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IN THIS ISSUE: GETTING A GRIP ON PAIN

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Locked and Loaded www.hhmi.org HORWICH This bullet-shaped structure serves as a changing room of sorts for bacterial proteins. Called GroEL, the molecular complex has KEEPING STEM a cap called GroES (blue) that pops open to allow an unfolded protein TEACHING FRESH to move inside. With the protein sequestered, the top closes, sealing it off from the cellular environment. Once folded, the protein is released, free to move on to its job. Without the GroEL/GroES complex, proteins clump together before they have a chance to fold, and the cell dies. Over three years of painstaking work, HHMI investigator Art Horwich and colleagues determined the molecular structure of the complex by x-ray crystallography, an effort for which he shared the 2011 Lasker Award (see “An Intentional Life,” page 18). (1977) 388:741–750. Nature FORCE MARRYING PHYSICS WITH BIOLOGY

vol. TO STUDY THE PUSH AND PULL OF

25 MOLECULAR MACHINES Illustration by Cassio Lynn (Lasker Awards 2011); adapted from Xu Z, Horwich AL, Sigler PB. 2011); adapted from Xu Z, Horwich (Lasker Awards Illustration by Cassio Lynn / no. 01 12 Read about the work of her team and others in our cover story. cover our in others and workofherteam the about Read motor. DNA-unwinding active but an DNAstrands the of acceptor nota passive is helicase the toshow that trapping optical Wang used Michelle investigator HHMI replicate. to strands single two freeing DNA, double-stranded it unwinds (yellow) as ahelicase called enzyme acellular shows image This byamolecule. exerted force the (red) tomeasure beam laser focused atightly ofusing aclever way butit’stechnique, actually vision-correction latest the like Sounds trapping. Optical

Chris Pelkie and Daniel Ripoll / Cornell Theory Center

illustration by Ciara Phelan, photography by Sam Hofman building, you would probably have enough time (you would have about Newton’s laws bedeviling another!Ifyou could jumpoffathirty-story react nearlyfast enough,since there isinertiaintheirsprings. Oneof scales. The problem isthatthescalesyou canbuycommercially don’t but don’tbother;trust me, Itrieditmany timesandonly broke many would indicate zero. Imightrecommend thatyou trythisyourself, that for thehalfsecond orsothatIwas infree fall thebathroom scale I could somehow show my students—by riggingupaspecialcamera— scale thatwas tiedvery securely to my feet? Ithoughtthen maybe ness—in class. What ifIclimbeduponatable, standing onabathroom wanted to beableto demonstrate thisphenomenon—even weightless- The wholeideaofchangingweight issofascinating thatIreally don’t approach like aphysicist—yet.” world,” hesays. “Theworld they live inand are familiar withbut book approaches physics withevangelical zeal, asevidenced inhisnew theatrical anticsmadehimaYouTube celebrity. Now retired, hestill than 30years. When hislectures becameavailable online, his for students attheMassachusetts Institute ofTechnology for more recipe for instant fun.Hemadeeveryday physics understandable Putting physicist Walter Lewin infront ofaclassroom isaguaranteed FREE FALL OBSERVATIONS For theLove ofPhysics . “Iintroduce peopleto theirown Reprinted by permission ofFree Press, aDivision ofSimon&Schuster. Warren Goldstein. Copyright © 2011 by Walter Lewin andWarren Goldstein. Of Time—A Journey Throughthe Wonders ofPhysics From per second, just asyou are. You andthejugare bothinfree fall. become zero. The jugwillnow beaccelerated at9.8 meters per second you have beenpushinguponthejug,to keep itin your hands,has float. Why? Because asyou accelerate downward theforce withwhich back inslow motion,you willvery clearlyseethejugofwater start to get afriendto make adigitalvideoofyou takingthejump, andplay it the airyou willseethejugstart floatingabove your hands.Ifyou can resting onyour hands.Now jumpoffthetable, andwhileyou are in lightly ontop ofthem, notholdingthesidesofjug.Ithasto bejust half-gallon jugofwater inyour outstretched hands,just cradling it in front ofmy classroom. Climbuponthetableandholdagallonor if you have apicnictableandgoodknees.Idothisfrom the lab table thing you cantryinyour backyard to experience weightlessness, So rather thanbreaking scalesorjumpingoffbuildings,here’s some- problems withthatexperiment. 4.5 seconds) to seetheeffect, butofcourse there would beother FOR THELOVE OFPHYSICS: FromtheEndofRainbow to theEdge by Walter Lewin with february ’12 vol. 25 · no. o1

12

18

Web-Only Content See students as flintknappers, turning stones into tools, at the Holiday Lectures.

Learn how researchers discovered a safe way to shut down the tuberculosis bacterium. Watch a mouse sniff out a predator’s presence in mere moments, thanks to special receptors in its nose. View an animation of how a compound from the venomous cone snail acts to dampen pain in mammals.

Join us at www.hhmi.org/bulletin/feb2012.

GO GREEN Prefer to receive your Bulletin digitally? Go to hhmi.org/bulletin/subscribe. 24 30 Features Departments

COVER STORY PRESIDENT’S LETTER INSTITUTE NEWS FORCE FACTOR 03 Fundamentals for Uncertain Times 40 Short Films Make Evolutionary 12 Borrowing tricks from physics, Biology Memorable CENTRIFUGE biologists are getting a handle on 40 New Open Access Journal Gets 04 Born to Tackle the minimachines that provide Name and Editorial Team 05 High-Tech Reboot push and pull inside living cells. 41 International Early Career Awards 06 True Grit AN INTENTIONAL LIFE Provide Connections and Funding UPFRONT 18 A hands-on scientist with a clear LAB BOOK 08 Changing Channels vision, Art Horwich lets nothing 42 How Much Is Too Much? 10 The Twists and Turns of Immunity stand in the way of his mission. 43 Protein Precision in the Brain PERSPECTIVES AND OPINIONS RAISING THEIR GAME 44 Now You See It, Now You Don’t 34 Inspired to Serve 24 Science and math teachers need ASK A SCIENTIST 36 Q&A—What’s your favorite science- to be relentless learners to keep up themed film and why does it appeal 45 How much energy does the brain with the science and effective to you? use to perform different tasks? teaching principles. NOTA BENE CHRONICLE WHERE DOES IT HURT? SCIENCE EDUCATION 46 News of recent awards and other 30 Researchers are getting to the 38 Bones, Stones, and Genes notable achievements molecular details of pain’s OBSERVATIONS circuitry to answer the question Free Fall with real specificity.

VISIT THE BULLETIN ONLINE FOR ADDITIONAL CONTENT AND ADDED FEATURES: www.hhmi.org/bulletin contributors

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Mark Smith upfront

08 CHANGING CHANNELS Appetite and other deep-seated desires could be modified by altering brain ion channels, according to research at Janelia Farm.

10 THE TWISTS AND TURNS OF IMMUNITY The diversity of the immune system’s antibodies depends on the three-dimensional structure of DNA.

web-only content

A SAFER SHOT AT TB While trying to understand tuberculosis bacteria genes, researchers discovered a safe way to shut down the pathogen. Read about it at www.hhmi.org/bulletin/feb2012.

Mysteries are irresistible, for scientists especially. Solving some biological puzzles can take years of persistence, with progress coming in arduous steps. Other times, answers arrive like a bolt from the sky. Whether it’s delving into the drive behind hunger, or how antibody diversity is generated, or the best way to cripple the TB pathogen, the scientists trying to plumb these enigmatic problems get downright gleeful when big pieces of the puzzle fall into place. See for yourself.

February 2o12 | HHMI BULLETIN 7 upfront

Changing Channels Appetite and other deep-seated desires could be modified by altering brain ion channels, according to new research at Janelia Farm.

SCOTT STERNSON HAS ALWAYS WONDERED WHAT DRIVES

behavior, especially those fundamental motivations required what types of ion channels they contain. for survival. Hunger, for example, is so crucial that it must Neuroscientists can study how isolated be evolutionarily “hard-wired” deep within the brain. After neurons work in a lab dish. However, to all, as Sternson observes, “if the animal doesn’t eat, it dies.” connect neural circuitry to complex behav- iors, Sternson wanted to probe the neuronal Melding the diverse disciplines of synthetic mass transit counterparts, some ion chan- wiring in living mice. To do that, he needed chemistry, structural biology, and computa- nels, called ligand-gated ion channels, won’t a way to “re-ticket” individual ion channels tional modeling, Sternson and Loren Looger, budge until presented with a ticket—in this within a neuron or small group of neurons both group leaders at HHMI’s Janelia Farm case, a chemical neurotransmitter. The by forcing them to respond to a unique, syn- Research Campus, have uncovered clues ensuing electrochemical impulses that race thetic neurotransmitter—one not normally about the brain circuitry that controls deep- through neurons create thoughts, emotions, seen in nature. seated behaviors, like that irresistible urge to and, ultimately, behavior. Sternson began by collaborating with visit the dessert table. Sternson’s scientific interest in hunger Looger, a protein chemist, to exploit the The pair devised a noninvasive method began when he was a postdoc in the labora- modular structure of ligand-gated ion chan- to stimulate individual brain neurons or tory of HHMI investigator Jeffrey Friedman nels. In these channels, the ion pore domain clusters of neurons in live, conscious ani- at the Rockefeller University. In the mid- (IPD) is tethered to an independently func- mals—a remote control for the brain, of 1990s, Friedman identified a hormone tioning ligand-binding domain (LBD). sorts. They demonstrated the technique by called leptin that exerts powerful control Scientists had previously engineered “chi- converting gluttonous mice into champion on appetite by acting on a region of the meric” ion channels by genetically splicing dieters. The researchers published their brain called the hypothalamus. Sternson’s the LBD from one type of channel to the findings September 2, 2011, inScience . goal was to understand the neuronal wiring IPD from another. Such hybrid channels You can blame those dessert cravings in the hypothalamus that controls appetite. transport ions specified by the IPD but in in part on ion channels, explains Sternson. He wanted to identify the different neu- response to the neurotransmitter recognized Ion channels are molecular pores, donut- rons and deduce the contribution of each by the grafted LBD. shaped proteins embedded in the surface toward evoking hunger. The problem was To create an ion channel that could of neurons that allow charged particles to that no tools were available to systemati- respond to a novel neurotransmitter, Stern- enter and exit the cells. Like a subway sys- cally probe brain wiring with the precision son and Looger needed to design a new tem’s turnstiles, ion channels have moving he needed. LBD and synthesize a neurotransmitter that parts, opening and closing to ensure pas- Neurons perform their assigned duties could bind and activate it—two tall orders, sage of only the proper type of ion, single by firing or turning silent in response to Sternson says. “The thinking was that it file, by the millions every second. Like their chemical neurotransmitters, depending on would be very difficult. It was an uncertain

8 HHMI BULLETIN | February 2o12 Jing Wei nels. Starting with achemical analogofnels. Starting would unlocktheir newfangledionchan- acetylcholine binding. on theLBDpredicted for tobeimportant mutation atoneormoreofthe 19 positions a ated dozensofchannels,eachcontaining natural neurotransmitter. Theythencre- this of theLBDweremostlikelytocontact molecular modelingtopredict whichparts nation ofprotein structuralchemistry and acetylcholine, theteamappliedacombi- domains.” Nonetheless,they persevered. even modify thesecomplexligand-binding challenge foruswhetherornotwecould Next, theydesignedacompound that withtheLBDthatrecognizesStarting When Sternson injectedtheanimals with stimulate voracious appetitesinthemice. theseneuronsto had previouslytailored called AGRP neurons,inmice. Histeam nels intospecific hypothalamus neurons, version ofonehisdesigner ionchan- So Sternsoninsertedaneuron-silencing would betryingitoutinalivingorganism. channel system,theresearchersknew, many combinationsthatworked. each ofthehybridionchannels,theyfound for itsabilitytoselectivelyactivateorsilence the compound.Whentheytestedeachone collection of71slightlymodified versionsof acetylcholine, theresearcherssynthesizeda The ultimatetestoftheartificial ion lie whywedowhatdo,” Sternsonsays. demystify someoftheprocessesthatunder- neuroscience andwillultimatelyallow usto behaviors. “To me,that’s arealfrontierfor role ofspecific neuronsinothercomplex Farm researchersintendtoexamine the and neurotransmitters inhand,the Janelia dramatically. ter, their overindulging habitssubsided the appropriatesyntheticneurotransmit- W

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HHMI

BULLETIN 9 upfront

The Twists and Turns of Immunity The diversity of the immune system’s antibodies depends on the three-dimensional structure of DNA.

