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Juan Young / Zoghbi lab
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The fi nding raises questions about the ]`aQ`SO[W\UeVS\bVSaV]dW\UVOR\]STTSQb QOcbW]caTSSZS`aW\b]Oe]`ZRW\eVWQVbVSgVOdSPSS\b]bOZab`O\US`a possibility of genes being “reawakened” in embryonic stem 6SeOaaSS\OUOW\Ob"gSO`a%[]\bVaO\ROUOW\Ob#gSO`a T`][bVSPSUW\\W\U cells after normal genetic silencing. []\bVa]TOUS 6SabWZZRWR\]ba^SOY 0]bVbW[SaVSS\bS`SRbVS ]T¿QSeWbV]cb^OgW\UbVSaZWUVbSabObbS\bW]\b]bVS^S]^ZS^`SaS\b 4`][bVS^O^S`µ/cbWabWQ2Wabc`PO\QSa]T/TTSQbWdS1]\bOQb¶:S] 6SeS\bOTbS`bVSASUcW\T]`[P]O`RO\RW\abO\bZgPcaWSRVW[aSZT 9O\\S` 23>/@B;3 >@3A723 13 C>4@= >3@A>31B7D3A/<2=>7<7= 16@=<71:3 AQWS\QS3RcQObW]\ "" Cue the Crickets "$ Strategizing to Diversify Science 7\abWbcbS =0A3@D/B7= 43/BC@3A 14 2o 26 32 Teaching Invisible Barriers Genetic Sources of Renewal Young Biologists Children with the subtlest Balancing Act As scientists learn more New Tricks form of autism suffer social Animals have evolved about how to produce and Long the science where isolation; those with more intricate ways to ensure manipulate stem cells— math mattered less, biology severe disease face a much that gene activity is amid high expectations increasingly demands tougher road. New genetic the same in males and and close scrutiny—no one powerful quantitative skills. clues put the spotlight on the females despite the is ready to choose any one Teaching students the math communication hubs of the inherent imbalance approach over another. they’ll need, though, is brain’s neurons—the synapses. of X chromosomes. more than just 1+1=2. [COVER STORY] VISIT THE BULLETIN ONLINE FOR ADDITIONAL CONTENT AND ADDED FEATURES: www.hhmi.org/bulletin COVER IMAGE: LUKE BEST contributors /TO\]TRSaS`bae`WbS`;7B16:3A:73a][SV]eS\RSRc^W\R`WhhZg>]`bZO\R=`SU]\eVS`S VSQ]dS`aQSZZPW]Z]UgO\RW[[c\]Z]UgT]`AQWS\QS[OUOhW\S 0SbeSS\aSba]TbS\\WaVSVOa OZa]e`WbbS\T]`1SZZA[WbVa]\WO\O\R 2Sa^WbSO\]\ZW\S_cWh\O[W\UVS`WRSOZQO`SS`OaWQSQ`SO[bOabW\UA/@/61 > E7::7/;A RSQWRSRb]PSQ][SOaQWS\QSe`WbS` /U`ORcObS]TbVSaQWS\QSe`WbW\U^`]U`O[ObbVSC\WdS`aWbg ]T1OZWT]`\WOAO\bO1`chaVSVOae`WbbS\T]`AQWS\QS<=EGOZS;SRWQW\SO\RAbO\T]`R;SRWQW\S O\RWa\]eOaaWabO\bSRWb]`]TbVS66;70cZZSbW\ EWZZWO[aZWdSaW\EOaVW\Ub]\2 1 eWbVVS` 5`SOb2O\SO\ROT`SShS`eSZZab]QYSReWbVWQSQ`SO[ ! 1cb]cbPWba]T^O^S`T`OU[S\ba]TVO\RR`Oe\¿Uc`SaO\RQ]Z]`TcZ^ObbS`\aO`SXcaba][S ]TbVSSZS[S\babVOb[OYSc^bVSWZZcab`ObW]\e]`Y]T:C9303AB 6WaRWdS`aS]cb^cbW\QZcRSa dWRS]O\RO\W[ObW]\eW\R]eRWa^ZOgaO`bRW`SQbW]\TOaVW]\O\RV][S[ORSa^OQSacWba 0Sab ZWdSaW\:]\R]\eVS`SVSe]`YaOa^O`b]TO\O`bWabWQQ]ZZSQbWdSY\]e\Oa>SS^aV]e :3/64/AB3<aOgaaVSZ]dSabVSeOgaQWS\QSZ]]YaOR[WbbW\UbVObWb^`]POPZgQ][SaT`][ b]][cQVbW[Sa^S\bVO\UW\UO`]c\RVS`VcaPO\R¸aPW]QVS[Wab`gZOP :SOVZSTbOQO`SS`W\ OW`ZW\S¿\O\QSb]^c`acS^V]b]U`O^VgTcZZbW[S AW\QSZOc\QVW\UVS`0]ab]\abcRW]W\ !aVS " VOa^V]b]U`O^VSRaQWS\bWabaT]`bVS;OaaOQVcaSbba7\abWbcbS]TBSQV\]Z]Ug6O`dO`RC\WdS`aWbg BVSAQWS\bWabO\R;OYS[OUOhW\SO[]\U]bVS`a 66;7B@CAB33A 6 6;7=44713@AA3<7=@/2D7A=@A 8O[Sa/ 0OYS`7773a_ BV][Oa@ 1SQV>V 2 / President Senior Partner / Baker & Botts 1`OWU/ /ZSfO\RS` / V.P. & General Counsel /[POaaOR]`1VO`ZS\S0O`aVSTaYg >SbS`8 0`c\a>V 2 / V.P. for Grants & Special Programs Senior International Partner 2OdWR/ 1ZOgb]\>V 2 / V.P. for Research Operations WilmerHale 8]aS^V2 1]ZZW\a / V.P. for Information Technology @WQVO`R5 2O`[O\ 8OQY3 2Wf]\>V 2 / V.P. & Chief Scientific Officer Partner / The Carlyle Group 8]O\A :S]\O`R3a_ / Senior Counsel to the President Chairman of the Board / AES Corp. /dWQS/ ;SSVO\ / V.P. for Communications & Public Affairs (Through January 25, 2008) 3ReO`R8 >OZ[S`W\] / V.P. for Finance & Treasurer 8]aS^V: 5]ZRabSW\; 2 5S`OZR; @cPW\>V 2 / V.P. & Director, Janelia Farm Research Campus Regental Professor & Chairman, Department of Molecular Genetics :O\RWaHW[[S`[O\ / V.P. & Chief Investment Officer University of Texas Southwestern Medical Center at Dallas 66;70C::3B7<AB/44 6O\\O6 5`Og>V 2 1VOW`[O\ President Emeritus & Harry Pratt Judson ;O`g0SbV5O`RW\S` / Editor Distinguished Service Professor of History 1]`WDO\QVWS`W / Story Editor The University of Chicago 8W[9SSZSg / Science Editor 5O`\Sbb: 9SWbV >Ob`WQWO4]abS` / Associate Director of Communications Chairman / SeaBridge Investment Advisors, L.L.C. for Web & Special Projects Former Vice Chairman & Chief Investment Officer AO`OV1 > EWZZWO[a / Assistant Editor The Prudential Insurance Company of America 2SO\B`OQY[O\;OgO>W\Sa / Contributing Editors 8S`S[g@ 9\]eZSa2 >VWZ /227B7=Biochemistry BVS]^W\W]\aPSZWSTaO\RdWSe^]W\baSf^`SaaSRPgOcbV]`aW\bVS 66;70cZZSbW\R]\]b\SQSaaO`WZg`SÀSQbbVS]^W\W]\aPSZWSTadWSe^]W\ba ]`]T¿QWOZ^]ZWQWSa]TbVS6]eO`R6cUVSa;SRWQOZ7\abWbcbS Mitch Leslie: Christie Aschwanden, Sarah Williams, Luke Best, Leah Fasten Sarah Williams, Leslie: Christie Aschwanden, Mitch HHMI BULLETIN | May 2oo8 president’s letter A Season of Change EVEN THE DAMP, GRAY DAYS SO PERVASIVE THIS SPRING CAN’T diminish the extraordinary magic with which the season unfurls outside my office here at HHMI’s headquarters in Maryland. Arrayed to the right, in all their diaphanous glory, the pale pink blossoms of cherry trees rim the oval pond. Out another window, I glimpse the spreading forms of flowering crab apples with blooms of deep rose. It’s a season of change here at HHMI, and that change is not restricted to the surrounding landscape. For example, the Institute has just announced a major new program for highly talented, early career scientists. It’s an initiative “This is an exciting moment in we hope will inject some much-needed optimism into a research community dispirited by the dim prospects of being funded by the HHMI’s history, and I look forward National Institutes of Health. The scientists we are targeting—those to the outcomes of several within two to six years of their first appointment as an assistant professor or equivalent position—are often at a high point of their initiatives now under way. creativity but face daunting odds in winning stable funding for their B6=;/A1316 research. As we move into year five of flat budgets at the NIH, our ” colleagues there are concerned about the issue and are trying to address it but lack the flexibility we enjoy. The HHMI initiative comes at a critical moment for the nation, This is an exciting moment in HHMI’s history, and I look forward and we’re fortunate to be able to respond in a meaningful way. to the outcomes of several initiatives now under way. For example, Having said that, we’re mindful that nonprofit organizations face a we’re in the final stages of selecting a new group of investigators, the surfeit of opportunities to respond to gaps in federal funding. They result of our first general competition in which scientists applied must exercise care in deciding when to intervene, or they risk dissi- directly to HHMI. The process of soliciting institutional nomina- pating that flexibility. We balanced that appropriate caution against tions worked well in the past, but direct applications are bringing the views of scientists who believe the situation is dire—in other us a broader and deeper pool of candidates. The open application words, if someone seems to be drowning, you throw that person a process is stimulating our long-term efforts to expand the definition life preserver and debate the finer points about whether the sea is of biomedicine to embrace interdisciplinary work involving chemists, rising due to global warming at a later date. physicists, engineers, and computer scientists. The opportunity to act decisively to stimulate biomedical research Under the leadership of Jack Dixon, HHMI’s chief scientific and science education makes being president of HHMI a unique officer, we’re undertaking another initiative called the collaborative position in scientific leadership. Yet, as many readers of this column innovator awards to further interdisciplinary research and extend already know, I will step down from this extraordinary position a year HHMI’s support into the wider scientific community. For the pilot from now to return to my laboratory at the University of Colorado on round, we asked our investigators to propose particularly challenging a full-time basis. This decision reflects my desire to be fully engaged and potentially transformative research opportunities that involve in research and teaching but also the realities of charting new strategic collaborators outside the HHMI community and to devise plans for directions for HHMI. tackling them. We hope to select the first recipients shortly; as the The Institute is beginning to plan its next scientific initiatives, and effort proceeds, we will consider expanding the program to a larger I think new leadership should be in place before those are launched. group of scientists. As I have shared with HHMI staff, continuity of leadership was very The work of HHMI will continue to unfold over the next year as important for building the Janelia Farm Research Campus. The the Trustees seek my successor, who will have the responsibility and same leadership team was involved in the entire process—beginning joy of planting new ideas and watching them flower. I will have the with the early vision that developed from a conversation I had with privilege of returning to a cherished role, that of an HHMI investi- Gerry Rubin, now Janelia Farm’s director, and David Clayton, now gator, and the joy of discovery. vice president for research operations—through to program plan- ning, architectural design, construction, staffing, and the emergence of a lively scientific community. The “next great thing” deserves that Bruce Weller same leadership commitment over an extended period of time. May 2oo8 | HHMI BULLETIN ! centrifuge Men Overboard @]R;OQ9W\\]\O\R1ZOg/`[ab`]\U Q]ZZSOUcSaT]` gSO`a[OgY\]e OZ]bOP]cbSZSQb`]QVS[WQOZaWU\OZW\U PcbbVWa^Oabac[[S`bVSbe]eS`S `S[W\RSR]TOTc\RO[S\bOZTOQbOP]cb bVSaSO´]\SbVObbVSgOR[Wbb]]dS` Z]]YW\UW\O[][S\b]TT`WS\RZg Q][^SbWbWdShSOZ 3O`Zg]\OAc\ROg[]`\W\UZOab 8c\SbVSbe]aSb]TTW\YOgOYaT`][ E]]Ra6]ZS;OaaOQVcaSbbab] S\X]gOROg]T^VgaWQOZSfS`bW]\W\ eObS`abVSgP]bVVOdSQ][Sb]Z]dS ;OQ9W\\]\O\66;7W\dSabWUOb]` O\R<]PSZZOc`SObSOb@]QYSTSZZS` `c\a[O`ObV]\aO\RWaO\OQQ][^ZWaVSR W\]\ZgbV`SSV]c`a /TbS`Zc\QVbVSg C\WdS`aWbga^S\bVWag]cbVW\Q]OabOZ aOWZ]` " HHMI BULLETIN | May 2oo8 The Sweet Smell of Exhaust µ7¸dSPSS\O`]c\Ra^]`baQO`aO\R`OQW\UQO`aT]`Oa Z]\UOa7¸dSPSS\O`]c\RaQWS\QS¶aOga\Sc`]Z]UWab >SbS`Ab5S]`US6gaZ]^ µ;g^O`S\baeS`SaQWS\bWaba O\R[gTObVS`VORO^OaaW]\T]`QO`a 7RWabW\QbZg `S[S[PS`bVSa[SZZ]T`OQW\UTcSZO\R1Oab`]Z@T`][ eVS\7eOabe] ¶ Ab5S]`US6gaZ]^WaO\66;7W\bS`\ObW]\OZ`SaSO`QV aQV]ZO`ObbVSC\WdS`aWbg]TB]`]\b]eV]e]`Ya]\ bVS[]ZSQcZO`[SQVO\Wa[abVObQOcaS\Sc`]\ab] RSUS\S`ObSW\/ZhVSW[S`¸aRWaSOaS 7\VWa]T¿QSbVS ]`WUW\OZS\UW\SPZ]QYT`][OdW\bOUS8OUcO`VS¸a `SPcWZRW\UaS`dSaOaOQ]TTSSbOPZS A^]`baQO``Sab]`ObW]\Wa`ST`SaVW\UZgµO[]`S Q]\ab`OW\SR^`]PZS[¶bVO\^`]PW\UbVSW\bS`\OZ [OQVW\S`g]TOQSZZVSaOga µEVS\a][SbVW\UR]Sa\¸b e]`YW\bVSQO`g]cQO\VWbWbeWbVOa^O\\S`aeSO` ObWbO\ReOZYOeOg EWbVaQWS\QSWTWbWa\¸be]`YW\U aSOba7Q]cZR_cOZWTgWbT]``OQW\U 0cb7¸[\]bOZZ]eSR g]c¸dSabWZZU]bb]YSS^^ZcUUW\U ¶AbWZZPW]Z]UgµR]Sa b]R]bVOb´¶OaWUVaZW^a]cbµ´RcSb]OVTO[WZg UWdSg]cTSeS`aYW\\SRY\cQYZSa ¶ SRWQba ¶BVSTO[WZgW\QZcRSaOeWTSO\RbV`SSbSS\OUS Ab5S]`US6gaZ]^RWROPWb]T`OQW\UOaOabcRS\b ROcUVbS`a 6S\]bSaeWbVaObWaTOQbW]\V]eSdS`bVOb W\bVS '% aO\R\SdS``SOZZgVc\Uc^VWaR`WdW\U ]\S]TbVSUW`ZaµWaOQO`\cb ¶ UZ]dSa µ<]VOW`gQ`OaVSaPcb7QVSQYSR]cbbVSU`Oaa EVS\VSUSbabW[S]cb]\bVS`]ORbVSaQWS\bWab O\ReSSRaW\bVSRWbQV]\aSdS`OZ]QQOaW]\a ASdS`SZg ObbVSeVSSZWaT`SSb]`SdSZW\]bVS`aS\aObW]\a W\Xc`W]cab]]\S¸a^`WRSPcb\]bb]]\S¸aQO` AW\QS µBVSdWP`ObW]\abVSTSSZW\U]TOQQSZS`ObW]\O\R bVS\7¸dS]e\SR8OUcO`aO\RaW[WZO`a]`ba]Ta^]`bg Q]`\S`W\UO\ReW\RW\g]c`TOQS BVSaeSSbO`][ObWQ QO`aW\QZcRW\UOa]c^SRc^>]`aQVSS\UW\SRDE a[SZZa]TV]b]WZO\R`OQW\UTcSZSfVOcab¶VSSfcZba O\ROB`Wc[^VB@$ VWaOQQ]c\b^WQYW\Uc^a^SSR µBVS`c[PZS]TbVS µEVOb7¸dSOZeOgaR]\SeWbV[gQO`aVOaPSS\b] QgZW\RS`¸aSfVOcab^W^Sab`OWUVbT`][bVSVSORS`a bOYSbVSS\UW\S]cbbSO`WbO^O`bO\R^cbWbb]USbVS` ]cb BVWaRSS^POaa`c[PZS(WbabO`ba]cbZ]eO\Ra][S OQQ]`RW\Ub]IQ][^SbWbW]\KPZcS^`W\ba BVSQO`7¸[ eVObc\SdS\O\RbVS\Oag]cOQQSZS`ObSc^b]aSdS\ e]`YW\U]\\]eWaO '%"D 3bg^S8OUcO``]ORabS` ¶ ]`SWUVbbV]caO\R`^[WbPSQ][SaO[SZ]RW]caV]eZ 6S^]W\bab]bVS\]eµ]`\O[S\bOZ¶S\UW\SPZ]QYW\ BVS^]ZWQS[O\ObbVSaWRS]TbVS`]ORZ]]Yac^O\R VWa]T¿QS µBVWaQO`¸aPSS\`SPcWZbb]bVSa^SQW¿QObW]\a e]\RS`a·/[7U]W\Ub]QVOaSOTbS`g]cO\RP]]Yg]c eScaSRW\A^]`ba1O`1ZcP]T/[S`WQO0>`]RcQbW]\ ]`bc`\OPZW\RSgSPSQOcaSPgbVSbW[S7Q]cZRUSbW\ @OQW\UW\bVS '% a EWbVO`]ZZPO`O\Ra][S^`]^S` [gQO`g]c¸RPSZ]\UU]\S-¸¶´5S]`US6SWRSYOb ;OQ9W\\]\aOWRµWabVOb7¸[U]W\Ub] b]eg]cT]`OeVWZS ¶ /`[ab`]\UUZO`SROb;OQ9W\\]\( µG]c¸`S\]bU]W\Ub]b]e[SO\geVS`S 7¸ZZaZSS^VS`S]\bVSPSOQVWT7VOdSb] Pcbg]c¸`S\]bU]W\Ub]b]e[S¶ µ6WaW\aWabS\QS]\b]eW\U[SYW\R ]Te]YS[Sc^¶/`[ab`]\UOR[Wba 6S^ORRZSReWbV`S\SeSRdWU]`O\R µ<]\]\]\]\] 6S¸aUWdW\U[S bVSg`SOQVSRE]]Ra6]ZSeWbVROgZWUVb Q`SRWbbVOb7R]\¸bRSaS`dS¶/`[ab`]\U b]a^O`S W\aWaba µBVSTOQbWa7Z]ab[g^ORRZS BVS]`RSOZµQS`bOW\Zg`SW\T]`QSR[g BVOb¸aeVg7`S[OW\SRc^aWRSR]e\ 7 bVS[ µ1ZOgYS^b^caVW\U]\PcbeOa `SQ]U\WbW]\]TbVSTOQbbVObbVSaSO VOR\]bVW\Ub]`WUVb[gaSZTeWbV¶7b bW`W\U¶`S[S[PS`a;OQ9W\\]\ QO\YWZZg]c¶;OQ9W\\]\aOga µ0cbWb eOaOVO``]eW\UTSe[W\cbSaW\eVWQV gSO`a/`[ab`]\U¸aXc\W]` µ7abO`bSR OZa]^cb[SW\SdS\U`SObS`OeS]T[g /`[ab`]\U¿Uc`SR]cbObZOabµV]eb] Z]]YW\UOb[geObQV 7¸[Q]\abO\bZg T`WS\R 1ZOg/`[ab`]\UT]` gSO`a USb]cb]TbVSRO[\SRYOgOY¶O\RbVS QOZQcZObW\UbVW\Ua(bVSbW[SbVSQc``S\b VOaPSS\bSOQVW\U[S´O\R\]b]\Zg be][O\OUSRb]R`OW\VWaP]ObO\RaSb bVSeW\RV]c`a]TROgZWUVbZSTb ES OP]cb^]bOaaWc[W]\QVO\\SZa¶ VW[W\[]bW]\OUOW\ ^ORRZSRc^]\b]OPSOQV 7b]ZR1ZOg /`[ab`]\UT]`VWa^O`b`S^]`babVOb 0cbbVS`S`S[OW\SR [WZSab] eSeS`S\¸bU]W\Ub][OYSWb ¶6SRWR\¸b VSWa`SORgT]`O\]bVS`U]bVWaac[[S` Finn O’Hara Finn b`OdSZeWbVeW\RO\ReOdSaOUOW\ab aOgO\gbVW\U µEVOb7¸[USbbW\UOb¶ ´>SbS`BO`` May 2oo8 | HHMI BULLETIN # $ HHMI OZWTSZ]\UW\TObcObW]\bVOb^`SRObSa ]`Oa[OZZQ]UeWbVW\OZO`USaQ]`S ¶ g]cR]\]bTSSZSWbVS`O`][O\bWQVS`] S\aS[PZS 7\aWRSbVSPO`]_cS]`QVSab`O PcbTSSZW\Ug]c`aSZTO^O`b]TbVSS\bW`S [O\gTSSZeVS\^ZOgW\UOa]Z]^O`b \]bXcabeVS\Sf^`SaaW\Ug]c`aSZTZWYS ]T]\S¸aSU] G]cTSSZg]c`aSZTVO^^g aOga µBVWa[caWQP`W\UaORWaQW^ZW\S OTSSZW\U]TVO`[]\g9]\abO\bW\]d PST]`S0OQV0SSbV]dS\O\RDWdOZRW ZSaaS`Y\]e\Q][^]aS`aeV]QO[S @]aS\[ZZS`O\REWZZWO[:OeSa´ Pg8]VO\\6S`[O\\AQVSW\8]VO\\Sa QVO[PS`]`QVSab`O BVSg^ZOg^WSQSa AbObSC\WdS`aWbgZSORabVSc\WdS`aWbg¸a `SaSO`QVaQV]ZO`Ob;]aQ]e:][]\]a]d 0O`]_cS[caWQ RSQ]`ObSRa]c\Ra]TSO`Zg %bVQS\bc`g a^SQWOZaWZYab`W\UaQ`SObW\UbVS`WQVZg VWaQVW\O\RaZWRSabVSP]eOQ`]aaWba W\ab`c[S\b 6SR`OeabVSdW]ZW\b] O\R^WQYac^ORWTTS`S\b¿ eOZYa PW]QVS[Wab/ZSfO\RS`9]\abO\bW\]d =\BcSaROg Biochemist A Baroque centrifuge 9]\abO\bW\]d¸a^OaaW]\T]`[caWQWa 0O`]_cSQ][^]aWbW]\aS\Q]c`OUS 9]\abO\bW\]dO\66;7W\bS`\ObW]\OZ BULLETIN OeOgT`][VWaa^SQb`]^V]b][SbS` O\R4`WROgSdS\W\Ua | May 2 oo 8 “ that Ichosescience. the scientificworld, ithappened As bothmyparents werefrom \Sbc\SR /:3F/<23@9= Illustration: Peter Arkle Photo: David Rolls upfront & 9\]eEVS\b]4]ZR¸3[ When the cell’s protein-folding machinery is stressed, timing is everything in the decision to keep going or die. 4`SShS4`O[W\UO4WRUSbg;]ZSQcZS A sister-brother team conspires to pin down the ultrafast movements of enzymes in action. 