achievements. Pharmaceutical Research. HHMI the 2007 Novartis Basic Immunology HHMI investigator 2/D7237A3<03@5, professor @716/@2< H/@3, Stanford Prize for his discovery of the mechanisms University of California, Los Angeles, and University, will receive the 2008 George of antigen receptor rearrangement in B his former graduate student @30311/ C. Pimentel Award in Chemical lymphocytes. /<<3 <3:A=<, will receive the 2008 Education. Nobel Laureate Signature Award for HHMI international research scholar Graduate Education in Chemistry; HHMI AB/<:3G473:2A, an HHMI investigator >/A1/:3 4 1=AA/@B, of the Pasteur investigator :7<2/1 6A736E7:A=<, at University of Washington School of Institute of Paris, France, received the California Institute of Technology, will Medicine, received the 2007 Vollum 2007 Robert Koch Award for her work on receive the 2008 Arthur C. Cope Scholar Award for Distinguished Accomplishment the food-borne disease listeriosis. Award for “excellence in organic chem- in Science and Technology from Reed istry”; and HHMI investigator 8 /<2@3E College. Fields developed the yeast two- Three HHMI investigators and one ;11/;;=<, University of California, hybrid system, a method for detecting HHMI professor will be honored in 2008 San Diego, will receive the 2008 ACS protein-protein interactions in living cells. Photos from “Roast”: Carmel Zucker #" HHMI BULLETIN | November 2oo7 2/D7257 E7::7/;5 9/3:7<8@ , an HHMI inves- tigator at the Dana-Farber Cancer Institute, received a 2007 Distinguished Molecular Biology (ASBMB) for their HHMI investigator ;716/3:4 AC;;3@A, Alumni Award from Duke University significant scientific contributions. HHMI University of Maryland, Baltimore School of Medicine. investigator 8=6< 2 A1=BB, Oregon County, will receive the 2008 ASBMB Health & Science University, will receive Award for Exemplary Contributions to Two HHMI investigators and one HHMI the 2008 William C. Rose Award for his Education. HHMI professor A1=BB / professor will be honored in 2008 by the research and his “demonstrated commit- AB@=03:, of Yale University, will receive American Society for Biochemistry and ment to the training of younger scientists.” the ASBMB–Schering-Plough Research Institute Award, an honor given to researchers within 15 years of receiving a doctorate, for “outstanding research A>=B:756B contributions to biochemistry and molecular biology.” HHMI Researchers Receive B3@@3<13 8 A38<=EA97, an HHMI Paul Marks Prize investigator at the Salk Institute for Biological Studies, was honored with a surprise symposium in recognition of his 60th birthday and his work on the biophys- ical properties of neuronal synapses. 7A7/6; E/@<3@, an HHMI professor at Louisiana State University, received the 2007 Anachem Award from the Federation /<53:79//;=< B=225=:C0 5@35=@G6/<<=< of Analytical Chemistry and Spectroscopy Societies for “his fundamental contribu- BV`SS66;7W\dSabWUOb]`aVOdSPSS\V]\]`SReWbVbVS %>OcZ tions to luminescence spectroscopy and ;O`Ya>`WhST]`1O\QS`@SaSO`QV Amon: Paul Fetters Golub: Robert Bachrach for the Broad Institute Hannon: Zack Seckler / AP ©HHMI Druker: Courtesy of OHSU Seckler for the Broad Institute Hannon: Zack Golub: Robert Bachrach Fetters Amon: Paul Zare’s work in nanotechnology. November 2oo7 | HHMI BULLETIN ## 1= A/D3B632/B3 /72A(3D=:CB7=<=4/<3>723;71 Howard Hughes Medical Institute 2007 Holiday Lectures on Science Live Webcast Speakers 2SQS[PS`$ % 0`cQS2 EOZYS`; 2 0Wa]ZO= =XWYcbc; 2 ; > 6 :SQbc`Sa 66;7W\dSabWUOb]` 2W`SQb]`=T¿QS]T7\bS`\ObW]\OZ>`]U`O[a 2W`SQb]`1S\bS`T]`/72A@SaSO`QV 2WdWaW]\]T/72A 2SQS[PS`% % 6O`dO`RC\WdS`aWbg 6O`dO`R;SRWQOZAQV]]Z :SQbc`Sa!" ( O [ 3B For More Information ( O [ >BRSZOgSR DWaWbeee V]ZWROgZSQbc`Sa ]`U #$ HHMI BULLETIN | November 2oo7