Fred Alt has built a career making sense of the immune system—specifically, the diverse

antibodies that fight off invading molecules, from viruses to cancer cells to pollen. Leeds Jared

10 HHMI BULLETIN | February 2o12 IMAGINE THAT THE ONLY ROAD CONNECTING TWO CITIES HAD rollercoaster-inspired loops. Cars and trucks attempting to make the journey would plummet off the highway. It would surely discourage direct traffic between the towns. ¶ In the cell, where molecular “We saw a very unordered pattern of anti- body gene generation,” says Alt. Segments machines constantly travel along strands of genetic material, such unin- from the V genes joined with Ds before the viting loops and curls are commonplace. They help keep proteins from Js were tacked on. And only a few of the pos- sible V segments were used, leading to fewer accessing genes the cell doesn’t need at of unique combinations. Three gene seg- unique antibody possibilities. Moreover, the time. Later, when the cell needs the ments—dubbed variable (or V, for short), cells lost the ability to ensure production of genes to be activated, the dizzying round- diversity (D), and joining (J)—are the basis only one antibody at a time. Both specific- abouts can be straightened out to support for these permutations. ity and diversity were obliterated. His group, molecular traffic. In 1984, Alt discovered that immune cells led by postdoctoral fellow Chunguang Guo, In the late 1970s, when HHMI investiga- always combine a D and J segment before published the observations September 11, tor Fred Alt at Children’s Hospital Boston adding a V. Cells early in their development, 2011, in Nature. started studying the human immune system, he found, contained partial antibody genes “This site impacts every regulatory pro- he had no idea this higher-order structure of composed of only Ds and Js. When Alt grew cess that we’ve been studying for 30 years,” DNA even existed. Today, he’s found that those cells in the lab, the antibody genes Alt says of the CTCF. the way DNA is packaged into three-dimen- added a V later in the cell’s development. The CTCF protein is normally bound sional structures is crucial to every immune He has since worked out some of the pro- to the CTCF-binding site during devel- process he’s looked at. teins responsible for combining these gene opment. Alt’s team discovered that the Alt studies how the immune system segments in different ways. And he’s pin- antibody gene forms a number of loops that generates antibodies against any potential pointed how the cell makes sure only one require the bound protein. Transcription invader to the body—from a virus to a can- antibody is produced—by suppressing alter- proteins—which travel along DNA and use cer cell or bit of pollen. When an antibody nate antibody genes once a combination is it as a blueprint for RNA strands—get stuck recognizes an invader, it signals the rest of successfully produced. between the D and V segments because of the immune system to destroy it. This means But Alt wanted to know how the cell these loops, Alt thinks. The arrangement millions of different antibodies are somehow ensured the order in which the genes were allows developing cells to produce antibod- encoded in the DNA of immune cells to combined. The hint came when he was ies with only the D and J regions; the V recognize all types of invading molecules. looking at the DNA between D and V gene segment is added later. “It’s important for a cell to make only segments. He noticed a stretch of DNA “Genes have incredibly complex three- one type of antibody at a time,” says Alt. that’s found elsewhere in the genome and dimensional organization,” Alt says. “And In immunology, that quality is called is known to regulate DNA transcription. we’re learning that all of biology depends specificity. “But it’s also important that dif- A protein called CTCF that attaches to on that organization.” ferent cells make different antibodies.” This certain DNA sequences to regulate gene Alt’s next task is to uncover the other is diversity. expression can bind to the region. It folds proteins responsible for controlling the If the immune system had enough the surrounding DNA into loops. CTCF site. Now that he’s found a mas- genes for every possible antibody the body Alt wanted to know the role of the ter control site that keeps the V from might need, our genomes would be expo- so-called CTCF-binding element in con- being added to antibodies too early, he nentially larger than they are. Instead, trolling the assembly of antibody genes. So wants to know what signals the cell to immune cells combine different bits of he mutated the binding element, with dras- finally add the V segment. Stay tuned. genes in different ways to make millions tic results. W –SARAH C.P. WILLIAMS

February 2o12 | HHMI BULLETIN 11 Illustration: Firstname Surname Photo: Firstname Surname Firstname Surname THE AND BIOLOGISTS THAT LIVING TRICKS BORROWING HANDLE

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SCI- Bustamante, an HHMI investigator at the University of Califor- nia, Berkeley. “There are different centers, each specialized in certain functions. Those centers are primarily made up of pro- tein machines. And those machines work as motors that produce torque and movement and force.” EN- Today, thanks to techniques that Bustamante helped bring from physics to biology, scientists can quantify the forces and movements generated by molecular motors. They can precisely measure the force it takes to unfold a protein or unwind a strand of DNA. The innovative methods not only provide fascinating insight into the magnitude of force being generated inside living TISTS cells, they also offer ways to change this force and study the con- sequences. Scientists can play tug of war with a strand of DNA or in the early 1900s invented a relatively easy way to measure the pull a protein backward along a track to see how the molecules force generated by a muscle. They would hang muscle fiber, biop- behave under stress. sied from an animal, between two finely calibrated springs and then probe the muscle with an electric shock to make it contract. Shining a Light on Force The stronger the muscle, the more it pulled the springs. In the 1980s, Bustamante worked at the University of New Mexico But physiologists soon learned that individual molecules in studying how pieces of DNA moved through gels. When coaxed cells generate the collective force in muscles. And the crude through the gel by an electric current, fluorescently stained DNA spring experiments couldn’t be applied to these tiny molecules. strands moved at different speeds depending on their sizes. The challenge of how to measure molecular forces became even “As I was watching this separation, what became evident to me more vital as they discovered other molecular motors—molecules was how elastic these molecules appeared,” he says. “Sometimes in a cell that convert energy to movement. Motors, scientists real- a little piece would get caught and the DNA would stretch out, ized, help sperm swim, pull DNA apart so it can be copied, and and then it would snap back like a spring.” carry molecules from one side of the cell to the other. Every He became curious about the elasticity of DNA and how directional, nonrandom movement that had been visible under to measure it. How much force would he need to stretch out a microscopes for centuries was, at some level, due to molecular strand like the gel was doing? motors generating force inside cells. In his earliest calculations, Bustamante estimated that he Force is anything that makes an object change its speed, needed a tenth of a piconewton to begin to stretch DNA. “A new- direction, or shape. In the context of cells, forces are required to ton is about the weight of an apple on the surface of the earth,” move molecules. Quantifying these forces gives scientists a way he says. A piconewton is a millionth of a millionth of that, around to compare and contrast different molecular motors. Without the weight of a red blood cell.” measurements of force, they were missing a crucial entry in the To generate this small amount of force, Bustamante attached equations of how cells use energy. one end of a DNA strand to a glass coverslip and the other end “The bottom line is that the cell is not just a little bag of to a tiny magnetic bead. Then, he used a second magnet, with concentrated reactants. The cell resembles a factory,” says Carlos a known magnetic strength, to tug on the magnetized end of the

14 HHMI BULLETIN | February 2o12 Jaosn Grow cell byavirus. strands ofRNAortorecognize foreign RNAbrought intoa off theRNA.Otherhelicases arerequired tounwinddouble As theymove,someRNAhelicases pushothermolecules the geneticmaterialthattranslates DNAcodesintoproteins. shuffling movementsofRNA helicasesalongstrandsofRNA, At Yale University, HHMIinvestigatorAnnaPylestudies the Measuring Moving Parts in measurement oftheelasticity ofastrandDNAandwasreported be tostretchtheDNAbydifferent amounts.Itwasthefirst direct DNA strand.Hecouldmeasurehow strongthemagnethadto study their behavior. way forbiologiststopushandpullonindividual molecules to these experimentsarereality, andopticaltrappingisthego-to pull proteins apartordragmotorsalongpiecesofDNA.Today, any moleculethathewanted.Heimaginedusingopticaltraps to the chancetolearnaboutotherinterestingthingsincell.” learning whattheelasticity ofDNAwas,thesetechniques offered before,” “Butwecametorealizethatbesidesjust saysBustamante. put itunderthelaser,andslowly movethelaserinonedirection. aplasticbeadinplaceofthemagnet, couldattach Bustamante force generatedbythelaserbeam.To stretchapieceofDNA, toastrandofDNAorprotein andpulledusingthe attached tists whopioneereditsuseinbiologyforsingle-moleculestudies. wasamongahandfulofscien- in thebeamoflight.Bustamante of thistechnique, calledopticaltrappingbecauseittrapsaparticle 1997 NobelPrizeinPhysicsforhisquantum physicsapplication and theamountofforceexertedonbeadchanges. bead toward thecenterofbeam.Changeintensity light, opposite reaction—thisminiscule amountofforcepullsthetiny ing toNewton’s thirdlaw—for everyactionthereisanequal and of thelightbeamrequires atiny amountofforce.Andaccord- is slightlydeflectedatthebead’s surface.Thischangein direction ments andapplyevensmallerforces. These methodsallowed themtomakemoreprecise measure- of usingmagnetism,their techniques reliedonoptics,orlight. the methodandbroughtcutting-edgephysicstobear. Instead Science Suddenly, hadawaytophysicallymanipulate Bustamante “We knewweweredoing experiments thathadn’tbeendone The smallplasticbeadusedinopticaltrappingcanbe Physicist StevenChu,now ofEnergy, theU.S. wonthe Secretary If apowerful lasershinesthroughaplasticbead,thelightbeam andhiscolleaguesrefined Over thenextdecade,Bustamante in1992.

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BULLETIN Wang’s teamdevisedopticaltrapstoholdtwoDNAstrands “When youdoanexperimentlikethat,don’tknow the T7 helicasecanbindtwoformsofcellularenergy. One,called Optical trappingexperimentsbyMichelleWang, anHHMI

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hY[iÆ around andthesinglestrandswon’tbelefthanging. binding tothehelicasesignalsthatthereareplentyofnucleotides dTTP isanucleotide thatcanbeincorporatedintothestrands,its around toquickly bindandpairwitheachsinglestrand.Since cell toslow unwinding ofDNAwhentherearen’tnucleotides was happening.” bythe Shethinkstheslippageisanadaptation all inthepresenceofATP,” saysWang. “Sowedidn’t know this end. Thegrouppublishedtheir workOctober6,2011,in slippedbackwardontheDNA,nevergettingto but constantly has to cross a membrane, or needs to be remodeled, she explains. has tocrossamembrane,orneedsberemodeled,sheexplains. Unfolding aprotein inactivatesitiftheprotein isnolongerneeded, critical timeswhenthecellneedstounfoldthem,” saysBaker. unfolds entireproteins ratherthanDNAstrands. helicase. ButBakerstudies how onemolecularmachine,ClpXP, ments thataresimilar tothoseMichelleWang setuptostudyT7 HHMI scientific reviewboardmemberBobSauer,runsexperi- investigator Tania Baker,aspartofalong-termcollaborationwith ping offeredawaytodothisphysicalwrangling. conformations, unfold,andinteractwitheachother. Opticaltrap- proteins ontheir own—to studyhow theycanaltertheir complex by thenucleic acids. Butscientists soonwantedtomanipulate point forotherexperimentsontheforcesexertedor starting the elasticity ofthemolecules,thesemeasurementsprovideda hadalreadycalculated around DNAandRNA.SinceBustamante The firstapplicationsofopticaltrappinginbiologyrevolved Molecular Tug ofWar “In bulkstudies, researchersdidn’t getanunwinding signalat ClpXP, likehelicaseT7,isringshaped,andpullsproteins incells,butthereare “Proteins aredesignedtobereallystable At theMassachusettsInstituteofTechnology (MIT),HHMI

is forClpXPtoyank protein sections apart. question ofwhatdetermines how hardit thetougher Next, she’lluseittotackle motionoftheunfolding stop–start process. that thetechnique works,quantifying the between thetraps.Sofar,she’s shown surable bydetermining thedistance the protein, the strandlengthened—mea- protein strand inplace.AsClpXPunfolded trap setup.Two trapsheldeither endofa Vanderbilt University, todeviseanoptical cist MattLang, thenatMITandnow at ferent partsofaprotein. at whichClpXPmovesasitunwindsdif- wanted awaytostudytherangeofspeeds once aneighboring bitisunfolded.Baker teins orsectionsunraveleasily, especially whileotherpro- and causeClpXPtostall, or partsofproteins, arehardertounfold move atasteadyrate—someproteins, through itscenter. Butitdoesn’talways So shecollaboratedwithbiophysi- Nature .