0O`W\U67D¸a2S^S\RS\QWSa New atlas reveals that HIV commandeers almost 300 human proteins to do its dirty work. They’ve set their sights on a goal. Formulated a scientific question. Creative juices start to flow. How to reach a solution? Science is becoming more collaborative, and that’s certainly true for the researchers spotlighted on these pages. Conversations—with a colleague on campus, a sibling on another continent, maybe even a pet parrot—bring a fuzzy, seemingly unattainable goal into focus. Then there are those who see a challenge and jump in—even if it’s outside their field—thinking, “I can contribute something.” They shift direction, apply their know-how in a new way, and decipher an intractable puzzle. Talk about inspired resourcefulness. May 2oo8 | HHMI BULLETIN % upfront Know When to Fold ’Em When the cell’s protein-folding machinery is stressed, timing is everything in the decision to keep going or die. ON THE MISSION BAY CAMPUS OF THE UNIVERSITY OF CALIFORNIA, SAN Francisco (UCSF), Peter Walter’s corner office is distinctive for its tall, elegant cactus-like plants—and its poetry-quoting African grey parrot. regain equilibrium, the UPR prompts the After months of effort, Walter has trained the parrot, named Beaker, to cell to commit suicide. In a study published badger lab members on what’s most important: “We need more data.” ¶ in Science last November, Lin, Walter, HHMI investigator Kevan Shokat, and That’s a common refrain from research leaders, but “in this case, Peter’s colleagues explored how the same signaling got a parrot to say it,” says postdoctoral researcher Jonathan Lin, laughing. pathways could cause such diametrically opposite fates. In keeping with Beaker’s command, three enzymes, molecular sensors called T he team exposed cultured human cells Walter’s team has collected convincing data IRE1, ATF6, and PERK, detect the glut to drugs that prevent proteins from folding to explain exactly how the endoplasmic of unfolded proteins. They then activate and eventually cause cell death. Over 24 to reticulum (ER), a maze-like compartment various genes that expand the ER and step 30 hours, the researchers measured the that fans out around the nucleus inside the up its folding capacity, reduce the synthesis activity generated by the UPR. Initially, all cell, can determine whether a cell lives or of new proteins, and crank up the protein three pathways rapidly turned on, but results dies. The ER serves as a cellular factory degradation process. unexpectedly showed IRE1 shutting off after where newly synthesized proteins are folded Those protective measures bring the about 8 hours, around the time when cells into their proper structure. A protein must be system back into balance. “It’s a feedback began to deteriorate. ATF6 activity followed folded correctly to do its job. loop that adjusts supply to demand,” Walter a similar pattern. By contrast, responses trig- “Only the perfectly made proteins pass says. Yet, paradoxically, if the ER cannot gered by PERK—including production of quality control,” says Walter, an HHMI investigator. Proteins that fail to attain the right conformation are degraded before they /5==247B can cause cellular dysfunction and disease. If the ER machinery is insufficient or IT’S A TALE OF GREAT CHEMISTRYPSbeSS\be]66;7W\dSabWUOb]`aObbVSC\WdS`aWbg]TAO\ 4`O\QWaQ](O`]c\R >SbS`EOZbS`bOZYSRb]9SdO\AV]YObOP]cbRSdWaW\UOR`cUbVOb defective, however, unfolded proteins pile e]cZRe]`YW\gSOabb]aSZSQbWdSZgac^^`Saa7@3 eVWQVPSZ]\Uab]OdOabTO[WZg]TS\hg[Sa up. Fifteen years ago, in studies of yeast, QOZZSRYW\OaSa AV]YObOZ`SORgVORORSaWU\S`Q][^]c\RW\VO\RbVObPZ]QYSR]bVS`YW\OaSa Walter and his colleagues discovered that OTbS`VS[]RWTWSRbVS[b]`Sa^]\Rb]Wb BOYW\UbVSaO[SO^^`]OQVVScaSRUS\SbWQbW\YS`W\U the ER copes with the stress of such overload b]aZWUVbZgeWRS\7@3 ¸aOQbWdSaWbSbVS^]QYSbeVS`SS\S`Ug[]ZSQcZS/B>\]`[OZZg^ZcUa by triggering a set of biochemical reactions, W\O\ROQbWdObSabVSS\hg[S BV]aSQVO\USa^S`[WbbSRAV]YOb¸aR`cUb]TWb]\ZgW\b]bVOb known as the unfolded protein response, [cbObSR^]QYSbPZ]QYW\U/B>PW\RW\U AV]YObSf^SQbSRbVWaQVS[WQOZUS\SbWQaab`ObSUgb] aVcb]TTbVSS\hg[SPcbbVS`SdS`aSVO^^S\SR µES¸dSR]\SbVWaeWbV YW\OaSaO\R7@3 Wa or UPR. Later work by various research bVS]\Zg]\SeVS`SbVSR`cUOQbcOZZgbc`\SR]\bVSTc\QbW]\]TbVSYW\OaS¶VSaOga µA]bVOb groups uncovered a similar mechanism in eOaO\OPa]ZcbSac`^`WaS ¶/ac`^`WaSbVOb^`]dSRVSZ^TcZeVS\EOZbS`\SSRSRO^S`aWabS\b mammalian cells, including human cells: `ObVS`bVO\Oac^^`SaaSR7@3 Andy Smith a protein that promotes cell suicide—stayed and sustained IRE1 levels in the cells—and The study raises fresh questions: could on the whole time. substantially fewer of them died, confirming future drugs be designed to enhance the The drop-off in IRE1 appeared to be “a the researchers’ theory that the enzyme was UPR’s protective responses or stave off switch between the pro-survival versus the pivotal for cell survival. overzealous cell suicide that occurs in this pro-death phases of the UPR,” says Lin. To Going a step further, the researchers and other diseases—such as diabetes and test that hypothesis, he and Walter wanted examined developing eye cells in rats with Alzheimer’s disease—in which cells die from to see what would happen if IRE1 did not retinitis pigmentosa. This inherited form protein-folding glitches? Lin is exploring that power down. Fortunately, UCSF colleague of blindness results from degeneration of possibility in the blind rats. Shokat gave them a “wonderful trick” to do retinal cells that make misfolded light- Walter is investigating the other side of the just that, says Walter. Shokat used genetic sensing proteins. Those experiments revealed coin. Could inhibiting the UPR’s protective methods in yeast to alter IRE1’s structure so a downturn in IRE1 signaling, typical of side within cancer cells, which must crank that the sensor could be selectively turned cell suicide. out many proteins to sustain rapid growth, on by a designer drug (see sidebar). put an end to a tumor’s growth? Beaker the Lin and Walter repeated their cell culture parrot’s likely response is: “We need more experiments, this time using human cells data.” . —INGFEI CHEN engineered with the mutant version of IRE1. Adding Shokat’s drug artificially stimulated upfront Freeze-Framing a Fidgety Molecule A sister-brother team conspires to pin down the ultrafast movements of enzymes in action. 2]`]bVSS9S`\WaQVO\UW\UbVSeOgaQWS\bWababVW\YOP]cbS\hg[Sa´ ^`]bSW\abVOba^SSRc^QVS[WQOZ`SOQbW]\a Leah Fasten HHMI BULLETIN | May 2008 DESPITE THEIR HEATED SCIENTIFIC DEBATES AS KIDS IN GERMANY, DOROTHEE Kern never imagined turning to her little brother to collaborate on her research. But Christian Huebner, three years her junior, is now a phys- the clam-shaped enzyme and tracking its icist and offered just the know-how Kern needed to resolve a puzzle opening and closing by measuring changes in fluorescence. Huebner had designed about the behavior of a restless protein. ¶ With his help, Kern, who has and built a unique ultrasensitive laser that previously collaborated with her parents—also scientists in Germany— allowed precise measurements and time resolution in microseconds. made sense of her experimental observations “We had one crystal of one unique The siblings found that every few nano- that the protein could adopt three distinct protein, but three conformations of the seconds—as the computer simulation had conformations in one crystal. In the process, protein,” says Kern. “These are just snapshots shown—the enzyme twitches partially shut. she turned a long-standing biochemistry though—static and frozen in the crystal.” But every few milliseconds—as suggested assumption on its head. What Kern needed was a way to measure by NMR—it closes all the way. Kern, an HHMI investigator at Brandeis whether the protein, when it wasn’t stuck in The traditional view had been that an University, studies the dynamics of enzymes— a crystal, actively alternated between these enzyme snaps shut only when it makes proteins that speed up chemical reactions by structures. Nuclear magnetic resonance contact with its substrate. But Kern and clamping onto one or more substrates and (NMR), which can detect the movement Huebner showed that an enzyme can efficiently converting them into products. In of atoms, provided just such an approach. constantly fidget and take on a new structure this case, she was studying adenylate kinase, Using NMR, Kern’s team calculated that without that contact. And it’s not just in this an enzyme that processes ATP, ADP, and the protein switched conformation about one instance—Kern has detected twitching AMP—molecules that give cells energy every millisecond or so, but they were not in the handful of other enzymes she’s tested and are building blocks of DNA. Adenylate able to see exactly which conformations. so far using NMR. “This is really a para- kinase exists in every organism, from bacteria To bridge the information obtained by digm shift,” she says. “We want to encourage to humans. Kern wanted to know how the crystallography and NMR, Kern’s team scientists to consider that this happens with enzyme adapted to one of its most extreme performed a third experiment—a computer their own systems. So far, it seems that these environments—inside bacteria that thrive at simulation that calculated how fast the mole- short-lived, higher energy states quite often 220 degrees Fahrenheit in deep ocean vents. cule could move between the structures seen are the biologically active states.” Most proteins unravel at such high tempera- in the crystal. The simulation only added Returning to her original question tures. confusion. It indicated that the enzyme could on heat-loving adenylate kinase, Kern She already knew the molecular struc- move between the open and partially closed performed new experiments showing that ture of adenylate kinase at more moderate states seen in the crystal in nanoseconds— the hinges between the lids of the enzyme temperatures but not what the heat-loving that is, thousands of times faster than the are more rigid in heat-loving bacteria, which version looked like. “We really needed a milliseconds suggested by NMR. slows the enzyme’s movements, presumably high-resolution structure to see subtle differ- Kern had an idea of what was going on keeping it from unraveling at high tempera- ences,” says Kern. but needed the help of her brother, a physi- tures. The team’s findings appeared in two She and her colleagues turned to x-ray cist at Germany’s Martin Luther University papers online in Nature on November 18, crystallography—they bombarded crystallized Halle-Wittenberg, to experimentally reveal 2007. Next, Kern wants to find out just how protein with x-rays and used the resulting the inner workings of adenylate kinase. the protein manages to switch states without diffraction pattern to determine the protein’s “It was a real collaboration where we were losing its structure. three-dimensional arrangement. “We thought flying back and forth across the ocean,” says “The risk of a protein being flexible is it would be easy,” says Kern. Kern, who credits her light-hearted brother that it can fall apart,” she says. “The fasci- Not quite. The data gave a jumbled for making the partnership lots of fun. nating part to me is how nature keeps that picture of atoms that seemingly existed in They performed single molecule from happening. These proteins are really three places at once. Kern’s take on this fluorescence resonance energy transfer living on the edge.” puzzling result: three different structures (FRET) experiments—tacking fluorescent As for the sibling team, the collaboration were present in a single crystal. molecules onto the upper and lower lids of continues. “He’s simply the best,” says Kern of Huebner. Calling the teamwork between the labs “electrifying,” Kern says, “The combina- “The risk of a protein being flexible is that it tion of these different biophysical techniques can fall apart. The fascinating part to me is how provided us with a much deeper under- nature keeps that from happening. standing of the fundamental principles of protein function. We’re already planning new 2=@=B63393@< ” projects together.” . —SARAH C.P. WILLIAMS May 2008 | HHMI BULLETIN upfront Baring HIV’s Dependencies New atlas reveals that HIV commandeers almost 300 human proteins to do its dirty work. VIRUSES ARE NEEDY. EQUIPPED WITH FEW GENES, THEY LEAN HEAVILY ON their host cells to help them successfully invade. ¶ This is true of the human immunodeficiency virus (HIV), which has just nine genes that make only 15 proteins. With such a sparse molecular tool kit, it is a anyone could have imagined how many wonder that HIV can wreak such havoc. But its ability to take over the would turn up.” very immune cells intended to protect us from disease is well known. An The study greatly expands the number of known HDFs, painting a newly detailed atlas of those host cell factors the virus hijacks would provide a deeper portrait of the virus and its dependencies. Only understanding of the virus, perhaps providing potential ways to thwart it. 36 of the human proteins commandeered by HIV had been previously identified. In January, a team led by HHMI inves- “This is a tremendous resource for the To produce the expanded catalog of tigator Stephen Elledge of Brigham and entire field of HIV research,” says Dan R. HDFs, Elledge’s group, which included Women’s Hospital in Boston produced just Littman, HHMI investigator and an HIV postdoctoral fellow Abraham Brass and such a roadmap. Writing in the journal expert at New York University Medical Harvard Medical School’s Judy Lieberman, Science, Elledge’s team reported that HIV Center. “It’s been known for a long time tapped newly available commercial libraries requires at least 273 human proteins, called that these host factors were out there, of what are known as small interfering RNAs. HIV-dependency factors (HDFs), to do its but there had never been a systematic These genetic molecules can switch genes molecular dirty work. approach to identify them. I don’t think off, preventing them from making proteins. 47<27<51/<13@B/@53BA IT’S NOT JUST HIV THAT STEVE ELLEDGE Wa^`]PW\UT]`eSOY\SaaSa 6S¸a [cZbW^ZgO\RbV`WdS BY TRACKING THE ABUNDANCE ]TSOQVaV@ EWZZWO[a HHMI BULLETIN | May 2008 By turning off genes in human cells one by one and then observing whether HIV could establish itself and reproduce, Elledge’s team plodded through 21,000 disrupted genes to isolate those the virus required. “We were looking for any genes that HIV needs for its life cycle,” Elledge says, pointing out that the proteins those genes make have the potential to be drug targets. Drugs now in use directly attack HIV, and they must be used in combination since the virus has evolved resistance to individual compounds, explains Elledge. Making drugs that target host proteins could bypass resistance; if a host protein the virus requires is disrupted, the virus would have to /[]\UbVSV]abQSZZ^`]bSW\acaSRPg67DeVS\bVSdW`caW\TSQbaQSZZaWa]\SQOZZSRVc[O\ do much more to overcome the challenge b`O\a^]`bW\! EVS\aQWS\bWabaVOZbSR^`]RcQbW]\]TbVOb^`]bSW\W\V]abQSZZaPZcSZSdSZa than simply rearrange a few amino acids ]T67D`SRW\bVSQSZZaeS`SR`OabWQOZZg`SRcQSRZ]eS`^O\SZQ][^O`SRb]W\TSQbW]\ c\RS`\]`[OZQ]\RWbW]\ac^^S`^O\SZ of genetic material. The new study reveals that many host proteins play coopted roles throughout the cycle of HIV infection—for tance to drugs that target cellular proteins. first, if dramatic, foray into HIV biology. example, helping the virus glom onto and “However,” he adds, “for the same reason, His lab also has ongoing gene discovery enter cells, converting RNA to DNA, and the drugs will have to be carefully charac- projects focused on other viral pathogens, creating new infectious particles. terized for toxicity.” as well as cancer, stem cells, and diabetes. “Many of the proteins identified in Elledge acknowledges that starving He plunged into HIV to spur HIV drug this study would probably be good candi- viruses of required host proteins could have development by industry, which he says dates for screening to find new anti-HIV unintended effects. “The cells do need is lagging: “I wanted to point out using drugs,” notes David Baltimore, a leading the proteins,” he says. “That needs to be genetics that there are real targets in cells HIV authority at the California Institute worked out.” and get [drug developers] thinking about of Technology, who agrees that the virus For Elledge, who is best known for his mining those pathways.” . Abraham Brass / Elledge lab will have a harder time developing resis- DNA cell cycle work, this new study is a —TERRY DEVITT May 2008 | HHMI BULLETIN ! 