Wang: Kevin Rivoli / AP, ©HHMI Bustamante: Andrew Nagata “It’s like trying to analyze a whole bunch of runners going at different speeds. But instead of measuring the speed of each runner, you measure how long it takes until the last runner crosses the finish line.” —Michelle Wang

“We do a lot of biochemistry and a lot of structural studies, details of protein structure can be obtained by x-ray crystallog- and now this is another tool to study this family of enzymes,” says raphy but are not visible under a light microscope; thus optical Baker. “One of the things this protein does is create force, so it’s traps alone do not provide data on structural changes. important to study that aspect of it.” “I’m fascinated by the idea of putting these two worlds of Not all motors in the cell are pulling molecules apart. Some x-ray crystallography and light microscopy together,” says Vale. are vehicles, carrying cellular supplies from one location to “What are the real structural changes that are occurring during another. A neuron, for example, has a long process—the axon— force generation?” that can extend up to one meter. Proteins, membranes, and HHMI investigator Taekjip Ha, at the University of Illinois at chemicals must move rapidly from one end of the axon to the Urbana–Champaign, has developed a technique that offers a way other, requiring a molecular motor. to pair structural data with the force control of optical trapping. In 1985, HHMI investigator Ron Vale of the University of In 1996, Ha developed a method to determine the proximity California, San Francisco, discovered kinesin, the molecular of two fluorescent molecules based on the light they give off. motor that transports materials through neurons on filaments The technique, called fluorescence resonance energy transfer called microtubules. In his early experiments, Vale could watch (FRET), had been around for decades, but he showed that it kinesin moving a plastic bead along microtubules under a micro- could be used on two single molecules, rather than as an aver- scope and later could follow the movement of the motor by age. The fluorescent tags can be attached to two molecules or single-molecule fluorescence microscopy. But in their natural two parts of a molecule. As the two tags come closer together or state, molecular motors of the neuron need to produce a rea- move apart, the fluorescence changes. He uses FRET as a mea- sonable amount of force to drag their cargos through the dense sure of distance, and therefore movement, between any molecules environment of the cytoplasm. Vale found optical traps to be a or parts of molecules. useful tool for studying this force. In a test of the method, Ha collaborated with Pyle to uncover “It’s like learning how an engine works by studying how it per- details of how one particular helicase—from the hepatitis C forms under different loads,” says Vale. virus—unwinds DNA. Its DNA-unwinding function is vital In his latest experiments, optical traps have allowed him to for the virus to make new DNA and infect cells. The scientists push and pull a single kinesin molecule along microtubules attached fluorescent tags to two strands of DNA and attached the and observe how it responds. Unexpectedly, he found that sim- strands to optical traps. As the helicase moved along the double ply pulling on the kinesin causes it to take regular steps along strand, separating it, the researchers could observe the unwind- the microtubule, even in the absence of the chemical energy ing of the DNA, base pair by base pair, as the fluorescent tags that it usually needs to produce movement. He also found that got farther apart. he could pull the molecule backward along microtubules, but The pair discovered that the helicase unwinds three base it takes more force. The difference in the required force pro- pairs at a time, then releases tension in the strand, letting it vides clues about how kinesin works and how it moves in the relax, before unwinding three more. The discovery could help correct direction. them understand how to block the helicase from helping the virus replicate. The Force of Innovation Next, they want to know how much force this unwinding While optical traps have answered some questions posed by biol- takes. So Ha is combining FRET with experiments measuring ogists and given them a way to quantify force in their systems, force. By measuring how the distance between two parts of a pro- the method has also led to more questions. tein changes as a result of force, scientists can get a fuller picture Vale, for instance, now wants to know how kinesin’s struc- of how unfolding or conformational changes happen. ture changes while it’s stepping along microtubules. The atomic (continued on page 48)

February 2o12 | HHMI BULLETIN 17 A

T LI A hands-on scientist with a clear vision, Art Horwich lets nothing stand in the way of his mission.

by Sarah Goforth photography by Mark Mahaney N INTEN- IONAL FE FOLLOW ART HORWICH into his first-floor laboratory at Yale’s Boyer Center for Molecular Medicine, and you will quickly see where status ranks among his priorities. Dressed for comfort in khaki corduroys and a worn North Face fleece, the 61-year-old medical geneticist drops his bag on a cluttered corner desk and reaches for a tray of DNA samples left on the lab bench in an overnight experiment. He grins from behind round wire glasses and an Einsteinian moustache. “I’m a little stunted,” he apologizes as he completes a task normally reserved for students and technicians. “I still function as a postdoc.”

Loathe to distance himself from data, Horwich keeps four micro- his brain to the muscles operating his arms, legs, and lungs. Just a scopes (three dissecting, one confocal) in his small office down couple of months after that game, Gehrig was diagnosed with the the hall. Chin-high piles of manuscripts are stacked against the far neurodegenerative disease that would thereafter be linked with wall; he is on the editorial boards of three scientific journals. Photos his name; he lived just over two more years. of his wife, three grown children, and lab members, along with These days, the prognosis for a patient diagnosed with amyo- a former patient’s yellowed thank-you letter, decorate his bulletin trophic lateral sclerosis (ALS) remains grim. For Horwich, a sad board. What’s missing is any evidence of the many honors he’s reminder of that fact came in 2003 when his children’s beloved received—including the prestigious Albert Lasker Basic Medi- tennis coach began limping on the court and struggled to commu- cal Research Award, which he shared in 2011 with Franz-Ulrich nicate. Like Gehrig at the time of his diagnosis, this man was in his Hartl of the Max Planck Institute of Biochemistry—for his game- 30s and otherwise healthy; he died a year after his ALS diagnosis. changing contributions to our understanding of protein folding. “It really affected me,” says Horwich, whose career has strad- “In science, it’s not what did you do for me 20 years ago, it’s dled clinical medicine and basic science. Having spent decades what have you done for me today,” says a cheerful Horwich, who studying cellular machines called chaperones that help proteins has been an HHMI investigator since 1990. Today his full attention fold properly into their useful forms, Horwich turned his atten- is on a mystery of biology gone wrong that has eluded scientists for tion to a scientific problem with a human face: “Why, in ALS decades and a disease that takes thousands of human lives every and other neurodegenerative diseases, are chaperones failing to year. His goal, pursued with relentless open-mindedness, is nothing do their jobs?” he asked. short of a cure. And so five years ago, Horwich transformed a laboratory dedicated to the biology and kinetics of protein folding—a field THE VIEW FROM THE BENCH in which he is widely recognized as a pioneer—to a multidisci- On a chilly Sunday afternoon in April 1939, New York Yankees’ plinary combat zone against a brutal human disease. “I felt a deep first baseman Lou Gehrig went to bat in the Bronx for the last obligation to go in this direction,” he says. time. Having played a record-setting 2,130 consecutive games, Gehrig’s power and once uncanny aim were fading visibly. He REVISITING A CLASSIC struck out. Inside his body, clumps of misfolded proteins wrecked Although that decision required Horwich to become expert in the nerve cells that for 35 years had faithfully sent messages from disciplines in which he had little experience—mouse genetics,

20 HHMI BULLETIN | February 2o12 stem cell biology, neuroscience—it was also a natural extension family history of the disease to determine whether a fetus carries of his past work. the often lethal mutation. Proteins are made from chains of amino acids that fold in intri- cate, specific ways into three-dimensional structures. The physical CAPTURING A COMPLEX PICTURE shape of a protein, once folded, governs its behavior. The process Horwich established his own lab at Yale and was soon joined by sometimes goes awry, however, and misfolded proteins are asso- Krystyna Furtak, his technical “right hand” to this day, and gradu- ciated with a number of neurodegenerative and other diseases. ate student Ming Cheng. They had learned that to do its job, In the 1950s, American biochemist Christian Anfinsen unfolded OTC must first be delivered to the mitochondria, the oval organ- a protein—a common mammalian enzyme—in a test tube and elles that supply energy to cells. Curious about how this happens, found that it spontaneously refolded into its useful conformation. the group inserted the human OTC gene into yeast. They then His conclusion, and that of most scientists who conducted pro- created mutant forms of the yeast, looking for failures in the OTC tein research in the following three decades, was that proteins pathway that might help them decipher the steps involved. don’t need help from the cell to get into shape. By then it was known that proteins generally can’t enter mito- Horwich was just a boy, growing up in a western suburb of chondria in their bulky three-dimensional forms. To pass through Chicago, when Anfinsen conducted his famous experiment. tiny entryways in the mitochondrial membranes, they must first But he remembers the day he learned about it, the day Anfinsen unfold. Once inside, before they can do their jobs, they must fold received the Nobel Prize in 1972. Horwich was an undergraduate up again. One evening in 1987, after a day of examining mutant at Brown University, having joined the first class of students in a yeast for variations, Horwich and Cheng, looked across the lab program that combined an undergraduate degree with a medical bench at each other and asked a question no one else had: might degree. That evening, he says, “we went to the lab and looked for the OTC protein need help folding after it has entered the mito- every protein we could find to duplicate Anfinsen’s experiment, chondrial chamber? it was so astonishing.” Taken as he was by Anfinsen’s discovery, Anfinsen’s experiment, after all, had been conducted in the Horwich could not have predicted that decades later his own work protected isolation of a test tube; the environment inside a cell is would forever amend it. a cacophony of enzymes, chemicals, and tiny protein machines. Horwich completed medical school, graduating first in his Some of these machines were known to help refold proteins class at Brown, followed by a residency in pediatrics at Yale School under stressful conditions that disrupt their shape, such as heat. of Medicine. He loved the human contact that came with clini- What if such machines were also required for a protein to fold cal medicine but knew the life of a physician wouldn’t satisfy his under normal conditions? Horwich and Cheng decided to look curiosity. Lured by the California climate and a chance to study a for a mutant yeast strain in which OTC made it into the mito- particular virus, polyoma, with Walter Eckhart and Tony Hunter, chondria but didn’t fold properly once there. That, they guessed, he took a postdoctoral research position at the Salk Institute would signal the absence of any such protein-folding machine before returning to Yale in 1981. There, in the lab of Leon Rosen- if it existed. berg, Horwich began his work on a human enzyme—ornithine Within days, Cheng had identified such a mutant, which transcarbamylase (OTC)—that would prove key to overturn- seemed to confirm their hypothesis. Hartl, an expert on how pro- ing the dogma, grounded in Anfinsen’s work, that proteins fold teins are imported into the mitochondria, then at the University on their own. of Munich, heard about these experiments and called Horwich to OTC facilitates the conversion of ammonia to urea in see if he needed assistance on the biochemistry side of the prob- human cells, neutralizing waste. In newborns with a rare, lem. “And of course we did,” laughs Horwich. “We were three X-linked genetic mutation, OTC deficiency can cause ammo- people in a new lab who had little or no experience with yeast nia to accumulate. Seemingly normal at birth, the infants can biochemistry and were stumbling our way around.” fall into a coma within days. Rosenberg, Horwich, and col- Horwich shared the mutant strain, called mif4, and heard back leagues cloned and sequenced the gene responsible for OTC, from an excited Hartl two weeks later. “He said, ‘you’re absolutely ultimately developing a genetic test that allowed patients with a right,’” remembers Horwich. “His work suggested that whatever

February 2o12 | HHMI BULLETIN 21 was going wrong with this mutant, it had something to do with cell dies. The scientists named the complex a chaperonin and polypeptide chain folding inside the mitochondrial matrix.” placed it in a class of proteins—called chaperones—believed to The mutation carried by this strain, it turned out, was in a assist other proteins in their tasks. gene that encodes a mitochondrial protein whose production “From the time of Anfinsen we thought that proteins fold is amped up when cells overheat—one of the class of protein and that’s all there is to it,” says Richard Lifton, an HHMI machines thought to help refold proteins under stressful condi- investigator and Horwich’s department head at Yale. “Art’s work tions. For that reason it had been dubbed heat shock protein 60, completely overturned that paradigm because actually, no, if or Hsp60. Versions of this protein are found in nearly every cell of you didn’t have these chaperonin machines, the proteins would every organism in the world. The surprising thing was that Hsp60, come crashing down.” in Horwich’s mutant yeast, appeared necessary for protein folding Anfinsen’s principles, Horwich hastens to point out, were alive under normal conditions. and well throughout these experiments. Horwich’s belief has The notion that Hsp60 could be necessary for protein folding always been that chaperonins facilitate a process that happens provided “enormous focus” for the group, according to Wayne quite naturally by creating a sheltered “changing room” for pro- Fenton, a senior member of Horwich’s lab. The researchers teins much like Anfinsen’s test tube. probed a related protein found in bacteria, called GroEL, from every angle possible to understand how it worked. “If we didn’t AN OBLIGATION TO EVOLVE have the tools or the skills to answer the question we needed to Horwich and his collaborators still study GroEL—most recently answer, then we figured someone else did and we found a col- using electron microscopy with Saibil and collaborators in laborator,” says Fenton. “Usually they would teach us a thing or California to capture images of proteins moving through the two, and we’d say, ‘hey, this isn’t so hard,’ and then start doing it machine—but with the larger mystery of its structure and func- ourselves. Art and I share that point of view.” tion solved, the ALS work now occupies most of his time. “In whatever direction the project needs him to go to become expert, he does that. It’s one of the hallmarks of a great scientist, following the trail wherever it leads.” RICHARD LIFTON

A biochemist by training, Fenton was a research scientist “While we were busy trying to understand the mechanism of in the Rosenberg lab at Yale when Horwich joined as a post- chaperones,” Horwich says, “a whole industrious group of people doc. He ran his own lab for a time but lacked patience for the was learning that many common neurodegenerative diseases are administrative duties that came along with being a principal associated with protein misfolding and aggregation. It was shock- investigator. When Horwich established his own lab, sights set ing to see that a number of these aggregates are occurring in the on OTC, Fenton joined up and has been working at Horwich’s cytosol—the cell’s watery interior—where there should be a good side ever since. Both avid sailors, the two men are friends as well supply of chaperones.” as colleagues. In ALS, the aggregates form almost exclusively in the spindly In the 1980s and early ’90s, Horwich, Fenton, Cheng, and motor neurons that extend down the body’s limbs and operate the a growing group of collaborators focused their attention on muscles. Despite years of study, no one knows why this happens GroEL. In a painstaking three-year effort with Yale crystal- or whether the aggregates are a cause or a symptom of the disease. lographer Paul Sigler, who died in 2000, the group elucidated Tackling those questions requires the kind of experimental open- GroEL’s molecular structure by x-ray crystallography. Working ness Horwich is known for. “We just have to look at it at all levels,” with Helen Saibil at Birkbeck College in London, the team he says. “Electron microscopy, light microscopy, whole animal, captured further details of the machine in various states via embryonic stem cells if they’ll work, genomics.” electron microscopy. On a given day, you might find Fenton bent over a microscope, Snapped together in the cell with a protein cap called GroES, his long white beard dangling as he examines fledgling motor the GroEL complex is shaped like a hollow bullet whose tip pops neurons cultured from stem cells. In the next room, postdoctoral on and off to chauffeur in unfolded proteins and close them off researcher Urmi Bandyopadhyay might be examining a spinal from the cellular environment. Safely inside, the proteins fold on cord cross-section from a mouse in the last stages of the murine their own, as Anfinsen predicted. But without GroEL, the pro- equivalent of ALS. She guides a fine laser to cut out and capture, teins clump together before they have a chance to fold, and the for further study, the protein clumps associated with the disease.

22 HHMI BULLETIN | February 2o12 Mark Mahaney to explaintherole ofgeneticsinsporadic forms ofthedisease. tions ofgenomesALSpatients. Indoing so, thescientists hope With Lifton,Horwichisalsosequencing theprotein-coding por- as aresultofthemutationassociated withthe disease isanother. that Horwich’s labispursuing.Pinpointing thefunctiongained abundant isoneofthemanyquestions intheoverallALSpuzzle animals survive. function, notthelossofone:deletegeneentirely, andthe appearstocauseagainof inside motorneurons.Themutation ALS inhumans,including partialparalysisandclumpedproteins properly andcausesfeaturesofdisease likethoseassociated with mutant formoftheSOD1protein, calledG85R,thatcannotfold precise role in ALSisunknown. Horwichbredmice witha for roughly1percentoftheproteins inacell’s cytosol—whose members ofwhichhavebeenbredtoexpressmutationsin He beginseverydaybycheckinginonhismousecolony, many of them,called with familial formsofALS,andHorwichhashomedinonone the next.Scientists haveidentifieda number ofgenesassociated 10 percentofcasesarefamilial, inheritedfromonegenerationto ily oftheaffectedpersonhasnohistorydisease. Butroughly of thebuilding nextdoor,making hisdailyrounds. If it’s early inthemorning, Horwichcanbefoundinthebasement MAKING THEROUNDS hands intheworkatlabbench. boards ofthreescientificjournals—hestillmakestimetokeephis Though ArtHorwich hasafullschedule—he’s ontheeditorial How ananimal couldsurvivewithoutaprotein normallyso The Most ALScasesinpeoplearesporadic, meaning thatthefam- SOD1 genecodesforanabundantprotein—it accounts SOD1 , tostudyamousemodelforthedisease. SOD1 . my group.” going tocomework.I’mstillgoing totinkersideby with trying thishugethingthatwe’re ornot,I’mstill tryingtotackle thing wecantrack,” hesays.But“whetherwe’re successfulat able toseeananimal whosedisease improvesbecauseofsome- characteristic optimism isonfulldisplay. pleted inasingleday, theworkismaddeningly slow. Still,his accustomed toexperimentsthatcouldbeconceived andcom- a viabletreatment.For Horwich,whointheGroELdaysgrew clump together. to capturefree-floatingunfoldedproteins that might otherwise their production ofchaperoneproteins, amplifyingtheir ability He isalsoexploringwhetherit’s possibletogetcellsrampup variations inthe therapies;inothers,heisinvestigatinghow with experimental still bealive,” hesays.“Thatwouldbethedream.” process associated withaggregationoftheseproteins, hewould limpingwehadknown whattodoarrestthe coach firststarted not shyabouthisultimategoal.“If,whenmychildren’s tennis hallmarks ofagreatscientist, following thetrailwhereveritleads.” needs himtogobecomeexpert,hedoesthat.It’s oneofthe mission hasbeen,” saysLifton.“Inwhateverdirection theproject “I keepgoing inthemouseroomandhoping thatwewillbe It’s toosoontosaywhetheranyoftheseapproacheswillyield To thatend,Horwichhastreatedsomeofhismutantmice But beyondelucidating thebasicbiologyofALS,Horwichis “There hasn’tbeenalotofambiguityinArt’s labastowhatthe W SOD1 geneaffecttheprogressionofdisease. February 2o12

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BULLETIN 23

by Dan Ferber illustration by Josh Cochran Science and math teachers need to be relentless learners to keep up with the science and effective teaching principles. PART 2 OF 2: This article focuses on in-service training—professional development for teachers once they are in the classroom. Part 1 of the series, on preservice training for college students and graduates who intend to be STEM teachers, appeared in the November 2011 Bulletin.

teaching high school and middle school science, Wendy Bramlett teachers already in classrooms, and the 1.5 million elementary had taught every topic in the book. No joke. school teachers who teach some science and math? They’re “I used to think you had to cover every concept in the text- going to have to raise their game. book,” says Bramlett, a science teacher at Tuscaloosa Magnet For that they’ll need good professional development. It’s no Middle School in Tuscaloosa, Alabama. Her students would duti- easy task, however, for trainers to change teachers’ practices fully regurgitate the information on tests. enough to improve student learning, says Deb Felix, senior pro- Laboratories, when she could afford them, were low-tech gram officer for HHMI’s precollege science education initiatives. affairs. She taught mitosis by giving her students pipe cleaners to Good programs help teachers acquire a firm grasp of modern model chromosomes in a dividing cell. Often she just did what scientific techniques and the teaching methods they need to she calls “pencil and paper” labs, in which students plodded enable their students to learn through inquiry. They also cre- through problems in a workbook. “For the students it was boring. ate opportunities for teachers to test and refine new lessons and Science wasn’t one of their favorite subjects,” Bramlett says. carve out ample time for training, mentoring, and peer support— “It really wasn’t fun for me either,” she adds. often despite tight and shrinking training budgets (see sidebar, Then Bramlett got some training. She enrolled in the Alabama “STEM Teaching 2.0”). A mix of large nonprofit agencies, uni- Math, Science, and Technology Initiative, an extensive, state-run versities, states, and school districts are incorporating these tested teacher training program for science and math teachers aimed at approaches. The work they’re doing is beginning to pay off. boosting student performance. Bramlett took advantage of every aspect of the program: She completed a two-week workshop two LOTS OF OPTIONS, NOT ENOUGH TIME summers in a row, connected with a science-teaching mentor, U.S. schools invest 1 to 12 percent of their budgets on staff pro- and began borrowing modern laboratory equipment and teach- fessional development, according to Learning Forward, a trade ing her students how to use it. Her teaching—and her students’ group for teacher trainers. This spending creates a huge market learning—turned around. for teacher professional development, and there is no shortage of Today only about one-third of eighth graders in the United organizations that offer it. School districts often develop and run States show proficiency in math and science. Several standard-set- their own programs, sometimes with advice from companies and ting groups have taken action to boost U.S. performance in science independent consultants. Universities, colleges, medical schools, and math. Last summer the National Research Council outlined and museums hold summer workshops and develop teaching new science teaching standards that lean heavily on inquiry-based modules. Some companies sponsor programs for teachers, such as learning. The College Board has overhauled the Advanced Place- Intel’s Thinking with Technology course. Nonprofit organizations, ment Biology curriculum to emphasize scientific inquiry and such as WestEd and the National Science Teachers Association reduce the emphasis on rote memorization. And 45 states have (NSTA), offer workshops and online programs for teachers, some adopted the Common Core State Standards for Mathematics, a of them supported by federal funds. “Anybody can get into this mix state-led initiative that raises the bar for K–12 mathematics educa- who can sell it,” says Julie Luft, a science education researcher at tion. These efforts are built on an education research base that the University of Georgia and former director of research at NSTA. says students understand science better by doing it and they learn Still, most teachers receive far less training than they need, math best by applying it to real-world problems. and not by choice. More than half of U.S. teachers are offered Educators and funders are revamping preparation of prospec- at most two days of paid professional development per year from tive teachers (called preservice training) to help them learn how their districts, according to a large 2003–2004 survey by the U.S. to teach in these new and more effective ways (see “Calling All Department of Education. More than half of science teachers Teachers,” November 2011 HHMI Bulletin). But what about surveyed by NSTA in 2009 said they wanted more. In many the nation’s 250,000 middle and high school science and math school districts, professional development is limited to a single