5FBDIJOH :PVOH #JPMPHJTUT /FX 5SJDLT Long the science where math mattered less, biology increasingly demands powerful quantitative skills. Teaching students the math they’ll need, though, is more than just 1+1=2. by Marc Wortman illustration by Luke Best " HHMI BULLETIN | May 2008 the first day of a year-long introductory chemistry course at Atlanta’s Emory University, students walked in to find three large round tables surrounded by white boards, no lectern, and a professor who 0Odidn’t stand still. Their instructor, Tracy Morkin, really baffled them. She projected some charts with numbers on the wall and Recent reports showing an ever-increasing need for biomedical told the students they would be teaching one another chemistry. scientists with stronger math skills and a yawning gap between the “They didn’t know what they were getting into when they need and the preparation being offered. So, Emory and a growing arrived last fall,” Morkin recalls with a smile on an early February number of other academic institutions are experimenting, even at morning. She bounds around the room, stopping occasionally to the precollege level, with new ways to integrate quantitative check in with students and their tablemates as they study data sets reasoning into the traditional biological sciences curriculum. on the freezing and boiling points of solutions with differing Putting more mathematics into biology and related courses, concentrations and under different pressures. They need to figure though, is not a simple matter of adding statistics, calculus, and out, from the data she gave them, which formulas can be used to computer science to already challenging subjects. It requires come up with the numbers. “It’s an inversion of the typical way of changing minds about the importance of such skills in a field that doing things,” says Morkin. The room buzzes as they puzzle historically shortchanged them and revamping longstanding atti- through the problem. Finally, she asks a student to step up to a tudes about how to educate future biomedical scientists. whiteboard. With Morkin’s coaching and input from other students, he lays out the equations from which the freezing and 5IF3VMFT)BWF$IBOHFE boiling points had been derived. many teachers and students question the need for Such nontraditional, active-learning approaches to introduc- change. “There’s an uphill battle,” attests Emory neuroscientist tory science and math courses are being tried at other colleges as Ronald Calabrese. “I’ve heard faculty members at department well, among them North Carolina State University and the meetings say, ‘Why do premed students need differential calculus? Massachusetts Institute of Technology. Morkin’s students are They’re going to medical school!’” delighted to be the first at their school to experience the alterna- His colleague Dieter Jaeger notes that resistance among tive to a standard lecture-style course. Sitting in a lounge after students is also a factor. “You have to convince them,” he says, class, freshman Amol Koldhekar says, “If you talk to people “that it’s more than just making biology harder.” taking the regular chemistry class, they get the right answers, but In fact, even though some students might never need to derive they don’t understand it. They plug ’n chug,” putting numbers an equation in their biomedical careers, studying math contributes into memorized equations without knowing where those equations significantly to those careers. A recent study of 8,500 students at come from. 77 U.S. colleges and universities showed that the stronger a Fellow freshman Remy Weinberger agrees. “In this class,” he student’s high school preparation in math, the better he or she is says, “you have to understand the theory behind the formulas so likely to do not only in chemistry and physics but also in biology. you can derive them yourself and know how to use them.” Writing in Science last July, the study’s authors—Philip M. Sadler, Like most of their classmates, they want to attend medical director of science education at the Harvard-Smithsonian Center school or pursue a career in another health care or biomedical for Astrophysics, and Robert H. Tai, a professor of science educa- science field. Morkin designed her chemistry course to give them tion at the University of Virginia—described “more advanced a running start in acquiring the quantitative, problem-solving, study of mathematics in high school” as one of the “pillars and interdisciplinary scientific skills they will need. supporting college science.” $ HHMI BULLETIN | May 2008 Perhaps the most important factor driving the increased emphasis on quantitative skills is the changing nature of biology. From discoveries about neural networks, genetics, and cardiac blood flow to understanding disease pathways within cells and throughout entire populations, many of the most important advances in the field now rely on mathematical modeling, quan- titative analysis, and bioinformatics (see sidebar). “I wasn’t good at math in high school,” admits biology professor Karl Joplin, and that influenced his choice of career. “I thought biology was a field with no math. But boy, was I wrong.” Accepting “Biologists of the future are going to need additional skills, more that the rules have changed, he now leads efforts at East Tennessee quantitative reasoning being chief among them,” says Adam P. State University, in Johnson City, and a consortium of other Fagen, a program officer at the NRC’s Board on Life Sciences. universities to promote more quantitative education in biology. “Bioinformatics, for one, didn’t even exist until a few years ago. Fernán Jaramillo, a neuroscientist at Carleton College in Now it’s a field in itself and essential to more and more people Northfield, Minnesota, agrees that “the nature of the problems across the life sciences.” we study has changed in the past 20 to 25 years. Quantitative issues “All of us are driven by Bio2010,” says Joplin. But even before are much more central, and that is an accelerating trend. Students the appearance of the report, HHMI—in conjunction with other have to realize they won’t do well without some quantitative supporters of science education reform—invested heavily in competencies.” Jaramillo directs the Interdisciplinary Science helping schools design and implement innovative strategies to and Math Initiative, an HHMI-funded multidepartmental effort bring more math into biology classrooms at all levels. to bring more quantitative and interdisciplinary approaches to For example, with HHMI support Joplin helped develop a science courses at his school. three-semester introductory biology course at East Tennessee #VJMEJOH4PMJE'PVOEBUJPOT recent surveys have shown that american college students tend to perform poorly in tests of quantitative skills compared with students in other countries. “The rest of the world is catching up, and by some measures has already overtaken us,” according to a 2006 report from a federal Commission on the Future of Higher Education. The problems persist among some with advanced degrees as well. A study published September 5, 2007, in the Journal of the American Medical Association found that 75 percent of U.S. physicians-in-training surveyed did not understand the statistics they encountered in medical literature, thereby calling into question their ability to interpret important clinical research data. Advocates for science education reform at several national organizations, including HHMI, have been urging educational institutions to rethink how they prepare their students in the biomedical sciences. A National Research Council (NRC) committee commissioned by HHMI and the National Institutes of Health to investigate education in the biological sciences issued an influential 2003 report, called Bio2010: Transforming Undergraduate Education for Future Research Biologists. It outlines a strategy to improve the quantitative skills and math, chemistry, and physics comprehension of students preparing for biomedical careers. The report encourages faculty to implement East Tennesee State University’s Karl Joplin pulled together teaching strategies that promote the skills required for problem 30 academic institutions to revamp how biology majors are Fresh Air Photo Fresh solving in an increasingly interdisciplinary world. taught quantitative reasoning skills. May 2008 | HHMI BULLETIN % #VJMEJOH#SJEHFT patricia marsteller calls herself emory’s “director of subversive studies” because of her work to build bridges between traditionally distinct departments, courses, and laboratories. That’s one of her charges as director of the university’s Center for Science Education. To push faculty members to rethink how and what they teach and get them to reach beyond their traditional disciplinary bound- aries takes provocation and rewards, according to Marsteller. “It’s difficult,” she says, “because it requires collaboration and coop- eration between departments that don’t work in the same way and don’t think in the same way about education. Faculty are torn by their disciplinary loyalties, and of course it’s always hard to teach As a science education leader at Emory University, Patricia Marsteller encourages faculty members old dogs new tricks.” to cross departmental boundaries to make math When Bio2010 appeared, she saw it as an opportunity to spark come alive for students in the sciences. interdisciplinary conversations, if not out-and-out insurrection. She sent copies to every faculty member of Emory’s biology State that integrates calculus, statistics, modeling, and other department and to many in the chemistry, physics, and mathe- mathematical skills into the traditional curriculum. He also initi- matics and computer science departments. Soon discussions ated an HHMI-sponsored consortium of 30 academic institutions began and an interdepartmental working group on science educa- working to develop strategies and materials for teaching students tion started meeting regularly. quantitative methods. (That group will hold its second annual Other efforts were already under way to bolster math prepara- summer workshop at HHMI’s headquarters in July.) “We’re trying tion at the undergraduate level, including a two-semester to generate the resources to teach this type of material,” says calculus course, now a requirement for all biology majors. Joplin. “It’s so brand-new.” Mathematics professor Dwight Duffus, who created the course Those working to develop new approaches and teaching mate- a decade ago, covers differential equations, probability and rials find themselves facing many other hurdles, including the statistics, and modeling by using a range of biological topics— legacy of mathematical concepts being taught without showing such as predator–prey systems, movement of species across how they apply to biology. “The textbooks haven’t changed,” regions, the spread of disease, and the firing of muscle neurons— Joplin observes. “There’s lots of quantitative information, but no to make the math immediately relevant. connection between the different subjects. It’s not conceptual.” Duffus is still learning how to teach math for biology students. So he has been developing mathematics-teaching modules based “The problem that I have, as a mathematician,” he says, “is under- on biological examples. “We want students to look at a data set standing the math and computing skills and knowledge biologists and not see a blank wall. Instead, they should be able to describe need in their majors. Should they be able to construct a mathe- the data and see something interesting in them.” However, just matical model on their own or just be familiar with the main coming up with data sets to teach quantitative reasoning skills for concepts? You have to be aware of the diverse math backgrounds biologists requires starting virtually from scratch. and aptitudes of students.” Claudia Neuhauser, an HHMI professor and applied mathe- Vaidy Sunderam, who chairs the department of mathematics matician at the University of Minnesota, is a pioneer in teaching and computer science at Emory, believes that more interdepart- biology undergraduates the calculus and other math they will mental dialogue is needed. “There’s still this gap,” he says. need (see Perspectives and Opinions, “Making Math Relevant”). “Mathematicians talk of matrices and equations, and biologists “There’s a problem with the way we teach,” she says. “Teaching is talk about structure and function.” being done in silos”—within traditional departmental boundaries— However, Sunderam and chemistry department chair David “but now we’re asking faculty and students to do work outside Lynn come together regularly as codirectors of the university’s those silos, and it’s a challenge.” Computational and Life Sciences Initiative, launched two years Gregory Miller & HHMI BULLETIN | May 2008 H3@=7<57<=<1/<13@53<3A EVObR][ObVO\RQO\QS``SaSO`QVVOdSW\Q][[]\-/Z]b OQQ]`RW\Ub]0S`bD]USZabSW\ /\66;7W\dSabWUOb]`Ob8]V\a 6]^YW\aC\WdS`aWbgAQV]]Z]T;SRWQW\SD]USZabSW\aSO`QVSa bVSVc[O\US\][ST]`US\SbWQ[cbObW]\abVObQOcaSQO\QS` µBVS`SO`SOP]cb US\SaO\RSOQVUS\SVOa]\ OdS`OUS 2S\\agZdO\WO had to be sold on it,” she recalls. QOZZaPW]W\T]`[ObWQaOeOgb]µRWabWZZbVSeVSObT`][bVS She showed them studies done at North Carolina State QVOTT ¶6SaOgabVS¿`ababS^Wab]`c\Q][^cbS`aW[cZObW]\a ]\2`]XSQbb]USbO University demonstrating that students who had taken this type of aS\aS]TV]e]TbS\W\RWdWRcOZ[cbObW]\aVO^^S\RcSaW[^Zg course—so-called “active learning” in a nontraditional classroom b]QVO\QS BVS\VScaSaOZU]`WbV[ab]Q][^O`SbV]aS[]QY setting—earned better grades than their peers in traditional [cbObW]\T`S_cS\QWSaeWbV`SOZRObOT`][QO\QS`QSZZa 1O\QS` lecture classes. She told them they would need to learn to work QSZZaeWZZ]\OdS`OUSVOdS[]`S]Ta][Sbg^Sa]T[cbObW]\a together and “figure out the chemistry.” Her enthusiasm—and bVO\bVS`O\R][POaSZW\SQ`SObSRPgbVSaW[cZObW]\aOga the data—won them over. D]USZabSW\O\RbVSOZU]`WbV[aÀOUbV]aS[cbObW]\a 6]eSdS`\]bOZZ]TbVS[O`Se]`bVg]TTc`bVS`abcRg)a][S Now, seven months later, the students talk back and forth O`SXcabµ^OaaS\US`a´OZ]\UT]`bVS`WRSPcb\]bOQbcOZZg across the tables. Papers rustle as they share notes and calculations. R`WdW\UbVSQO\QS` ¶CaW\U`SaSO`QVS`a¸Y\]eZSRUS]TUS\S “If it gets too quiet,” Morkin says, “they know I’m going to bother Tc\QbW]\Q][^cbS`a^`W]`WbWhSSOQV[cbObW]\POaSR]\Wba them. It’s tough for me not to talk too much, but as long as they ^`SQWaSQVO`OQbS`WabWQaO\RbVSUS\SW\eVWQVWb]QQc`a µ/b have each other, they don’t need me.” bVSS\Rg]cS\Rc^eWbVO`SZObWdSZga[OZZZWab]TUS\Sa¶bVOb Several students confirm what she says. Premed freshman O`Se]`bVSfO[W\W\UTc`bVS`W\ZOP]`Ob]`gabcRWSaaOga Weinberger says, “It’s nice to have your peers explain concepts to D]USZabSW\ BV]aSabcRWSaeVWQVµY\]QY]cb¶US\Sa]T W\bS`SabT`][QO\QS`QSZZa]`bVSUS\][Sa]T[WQS`S_cW`S you. Their thinking is more similar to yours than the professor’s is.” VcUSSTT]`bO\RbW[S µ0ST]`Sg]cW\dSabO\gbW[SW\bV]aS Adds classmate Ryan Makinson, who wants to attend graduate RSbOWZSRabcRWSag]c\SSRa][Sa]`b]T]dS`OZZ^WQbc`S¶VS