26 HHMI BULLETIN | February 2o12 Rob Culpepper son’s teamreportedin2010 34 percentpassrateamongstudentsofthecontrolteachers,John- passed theOhioGraduationTest ontheir firsttry,a comparedwith had learnedfromthespecially trainedmiddle schoolteachers the effectslasted.In10thgrade,88percentofstudentswho them,” Haroldsonrecalls. that seemedtohaveaprofoundimpacton that theywereweakening it[with drugs], thought abouttheir brainasamuscle and endogenous cannabinoids. “Whenthey lobesandhow marijuanamimicsfrontal alcohol affectsdecision makinginthe to yourbody?Thestudentslearnedhow adrug,whatdoesitdo drug? Ifyoutake them investigatequestions like:Whatisa they studied neuralsignaling,shehad model neuronsfrombeadsandstringas brain. Andafterherstudentsassembled how itcomparedstructurallywithahuman were dissecting asheepbrain,exploring high schoolscience teachers,herstudents completed BrainU’s partnerprogram for classroom,” Roehrigsays. really transformativeintermsofhow they’re usinginquiry inthe Science Teacher Education.However, “afterthesecondyearit’s Dubinsky reportedatthe2011conferenceofAssociation for teachers adoptedthemethodsimmediately afterthefirstyear, the impactofcurriculum,calledBrainU, theyfoundthatthe roscientist tested JanDubinskyoftheUniversity ofMinnesota Whenscience educatorGillianRoehrigandneu- Minnesota. curriculum wasabighelpformiddle schoolscience teachersin how scientific inquiry works. Butmanyare inquiry, teachersmust firstunderstand To helpstudentslearnscience through HONING SCIENCESKILLS 2007 inthe dents ofuntrainedteachers,Johnsonandcolleaguesreportedin knowledge andreasoning. Theyscored50percentbetterthanstu- team gavetheseventh-gradersa29-point testtogaugescientific of instructionbythesenewlytrainedscience teachers,Johnson’s school inthesamedistrict withnosuchprogram.Aftertwoyears tice it.Their studentswerecomparedwithatamiddle which trainersmodeledeffectiveinstructionandletteachersprac- fessional development,including monthlyin-schoolsessionsin where allscience andmathteachersreceived comprehensivepro- Cincinnati, andtwocolleaguestrackedstudentsatamiddle school real difference forstudents.CarlaC.Johnson,oftheUniversity of When doneright,however, professionaldevelopmentcanmakea SEEING STUDENTSBENEFIT yet districts keepdoing them,shesays. Felix points out.Theseworkshopsaretooshorttobeofmuch use, workshop. “Theygetadayrightbeforetheschoolyearbegins,” That wasRachelleHaroldson’s experience.Ayearaftershe Two summersoftraining inaninquiry-based neuroscience Journal ofResearch inScienceTeaching School ScienceandMathematics shifted fromlectures tohands-onlessons—andher students’sciencescoressoared. Spurred byworkshops,mentoring, andaccesstoequipment,AlabamateacherWendy Bramlett . What’s more, . the state,” shesays. we gobacktotheclassrooms,findtheseinquiry boardsallover teacher’s homeschool,oftenbringingequipment tolend.“When results, lookingforpatterns,andanswerstheoriginalquestion. predicted outcome.Afterthestudy iscompleted,theclasstabulates setup,andthe the variablestotest,controls,experimental on aneight-section posterboardastheclassbrainstormsaquestion, tion usingatoolcalledaninquiry board.Theteacherrecordsideas They trainteacherstowalkstudentsthroughascientific investiga- studying lentilseedgermination, orobservingfruitflymatingrituals. materials—for example,testingtheadhesivepowers ofslug slime, ers how tocreatesimpleinquiry-based lessonswithreadily available enough togetthemexcited aboutscience,” Wakimoto says. dents foroneperiodaday, theseteachers“arewithstudentslong teachers because,unlikehighschoolwhoseetheir stu- andmiddle school K–8 teachers.Theyfocusonupperelementary summer lifesciences teachinginstitutefor20Washington State a hugeresourceforfutureteachers.” with scientists, whocanhelpdevelopthosetools,andtheybe teacherscanbetheprincipal partners their teaching. In-service excellent waysforin-serviceteacherstobuildmoreinquiry into director. “The community ofscientists, inparticular,canprovide David Asai,HHMI’s undergraduatescience educationprogram involve scientists aswellpreserviceandin-servicetraining, says science educationrequires amultifaceted strategythatshould ing theresearchexperienceandinquiry-focused approach.K–12 Wakimoto oftheUniversity ofWashington inSeattle. biologistBarbara which theyweren’ttrained,saysdevelopmental especially inmiddle schools—theymaybeteachingasubjectfor simply notuptospeed.Theymaylackresearchexperienceor— Wakimoto’s colleaguesfollow upbyvisitingeachparticipating Wakimoto andprogrammanagerHelenButtemershow teach- Wakimoto andtwocolleaguesrunanintensivefour-week Scientists, likeWakimoto, roleoffer- canplayanimportant February 2o12

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BULLETIN 27 High school teachers need the hands-on experience as well. students assist with school science days, encourage kids to enter In Louisiana, for example, many teachers are certified to teach science fairs, and help students envision getting a science, tech- high school biology or chemistry with just a smattering of college nology, engineering, and mathematics (STEM) degree, even if courses in the subject. They “have a working knowledge of the no one in their family has gone to college. discipline, but they have no lab skills and no research experience The ULM workshop “gets teachers excited about teaching sci- as an undergraduate with respect to how science is really done,” ence,” Grover says. Students, too. The program has trained more says Ann Findley, a biology professor at the University of Louisi- than 500 students since it launched in 2000. Ninety-five percent ana at Monroe (ULM). of them go to college, according to years of follow-up surveys, and To build their laboratory skills and confidence, each summer many major in science—no small accomplishment in an area Findley and her colleagues invite eight Louisiana high school with many schools like Richwood High School, where fewer than teachers and up to 60 of their students for an HHMI-sponsored half of the students’ parents attended college and about 90 per- month-long summer science workshop. The teachers and cent of students qualify for a free or reduced-price lunch. “You students work together through four successive one-week investi- look at the poverty rate, and the area surrounding the school, and gations, each in a different field of biology. “You might be tagging there’s nothing in the community [for the kids] to look forward DNA with fluorescent dyes this week, and next week you may be to,” Grover says. “So if you find something to light their fire, man out seining in the bayou to get the biomass of life in an aquatic you just want to keep that fire going.” environment,” says Brenda Grover, science chair at Richwood High School in Monroe and a workshop veteran. “Then you PEER SUPPORT might move to geography, looking at satellite views of our area.” Peer coaching helps teachers shift their focus from what teach- Teachers learn best how to lead inquiry-based lessons by ers are teaching to what students are learning. An HHMI-funded working through them, according to research on professional program run by Occidental College in Los Angeles uses peer development. Findley and her colleagues advise teachers privately coaching in a method called Lesson Study. The college runs about how to turn workshop exercises into lessons that will benefit summer workshops in biology, chemistry, and physics for middle their students. They also challenge teachers to prepare supplies and high school teachers in the area, and they employ two sci- and solutions for an exercise and discuss how to troubleshoot it. ence educators who visit schools and coach teachers throughout During the school year, the ULM team lends financially the school year. strapped high schools trunks with PCR machines, microscopes, Robert de Groot is one of those science educators. He super- centrifuges, and other equipment and supplies. Findley and vises Lesson Study at Jerry D. Holland Middle School in Baldwin her students act as science ambassadors to the 20 participating Park, California, where six science teachers take turns teaching schools, modeling a culture of science for teachers and their one of three inquiry-based science lessons. While one teaches, students. Undergraduate biology majors help less-experienced the other teachers and de Groot observe the students’ reac- teachers run lab investigations. Findley and biology graduate tions. They note how well kids follow lab procedures, collect and report data, grasp scientific concepts, and use scientific vocabulary. Afterward, the teachers meet, discuss how the les- son can be improved, and offer tips to their colleague. Then STEM TEACHING 2.0 the teachers switch roles; another teacher in the group teaches the revised lesson, and his or her classroom becomes the teach- Education researchers say they ing laboratory. have enough data to know what makes for Chris Craney, a professor of chemistry at Occidental who supervises their science outreach program, reported in the Journal good professional development. of Chemical Education in 1996 that the program increases stu- dent interest in science as well as chemistry and biology teachers’ • MODEL EFFECTIVE TEACHING knowledge of scientific topics. And inquiry-based laboratories taught by the newly trained teachers significantly improved stu- • BE IN-DEPTH AND SUSTAINED dents’ understanding of chemistry, biology, and physics concepts, according to the Occidental team’s unpublished assessments of • LET TEACHERS HELP TEACHERS 3,000 students before and after the labs. • DEVELOP TEACHER LEADERS Although Lesson Study keeps the focus on student learning, where it belongs, it’s expensive because substitutes must cover for • GET SYSTEM SUPPORT the teachers who are observing, says Roehrig. As co-director of Minnesota’s Math and Science Teacher Partnership, a statewide • DON’T FORGET ESTABLISHED TEACHERS professional development program for K–12 science and math teachers, Roehrig instead fosters what educators call “professional To learn a little more about each of these ideas, visit learning communities.” Science and math teachers are allowed WWW.HHMI.ORG/BULLETIN/FEB2012. paid time to meet at the school after hours to discuss what worked in the classroom and how they can improve next time.

28 HHMI BULLETIN | February 2o12 One common strategy is to appoint as a mentor a more experi- enced teacher who covers the same subject and grade level. NSTA and the National Council of Teachers of Mathematics have called for more intensive induction programs in which competent, expe- rienced science and math teachers mentor novices. But “there are actually very few” good induction programs, says NSTA’s Eberle. Roehrig runs one of them, an induction program for middle and high school STEM teachers in Minnesota. Mentors and new teach- ers in the Teacher Induction Network can hold video chats using Skype-like technology, share lesson plans via Google Docs, or take part in virtual classroom observation. Rookies videotape themselves teaching, post the video, and then peers and mentors use video annotation technology to comment on the teacher’s interactions with the students. “It’s as good as, if not better than, being in a class- room,” Roehrig says. And it makes effective mentoring possible even when the beginning science teachers work in northern Minnesota, hundreds of miles from her university’s Minneapolis campus.

Louisiana biology professor Ann Findley trains high school teachers SCALING UP and offers on-site support to build a culture of science at their schools. With budgets tight everywhere, district training programs have to do more with less. Anita O’Neill supervises professional development Teams of science teachers can also help develop an inquiry- programs in science, technology, and engineering for Montgomery based curriculum. Ninety-six middle school science teachers from County Public Schools in Maryland, a district with 200 schools Loudoun County Public Schools in Northern Virginia collabo- and about 600 teachers at each grade level. In 2006, she and proj- rated with faculty at Penn State College of Medicine in Hershey, ect manager Mary Doran Brown began building a district-wide Pennsylvania, over five years to develop an inquiry-based middle cadre of teacher leaders to help train their elementary school peers school science curriculum. When that HHMI-funded program to teach science better—and they are moving it online. ended in 2008, about a dozen of the teachers began meeting They recruited prospective teacher leaders from 90 of the each summer to update and expand the curriculum, which now district’s 131 elementary schools—not all of them, as they had underlies middle school science instruction countywide, and hoped. Then, with HHMI support, they trained those teachers to to design HHMI-funded training programs for their colleagues help colleagues at their respective schools teach inquiry-based sci- around the district. Now “the teachers own the program,” says ence lessons. At some elementary schools, the teacher leaders got Odette Scovel, the district’s K–12 science supervisor. their colleagues to take students to annual “inquiry conferences” at a local college. There, the students presented a science project HELP FOR ROOKIES to their peers and fielded questions from them, just as practicing Peer support is particularly important for new teachers, who strug- scientists do at a scientific conference. The program lasted four gle to get the hang of content and lesson plans as well as issues years until the district’s budget tightened in 2010. that more experienced teachers have mastered, such as how to To affordably reach the district’s throng of elementary school manage their classrooms and deal with student misbehavior, says teachers, O’Neill’s team enlisted its teacher leaders to help move Francis Eberle, president of NSTA. In the past, fledgling teachers the training online. At a summer workshop, teacher leaders from were often tossed into the classroom to sink or swim. That still elementary and middle schools learned to videotape a lesson, happens, but today more school districts try to ease their transition edit the video, and then post it as an example of effective teach- into the job, a process educators call “induction.” ing. Ultimately, O’Neill’s team wants an interactive website for It’s important that induction for new science teachers focus on all K–12 teachers that allows them to review the district’s sci- teaching science, and not simply teaching, according to research by ence, technology, and engineering curriculum and plan lessons Luft and Roehrig. Teachers in science-specific induction programs or learn inquiry-based teaching in line with national standards. use more inquiry-based lessons than those in general induction pro- “Our vision is a professional learning community,” O’Neill says. grams or those who’ve had no induction at all, the two reported in To change science and math teaching nationwide, though, 2003 in the Journal of Research in Science Teaching. And teaching there’s really no substitute for investment. And no state has habits acquired early often last. Those first years are “when teachers invested as much as Alabama. Thanks to an enthusiastic state are really forming who they’re going to be as teachers,” Roehrig says. superintendent and a powerful booster group that included lead- And beginning science teachers still need strong support during ers of the state’s high-tech businesses, Alabama has invested up to their second year, according to Luft. Otherwise they’re apt to revert $46 million per year in the Alabama Math, Science and Technol- to the easier but less effective methods that rely on lectures and ogy Initiative (AMSTI), says Steve Ricks, who directs the program textbooks, her group reported in 2011 in the Journal of Research at the state’s education department. AMSTI employs 850 teacher

Misty Keasler in Science Teaching. (continued on page 48)

February 2o12 | HHMI BULLETIN 29

WHERE DOES IT HURT?

Researchers are getting to the molecular details of pain’s circuitry to answer the question with real specificity. BY MARC WORTMAN | ILLUSTRATION BY SAM GREEN Neuroscientists often use natural signals running along a complex, inter- ingredients—like menthol, capsaicin, and connected neural perception system wasabi extracts—that stimulate nerve cells geneti cally encoded to detect and respond to react just as they would in response to to painful stimuli. painful cold and heat, for example, or The body detects and converts pain to inflammation and chemical irritants. stimuli into electrical signals at the fine Drawing on electrical recordings, imag- nerve endings of “nociceptors,” sensory ing, molecular techniques, mouse models, neurons specialized to respond to pain. and genetic studies, scientists can explore Their axons, which conduct electrical the nervous system as it reacts to “pain” signals, are only a millionth of a meter at the subcellular level. Their studies in diameter but can be more than a have revealed many molecular pathways meter long, with one end located where that regulate pain perception, including a stimulus is detected—at a fingertip, for specialized ion channels that open and example—and the other end in the spinal close to send pain signals along nerves to cord, where it forms a synapse, or com- the spinal cord and brain. They have also munication junction, with a second cell begun to explain the systemic changes in that sends the signal to the brain. The response to pain sensation that can cause nociceptor’s spinal synapse is highly sensi- chronic disorders. tive to opiates and other agents that can shelves in david julius’s lab at the HHMI scientific officer Ed McCles- alter pain perception. The cell bodies of THEUniversity of California, San Francisco, key, who spent much of his research career nociceptors and other sensory neurons could be confused with those in a tradi- studying pain, believes such progress sit just outside the spinal cord in clumps tional herbal medicine shop. They hold will translate into health care benefits. “We called dorsal root ganglia; action poten- bottles labeled “menthol extract” and have been using more or less the same tials—short-term changes in electrical “capsaicin,” the substance that gives heat aspirin and morphine variants for centuries charge—pass through the ganglia on the to hot peppers. The eye-watering scents now. But a wave of recent basic science way to the spinal cord. of Szechuan peppers, wasabi, and herbs discoveries has begun to transform the To convey signals from a peripheral waft through the air. They might seem pain field, and they are already yielding organ to the spinal cord, the axon depends unlikely tools for one of the world’s most insights for finding new ways to treat pain.” on a variety of molecules. Some convert advanced neurobiology pain research a physical or chemical event into a small centers, but Julius uses this trove of natu- THE MANY TYPES OF PAIN electrical signal at the peripheral nerve ral ingredients to probe the molecular Aspirin and opiates work just fine for ending; others amplify the signal and send world of pain. most of us most of the time. But plenty it along the length of the axon. Molecules Neurologists and pain specialists long of people don’t benefit from either drug at the synapse convert the electrical signal struggled to prove that controlling pain or can’t handle their serious drawbacks, into a chemical signal, triggering release can speed a patient’s recovery after sur- which range from stomach irritation and of a neurotransmitter that activates the gery or an injury and that people with excessive bleeding to addiction and respi- postsynaptic neuron. Other molecules chronic pain have a genuine malady ratory suppression. The devastating daily tune transmission of pain signals. Vari- that’s not “all in their head.” Today the reality of uncontrolled chronic pain far ous types of ion channels—proteins that biomedical world recognizes that pain exceeds the ability of today’s medicines to create pores in cell membranes—serve is a real and pressing health care issue help. Every year, at least 116 million adult as detectors, amplifiers, and electrical-to- that needs improved diagnosis and more Americans experience severe chronic chemical translators, while receptors for effective treatments. Until about 15 years pain—more than the number affected by hormone-like molecules modulate the ago, though, researchers could study heart disease, diabetes, and cancer com- activity of the channels. pain based only on patient behavior and bined—at a cost of $560 billion annually in When everything works, the pain sys- subjective responses to questions about direct medical expenses and $635 billion tem triggers behaviors that lead us to flee “where” and “how much” it hurts. As a in lost productivity, according to a June danger or to rest and recover from an result of emerging molecular findings, 2011 report from the Institute of Medicine. injury. But it doesn’t always work right. new pain medications and diagnostic tools Researchers today recognize several In chronic pain, for instance, signaling are being developed. pain subtypes, which develop via electrical can become hyperactive so that even the

32 HHMI BULLETIN | February 2o12 Paul Fetters to dullpain. target anMrgreceptorthatappears scientist, istestingcompounds that Xinzhong Dong,anHHMIearly career exploring thevarietyofsodium-selective at NewYork’s StonyBrookUniversity were leagues SimonHalegouaandPaul Brehm and Science University, andhercol- HHMI investigatorattheOregonHealth related topainsensation. avalanche ofdiscoveries ofion channels age. Thepasttwodecadeshaveseenan transiently altersthecell’s membrane volt- membrane createsanelectriccurrentthat The movementoftheseionsacrossa calcium, andanegativeion,chloride. positive ionsofsodium,and potassium, the passageoffourtypeschargedatoms: Nerve cellionchannelsselectivelyallow PAIN CHANNELING inflammatory pain,andfibromyalgia. disorders, suchasneuropathy, chronic in somemysteriousandhard-to-treatpain apses dangerouslyhyperactive,asoccurs central sensitization,makesnociceptor syn- describe how thismalfunction,known as son. Researchershaverecentlybegunto electrical signalsfirefornoapparentrea- lightest touchhurtsor,inextremecases, In the1990s,GailMandel,now an “WE HAVE BEEN USING MORE OR LESS THE SAME ASPIRIN AND MORPHINE VARIANTS ASPIRIN AND SAME FOR ies usingnatural ingredients tosimulate also providedamodelforfuture painstud- in peripheralnociceptors. Thatdiscovery specifically activatestheTRPVchannel icin todemonstratethatburning heat “trip-vee”) channels.Julius usedcapsa- receptor-potential vanilloid (TRPV, called subfamily of ion channelscalledtransient perception emanatingfromoneamonga colleagues publishedfindings aboutpain found thesodium channel,Julius and cines From UndertheSea”). suppress pain(seeWeb Extra,“Pain Medi- compounds tocontrolNav1.7asaway pharmaceutical companies aretesting some otherkindsoftissuedamage.Afew are profoundlyinsensitivetoburnsand causes araredisease inwhich patients mutation thatdiminishes Nav1.7activity ing nociceptors Another hyperexcitable. that increasesNav1.7activity, render- sory stimulus, iscausedbya mutation feel severeburning painwithoutanysen- disease inwhichpatientsperiodically port theidea.Erythromelalgia,arare role inpainperception. the researcherstheorizedthatitplaysa From thechannel’s location anddensity, which isabundantonsensoryneurons. a sodium channel,now calledNav1.7, an axon.In1997,Mandeldiscovered that canconductforlongdistancesalong electrical signalsintoactionpotentials act asmolecularamplifiers,turning small channels inmammals.Sodium channels BASIC SCIENCE DISCOVERIES HAS BEGUN TO CENTURIES NOW. BUT AWAVE OF RECENT NEW WAYS TO TREAT PAIN.” FINDING YIELDING ALREADY INSIGHTS FOR THE PAINTRANSFORM FI The sameyearthatMandel’s group Human geneticstudies strongly sup- ELD, AND THEY ARE ARE THEY ELD, AND to irritations and allergies. andallergies. to irritations TRPA1, andotherTRPchannels,leading insecticides thatactivateTRPV3,TRPV1, mon plantcompoundsusedasspicesand sensitivity. Hislabalsoidentified com- in controllingsomeaspectsoftemperature major organs,andshowed itsinvolvement family, TRPV3,foundintheskinandother a memberofthehumanvanilloid TRPsub- in avarietyofsensations.Hecharacterized studies thechannels,lookingat their roles Boston andHarvardMedical School,also ion channelexpertatChildren’s Hospital HHMI investigatorDavidClapham,an interconnected rolesinsensoryperception. acterized severalTRPchannelsandtheir of otherfindings. painful stimuli, opening thedoortoahost is testing compounds that target thisMrg is testingcompoundsthattarget receptors, whichhelptodullpain. Dong like thebody’s naturallyoccurringopioid itch sensation,oneappearsto function Mrgreceptorsfunctionin while certain School ofMedicine, hasshown that early careerscientist atJohnsHopkins sensory neurons.Dong,now anHHMI Mrg receptorsarefoundexclusivelyin at theCalifornia InstituteofTechnology. his colleagues,including XinzhongDong, HHMI investigatorDavidAndersonand of Mas-relatedgene(Mrg)receptorsby began withthediscovery ofthefamily A majornewdirection inpainresearch RECEPTORS TODULL PAIN Since then,Julius andothershave char- ED MCCLESKEY ED February 2o12 (continued onpage 48) | HIBULLETIN HHMI 33 F;HIF;9J?L;I

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Jeffrey Kieft INSPIRED TO SERVE EASING THE CONFLICT BETWEEN FAITH AND EVOLUTION Matt Nager

34 HHMI BULLETIN | February 2o12 Jeffrey Kieft has always been willing to step out of his comfort zone to make a difference. The HHMI early career scientist attended West Point and served as an army tank platoon leader in Mannheim, Germany. Then he worked as a policy fellow at the White House. Now, in addition to running his University of Colorado lab, he engages church groups on the theory of evolution. He’s driven to advocate for science.

I think the scientific community has to be careful that we wolves. If you understand that, then you understand a key don’t adopt the attitude that science belongs to scientists. part of what Darwin proposed. We need the public to see some connection to their lives. People also love hearing about vestigial structures—for The discoveries that we make really do belong to everyone instance, the fact that when you get scared, your hair stands and should be communicated. I don’t see this as service out- on end. That’s a vestige of our ability to puff up and look side of my job but rather integral to the job. bigger—that is, if we still had fur. We are still carrying in our When I started as an army officer, I naively thought my bodies evidence of our lineage. goals matched those of all of my subordinates. I learned that I never serve up a watered-down version of evolution, and everyone is motivated by different things. Motivating diverse I am clear that intelligent design is not science and is logically people became a challenge I enjoy—in the lab and when I flawed. But I show people than none of this requires them to speak with the public. give up their faith. Evolution is a ‘How did it happen?’ story, During a AAAS policy fellowship in the White House not a ‘Who dunnit?’ Office of Science and Technology Policy, I got a bird’s eye I respect the view of a friend who is a pastor in Iowa. He view of science. I saw that the public and policymakers don’t says his faith is enhanced by a God clever enough to think up necessarily understand how science works. Many don’t see evolution. Some people are not placated, but if they go home it as an investment in the future. That experience made me and think about it or talk about it around the dinner table, eager to speak at places such as church forums, Cafe Scienti- then I’ve had a positive influence. fiques, and community colleges. For me, talking to the public And sometimes people ask questions that send me home satisfies that itch to get science’s voice out there. When I read thinking. Once, a woman asked, “If we are all evolved from something in the newspaper or hear something that is an common ancestors, us and gorillas and fruit flies, and I believe obvious misunderstanding or misstatement about science, I that humans have a soul, then when did the soul evolve?” I can’t not do something about it. gave her the standard answer that science could not answer But I don’t get confrontational. When speaking to a church that. She replied, “But if my faith says I have a soul and the group, for example, I don’t gear myself up for a debate. My fruit fly doesn’t, and if we both came from the same thing bio- goal is to find some common ground and move the discussion logically, how is that not in conflict?” That made me realize forward. I say, let’s examine evolution and see if it really must that, for some people, it is really hard to separate evolutionary conflict with religion. I cover the basic tenets of evolutionary theory from their faith. theory and, even more importantly, what evolution is not. I’ve But, even with this challenge, if we as scientists don’t been asked, “Isn’t the first rule of evolution that there is no step out and say something—even in little bits and pieces God?” I reply, “Well, no actually, that isn’t in any science text- and in small forums—then we’re shooting ourselves in the book.” Just teaching these basic concepts puts people more foot because the misinformation and antiscience voices at ease because they’ve never learned what evolution means. win by default. To explain a concept like natural selection, I start with a story that everyone can understand. Imagine a valley where rabbits live with few predators. Then wolves move in and that pressure selects for survival and reproductive success of rabbits INTERVIEW BY KENDALL POWELL. Jeffrey Kieft studies with certain genes, such as those that make them faster. Over RNA structural biology at the University of Colorado Denver time the rabbit population adapts to become better at evading School of Medicine.