school in neuroscience: “I understand a theory better by explaining aOga µBVS]\ZgeOgb]R]bVOb`WUVb\]eWab]caSPW]W\T]` it to a classmate. It’s pretty cool.” [ObWQb]]Za ¶´0S\XO[W\:SabS` According to Lynn, the success of Morkin’s experimental course is spurring the department to “completely change the way chemistry is taught” at Emory. At the department’s urging, the ago to foster interdisciplinary scholarship. They have begun university has begun restructuring its principal lecture hall into an hiring faculty and bringing in graduate students who pursue “active-learning environment,” while redesigning courses to fit it. interdepartmental research in emerging areas that require Marsteller, who helped the chemistry department launch powerful bioinformatics and other quantitative capabilities. Lynn, Morkin’s course with HHMI support for its development, thinks an HHMI professor, has also tapped this workforce as a source of active learning is a useful tool for boosting math competence teaching skills geared to the new emphasis in biology. For example, among science students. She hopes other Emory courses will adopt he developed a freshman course in which graduate students from a similar active-learning approach. “We’ve been training a lot of a variety of disciplines teach about their research. scientists who don’t understand the quantitative methods they are Emory’s Computational and Life Sciences Initiative has using,” she says. “Students need to struggle with them. If they’re just quickly “captured the imagination of a broad spectrum of the hearing the solution, all they do is write it down and forget it.” community,” says Lynn. “We don’t want to weaken the depart- For students in Morkin’s class and others like it around the ments, but we do want to catalyze new opportunities between country, the numbers have started to add up. They will know how them. That’s where the future discoveries will emerge.” to get the answers they need long after the course grades are in. . May 2008 | HHMI BULLETIN ' 1VWZR`S\eWbVbVSacPbZSabT]`[]TOcbWa[acTTS`a]QWOZWa]ZObW]\)bV]aSeWbV []`SaSdS`SRWaSOaSTOQSO[cQVb]cUVS``]OR Pg@WQVO`RAOZbcaj^V]b]U`O^VgPg4`SR`WY0`]R{\ people’s perspective and doesn’t under- the search for causes, according to stand why they don’t go along with what Fischbach, now scientific director of the she wants to do.” autism-focused Simons Foundation, a Sixty-five years after child psychiatrist private philanthropy launched by billion- Leo Kanner described the puzzling cluster aire hedge fund manager James H. Simons, She doesn’t share her sister’s pre-teen of cognitive, emotional, and social distur- whose daughter has mild autism. obsession with High School Musical or bances of 11 children with what he dubbed Discoveries of gene mutations in some instant messaging. She goes to a special “infantile autism,” much about autism autistic individuals support the growing school; she speaks in choppy, incomplete remains an enigma. An ever-widening array suspicion that the key problem in autism sentences, unable to explain anything of disturbed behaviors and developmental may lie within the synapse—the tiny, complicated; and when she walks past obstacles—from mild to devastating—now chemical-filled gap between the tip of a people in her home in Danvers, fits under the umbrella term “autism spec- transmitting neuron’s long, spindly arm Massachusetts, she shows little interest trum disorders” (see sidebar). and the receiving end of the next. and doesn’t make eye contact. Research into this mysterious disease, An estimated 100 billion neurons make Like many children with autism spec- however, has gotten a recent “kick in the up the human brain, connecting at synapses trum disorders, Nicole’s connection to pants,” says Gerald Fischbach, former to create powerful information-processing the world is an extremely narrow one. director of the National Institute of networks that enable humans to think and Her single overwhelming interest is Neurological Diseases and Stroke who has remember, interpret sensory information animals—her dog Lulu (she will read out served on the HHMI scientific review from the outside world, and navigate the loud only to Lulu), zoo animals, animals board. A convergence of funding, a handful challenges of social relationships. in photos, stuffed or plastic ones that she of key discoveries about the autistic brain, Sir Charles Sherrington, the neurolo- used to arrange in particular, ritualistic and technology advances that enable fine- gist and Nobel laureate who coined the ways. “She has her own agenda,” says her grained DNA searches have attracted term “synapse,” famously likened the brain mother, Maureen. “She can’t take other major scientific players who’ve narrowed to “an enchanted loom where millions /A>31B@C;=4036/D7=@A 7\VWaQZOaaWQ '"!^O^S`QVWZR^agQVWOb`Wab:S]9O\\S` b]a]QOZZSRµVWUVTc\QbW]\W\UOcbWa[ ¶@Sbbag\R`][SWa RSaQ`WPSRbVS^SQcZWO`PSVOdW]`a]T QVWZR`S\VSVOR a][SbW[SaW\QZcRSR]\bVS[]`SaSdS`SS\R]TbVSa^SQb`c[ ]PaS`dSRW\bVSZObS '! aO\RSO`Zg '" a 6SeOa[]ab /cbWabWQRWa]`RS`a]\QSQ]\aWRS`SR`O`SO`S\]e RWa[OgSR´O\RW\b`WUcSR´PgeVObVSQOZZSRbVSW`µ^`]T]c\R RWOU\]aSRW\OP]cb W\ # QVWZR`S\ BVSAW[]\a4]c\RObW]\¸a OZ]\S\Saa ¶BVSaSaSZTOPa]`PSRQVWZR`S\RWR\¸b`Sa^]\R 5S`OZR4WaQVPOQVPSZWSdSabVObbVSP`]ORS\W\URSTW\WbW]\]T b]bVSW`\O[Sa]`[OYSSgSQ]\bOQbO\RbVSW`Wa]ZObW]\eOa OcbWa[OQQ]c\baT]`[]ab]TbVSW\Q`SOaS 7\ORRWbW]\VSaOga SdWRS\bT`][bVSW`SO`ZWSabROga 7\US\S`OZ9O\\S`\]bSR bVSSf^O\aW]\]TaS`dWQSaT]`QVWZR`S\eWbVOcbWa[Q]cZRPS bVSgaV]eSR\][]`SW\bS`SabW\^S]^ZSbVO\W\µbVSRSaYbVS ^`][]bW\U[]`ST`S_cS\bRWOU\]aSa P]]YaVSZT]`bVSTWZW\UQOPW\Sb ¶BVSRWaSOaSWbeOabV]cUVbOb 2SZOgaW\\]`[OZRSdSZ]^[S\bQOcaW\UQ]U\WbWdSO\R bVSbW[SeOa`O`SbVSQOcaSc\Y\]e\ a]QWOZRSTWQWbcacOZZgO^^SO`W\bVSTW`abbe]]`bV`SSgSO`a B]ROgbVSZOPSZµOcbWa[¶WaO^^ZWSRb]Oa^SQb`c[]TeVOb /cbWabWQQVWZR`S\[OgeOZY]\bVSW`b]SaTZO^bVSW`VO\Ra O`SQOZZSRµ^S`dOaWdSRSdSZ]^[S\bOZRWa]`RS`a¶>22O\R ]`PSQ][STOaQW\ObSReWbVa^W\\W\UbVW\Ua BVSg[OgPS WbWaabWZZPOaSR]\ag[^b][aO\RPSVOdW]`a 2Wa]`RS`a]\bVS OPa]`PSRW\]PaSaaWdS`WbcOZaacQVOaZW\W\Uc^b]gaW\ a^SQb`c[´W\QZcRW\UOcbWabWQRWa]`RS`>22<=A\]b]bVS`eWaS ^SQcZWO`eOgaTZW^^W\UZWUVbaeWbQVSa]\O\R]TT]`c\`OdSZW\U a^SQWTWSRQVWZRV]]RRWaW\bSU`ObW]\RWa]`RS`O\R/a^S`US`¸a bVSW`a]QYabV`SORPgbV`SOR 0]gaO`SRWOU\]aSReWbVOcbWa[ ag\R`][S´`O\USW\aSdS`WbgT`][RSdOabObW\UZgRWaOPZW\U T]c`bW[Sa[]`S]TbS\bVO\UW`Za ´@ A HHMI BULLETIN | May 2008 of flashing shuttles weave a dissolving pattern, always a meaningful pattern though never an abiding one.” Perhaps the autistic brain is a loom that creates flawed patterns or can’t easily be programmed to weave new designs. 0/253<3A<=B0/2>/@3 Tsai: Matt Kalinowski Walsh: Joshua Dalsimer Joshua Tsai: Matt Kalinowski Walsh: no single gene has been linked to a large cognitive disorder,” observes Fischbach. halts nerve firing when appropriate. May 2008 | HHMI BULLETIN ! in autism spectrum disorders all seem to overlap in this particular area of synapse development.” A dramatic demonstration of how a single mutation can cause autistic symp- toms came when Südhof created lab mice containing the neuroligin-3 gene mutation previously found in humans. The muta- tion lowered the amount of neuroligin-3 protein in the animals’ forebrains by 90 percent, with a surprising consequence for BVS`SZSdO\QS]TbVSag\O^aSWaPSQ][W\UQZSO`T`][6cROH]UVPW¸a¿\RW\Ua their behavior. W\@Sbbag\R`][SO\RBV][OaARV]T¸a[]caS[]RSZ]TOcbWa[ Compared with control mice, the gene- altered rodents were less social: they spent A proper balance of excitatory and in 2003. He found that two pairs of Swedish less time interacting with a new mouse inhibitory events is key for learning, brothers with autism disorders had muta- placed in their cage. But they became memory, and other information-processing tions in the neuroligin proteins that Südhof smarter: they took fewer days to learn the tasks. If there’s a generalized excitatory- had identified seven years earlier. location of a platform submerged in murky inhibitory imbalance, it might well explain More recently, a larger international water, indicating enhanced spatial memory. why the autistic brain falters in trying to study revealed a gene for one of the “This is incredibly exciting,” Südhof says. build networks for learning, language, and neurexins in a chromosomal region linked “Usually when you impair mouse cognitive social awareness. In 2003, Zoghbi proposed to autism. Bourgeron has also found muta- function, they’re just stupid. These mice are that changes in the function of synapses tions in another gene expressed in synapses, not stupid—they have a huge positive change may be a fundamental cause of neurolog- Shank3, which interacts with neuroligins. in learning along with a modest social deficit. ical disorders—including autism. Other scientists have uncovered evidence This is the first genetic dissection of circuits That same year, another set of muta- that links the gene with autism. that underlie these different effects.” tions in autism came to light, causing “I suspect that Shank3 is one of at least The events leading from mutation to excitement because they, too, pointed to a dozen genes that have rare variants in altered behavior aren’t fully understood, components of the synapse-making them which likely are causative for the Südhof says, but the results “validate the machinery. In the 1990s, Thomas Südhof, disease,” comments Louis Kunkel, an whole idea that autism is related to an HHMI investigator at University of HHMI investigator at Children’s Hospital synapses.” Texas Southwestern Medical Center at Boston, who is hunting for autism genes. Dallas, identified genes for two key fami- “These will all likely be important in 1/AB7<5/E723<3B4=@53<3A lies of proteins involved in creating the neuronal maturation and learning.” Further progress in autism research means brain’s synaptic nerve connections. Another piece of the synaptic puzzle continuing the gene hunt on a broad front, The two gene-protein families, called recently emerged from the lab of HHMI deploying a variety of strategies. Many neurexins and neuroligins, are located on investigator Li-Huei Tsai at the Picower different kinds of genetic flaws appear to be opposite sides of the “cleft” or tiny space Institute for Learning and Memory at involved—mutations, deletions, copy where the neurons meet at a synapse. These MIT. Publishing in Neuron in 2007, she number variations (too many or too few two protein complexes extend out of the reported that a protein, Cdk5, modifies copies of critical genes), large and small nerve cells and physically bridge the synaptic another protein called CASK and promotes chromosome effects. Fortunately, new divide, but they also affect the excitatory- the interaction of CASK with neurexin genomic tools such as single nucleotide inhibitory balance of nerve signal traffic. proteins at newly forming synapses. polymorphism “chips” can spot increas- Thomas Bourgeron at the Pasteur “This general process seems to be ingly small genetic flaws. Institute in Paris first reported mutations extremely relevant to autism,” Tsai says, A genome search using these methods affecting these proteins in autistic patients “because a lot of the proteins implicated led to a January report by the Boston-based Südhof: Misty Keasler Thompson Zoghbi: Jack " HHMI BULLETIN | May 2008 Autism Consortium (a research collabora- Also collaborating with Greenberg at tion involving 14 Boston-area institutions) Children’s Hospital Boston is Kunkel, who of an abnormal chunk of chromosome 16 previously discovered the gene for found in several autistic patients. The Duchenne muscular dystrophy. He and segment harbors a mixture of gene deletions Children’s Hospital colleague Isaac and extra copies of genes that is estimated to Kohane have devised an unorthodox gene- account for 1 percent of unexplained cases hunting approach—looking for gene of autism spectrum disorder. Several of the “signatures” of autism in blood cells, rather genes are known to be expressed in the than in the brain. brain or in early nervous system develop- “We’re using microarrays to see if there ment. Researchers believe that a large is a signature of gene expression in whole number of rare “copy number variations” blood that distinguishes autism, and we are such as these may be waiting to be found. starting to see such signatures,” says Working with clinical genetics collabo- Kunkel. If gene expression in the blood rators in several Middle Eastern countries cells is similar enough to that in brain where intermarriage between cousins and cells to be a useful surrogate measure, large family size are common, HHMI inves- researchers could avoid the need to obtain tigator Walsh, a member of the Autism and test brain tissue, which is impossible in Consortium, has been trying another gene- living humans. Ultimately, a “proxy” signa- seeking strategy. He is attempting to find ture for autism could be used diagnostically ´;Oc`SS\0`O\Q]\\WS` rare recessive gene mutations, which are and in testing candidate drug therapies. more likely to be expressed when intermar- With a variety of intensive behavioral Bird’s finding offers another reason riage occurs over generations. “My therapies, the capabilities and lives of many why the synapse makes sense as the culprit collaborators bring in their tough cases,” autistic children, like Nicole Branconnier, in autism, says Walsh. “It may explain the says Walsh, who has visited countries have improved. There is no definitive later age of diagnosis of autism, and its including Dubai, Kuwait, Saudi Arabia, and treatment for the multifaceted, complex preferential effects on later-appearing Oman. “Our team of genetic counselors, disorders of autism, and a cure seems a skills—like language and social behavior— pediatric neurologists, clinical psychologists, distant prospect. and perhaps its greater likelihood of and others provide a second opinion, draw However, the biological underpinnings improvement in some fortunate children,” blood for DNA samples, and say that we’ll of autism are becoming clearer. And among speculates Walsh. “If we can develop try to figure out the genetic picture.” the recent findings, one in particular may medications to modulate these synaptic Walsh’s strategy has begun to pay off. He bode well for reversing symptoms with changes, we may be able to provide better has found several families in which a future therapies. therapies for this devastating disorder.” member with autism is missing both the In 2007, Adrian Bird, a geneticist at the Fischbach agrees: “The possibilities of paternally and maternally inherited copies of University of Edinburgh, showed that Rett reversal are very real.” That’s encouraging, genes, making those genes likely suspects. syndrome mice with a silenced MECP2 and so is the quickening pace of gene “We don’t yet know what the deletions gene could recover many of their lost discovery, which ultimately should shed do,” he says. But three of the missing genes functions when the gene was reactivated further light on causative mechanisms. turned out to be among those being studied in adulthood. This couldn’t be attempted How long this will take, though, is by Michael Greenberg, a Children’s in humans with Bird’s experimental anyone’s guess. Hospital Boston colleague. Greenberg is methods, but the implications are cause “The hunt is on,” says Fischbach, “but looking for autism clues by studying for optimism: apparently the MECP2 it’s going to be a while.” . nervous system genes that are silent until mutations don’t irreparably harm the FOR MORE INFORMATION: To learn more about the latest ap- activated, during learning, to make more neurons themselves, which develop very proaches to autism, visit the Websites for the Simons Foundation synapses and are logical candidates for early; rather, the mutations cause malfunc- (http://www.simonsfoundation.org/) and the autism research. tions in the synapses that form later on. Autism Consortium (http://www.autismconsortium.org/). May 2008 | HHMI BULLETIN # Two HHMI investigators, Meyer and Jeannie T. Lee of Harvard Medical School and Massachusetts General Hospital, are at the forefront of research on the intrica- EVS\WbQ][Sab] cies of dosage compensation. In more QV`][]a][Sa than 20 years of experiments on nema- todes, or roundworms, Meyer has shown [S\USbaV]`b This disparity leaves our cells in a jam. how cells count the number of X chromo- A woman’s cells carry twice as many copies somes they contain and revealed the QVO\USR /[]\U of most X chromosome genes as a man’s workings of a protein cluster that adjusts cells and—if the genes work at full gene activity on the X chromosome. bVSW` !^OW`a]T throttle—can crank out correspondingly Studying mice, Lee has deciphered details QV`][]a][Sa more of their protein products. Although of the molecules that regulate X inactiva- genes on the X chromosome are essential tion. Both scientists say their results have e][S\VOdSbe] for everything from filtering blood to surprised them at every turn. repairing DNA (most of them have Now their work is having an impact on ab`O^^W\UFQV`] nothing to do with sex differences), a biologists in other fields. Researchers are double dose of their proteins is disastrous looking to dosage compensation for clues []a][SaeVWZS for cells. about how cells orchestrate changes to And that’s not only true in humans. large tracts of DNA or entire chromo- [S\a^]`bO\F Animals as different as roundworms, fruit somes. And Lee’s recent findings of QV`][]a][SO\R flies, and opossums face the same problem. peculiarities in X inactivation among “It’s essential to have gene balance” embryonic stem cell lines have height- OG 7b[WUVbPS between the sexes, says HHMI investigator ened concerns about the safety of these Barbara J. Meyer of the University of stem cells when used to develop replace- bVScZbW[ObS California, Berkeley. If the numbers are ment tissues and organs. out of whack, “the animals are dead, it’s a]c`QS]T[OZS that simple,” she says. C3::C:A@A0A1CA \SaaPcbbVS Necessity, however, is the mother of To pull off dosage compensation, cells adaptation. Animals have evolved myriad need basic math skills. They have to be GQV`][]a][S mechanisms to keep gene activity the able to count the number of X chromo- same in the two sexes. Known as dosage somes and non-sex chromosomes (called WaR]e\`WUVb compensation, this type of gender equality autosomes) they harbor. Meyer uncov- can work in several ways. For example, ered the basis for this arithmetic ability RW[W\cbWdSeWbV female mammals shut down one X chro- in roundworms. ]\ZgOP]cb]\S mosome, preventing most of its genes The discovery began with an Alexander from yielding any proteins—what’s termed Fleming moment. Fleming, a Scottish bVW`ROa[O\g X chromosome inactivation. This process bacteriologist, stumbled on penicillin in is complete by the early stages of embry- 1928 when he took a close look at some 2 & HHMI BULLETIN | May 2008 and sickens or kills the worms. But the nematodes in one container were hale, and their population was booming. Meyer’s lab fi rst learned that the process Thinking that the culture had been operates differently in worms than in contaminated, Meyer’s lab technician mice and humans. Instead of turning off started to throw the animals away. “He one of its two X chromosomes, a hermaph- was literally pouring the culture down the compensation. This allows cells to turn on roditic worm dials down the activity of all sink,” recalls Meyer, “when I said, ‘Stop!’” another gene that triggers the animal to genes on both Xs by half, on average. Under the microscope, any nematodes develop male characteristics. Meyer’s group went on to discover that that survived the mutation should have With a pair of X chromosomes, a worms rely on a cluster of proteins called appeared short and squat, but she noticed hermaphrodite produces twice as many X the dosage compensation complex that they were long and sleek. Investigating signal elements as does a male. In this (DCC) to achieve this feat. The complex the animals’ mysterious survival led Meyer case, the “off” proteins from the X chro- attaches to the X chromosome and turns and colleagues to a gene called xol-1. mosomes win out over the “on” proteins gene activity down. But the DCC’s “That broke it open for us,” she says. from the autosomes, quieting xol-1 and proteins don’t unite and start working As she and her co-workers have revealed permitting dosage compensation. until the cell inactivates xol-1. over the last 20 years, xol-1 serves as a Meyer and colleagues continue to Some of the DCC’s proteins are similar cellular abacus, with its tallies dictating refi ne this story. In a November 2007 to proteins that help chromosomes not only whether dosage compensation paper, for instance, they reported identi- compact and then separate during cell kicks in, but also the animal’s sex. Worm fying another X signal element, the fi fth division. That finding suggests that the sexuality differs from our own. Male worms found so far. DCC is derived, evolutionarily, from a carry one X chromosome, but no Y. The They have also tracked down the protein combination that performs a other sex, with two Xs, is a hermaphrodite molecular “dimmer switch” responsible for completely different task. In other words, (an organism with male and female repro- dosage compensation in roundworms. when cells in some ancestral worm needed ductive systems). By hunting down mutated genes that turn xol-1 on or off at the wrong time, Meyer’s team identified the “counters” that tell worm cells how many sex chro- mosomes they have. Several genes on the X chromosome, the researchers found in a series of studies, code for proteins called X signal elements that can shut down xol-1. The researchers also found genes on the autosomes whose proteins, known as auto- somal signal elements, can activate xol-1. In other words, worm cells simultaneously fashion proteins that can turn xol-1 off and proteins that can turn it on. The fate of an X chromosome depends on a molecular scuffle between the X signal elements and the autosomal signal elements. The battle occurs at xol-1’s promoter, its on-off switch. “They’re all duking it out for xol-1’s promoter,” says Meyer. In the free-for-all, numbers prevail. Male worms have one X chromosome but two copies of each autosome. So their “on” signals from the autosomes overwhelm their “off” signals from the solitary X. 6=E/>@=B37<1:CAB3@/28CABA53<3/1B7D7BG=<B63F16@=;=A=;3 Mark Likosky Thus, xol-1 is active and thwarts dosage />@=13AA1/::322=A/531=;>3 May 2008 | HHMI BULLETIN ' this long. “I thought it would be solved by now,” she says. Yet scientists are far from having all the answers, in part because their studies keep throwing them curve balls, including odd molecular pathways, backward DNA silencing, and unexpected chromosomal liaisons. British geneticist Mary Lyon galva- nized research into dosage compensation in 1961, when she determined that the Barr body, a shadowy structure lurking at the edge of the nucleus in mammalian cells, was an inert X chromosome. On the basis of that fi nding, researchers posited that cells must have an “X inactivation center” that closed down the chromosome. But the responsible genes were elusive. It wasn’t until 1991 that Huntington Willard, 83/<<73:336/A723 didn’t envision that the work would take is all that’s needed to carry out functions in Leah Fasten ! HHMI BULLETIN | May 2008 pairing doesn’t normally occur once X inactivation is complete, and it requires at least three genes, including Tsix. Without the contact, the cell can’t figure out how directed to repair or replace damaged many X chromosomes it contains or tissue and organs. which of them to inactivate, so it might But only if X inactivation proceeds the cells. Willard’s lab demonstrated this shut down both or neither. During their normally. Lee’s group assessed the amount unusual behavior for Xist, whereas Lee’s brief dalliance, the two chromosomes of Xist RNA, viewed as an indicator of chro- group showed it for Tsix. appear to be communicating. What infor- mosome shutdown, in 11 stem cell lines That wasn’t the last surprise that mation passes between them “is something being maintained in the lab. The samples awaited Lee and colleagues as they delved we’re vigorously pursuing,” Lee says. included “approved” lines that scientists into Tsix’s actions. Because strands of Tsix can study with federal government money and Xist RNA are complementary, if they A4:A54=@AT3;C3::A and other lines provided by HHMI investi- meet they’ll stick together. A reasonable Findings by Lee and others also raise gator Douglas A. Melton, co-director of hypothesis is that Tsix RNA prevents X concerns about the safety of embryonic Harvard’s Stem Cell Institute, that had chromosome inactivation by grabbing and stem cells. Researchers have high hopes been developed without federal funds. disabling the Xist RNA. that these flexible cells, which can “When we looked at their X inactivation Reasonable but wrong, Lee and specialize into heart cells, liver cells, or state, they were all over the map,” Lee says. colleagues concluded in a 2006 Molecular any of the body’s other cell types, can be (continued on page 56) Cell paper. Inside the cell, a chromo- some’s DNA wraps around spool-like proteins called histones. To shut down a specific gene, cells typically coil the DNA /;GAB3@GB6/B5@/0A6=:2 strands tighter, denying access to essential DNA-reading proteins. But to silence the µBVWaWaOacPXSQbbVOb^S]^ZSTOZZW\Z]dSeWbV¶aOga6c\bW\Ub]\EWZZO`RO\66;7 Xist gene in fruit flies, Lee and colleagues ^`]TSaa]`Ob2cYSC\WdS`aWbgW\2c`VO[<]`bV1O`]ZW\O EWZZO`ReV]RS found, Tsix appears to do the opposite; it aQ`WPSaVW[aSZTOaµbVS]ZRUcg¶W\bVSTWSZRaOgabVObVWaObb`OQbW]\b]R]aOUS Q][^S\aObW]\O\RFQV`][]a][SW\OQbWdObW]\PSUO\W\bVSSO`Zg '% aeVS\VS loosens the DNA. Cinching up the DNA, eOaO6O`dO`Rc\RS`U`ORcObSe]`YW\U]\OZOP^`]XSQbeWbVbVSZObS66;7W\dSabW by contrast, turns on Xist. Only a few fruit UOb]`AO[:Obb 2c`W\U[Wb]aWaQSZZaQ]^gbVSW`QV`][]a][SaO\RbVS\RWdWRS fly genes are known to operate in this way, O\R:ObbO\REWZZO`ReO\bSRb]RSbS`[W\SeVSbVS`aWZS\QSRO\ROQbWdSFQV`][] she says. a][SaPSVOdSRRWTTS`S\bZgRc`W\UbVWa^`]QSaa BVSgRWR´bVSW\OQbWdSFeOa In retrospect, the seemingly backward aZ]eS`b]Rc^ZWQObSO\RQ]^WSRWbaaSQbW]\aW\ORWTTS`S\b]`RS`bVO\RWRWbaOQbWdS mechanism makes sense, she adds. To ^O`b\S` EVS\VS[]dSRb]GOZSC\WdS`aWbgT]`U`ORaQV]]ZEWZZO`RYS^bc^ VWae]`Y]\FW\OQbWdObW]\´Pcb]\ZgPg[]]\ZWUVbW\U 0gROgVSe]`YSR]\VWa close down an entire X chromosome, a ]TTWQWOZRWaaS`bObW]\^`]XSQbabcRgW\UbVSUS\SbWQa]TO\W\VS`WbSR[SbOP]ZWQRWa cell might compress all the chromosome’s ]`RS`QOZZSR[SbVgZ[OZ]\WQOQWRS[WO EWZZO`RVOaRWdWRSRVWaSTT]`bPSbeSS\F DNA. But if Xist were a conventional W\OQbWdObW]\O\R]bVS`US\SbWQ^`]XSQbaSdS`aW\QS 6SeOa^O`b]TbVSbSO[bVOb gene, that tightening would also shut it \OWZSRR]e\bVS2S\\agZdO\WOAbObS switching off Xist might permit the gene to C\WdS`aWbgUOdSbVSTWSZRa][SbVW\USZaSb]Sf^Z]`S BVSg[SOac`SRbVSOQbWdWbg remain active even when the rest of the ]T'#^S`QS\b]TbVSFQV`][]a][SUS\Sa´bVS[]abQ][^`SVS\aWdSac`dSga] chromosome is silenced, Lee says. TO` BS\b] #^S`QS\b]TbVSUS\SaSaQO^SRW\OQbWdObW]\S\bW`SZgO\RO\]bVS` Thanks to her team’s report two years ^S`QS\ba][SbW[SaaVcbR]e\ 6]eQSZZa[O\OUSb]W\OQbWdObS[]abF QV`][]a][SUS\SaPcbZSOdSa][Se]`YW\UWaO[gabS`g AQWS\bWabaVORbV]cUVb ago in Science, researchers have another bVObFWab@ May 2008 | HHMI BULLETIN ! Sources of Renewal As scientists learn more about how to produce and manipulate stem cells—amid high expectations and close scrutiny—no one is ready to choose any one approach over another. by Robin Mejia illustration by Shout Above the desk of HHMI investigator George Q. Daley hangs a striking impressionistic painting of a person lost in thought, called “On Learning My Diagnosis.” It’s by an attorney Daley began treating in 1993 for a chronic and reprogram its nucleus to create a cell with the potential to produce sometimes fatal blood disorder. With that diagnosis, the man put any part of the body.) If the egg is grown to a blastocyst—an early down his law books. He has been doing so well for so long, stage embryo—researchers can harvest stem cells from it. Daley’s however, that he’s returned to his legal practice. This is the kind team did that and more. They repaired the defective gene in the of outcome that a doctor hopes for. cultured stem cells, coaxed the repaired cells to become blood Not every patient is that lucky. “I just spent the last week in the stem cells in a Petri dish, transplanted the healthy blood cells into hospital taking care of kids with all kinds of blood diseases,” says diseased mice, and partially restored immune function in the Daley, a physician-researcher at Children’s Hospital Boston. animals; they published the results in 2002 in Cell. “Sickle cell anemia, for example, is exquisitely painful, and we This is the ultimate promise of stem cell research—fi xing don’t have a treatment for it. We give them narcotics and we illnesses at the genetic level and then using the modifi ed cells to hydrate them, but what we’d ideally like to do is repair their cells.” treat patients. No one has yet succeeded in creating human stem He envisions a day when he’ll be able to take cells from his cell lines with the technique Daley’s team used in mice, called patients, repair the damaged genes, and grow new blood cells to somatic cell nuclear transfer or therapeutic cloning. Researchers treat them. Daley, a leader in studying stem cells—embryonic have created human stem cell lines from embryos donated by in vitro stem (ES) cells, adult stem cells, and the tantalizing but still very fertilization patients, but these cell lines are not patient specifi c. new induced pluripotent stem (iPS) cells—has already managed There are groups with ethical or religious concerns that consider to do that kind of cellular repair in mice. the use of embryos destruction of human life or a step toward repro- For Daley and others who study stem cells, recent discoveries ductive cloning. President George W. Bush agrees, and announced make this an exciting and challenging time. They are learning in 2001 that the U.S. government would fund research only with how to manipulate these cells to produce the building blocks of human embryonic stem cell lines created before August 9, 2001. various organs. And the development of iPS cells opens the possi- Researchers like Daley cannot apply for National Institutes of Health bility of producing patient-specific stem cells without using (NIH) grants, or any other federal funds, to support development of human embryos, an achievement that could defuse many of the new human embryonic stem cells, nor can they use equipment ethical and political tensions that surround this area of biology. funded by federal grants to work with newer stem cell lines. But there is much work to do before researchers know how well Voters in some states as well as private donors have provided a these stem cells will deliver on their promise. few alternatives. In 2004, Californians passed Proposition 71, autho- rizing $3 billion in state bonds to fund stem cell research through a Working within Limits granting agency called the California Institute for Regenerative To achieve cellular