February 2o12 | HHMI BULLETIN 35 36 HHMI

BULLETIN “I likethemovie directed byafellow Kiwi.” information. Plus,itwas about personalgenetic introduce ethicalissues It’s wayto anentertaining many humangenomes. now thatwearesequencing 1997, itseemsprescient Although itcameoutin OFUNIVERSITY HHMI-GBMF INVESTIGATOR Simon W.-L. Chan CALIFORNIA, DAVIS CALIFORNIA, mixed reviews. What’s yourfavorite science-themed

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February 2o12 The portrayal ofscienceinfilmsoftengets Gattaca film andwhydoesitappealtoyou? unlike moviecritics,almostcometoaconsensusonanall-timefavorite. From . a hot-button topic. Here, fourscientistssharetheir toppicksand, Jurassic Park “I’m asci-fi junkie—I’llwatch JANELIA FARM RESEARCH realized it!” I wonderiftheaudience it’s justaroundthe corner. thesis plausible,butIthink Not onlywasthemovie’s hit incredibly close tohome. (sorry EthanandUma),it of special effectsandacting While itwasadudinterms me themostwas But thefilmthatintrigued ported toanotherworld. the feelingofbeing trans- effects, thetechnology, and mood created—thespecial about thevisualsand Park. Brazil. Alien. StarWars. Jurassic a favorite. films too,soit’s hardtopick But therearemanygreat even remotelyplausible. the worststuffaslongit’s GROUPJFRC LEADER Eugene W.Myers CAMPUS Blade Runner. It’s mostly to — Contagion EDITED BYNICOLEKRESGE Gattaca Q &A . , afilm’s scientificaccuracy is often “One ofmyfavoritescience- of myfavorites.” that reasonthisremainsone female scientist, andfor a sympatheticallyportrayed which theleadcharacteris is arareexampleoffilmin terrestrial intelligence.This on alonelysearchforextra- ing aheroic radio scientist did anexcellentjobportray- movie themed filmsisthe 1997 HHMI INVESTIGATOR Lora V.Hooper CENTER AT DALLAS AT CENTER MEDICAL SOUTHWESTERN OFUNIVERSITY TEXAS Contact . Jodie Foster “I wouldpick MASSACHUSETTS GENERAL I watchedthismovie.” made methinkalotwhile questions.and societal That interesting ethical,legal, unrelated todisease raises to selectforothertraits possibility ofmisusing PGD for adesiredgender,the people toprescreenembryos method isabusedbysome defects. Giventhatthis embryos forpotentialgenetic is widelyusedtoscreen diagnosis (PGD)—which genetic preimplantation a realscientific discovery— movie becauseitisbasedon favorite science [fiction] HOSPITAL HHMI EARLY CAREER SCIENTIST Konrad Hochedlinger Gattaca asmy

Chan: Steve Yeater / AP, ©HHMI Hochedlinger: MGH Photography Hooper: Amy Gutierrez / AP, ©HHMI Myers: Paul Fetters chronicle 38 SCIENCE EDUCATION Bones, Stones, and Genes

40 INSTITUTE NEWS Short Films Make Evolutionary Biology Memorable / New Open Access Journal Gets Name and Editorial Team / International Early Career Awards Provide Connections and Funding

42 LAB BOOK How Much Is Too Much? / Protein Precision in the Brain / Now You See It, Now You Don’t

45 ASK A SCIENTIST How much energy does the brain use to perform different tasks?

46 NOTA BENE Seven HHMI Scientists Elected to Institute of Medicine / Bassler Wins L’Oréal-UNESCO Award

At the base of the nasal cavity in some animals, two crescent-shaped structures sit enclosed in bony capsules. Each is packed with a network of neurons that travel directly to the brain. The structures make up the vomeronasal organ (VNO)—a specialized organ used by reptiles and most mammals to detect nonairborne scents, such as pheromones. When these chemical cues arrive at the VNO, they are recognized by specific receptors on the neurons.

Scientists have figured out how the mouse VNO reacts to pheromones from both friend and foe. This image shows the neurons lighting up in response to a ferret’s scent. Surprisingly, the VNO is more sensitive to cues from predators than from other mice. To read more about this research, visit www.hhmi.org/bulletin/feb2012. (478, 241–247), ©2011. (478, 241–247), ©2011. Nature Firstname Surname Firstname Reprinted by permission from Macmillan Publishers Ltd:

February 2o12 | HHMI BULLETIN 37 38 HHMI us fromotherspecies? Did our distantancestorslookand behave such as:Whereandwhendid humansarise?Whatdistinguishes area studentstolearnanswers questions abouthumanevolution past October. Theteachersjoined about200Washington, D.C., invited toattendthe2011HHMI HolidayLecturesonScience this who areopposedtowhatweteach,” saysShingleton. tion. “Butthatdoesn’tmeanIdon’thavestudentsinmyclassroom byShingleton’sHolland Hallstand decision toteachhumanevolu- a misconception thattherewerestilltoomanyunknowns.” she hasshiedaway fromthetopic,admitting, “Perhaps Ihadabitof vate Episcopal-affiliatedgradeschoolin Tulsa, Oklahoma. Yet even biology coursesthatcoverhumanevolutionatHollandHall,a pri- Keri Shingleton.ShehasaPh.D.inevolutionarybiologyandteaches you haveanadvanceddegreeinthesubject.Take biology teacher Teaching humanevolutionisnotalwaysstraightforward,evenwhen M;
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BULLETIN

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February 2o12 Berkeley, tookthe audience throughtime,describing fossilevidence bring thelatestscientific developmentsinto theclassroom. ferent researchfieldstoparticipate inthisannual seriesthataimsto prompted HHMItoinvitethree dynamic speakers fromverydif- leading figuresinthis quest.” We wanttoequip teacherswiththebestinformationavailablefrom tion, manykidsdon’tgetexposuretogoodinformationonthetopic. at HHMI.“Duetolocalcontroversiesabouttheteachingofevolu- for ages,” saysSeanB.Carroll, vicepresidentforscience education questionsis oneofthemostfundamental thathumanshaveasked because understandingwherewecomefromandhow wegothere Origin ofModernHumans.” live webcastofthelectures,titled“Bones,Stones,andGenes: The like us?Morethan10,000 otherstudentsandteacherswatcheda Tim D.White,apaleontologist attheUniversity ofCalifornia, Recent advancesinpaleontology, archeology, andgenetics “We chosetofocusontheoriginofmodernhumansthisyear

Sasha Prood for human evolution from Africa to Europe and explaining how the in modern populations. Students got to explore their own genetic great apes fit in the tree of life. variation by analyzing their saliva for different versions of a gene that The students and teachers learned about stone tools—the controls perception of one type of bitter taste. most durable evidence for human evolution—from John Shea of After the lectures, the 14 teachers had one-on-one time with the Stony Brook University. Shea, an archeologist and anthropologist, scientists, then stuck around for a few days exchanging ideas on how explained that these tools can give us clues to what life was like to craft educational resources based on the lecture series and imple- for humans who existed thousands, and even millions, of years ago. ment what they learned in the classroom. Many participants really After the lecture, the audience joined five experts in what may have appreciated this aspect of the lectures. “As a teacher you don’t get a been the largest stone tool-making session in the history of human whole lot of time to talk to other educators and exchange ideas; you evolution. Donning safety goggles, lab coats, gloves, and protective boo- “ ties, the students and teachers set to These are the skills that got our ancestors through work on about 550 pounds of dacite the last ice age. To get our species through the rock with 80 hammerstones. next one, it is important that these skills be passed Although two emergency medical technicians were on hand to deal with along to our descendants. I think of teaching injuries caused by flying rocks and flintknapping as a kind of ‘extinction insurance’ wayward hammerstones, only a few for Homo sapiens. Band-aids were needed. “I thought it was going to be difficult and that I @E>D
I>;7 ” would be hitting my fingers, but once I figured out the flip of the wrist, it worked pretty well,” says Leslie Mark, a student at Dominion High are kind of isolated in your classroom,” says Randi Neff, a science School in Sterling, Virginia. “After I got the hang of it and I was teacher at Tuscola High School in Waynesville, North Carolina. actually getting a shape out of my stone, it was pretty cool.” “Being able to exchange ideas with other people who are in the “These are the skills that got our ancestors through the last ice same business as you is a rare occasion.” age,” explains Shea. “To get our species through the next one, it is Shingleton left HHMI energized and ready to teach her important that these skills be passed along to our descendants. I students about human evolution. “There’s a lot more infor- think of teaching flintknapping as a kind of ‘extinction insurance’ mation than I realized,” she says. “I’ve never synthesized the for Homo sapiens.” ideas of archeology and paleontology. When you put all of Moving from the field to the lab, genetic anthropologist Sarah that together it paints a bigger, more complete picture that Tishkoff, of the University of Pennsylvania, explained how scientists I feel much more confident presenting in my classroom.” are using genetic methods to analyze DNA variation among early W –NICOLE KRESGE humans and learn about their relationships to modern humans. FOR MORE INFORMATION: Visit www.hhmi.org/biointeractive for a webcast of the lectures. Tishkoff studies the genetic variation in modern humans and The series will be available on DVD and as a podcast this spring. nonhuman primates, such as chimpanzees, to learn more about WEB EXTRA: To see a slideshow of the flintknapping activity, go to the evolutionary forces that shape and maintain genetic variation www.hhmi.org/bulletin/feb2012.

February 2o12 | HHMI BULLETIN 39 institute news

The idea for the series came to Carroll Short Films Make when he was a consulting producer for the Evolutionary Biology Memorable public television program NOVA. He saw how much footage was left on the cutting- room floor and recognized the potential of this unused film. The three movies were assembled by award-winning filmmakers Sarah Holt and Bill Anderson, using video already shot for NOVA specials as well as new interviews with scientists to tie the stories together. HHMI’s recently launched film produc- tion unit will begin making feature-length films soon, and the team plans to use foot- age from that effort to create additional short films. The goal is to have a library of dozens of short films, with companion The Antarctic icefish, which stars in a new short film by HHMI, has adapted to resources such as online animations, videos, an icy environment by getting rid of its hemoglobin and red blood cells. and lesson plans, to help teachers connect the movies to their curricula. A COLDWATER FISH, A TINY MOUSE, AND A MUTANT GENE ARE THE HHMI’s education resource group is already talking to teachers unlikely stars of three short films produced by HHMI. The movies to identify important topics for future films. “I think there’s a really premiered at a red carpet event attended by 600 teachers at the healthy dynamic, even a tension, between the way filmmakers want National Association of Biology Teachers annual meeting last Octo- to tell a story—with pace and drama—and the way educators want to ber. They are the first of a series of 10-minute science films that use make sure certain points are hit upon and made clear,” says Dennis storytelling to teach topics in evolutionary biology. W.C. Liu, who heads the group. “And so it’s important to us that this The stars were naturals for their parts. For example, the Antarctic is a collaboration, a constant back and forth, between those groups.” icefish, whose blood is as clear as the ice water it lives in, provides a More importantly, Liu and Carroll want the films to show stu- stunning illustration of an animal adapting to a hostile environment. dents the process of scientific discovery. “By telling these stories, we “Film is a powerful way to tell stories,” says HHMI Vice Presi- hope we will excite students and encourage them to look deeper dent for Science Education Sean B. Carroll. “You can have moving into these topics,” Liu says. W images and animations. You can hear scientists talking in their own words and see the places where they do their own work. The right FOR MORE INFORMATION: Visit hhmi.org/biointeractive/shortfilms to download the movies story, told well, can be engaging, informative, and memorable.” and companion resources.

New Open Access Journal Gets Name and Editorial Team

HHMI, THE MAX PLANCK SOCIETY, AND THE WELLCOME TRUST role in helping to launch the Public Library of Science and in estab- are a step closer to launching a top-tier journal with the recent lishing it as a pioneer of open access and innovative scholarly announcement of the publication’s editorial team and name. publishing in the life sciences.” The open-access research journal will be called “eLife,” reflecting Two deputy editors have joined the leadership team—Fiona Watt, its coverage of a full range of life and biomedical sciences, from the most at the University of Cambridge, UK, and Detlef Weigel, from the Max fundamental science to translational, applied, and clinical research. Planck Institute for Developmental Biology, Tubingen, Germany. eLife will aim to develop an unparalleled editorial service for The team has selected 17 active and prominent scientists to serve

authors, designed and run by an outstanding team of active research- as senior editors, and up to five more will be added in the coming ©2011 HHMI ers, led by editor-in-chief and HHMI investigator Randy Schekman. months. About 150 additional scientists will complete the roster as Schekman is joined at the helm of eLife by managing executive members of a board of reviewing editors. editor Mark N. Patterson, most recently director of publishing at the eLife is expected to publish its first issue in late 2012. W Public Library of Science. “Mark has enormous experience with online publications and in FOR MORE INFORMATION: Go to www.hhmi.org/news/elife20111107.html to learn more about eLife and its editorial team.

open-access publishing,” says Schekman. “He played a fundamental Birth and Death of Genes, The

40 HHMI BULLETIN | February 2o12 International Early Career Awards Provide Connections and Funding

“BACK IN SCHOOL, I ALWAYS HEARD THAT IF YOU WANTED TO DO challenging internationally. For example, funding to help new sci- research you would probably have to go work in other parts of the entists start up their labs can be quite variable, and often much less world,” says Miguel Godinho Ferreira, a researcher at the Gulben- money is available than in the United States. kian Science Institute in Portugal. “Being able to prove that advice Scientists from 18 countries were eligible to apply for the awards wrong gives me enormous pleasure.” and HHMI received 760 applications. A rigorous peer review process Godinho Ferreira is one of 28 scientists from 12 countries who narrowed the field to 55 semifinalists from 14 countries. were selected to receive HHMI’s inaugural International Early As part of the review process, the semifinalists gave a 15-minute Career Scientist (IECS) awards. “These are the people who, scientific presentation at a symposium in November at HHMI’s 10 years from now, we expect will be the scientific leaders in their Janelia Farm Research Campus, in Ashburn, Virginia. countries,” says HHMI President Robert Tjian. “The major criterion was really scientific excellence: what have These researchers—who have all run their own labs for less than they accomplished in their young careers; what kind of potential did seven years—will be integrated into HHMI’s scientific community, they have; could they explain their science in a clear way,” Dixon says. attending meetings and giving talks to the Institute’s U.S.-based Most of the awardees come from China, Portugal, and Spain, but investigators and early career scientists. recipients are also based in nine other countries: Argentina, Brazil, “This program is about building connections internationally,” Chile, Hungary, India, Italy, Poland, South Africa, and South Korea. says Edwin W. McCleskey, a scientific officer at HHMI who helps Nine of the 28 (32 percent) are women. Each International Early run the IECS program. “We have chosen talented people who we Career Scientist will receive $650,000: $100,000 a year for five years, feel can build connections with our scientists.” plus a $150,000 award in the first year for major equipment purchases. The IECS program is the latest incarnation of HHMI’s inter- Godinho Ferreira plans to use his award to gain insights into the national grants to individual researchers. When it came time to mechanisms that cause and direct aging—insights that might lead rethink those grants, Tjian and Jack E. Dixon, HHMI’s vice presi- to solutions for age-related ailments such as cancer and cardiovas- dent and chief scientific officer, wanted to design a program that cular disease. provided support for early career scientists who would benefit most from a financial boost and the connection with HHMI’s scientific FOR MORE INFORMATION: To learn more about the scientists and their work, visit community. The research arena for early career scientists can be www.hhmi.org/iecs20120124.