repair in mice, a team led by senior colleague Medicine. A handful of other states followed, with much smaller Rudolf Jaenisch and Daley, when he was at the Whitehead amounts. For its part, Harvard relied on private philanthropic dona- Institute, took the nucleus from the cell of an adult mouse with a tions to create the Harvard Stem Cell Institute, which now genetic defect and inserted it into a mouse egg. (An egg cell can encompasses labs at the medical school, other parts of the univer- sity, and 11 teaching hospitals. Daley, a member of the Stem Cell Institute along with several HHMI colleagues, lined up private funding to support his embryonic stem cell work, supplemented in February 2008 when he became an HHMI investigator. However, the administration’s position on human embryonic stem cells is seen as a barrier, as many researchers limit them- selves to projects that are eligible for funding from the NIH. “I have a junior investigator in my lab who’s a driving force behind our human ES research, which uses all private funding,” !" HHMI BULLETIN | May 2008 BE=AB3>A1:=A3@ 7\bg^S RWOPSbSabVSP]RgObbOQYaO\RYWZZaWba]e\W\acZW\ ^`]RcQW\U^O\Q`SObWQPSbOQSZZaZSOdW\U^ObWS\baRS^S\RS\b]\ W\acZW\W\XSQbW]\aT]`ZWTS C\ZWYSbVSZWdS`O\RaYW\bVS^O\Q`SOa R]Sa\]bVOdSOeSZZ]TORcZbabS[QSZZaObbVS`SORgb]`S^OW` RO[OUS EVS\bVSac^^Zg]TPSbOQSZZaWaSfVOcabSROaVO^^S\a W\bg^S RWOPSbSabVS`S¸a\]^ZOQSb]bc`\T]`[]`S 66;7W\dSabWUOb]`2]cUZOa/ ;SZb]\¸aaWUVbaO`SaSb]\ Qc`W\Ubg^S RWOPSbSaPg`SU`]eW\UPSbOQSZZaO\RVSWab`gW\U b] R] a] bVS ]\Zg eOg VS QO\ T`][ S[P`g]\WQ abS[ QSZZa 5cWRW\UbVS3AQSZZabV`]cUVaSdS`OZRSdSZ]^[S\bOZabS^aWaO Z]\UaZ]e^`]QSaa µ4WUc`W\U]cbV]eb]bSZZbVSaSQSZZaeVWQVeSY\]eQO\R] O\gbVW\UeVObb]R]WaOQVOZZS\US¶VSaOga @SaSO`QVS`aQO\ says Daley. “As he’s trying to get an independent faculty position, bSOaSabS[QSZZaW\b]a][Sbg^Sa]T\Sc`]\aO\RPZ]]RQSZZaPcb other mentors are saying, you need an NIH grant, you better ;SZb]\SabW[ObSabVOb¿dSb]aSdS\abS^aO`S`S_cW`SRb]Q`SObS focus on a mouse program.” PSbOQSZZa´O\RWbVOabOYS\bV`SSgSO`ab]¿Uc`S]cbV]eb]UcWRS 3AQSZZabV`]cUVXcabbe]]TbV]aSabS^a Excitement Tempered with Caution BVWaWaabS[QSZZ`SaSO`QVOaRSdSZ]^[S\bOZPW]Z]Ug ;SZb]\ Sf^ZOW\abVObbVS[]abW[[SRWObSPS\S¿ba]T[]ababS[QSZZ At the end of 2007, a new door swung open. Scientists in Japan and `SaSO`QVeWZZZWYSZgQ][ST`][eVObbVSaSQSZZaQO\bSOQVaQWS\ Wisconsin, and Daley at Harvard, reported that they had success- bWabaOP]cbV]eQSZZaRWTTS`S\bWObSV]ebWaacSaRSdSZ]^O\RV]e fully turned human adult skin cells into stem cells. In November, RWaSOaS]QQc`a researchers in the lab of Shinya Yamanaka at Kyoto University 4]`SfO[^ZS]\QS;SZb]\RWaQ]dS`aV]eb]U`]eOPSbOQSZZ documented in Cell, and, separately, a team led by James VSQ]cZRQ`SObSabS[QSZZaT`][a][S]\SeWbVbg^S RWOPSbSa O\RT`][a][S]\SSZaSeWbVVSOZbVgPSbOQSZZa BVS\VSQ]cZR Thomson at the University of Wisconsin reported in Science, that U`]eP]bVabS[QSZZaW\b]PSbOQSZZaO\ReObQVb]aSSeVS`SbVS they had created stem cells by inserting four genes into human RWOPSbWQ¸aQSZZaU]e`]\U adult skin cells. The genes appeared to perform the same func- 0g^`]RcQW\UbVSRWaSOaSW\O>Sb`WRWaVaQWS\bWabaQO\`c\ tion that insertion into an egg does in other animals: resetting the Sf^S`W[S\ba´O\RSdS\bSabR`cUa´W\eOgabVSg\SdS`Q]cZRW\ cell’s genetic state back to day one. ^S]^ZS BVWaWaeVgbVS6O`dO`RAbS[1SZZ7\abWbcbSVOaa^S\b Daley’s paper, published online in Nature in December 2007, []`SbVOb$ #[WZZW]\Q`SObW\UOZOPb]TOQWZWbObS^`SQWaSZgbVOb YW\R]Te]`Y described his ability to reprogram human adult skin cells using BVcaW\bVSPOaS[S\b]TbVSPcWZRW\UeVS`S;SZb]\Q]\RcQba even fewer genes. Scientists refer to the new cells as induced VWa`SaSO`QVOQ]ZZSQbW]\]TP]fg`]P]baWaObe]`Y BVSgV]ZR pluripotent stem (iPS) cells, meaning they have been coaxed to ^ZObSaPO`SZgZO`US`bVO\R`W\YQ]OabS`aeWbVSOQVQ]\bOW\W\Uc^ regress to a state in which they could become any of the various b]!&"QcZbc`SaW\aS^O`ObSbW\geSZZa ;SQVO\WQOZZW[Pa[]dSbVS cell types that make up the body. In human cell lines, such pluri- ^ZObSaO`]c\RO\RR`]^RWTTS`S\bQVS[WQOZaW\b]SOQV´Q`SObW\U W\STTSQb!&"RWabW\QbSf^S`W[S\ba May 2008 | HHMI BULLETIN !# From left: an easier route to his goal of making patient-specifi c stem cells, George Q. Daley, HHMI investigator none of his physician colleagues would consider using iPS cells Douglas A. Melton, HHMI investigator Sean J. Morrison, HHMI investigator as a treatment, at least for now. To insert new genes into cells to Stuart H. Orkin, HHMI investigator form iPS cells, researchers attached the genes to fragments of a HHMI scientists and others are exploring the possibilities and limitations of stem virus that can cause cancer. cells to understand tissue development Scientists are working on methods to revert cells to a pluripo- with hopes of curing disease. tent state without using such viruses—by employing drugs, for example, or by injecting proteins directly into the cell. “I think we’ll see this happen soon,” says Konrad Hochedlinger, a colleague of Daley’s at the Harvard Stem Cell Institute who also works on iPS cells. “Then the big question will be how similar these induced cells are to embryonic stem cells.” “People take it for granted that they are identical,” he says, but iPS cells are not yet as well understood as their ES counterparts. Thus, Hochedlinger wants to grow human iPS cells alongside >@7<17>/:>:/G3@A human ES cells and then direct both to become adult tissues 3[P`g]\WQabS[3AQSZZaO`SRS`WdSRT`][S[P`g]abVObRS such as muscle or nerve cells. He points out that with mouse dSZ]^T`][SUUaTS`bWZWhSRW\dWb`] 3OQVS[P`g]bg^WQOZZgT]c` cells, molecular analysis of the two cell types found no major b]TWdSROga]ZRWaOV]ZZ]e[WQ`]aQ]^WQPOZZ]TQSZZaQOZZSRO differences, but when he attempted to grow adult heart cells from PZOab]Qgab B]US\S`ObSQcZbc`Sa]Ta^SQWTWQbg^Sa]TRWTTS`S\ bWObSRQSZZa´VSO`b[caQZSQSZZaPZ]]RQSZZa]`\S`dSQSZZaT]` the mouse iPS cells using a protocol developed with ES cells, the SfO[^ZS´`SaSO`QVS`a QVO\US bVS QVS[WQOZ Q][^]aWbW]\ ]T iPS cells didn’t seem to form tissue as easily. bVSQcZbc`S[SRWc[OZbS`bVSac`TOQS]TbVSQcZbc`SRWaV]` “Superfi cially, things look okay, but as you look more closely, []RWTgbVSQSZZaPgW\aS`bW\Ua^SQWTWQUS\Sa BV`]cUVgSO`a]T the iPS cells don’t develop quite normally,” says HHMI investi- Sf^S`W[S\bObW]\aQWS\bWabaVOdSSabOPZWaVSRa][SPOaWQ^`] gator Stuart H. Orkin, at Children’s Hospital Boston. “They’re b]Q]Za]`µ`SQW^Sa¶T]`bVSRW`SQbSRRWTTS`S\bWObW]\]TS[P`g ]\WQabS[QSZZaW\b]a^SQWTWQQSZZbg^Sa pretty close but they ain’t perfect.” /RcZbabS[QSZZaO`Sc\RWTTS`S\bWObSRQSZZaT]c\RO[]\UbVS Orkin studies ES cells, trying to understand exactly what RWTTS`S\bWObSRQSZZabVObQ]\abWbcbSObWaacS]`]`UO\ BVS^`W processes keep them from differentiating into adult tissue. The [O`g`]ZSa]TORcZbabS[QSZZaW\OZWdW\U]`UO\Wa[O`Sb][OW\ initial iPS experiments reported last fall created something of a bOW\O\R`S^OW`bVSbWaacSeVS`SbVSgO`ST]c\R BVSORcZb “black box,” he explains. Scientists know that four specifi c genes bWaacSa`S^]`bSRb]Q]\bOW\abS[QSZZaW\QZcRSP`OW\P]\S[O` cause the cells to regress to a pluripotent state, but they don’t `]eaYSZSbOZ[caQZSaYW\O\RZWdS` A][ObWQQSZZ\cQZSO`b`O\aTS``S^`]U`O[aORcZbQSZZaOTSOb bVObVOaPSS\OQQ][^ZWaVSR]\ZgeWbVO\W[OZQSZZa /\ORcZb QSZZ¸a\cQZScaWaW\aS`bSRW\b]O\SUUQSZZeVWQVQ`SObSaO\S[ P`g] AbS[QSZZaO`SbVS\RS`WdSRbV`]cUVO^`]QSaaaW[WZO`b] bVObcaSRb]Q`SObSS[P`g]\WQabS[QSZZa 7\RcQSR^Zc`W^]bS\babS[W>AQSZZaO`SRS`WdSRT`][ORcZb a][ObWQQSZZaacQVOaaYW\QSZZa BVSaSQSZZaO`S`S^`]U`O[[SR eWbVbVSW\aS`bW]\]TOVO\RTcZ]TUS\Sab]OQbOaabS[QSZZa 7\ TOQbbVSgbVS\RWa^ZOgS[P`g]\WQabS[QSZZZWYSOPWZWbWSa / Orkin lab Orkin: Marie Palardy Dalsimer Morrison: Donna Terek Melton: Joshua Daley: Leah Fasten “We’re gathering a complete parts list of the things that are involved and required.” Stuart Orkin know how they do it, or why the process takes weeks longer than the development of stem cell lines created by somatic cell nuclear transferring a nucleus from an adult cell into an egg. transfer, the technique Daley used in his mouse work and In a series of experiments described in the March 21, 2008, continues to explore with human cells. issue of Cell, Orkin examined nine genes that are known to help This ban is a long-standing goal of groups opposed to human ES cells maintain themselves, including the four used in the embryonic stem cell research. They praised the iPS work and used recent iPS experiments and fi ve others. Each of those nine genes it as a reason to call (again) for a ban on therapeutic cloning. produces a transcription factor, a protein that causes other genes “These are the same political lobbyists that have been looking to turn on or off. Orkin identifi ed hundreds of genes that are for reasons to end this research all along,” says Morrison, who studies targeted by one or several of the transcription factors, work that he the mechanisms involved in adult stem cell renewal and aging. hopes will help scientists tease out the cellular-level processes “The positions they’ve taken in the past were not credible, and the that help ES cells maintain and reproduce themselves. Similar position they’re taking on iPS cells is not credible.” He points to work on iPS cells could help explain the differences between the earlier claims by several groups that 65 diseases had been treated two types of stem cells. with adult stem cells. That claim, “has been roundly dismissed.” “We’re gathering a complete parts list of the things that are “We haven’t had a logical debate,” adds Melton, who argues involved and required,” Orkin says. “Maybe adding something that if stem cell research were truly unethical, “you would never that hasn’t been considered yet might make it better.” say it’s okay as long as you don’t use federal funds.” Both Melton and Morrison are hopeful that scientists may Science Informing Policy eventually be able to focus only on iPS cells, but they argue that With each new discovery, stem cell researchers have learned to it’s too early to close the door on embryonic stem cell research. provide perspective and context to help a hopeful public and those “Certainly from a patient perspective that would be wrongheaded,” eager to fi nd alternatives to using human embryos to understand says Melton, whose position is echoed throughout the fi eld. the implications of the fi ndings and the questions that remain. This caution is based on history. In the early 1990s, researchers HHMI investigator Sean J. Morrison, director of the University thought they were closing in on treatments for genetic diseases of Michigan Center for Stem Cell Biology, testifi es to state and when they fi gured out how to insert working copies of genes directly national offi cials about stem cell research, writes op-eds, and into patients’ cells. “We could get genes to express in bone marrow,” frequently talks with reporters. says Daley, but those genes were inserted into cells by using viral Douglas A. Melton, a co-founder of the Harvard Stem Cell vectors much like those involved in creating iPS cells. Because that Institute, has discussed stem cell policy with President Bush. The treatment led to an unanticipated side effect—leukemia—iPS cells HHMI investigator doesn’t particularly enjoy policy work, but are not considered safe for human transplants. thinks it is important. “Some people believe that these are just technical obstacles The iPS fi ndings added to the ongoing debates. In his State of we will overcome,” says Morrison. “Others believe that the Food the Union Address on January 28, 2008, President Bush noted, and Drug Administration will never approve these lines, even if “In November, we witnessed a landmark achievement when we improve the technology and eliminate the viruses.” He pauses scientists discovered a way to reprogram adult skin cells to act like (continued on page 56) embryonic stem cells. This breakthrough has the potential to move us beyond the divisive debates of the past by extending the frontiers of medicine without the destruction of human life.” He urged Congress to pass a ban on cloning, which would preclude May 2008 | HHMI BULLETIN !% >3@A>31B7D3A=>7<7= Stuart L. Schreiber SMALL MOLECULES FOR BIG MEDICINES Leah Fasten !& HHMI BULLETIN | May 2oo8 Drug discovery is an expensive process that can take dozens of years and result in only a few compounds making it to market. Stuart L. Schreiber, an HHMI investigator at the Broad Institute of Harvard and MIT, hopes to improve those odds using small molecule “bioprobes” to study the causes of diseases and to find better therapeutic targets for drug companies to explore. The search for new drugs took an exciting turn in the mammalian target of rapamycin (mTOR) proteins. The past year when scientists linked variations in more than other drug, Zolinza (vorinostat) from Merck, treats cuta- 50 genes in humans to their predisposition to develop more neous T-cell lymphoma by modulating histone deactylase than a dozen diseases. While the ability to identify such links (HDAC) proteins. We discovered that the mTOR and opened the door for potentially discovering the role of thou- HDAC proteins might be good targets by using the small- sands of genes in diseases, it also posed new challenges to molecule probes rapamycin and trapoxin, respectively, pharmaceutical companies. That’s because insights from which cause behavioral changes in cells. research in human genetics aren’t made in a way that is The field of biological research that focuses on the compatible with how pharmaceutical companies tradition- science of small molecules, called chemical biology, is rela- ally practice drug discovery. tively new. Its coemergence with modern human genetics The pharmaceutical industry typically looks for treat- is leading to enormous opportunities for synergies between ments by first forming a hypothesis that a certain “target” these fields. In addition to information on genotype, or the molecule might be responsible for a disease, and then inherited instructions carried by a human or other organism, launching drug discovery efforts based on that assumption. modern human genetics is shining a bright light on the Human genetics research, however, tends not to point to phenotype of diseases—that is, the change in morphology, therapeutic targets, but rather to processes in the body that development, or behavior of an organism as a result of may have gone awry or imbalances that need to be corrected, disease. With chemical biology, we can provide powerful such as insufficient insulin secretion. methods for studying phenotypes of disease and making Our lab has developed a set of tools and techniques we sense of what we find. That’s where we can provide valuable believe can help bridge this gap using small-molecule information on likely targets to pharmaceutical companies. bioprobes. Small molecules have critical roles in all levels Under a new chemical biology program called the Novel of biology—including cell growth, proliferation, sensing, and Therapeutics Initiative, the Broad Institute is further refining signaling—so researchers in academia and at pharmaceutical our thinking on effective drug discovery processes. Rather companies alike have a great interest in them. But instead of than trying to convince the pharmaceutical industry that an using small molecules as therapeutics, we are using them as experimental lab technique is useful, we prefer to demon- bioprobes to examine the underlying causes of diseases. Our strate the capabilities of our overall process in the context approach is discovery-based rather than hypothesis-driven. of especially challenging diseases, such as schizophrenia, We want to define the properties of a cell in a particular state