NEW INTERNATIONAL SCIENTISTS

ANDRÉ BÁFICA LUÍSA M. FIGUEIREDO SIMÓN MÉNDEZ-FERRER CHUN TANG Federal University of Santa Catarina Institute of Molecular Medicine National Center for Cardiovascular Wuhan Institute of Physics and Florianópolis, Brazil Lisbon, Portugal Research Mathematics-Chinese Academy of Sciences Madrid, Spain Wuhan, China MEGAN R. CAREY JOSÉ L. GARCÍA-PÉREZ The Champalimaud Center Pfizer—University of Granada— THUMBI NDUNG’U ROSELLA VISINTIN for the Unknown Junta de Andalucía Center for Genomics University of KwaZulu-Natal European Institute Foundation Lisbon, Portugal and Oncological Research Durban, South Africa of Oncology Granada, Spain Milan, Italy PEDRO CARVALHO MARCIN NOWOTNY Center for Genomic Regulation RODRIGO A. GUTIÉRREZ International Institute of Molecular XIAOCHEN WANG Barcelona, Spain Pontifical Catholic University of Chile and Cell Biology National Institute of Biological Sciences Santiago, Chile Warsaw, Poland Beijing, China RUI M. COSTA The Champalimaud Center JUNJIE HU DONG-CHAN OH KARINA B. XAVIER for the Unknown Nankai University Seoul National University Gulbenkian Science Institute Lisbon, Portugal Tianjin, China Seoul, South Korea Oeiras, Portugal

LÁSZLÓ CSANÁDY BAVESH D. KANA GABRIELA C. PAGNUSSAT NIENG YAN Semmelweis University of Medicine University of the Witwatersrand National University of Mar Del Plata Tsinghua University Budapest, Hungary Johannesburg, South Africa Mar del Plata, Argentina Beijing, China

ÓSCAR FERNÁNDEZ-CAPETILLO FYODOR KONDRASHOV FENG SHAO HONG ZHANG Spanish National Cancer Research Center for Genomic Regulation National Institute of Biological Sciences National Institute of Biological Sciences Center Barcelona, Spain Beijing, China Beijing, China Madrid, Spain SANDHYA P. KOUSHIKA ROCÍO SOTILLO BING ZHU MIGUEL GODINHO FERREIRA National Center for Biological Sciences European Molecular Biology Laboratory National Institute of Biological Sciences Gulbenkian Science Institute Bangalore, India Monterotondo, Italy Beijing, China Oeiras, Portugal

February 2o12 | HHMI BULLETIN 41 lab book

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Since 1998, the federal government has required that most flour of supplements. To the researchers’ surprise, three of the five mutant be fortified with folic acid to help prevent some neurological birth mice strains experienced more neural tube defects and embryo defects. However, research by HHMI investigator Lee Niswander losses when fed a diet high in folic acid. indicates that, in some cases, folic acid may have the opposite effect. “Something else is going on there,” says Niswander. “By giving During the third or fourth week after conception, tissue des- folic acid to women, we see a decreased incidence of neural tube tined to become the nervous system rolls up to form the neural defects. That could be because the neural tube is closing. But it tube. But if gaps remain in the tube, birth defects such as spina could also reflect that some embryos with a genetic defect don’t bifida ensue. Studies have shown that folic acid fortification survive to the stage of neural tube closure.” reduces the chance of neural tube defects by 30 to 40 percent, Niswander still believes that leading to the recommendation that pregnant women supplement folic acid supplementation dur- their diets with the vitamin. ing pregnancy is a good idea, “It is still pretty much a mystery what folic acid does to help the but she advises caution before neural tube close,” Niswander says. “That’s really where we started increasing doses, as some groups our studies.” have advocated. Niswander and her colleagues at the University of Colorado “Our mouse studies indicate School of Medicine focused on just a handful of the more than that at least some genetic muta- 240 genes involved in neural tube closure. They created mice with tions can respond detrimentally defects in five genes essential to different steps in the closure process. to more folic acid,” says Niswan- As reported September, 15, 2011, in Human Molecular Genetics, der. “There may be a balance that Birth defects such as spina bifida the mice were fed either a regular diet or a diet supplemented with result when the neural tube (shown needs to be struck [to accommo- folic acid. The supplemented diet increased mouse serum folic acid here) fails to close properly during date all of our] different genetic development. to levels similar to those of a human taking recommended amounts make-ups.” W – NICOLE KRESGE

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Q A How much The brain consumes, on average, 20 per- small—local changes in blood flow dur- cent of the body’s total oxygen. This ing cognitive tasks, for example, are less energy does number is a good reflection of the amount than 5 percent. And finally, the varia- of energy, in the form of glucose, the brain tion in glucose use in different regions the brain use uses. However, it hides a more interesting of the brain accounts for only a small to perform story about the variation in energy use by fraction of the total observed variation. the brain, including how much energy So, the high level of constant activity different tasks? the brain uses for different functions. throughout the brain makes it very hard We know the brain’s use of glucose to detect small changes associated with Asked by Tom, varies at different times of day, from specific functions. a graduate student from California 11 percent of the body’s glucose in the Another major challenge is deter- morning to almost 20 percent in the eve- mining which regions of the brain are ning. In addition, different parts of the involved in those tasks. Functional brain use different amounts of glucose. imaging of the brain is powerful but We can use brain-imaging technology, the technology has its limitations. Brain such as functional magnetic resonance functions are complex, occur on a rapid imaging (fMRI) and positron emission timescale, and do not always occur in tomography (PET), to get an idea of this just one location; in addition, imaging variation in energy use. may not capture the full scope of func- The medial and lateral parietal and tional activation. The images produced prefrontal cortices use more glucose by fMRI and PET studies look very defin- than other parts. These regions are itive, but in fact they are the result of a involved in the brain’s default (non- lot of data processing that pulls a small task-related) activity as well as cognitive signal out of a very noisy background. control and working memory, which is As you can see, there are many rea- used for temporarily storing and manip- sons why we can’t say how much energy ulating information. The cerebellum, it takes the brain to solve a calculus used for motor control and learning, and problem or recite a poem. This area of medial temporal lobes, involved in long- research is exciting, however, as it ties term memory, use less glucose. Thus, together the neurophysiology of the different brain functions have different brain with our understanding of human metabolic requirements. behavior. With advances in brain imag- But the story is not so simple: Sev- ing and cell monitoring technology, eral factors make it difficult to identify researchers hope to shed light on this FURTHER READING: Raichle ME, Gusnard DA. Appraising the brain’s energy specific metabolic requirements. First, problem in the near future. budget. Proc Natl Acad Sci. 2002;99:10237–9. Accessible at we know the brain is constantly active, www.pnas.org/content/99/16/10237.full.pdf+html even at rest, but we don’t have a good Raichle ME. The brain’s dark energy. Sci Am. estimate of how much energy it uses for March 2010;302:44–9. Accessible at www.braininnovations.nl/Dark-Energy.pdf this baseline activity. Second, the meta- ANSWERED BY JAYATRI DAS, a senior bolic and blood flow changes associated exhibit and program developer at Brain Imaging Technologies: learn.genetics.utah.edu/ content/addiction/drugs/brainimage.html with functional activation are fairly The Franklin Institute Science Museum.

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And Bustamante is now using similar DNA strands—and nucleotides. His team think in the future we will see even more techniques to probe the basics of numer- discovered that when polymerases encoun- hybrid experiments that combine optical ous biological processes, including protein ter a nucleosome, they pause, not having trapping with other methods.” folding. He’s using optical traps and fluo- enough force to unravel the DNA from the He’s happy to see his technique mature rescent tags to see what happens when nucleosome. Instead, the protein waits for and change, he says, if it means applying it a protein strand is stretched and then the clump to spontaneously unravel. If he to more biological questions. released, allowing it to fold into its pre- can use optical traps to pull apart a fluores- “There are so many unknowns inside ferred conformation. cent chromosome, Bustamante says, he can the cell,” he says. Optical trapping lets He’s also applying the method to nucleo- observe its higher-order structure and the researchers get a physical handle on those somes—clumps of proteins that control the forces that proteins within the nucleosomes unknowns. While scientists can’t reach structure of DNA within a chromosome and exert on the nucleotides. inside cells and feel for themselves the influence when genes are expressed. He’s “It’s natural that as optical trapping starts forces at work, optical trapping has become already looked at the interaction between to mature, we now want to combine these their hands that work to sense and manipu- polymerases—enzymes that move along techniques with others,” says Bustamante. “I late these forces. W

CONTINUED FROM PAGE 29 H7?I?D=
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trainers to train up to 8,500 K–12 science and of laboratory materials and equipment desig- Wendy Bramlett, who used AMSTI to math teachers each year, offering them sub- nated for math and science teachers. raise her game, is a fan. “My whole way of ject-specific, grade-specific mentoring. Since The state’s investment is paying off in bet- teaching changed,” she says. “I went from 1999 they’ve trained half the STEM teach- ter student performance, according to eight a lecture class to no lecture and all hands ers in the state, Ricks says. Teachers come years of external evaluations. For example, on,” she says. Her students’ performance for two-week workshops for two consecutive Alabama students improved more in math has improved—92 percent scored at the top summers. AMSTI also employs 300 master than those in all but one other state, as judged level on the state science exam last year. And science or master math teachers who advise by an internationally recognized test called she hears something else she never heard in and mentor teachers and even co-teach if the National Assessment of Educational her first years of teaching. “I have children the mentees need a hand. AMSTI operates Progress. “The state has seen that if you really tell me, ‘Science is my favorite subject.’” W

11 regional 35,000-square-foot warehouses, want students to compete, they need top- WEB EXTRA: Read more about STEM teacher training where workers run forklifts to help sort bins notch math and science skills,” says Ricks. online. Go to www.hhmi.org/bulletin/feb2012.

CONTINUED FROM PAGE 33 M>;H;
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receptor, looking for ways to avoid narcotic using stem cell techniques to characterize pain will be treated completely differently and other side effects from opiates, which their differences and, perhaps, find ways to 10 years from now.” Physicians may one would benefit people with chronic pain (see regulate their firing without harming other day treat pain based on both the source of Web Extra, “Boosting the Body’s Natural necessary physiological functions. He is pain within the patient’s nervous system Painkilling Power”). also looking at ways to deliver pain reliev- and the individual’s genetic predisposition The initial discovery that abnormal ers directly to hyperactive nociceptors while for responding to a specific therapy. Perhaps central sensitization can lead to pain hyper- leaving normal ones untouched. the day isn’t too far off when a physician will sensitivity came from Clifford Woolf at Undoubtedly, other molecules of nor- ask where it hurts and nearly all patients Children’s Hospital Boston and Harvard mal and pathological pain signaling await will respond, nowhere. W

Medical School. Woolf is now generating discovery, thereby offering additional pos- WEB EXTRA: For more of the latest research on hypersensitive and normal human pain sibilities for improving pain treatment. “I understanding and controlling pain, go to www.hhmi.org/ neurons in his laboratory from fibroblasts tell my medical students,” says Woolf, “that bulletin/feb2012.

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