diabetes, and cancers. If we can find highly unusual, highly so we can study how they change as the cell becomes effective therapeutic agents for these diseases that could not diseased. To understand a bodily process, it helps to perturb have been discovered otherwise, the pharmaceutical industry it with the bioprobes and determine the consequences. We likely will pay attention. We’re encouraged by the outcomes believe this approach could lead us to choose more effective with mTOR and HDAC inhibitors. compounds as candidate probes, and as a result uncover We don’t expect the pharmaceutical industry, which has more relevant therapeutic targets for drug discovery. spent millions of dollars and decades on its current drug There already is evidence to indicate our method is discovery approaches, to slow down their process and switch working. Using small-molecule bioprobes, we identified two to a new one. My hope is that applying chemical biology proteins that pharmaceutical companies subsequently devel- research and methods to drug discovery may serve as a way oped as therapeutic targets with new mechanisms of action. for the academic community to broaden its ties with the Both won FDA approval in 2007. One drug, Torisel (temsiro- pharmaceutical industry, and demonstrate a path forward for limus) from Wyeth, treats renal cell carcinoma by inhibiting developing better and safer drugs. INTERVIEW BY LORI VALIGRA. The head of the chemical biology program at the Broad Institute, Stuart Schreiber received his B.A. in chemistry from the University of Virginia and his Ph.D. in organic chemistry from Harvard University. May 2oo8 | HHMI BULLETIN !' >3@A>31B7D3A=>7<7= Claudia Neuhauser MAKING MATH RELEVANT DO BIOLOGISTS NEED TO KNOW HOW TO BUILD CORRUGATED METAL ROOFS? John Christenson John " HHMI BULLETIN | May 2oo8 Math education needs to adapt to the needs of future biologists, says Claudia Neuhauser, an HHMI professor at the University of Minnesota, Twin Cities. According to Neuhauser, biology students are often fed math designed for engineers—with little relevance to their field of study. Now, she’s one of a number of faculty members around the country teaching her students quantitative skills within the context of biology. What’s driving the movement to revamp math education Are other schools making similar changes in their courses? for undergraduates? There’s been a shift at many schools toward focused calculus The math we teach biology students is not the math they courses for biology students. Lou Gross at the University of need. First, the quantitative education we give them is often Tennessee integrates data analysis and statistics into the first- restricted to calculus, but the calculus we teach them is year calculus course. He’s been one of the driving forces usually geared more toward engineering than biology. Second, behind the push for more statistics. In general, though, biologists need to be able to sift through large data sets, but there has been much less done with data analysis than with right now, we don’t teach undergraduates data analysis. calculus. I think part of the reason is that calculus is the Today, we can sequence entire genomes, and we’re devel- traditional bedrock in the curriculum, and it’s very hard oping networks of sensors that can continuously record to make the dramatic changes necessary to shift the focus to things like temperature and moisture from the environment. data analysis. Especially at large universities, courses are These systems produce huge amounts of data, and to work taught in different departments, and the faculty may or may with them students need a good grounding in statistical not know each other. It’s sort of a silo structure. You have analysis and computer science tools like data mining. to have a biology person and a math person or a computer However, I don’t think we can just send them out to take science person sit down and decide they want to break out a semester of computer science or a semester of statistics. of the silos. It’s a slow process. We need to integrate these tools into the biology curriculum, because when you learn something in context, you can see Is there a quicker way to make it happen? its relevance immediately, and it sticks a lot better. The best way is to create an integrated curriculum from the ground up. The big project I’m working on now is the When did it hit you that students weren’t getting what health sciences major at our new campus in Rochester. they needed? Many of these students will go on to become doctors, When I first came to Twin Cities, I taught the first-year dentists, nurses, and veterinarians. We’re going to build a calculus course. The students just hated it; there was this module-based curriculum, where the quantitative, life, and sense of hostility in the classroom. So I asked, “Who am I physical sciences and the humanities are taught in modules, teaching here?” It turned out the class was full of biology and then students will have to combine what they learn in majors. We used examples like calculating the amount of integrative lab courses. Biological information is increasingly material you need to build a corrugated metal roof, and the stored in big, minable databases. It’s going to be important students had no idea why we were teaching them this stuff. for these students to be able to analyze those databases and So I designed a calculus course based on biological scenarios do experiments based on the data. they may encounter later in school or once they graduate. Our goal is to give students the quantitative tools they’ll The students got much more interested. After I did that, I need in 10 to 15 years, when they finish their schooling and started working with other faculty members to make math— take jobs. We know it’s going to be a data-intensive world, especially data analysis—part of their own courses. and we know that the standard tools we currently teach them are not good enough. Can you give another example of making math relevant? Fishing is big in Minnesota, and there is a differential equation that describes fish growth, used by some states’ departments INTERVIEW BY BENJAMIN LESTER. Claudia Neuhauser, of natural resources to determine minimum catchable sizes. author of the textbook, Calculus for Biology and Medicine I used this sort of real-world system to teach differential (Second edition; Prentice Hall), studies theoretical equations in the calculus course. population biology. May 2oo8 | HHMI BULLETIN " Q & A How does chemistry affect the average person? Four HHMI scientists with chemistry backgrounds tell the Bulletin why modern life owes much to chemistry. — EDITED BY S a r a h C . P. W illi a m s Linda C. Hsieh-Wilson Jennifer A. Doudna Milan Mrksich David R. Liu H H M I i n v e s t i g at o r H H M I i n v e s t i g at o r H H M I i n v e s t i g at o r H H M I i n v e s t i g at o r C a l i f o r n i a I n s t i t u t e o f U n i v e r s i ty o f C a l i f o r n i a , t H e U n i v e r s i ty o f C hic a g o H a r va r d U n i v e r s i ty T e ch n o l o g y B e r k e l e y “Chemistry touches on “Chemistry is a body of “Chemistry is all around “Two specific ways that every aspect of our lives. knowledge, a set of tools, us—it’s the reason we exist. chemistry affects We live in a material world, and a philosophy. The From the enzymes that break (improves!) the average and molecules are the stuff knowledge and the tools down our food to blood person’s life come to mind: of materials. Over the next have enabled life-saving clotting and skin healing one is the Haber-Bosch 20 years, the need to develop drugs, computers, higher after we scrape our elbow, method of ammonia pro- new sources of energy and crop yields, ways to harvest everything is chemical and duction, developed in the to manage the impact of and store energy, and all biochemical reactions— early 20th century. It enables energy use on the environ- the non-natural substances molecules dancing with the abundant nitrogen gas ment will drive profound used by society including one another that give rise to in the atmosphere to be developments in catalysis— steel, paint, suntan lotion, everything we are and do.” converted to ammonia, the process of making reac- and modern anesthesia. which can then be turned tions more efficient. The philosophy embraces into nitrates and nitrites for Chemists will pave the way manipulating the structure fertilizer. The process has toward lowering the energy of molecules to change revolutionized modern it takes to produce materials their properties. It encour- agriculture. The second is and enabling recycling of ages us to improve upon the production of antibiotics, unwanted by-products.” nature’s substances and which came about initially dares us to design and through careful isolation and make our own molecules analysis of natural com- that might fight a disease, pounds. The challenge to make a better battery, or scientists and to society is shed light on life’s origins.” to use such advances wisely.” Linda C. Hayes Hsieh-Wilson: John ©HHMI / AP, A. Jennifer Doudna: Michael Marsland Milan Mrksich: Aynsley Floyd ©HHMI / AP, David R. Liu: Robert Klein ©HHMI / AP, 42 hhmi bulletin | May 2oo8 chronicle "" AQWS\QS3RcQObW]\ Cue the Crickets / Strategizing to Diversify Science "% 7\abWbcbS "& :OP0]]Y Of Fish and Men / Fixing Fragile X / A New Clarity # /aYOAQWS\bWab Do only the “long bones” of the arms and legs contain growth plates? And if so, how do all of the body’s bones stop growing at maturity? # C^1Z]aS Hearing Through the Din #" <]bO0S\S Lifton Wins Wiley Prize / Hynes Awarded Wilson Medal BVSaS[Wb]QV]\R`WO]TO[]\YSgYWR\SgQSZZeS`SdWacOZWhSRcaW\U !2AB=@;[WQ`]aQ]^geVWQVOZZ]eaaQWS\bWabab]^W\^]W\bTZc]`Sa QS\bZgbOUUSR[]ZSQcZSaW\bV`SSRW[S\aW]\OZa^OQSaSS^OUS# ;Wb]QV]\R`WOQ]Z]`SR`SRO\RgSZZ]eO`SW\bVST]`SU`]c\ReVWZS bV]aSaVORSR^c`^ZSO\RPZcSO`SRSS^S`eWbVW\bVSQSZZ Zhuang lab May 2oo8 | HHMI BULLETIN "! science education Cue the Crickets /<7 THE BELL SIGNALING THE PERIOD’S END HAD RUNG FIVE MINUTES young researchers’ hopes when crickets outside started dying earlier, but students in this morning biology class were still tightly off. Then, Jamil’s mother took time during a family gathering in huddled around lab tables. What could possibly keep teenagers so Pennsylvania to collect crickets from a field near her relatives’ riveted that teachers need to shoo them out? home. And Bowers reports that “my mom and I went to the A dozen students at the Academy of Science (AOS)—an National Arboretum, which was like the Garden of Eden: crickets HHMI-supported effort at Dominion High School in Loudoun everywhere!” The aquarium was then thoroughly cleaned, and County, Virginia—were in deep consultation with 12 colleagues “most of them lived long enough for us to record them,” says from the prestigious Hwa Chong Institution (HCI) in Singapore. Bowers, adding that, “One escaped during recording. I still These students, all 11th graders, had been collaborating for weeks haven’t found him….” via e-mail. For 10 days in early November, they finally had the Next, the vast differences in scientific approach between the chance to interact face to face. young scientists’ countries had to be reconciled when Beh and Teo T his program is the brainchild of AOS director George Wolfe, visited AOS, where the style tends to be “hands-on,” fostering an a former Peace Corps volunteer who includes among his professed goals to produce “globally aware citizens.” Three years ago, Wolfe was invited to Singapore to train teachers. While there on a later visit, he suggested to Har Hui Peng, HCI’s principal research @3/2G4=@>@7;3B7;3 consultant, that “our students collaborate like real scientists.” AOS requires that students undertake a two-year research project after 8O\SZWO4O`[¸a5ca:]bb`SQSWdSRO`]QYabO`¸aeSZQ][S their sophomore year. With the exchange program in place, those eVS\VSaV]eSRc^ObbVS/QORS[g]TAQWS\QS /=A´]\O6O`ZSg2OdWRa]\ #A^]`babS`\]ZSaa´ interested could apply to work with their counterparts at HCI. Rc`W\UbVSAW\UO^]`SabcRS\ba¸dWaWb /bTW`abbVSU`]c^ Two students from each school teamed up to tackle one of six O^^SO`SR[Sa[S`WhSRZWabS\W\U`SdS`S\bZgO\R\]RRW\U scientific ventures, which ranged from comparing the antibacte- bVSW` VSORa Oa bVS bOZZ Q]\TWRS\b O\R c\RS\WOPZg VW^ rial properties of Western and Asian herbs to looking at a possible aQWS\bWab´Q]eP]gP]]ba^SSYW\UT`][bVSVS[]TTORSR link between fish feminization and estrogen concentrations in PZcSXSO\a´RS[]\ab`ObSRVWaµU>@7;3¶a]TbeO`S EVS\/=AabcRS\b2SdW\0]eS`aOR[WbbSRb]TW\RW\U waste water. bVS^`]U`O[µW\bW[WRObW\U¶:]bbO\S\UW\SS`W\8O\SZWO¸a Devin Bowers, an AOS junior and avid guitarist, wanted to W\ab`c[S\bRSaWU\O\RTOP`WQObW]\aV]^UObVS`SR/=A¸a study something that involved acoustics. After consultation with 0]eS`a O\R /ZWgO 8O[WZ O\R AW\UO^]`S¸a 1SR`gQV 0SV Wolfe, he and classmate Aliya Jamil decided to investigate the O\RBaSGSO\BS]ObbVSeVWbSP]O`Rb]aV]eW\ZOg[O\¸a evolutionary divergence of cricket song, on scales both local and— bS`[aXcabV]eU>@7;3eVWQVbc`\aOQ][^cbS`¸aa]c\R thanks to the involvement of Singapore students Cedrych Beh and QO`R W\b] O b]]Z bVOb QO\ OQ_cW`S O\R O\OZghS aWU\OZa R]SaWbabVW\U 4]`a][S]\SeV]PSZWSdSaOa:]bbR]Sa Tse Yean Teo—global. The cricket song project also pulled in Gus bVObµbVSS\UW\SS`W\UWaSOageVWZSbVS`SZObW\U]TWbb] Lott, a scientist at HHMI’s nearby Janelia Farm Research Campus, aQWS\bWaba´P]bV SabOPZWaVSR O\R PcRRW\U´Wa RWTTWQcZb¶ who is interested in educational applications of software he devel- VS[ORSbVObZ]]YSOagb]] µ7\ bVS QOaS ]T Q`WQYSb oped that can be used to analyze insect sounds (see sidebar). QVW`^a bVS a]TbeO`S [SOac`Sa ^O`O[SbS`a acQV Oa B oth groups faced some real-world obstacles. For one thing, QVW`^T`S_cS\QgRc`ObW]\O[^ZWbcRSO\RbW[SPSbeSS\ QVW`^a¶ VS aOWR Xc[^W\U Ob ]\QS W\b] Q]ZZSOUcSb] urban Singapore does not have big cricket populations, so Beh and Q]ZZSOUcSRWaQ]c`aSeWbVbVSabcRS\ba 7\[S`S[W\cbSa Teo regularly traveled a mile-long causeway to cross the border to \SWbVS`:]bb\]`VWaQ][^ZSfQ][^cbS`^`]U`O[aSS[SR Malaysia and its cricket-rich fields. Because they could not carry _cWbSa]W\bW[WRObW\U 0]eS`aZObS`RSaQ`WPSRU>@7;3Oa live insects across the border, the boys, crouched side by side in OµU]RaS\R¶W\bVSW`O\OZgaWa]TQ`WQYSb[ObW\Ua]\Ua 0g the tall grass that crickets favor, made their recordings on site. bVSbW[S:]bbVSORSRPOQYb]8O\SZWO4O`[bVSabcRS\ba Back in Virginia, Bowers and Jamil had their own prob- eS`SeSZZdS`aSRW\U>@7;3O\RbVSW`OeSab`cQYabO`Sa VORbc`\W\b]a[WZSa]TQ][^`SVS\aW]\O\RU`ObWbcRS lems. One batch of crickets died in an unsanitary aquarium. As winter approached and temperatures dropped, so did the "" HHMI BULLETIN | May 2oo8 1Z]QYeWaST`][Z]eS``WUVb(AbcRS\ba1SR`gQV0SV2SdW\0]eS`a /ZWgO8O[WZO\RBaSGSO\BS]ZSO`\OP]cbSOQV]bVS`a¸QcZbc`SaeVWZS O\OZghW\UQ`WQYSba]\U)BS]O\R0SVO`SabcRS\baObAW\UO^]`S¸a6eO 1V]\U7\abWbcbW]\)5ca:]bb`WUVbQ`SObSRa]TbeO`SbVSabcRS\baO`S caW\Ub]O\OZghSbVSW\aSQba]c\Ra)5S]`USE]ZTSRW`SQb]`]T:]cR]c\ 1]c\bg¸a/QORS[g]TAQWS\QSaSbbVSQ]ZZOP]`ObWdS^`]XSQbW\[]bW]\ appreciation of scientific inquiry for the sake of discovery. Tradition often are expected to be at school before sunrise. With time to kill (and financial realities) in Singapore means that all science proj- every morning, Beh and Teo usually could be seen in the mist- ects there, even in high school, must aim for practical applications; covered fields alongside Dominion High School collecting the embracing a less rigid approach was an adjustment for the visitors. season’s last crickets. “They both have pros and cons,” Teo says of the schools’ B ack in Singapore, the HCI students now no longer have free differing methods. “I’d prefer a combination of their relaxed envi- time in the morning, but they stay in touch with their Virginia ronment and our task-oriented approach.” collaborators—via e-mails that contain, in equal measure, details B etween experimenting and drafting reports, the hosting and of their projects and typical teenage banter. In August, using visiting students ate, toured, and lived together. Each boy from funds from an annual HHMI grant to Loudoun County Public HCI, an all-male institution, stayed with an American family. Schools, the American students are planning a trip to Singapore, W hat did the Singaporean students find most surprising about so the six teams can present their final results together. . James Kegley James America? For one thing, they got to sleep in. At HCI, students —LINDSAY MORAN May 2oo8 | HHMI BULLETIN "# science education Strategizing to Diversify Science 32C1/B7=3@73<13A/<2/5@33B= 1= THE FUTURE LOOKS BRIGHT FOR BRIAN LEÓN. “I AM IN A POSITION In her presentation at the last symposium, Baker explained where I cannot be disappointed about anything,” says the University that, of the 11 students who participated in the new program, 9 of California, Irvine (UCI), senior. He has already been accepted have continued in science courses in the second semester—a good into five graduate programs and is waiting to hear from three more. indication that they will pick a science as their major. Because of A fter transferring from a local community college, León joined this initial success, the college has committed to fund the program UCI’s Minority Science Programs (MSP), which provide a combi- when the HHMI grant currently supporting it runs out. nation of study-skill courses, research experiences, and career advice G iven the fact that the data identified a significant problem and to selected students from minority groups that are underrepresented inspired a seemingly effective solution, the symposium participants in the biomedical sciences. “I never go two days without some form were enthusiastic about continuing to collect data. And if institu- of contact [with program staff],” says León, whose family emigrated tions use commonly agreed-upon measures, it will provide a way to from Peru. Such steady interaction seems to pay off: in 2007, 15 compare them with their peers. “The data were difficult to collect seniors completed the MSP and 11 entered a Ph.D. program. because we had not done it before,” says Woodard, “but everyone U CI’s programs were among the initiatives spotlighted in agreed it is helpful and important.” “Diversifying Science: From Concept to Practice”—a workshop held T he symposium organizers—others include Robert Lue of Harvard at HHMI headquarters January 27–29, 2008, and the last in a series. University, Barbara Wakimoto of the University of Washington, and These four diversity symposia, sponsored by HHMI and the National John Matsui of the University of California, Berkeley—are now Institutes of Health, brought together institutions committed to gathering feedback from participants to determine how best to increasing the number of underrepresented minority students in the sciences. All the symposia showcased model programs at colleges and universities with impressive records of graduating minority students in science fields, but the fourth symposium went further by discussing challenges that participants have faced in implementing their programs and the strate- gies they’ve used to overcome them. For example, one accomplishment of the earlier symposia was that participating insti- tutions began measuring minority-student attrition from science majors—in large part by tracking the number of minorities in each A^SOYS`aObbVST]c`bVRWdS`aWbgag[^]aWc[a^]\a]`SRPg66;7O\RbVS<76W\QZcRSR biology and chemistry class and their grades 8]V\;ObacWC\WdS`aWbg]T1OZWT]`\WO0S`YSZSgO\R>O[SZO0OYS`0ObSa1]ZZSUS over a three-year period. A preliminary analysis of these data indicated that, at least for continue this multi-institutional collaboration. “One possibility is university biology, how students do in their first year determines to hold smaller regional meetings and invite institutions that did not whether they will graduate with a science major. “If students have take part in the diversity symposia,” says Woodard. “Also, participants bad experiences in the first science courses, they typically leave could in effect become consultants, making site visits and giving science,” says Mount Holyoke College’s Craig Woodard, one of the presentations about their programs.” The long-term goal would organizers of the final symposium. be to enlist many more colleges and universities in similar efforts, T his result helped convince Pam Baker and other administra- thereby triggering change at the national level. tors at Bates College to start a bridge program that brings incoming F or now, success lies in individual stories. “I will be the first to freshmen to the Lewiston, Maine, campus for six weeks during the earn a doctorate degree in the family,” says León. “When I think of summer to acclimate them to campus life and to accelerate their that I have a real sense of accomplishment, and I hope to inspire academic experience by taking chemistry and math courses. my brother to do the same.” . —LAURA BONETTA Kegley James "$ HHMI BULLETIN | May 2oo8 institute news In Memoriam Richard Gordon Darman 1943–2008 Richard Gordon Darman, a financial executive with a distin- award, the Alexander Hamilton medal, for his contributions to guished career in public service and a Trustee of the Howard the 1986 Tax Reform Act and two international monetary policy Hughes Medical Institute, died January 25, 2008, in Washington, accords. Darman subsequently served as director of OMB in the D.C. He was 64. administration of President George H.W. Bush from 1989 to Darman was a partner of The Carlyle Group, a global 1993 and was the principal executive branch negotiator for the private equity firm, and chairman of the board of AES Corp., 1990 budget agreement. an international power company. He became an HHMI Darman joined The Carlyle Group in 1993. He became a Trustee in 2005, served as chairman of the Institute’s Audit member of the AES board in 2002 and was elected chairman and Compensation Committee, and was also a member of its in 2003. Darman was also a trustee of several publicly traded Finance Committee. mutual fund groups and was the current chairman of the board Throughout his tenure in the federal government, Darman of the Smithsonian National Museum of American History. played key roles in the development of tax, spending, and Darman graduated with honors from Harvard College in economic policies. He served four presidents, holding positions 1964 and from the Harvard Business School in 1967. A former in the White House, the Office of Management and Budget fellow of the Woodrow Wilson International Center for Scholars, (OMB), and six cabinet departments. he wrote widely about public policy and politics. He is survived As deputy treasury secretary during the Reagan Admin- by his wife, Kathleen Emmet, and three sons, William T.E. istration, Darman was recognized with the Treasury’s highest Darman, Jonathan W.E. Darman, and C.T. Emmet Darman. HHMI Offers Boost to “Many of these scientists who have led their own laboratories for a few years are at a high Early Career Scientists point of their creativity just as they see their start-up funds and other early career awards MANY EARLY CAREER SCIENTISTS LAUNCH most of whom will be assistant professors ending,” says Cech. “Some of them may their own labs with start-up funds from their at the time of the award, to receive full still be in line for their first NIH R01 grant, host institution. That support is provided salary and research support from HHMI. In while others may have their first grant but with the expectation that the scientist will selecting the early career scientists, HHMI are facing the very challenging first renewal establish his or her own research program will be guided by the principle of people, of that grant. It is this period of career with independent funding. In the current not projects—providing the early career vulnerability that the HHMI Early Career funding climate, that transition has become scientists with the freedom to pursue their Scientist Program aims to bridge.” a daunting hurdle. Now, a $300-million scientific interests wherever they lead. HHMI is seeking scientists from all areas of HHMI initiative aims to eliminate that This initiative comes at a critical time. basic biology and biomedicine as well as areas stumbling block for as many as 70 of the Funding for the National Institutes of of chemistry, physics, computer science, and nation’s best early career faculty, chosen Health (NIH), the nation’s largest supporter engineering that are directly related to biology through a national competition. of basic biomedical research, has remained or medicine. Candidates can apply directly to The new program is directed at researchers essentially flat during the last five years, HHMI, a new approach the Institute used who have run their own labs for two to six unable to keep up with inflation. Nowhere successfully in 2006 and 2007 competitions, years and who may be ready to move their has the impact of this constrained funding broadening its pool of applicants by moving research in creative, new directions. The been felt more intensely than by early career away from accepting nominations only from scientists will come from any of approxi- scientists who are competing with their peers applicants’ host institutions. mately 200 eligible U.S. medical schools, and more experienced researchers to win Detailed information about the competi- universities, and research institutions. research project (R01) grants from NIH. tion, including the list of eligible institutions, The six-year, nonrenewable appoint- HHMI President Thomas R. Cech and may be found on the HHMI Website (www. ments to HHMI will allow the scientists, his advisors saw this as a clear opportunity. hhmi.org/earlycareer2009/). . May 2oo8 | HHMI BULLETIN "% lab book Of Fish and Men B63A/;353<32@7D3AA97<1=:=@3D=:CB7=< 7<AB719:30/1947A6/<26C;/ At the end of the Ice Age, 10,000 years ago, marine stickleback fish “If we look at colonized the newly formed freshwater lakes and streams that dotted multiple [stickleback North America, Europe, and Asia. In each new, isolated habitat, the populations] along fish evolved traits that would help them thrive. the West Coast where Among these changes were darkening and lightening of skin light skin color had color, helping fish blend in or stand out in different water colors. By evolved, the same comparing modern-day stickleback from around the globe, HHMI mechanism was used investigator David Kingsley of Stanford University has revealed a over and over,” says gene responsible for those color changes. What’s more, he discov- Kingsley. Such a strik- ered that the same gene has likely played a role in changing skin ing pattern suggested /abWQYZSPOQYT`][bVS]QSO\c^^S`O\R color during human evolution. to him that perhaps the ]\ST`][OT`SaVeObS`Q`SSYZ]eS`aV]e RWTTS`S\baYW\Q]Z]`aO\RP]Rgbg^Sa Taking advantage of genetic crosses and the recently sequenced gene was involved in stickleback genome, Kingsley and colleagues first identified a region of skin color evolution of other species, including humans. a chromosome, encompassing 12 genes, that seemed to differ distinctly Indeed, when the scientists compared the Kitlg gene sequence of in fish of varying shades. From there, they narrowed the color control Africans and Europeans, they found regulatory differences in Kitlg down to one gene, Kitlg, which is involved in a number of develop- that contribute to skin color variety. They reported the work in the mental processes—including the development of pigment cells. December 14, 2007, issue of Cell. The researchers found that lighter-colored fish had a mutation in “It may be that the general mechanisms producing major the regulatory part of the gene, which decreased the gene’s expres- changes during adaptation to a new environment are pretty sion in gills and skin cells. Since skin color can be slightly affected constrained,” says Kingsley. “Mechanisms you find when studying by many genes, it was surprising that one single gene could have how one organism has evolved may help predict mechanisms used such a large effect. in very different animals.” . —SARAH C.P. WILLIAMS 7<0@734 ;/:/@7/>/@/A7B3A>C<16 2cQYW\UW\O\R]cb]TQSZZaZWYSZgVSZ^a bVSQSZZeVS`SWb¸a[ORSO\RaWU\OZa\SWUV B6@=C56A97<13::A bVS ^O`OaWbS Od]WR W[[c\S QSZZa aOga P]`W\UQSZZab]S\bS`VWPS`\ObW]\^`SdS\bW\U 2SbOWZSR]PaS`dObW]\a]T[OZO`WO^O`OaWbSa ;{\O`ReV]\SfbV]^Sab]RSRcQSSfOQbZg bc[]`T]`[ObW]\ []dW\UbV`]cUV[WQSVOdS`SdSOZSRbVOb V]ebVS^O`OaWbSaO`SOPZSb]^c\QVbV`]cUV EVS\bVS`SaSO`QVS`aW\XSQbSR7540>% bVS^O`OaWbSa^]eS`ab`OWUVbbV`]cUVQSZZa bVSQSZZa µ7b¸aO^`SbbgOUU`SaaWdSPSVOdW]`¶ W\b] [WQS bVOb OZ`SORg VOR bc[]`a bVS ]\bVSW`X]c`\SgT`][bVSaYW\b]bVSZWdS` VSaOgaµO\ReSVOdS\]WRSOgSbV]ebVSg ^`]bSW\ab]^^SRbc[]`U`]ebV BVSbc[]` EVWZSaQWS\bWabaVOR^`SdW]caZg]PaS`dSR R]Wb ¶ QSZZa5`SS\T]c\RVORbc`\SR]TT^`]RcQbW]\ bVS^O`OaWbSaXOPPW\UbV`]cUVZWdS`QSZZabVS ]T7540>% ;]ZSa]\bVS]bVS`VO\ROQbWdSZg \Se e]`Y ZSR Pg 66;7 W\bS`\ObW]\OZ B@/17<5B63>/B6B=/;3:/<=;/ Sf^`SaaSRbVS^`]bSW\YSS^W\Uac``]c\RW\U `SaSO`QVaQV]ZO`@]PS`b;{\O`RWabVS¿`ab AQWS\bWabab`gW\Ub]RSbS`[W\SeVOb[OYSa QSZZa T`][ PSQ][W\U QO\QS`]ca µ7b¸a O\ b]aV]ebVObbVWaa]QOZZSRQSZZb`OdS`aOZ OPS\WU\[]ZSRWTTS`S\bT`][ORSORZgaYW\ Sfb`S[SZg^]eS`TcZO\bWQO\QS`[SQVO\Wa[¶ PSUW\aObbVSaYW\ QO\QS`VOdST]c\RO^`]bSW\bVObVOZbabVS aOga 5`SS\ eV] V]^Sa bVS TW\RW\Ua ;{\O`R]TbVS>OabSc`7\abWbcbSW\>O`Wa U`]ebV]Tbc[]`a ^cPZWaVSRW\1SZZ]\4SP`cO`g& &eWZZ O\R VWa Q]ZZSOUcSa b]]Y ORdO\bOUS ]T O ;]ZSaO\RQO\QS`]ca[SZO\][OaP]bV ZSORb]O\Se[SZO\][Ob`SOb[S\b [cbO\bT]`[]T>ZOa[]RWc[PS`UVSW´bVS abO`b ]cb Oa [SZO\]QgbSa´^WU[S\b [OZO`WO^O`OaWbSbVObW\TSQba[WQS´eVWQV ^`]RcQW\UaYW\QSZZa EVS\O[cbObW]\W\ AG<2@=;31/CA320G;7AA7<5 QO\\]b[OYSV]ZSaW\QSZZa BVSgS\UW\SS`SR [SZO\]QgbSaQOcaSaO\W\Q`SOaSW\Sf^`Sa 16@=;=A=;3A35;3%O^`]bSW\bVOb ObOZO`US`U`]c^]T^ObWS\ba´[]`SbVO\ Z]\U]dS`Z]]YSRaYW\^VOaS]TbVS[OZO`WO [SZO\]QgbSa[OYSeVS\0@/4Sf^`SaaW]\ ´\W\S ^S]^ZS bc`\SR c^ eWbV bVS ^O`OaWbSRSaS`dSaQZ]aS`aQ`cbW\g W\Q`SOaSa BVS7540>%Wbbc`\a]cbZSOdSa aO[S [WaaW\U US\SbWQ [ObS`WOZ BSaba ]T Frank Chan, Craig Miller, and David Kingsley / Stanford University Frank "& HHMI BULLETIN | May 2oo8 Fixing Fragile X 9<=197<5=CB/A7<5:353<37<<3C@=B=;A=44@/57:3FAG<2@=;37<;713 By probing the network of genes and proteins active at the junc- explains Bear. This means that in fragile X syndrome, FMRP is not tions between neurons in the brain, HHMI researchers have around so the protein synthesis goes unchecked. unearthed a new strategy for treating fragile X syndrome—the Bear and his colleagues, in a study published in the December most common inherited form of mental retardation. 20, 2007, issue of Neuron, showed that getting rid of one copy of Mark Bear, an HHMI investigator at the Massachusetts Institute of mGluR5 in fragile X–affected mice eliminates the seizures and Technology, studies how the connections between neurons are memory impairments that such mice typically exhibit. strengthened or weakened as new pieces of information are retained The researchers bred mice with fragile X syndrome—charac- in the brain, and other memories terized by developmental delay, structural changes in the brain, fade. He previously found that a and epilepsy—with mice engineered to produce half the normal neurotransmitter receptor called level of mGluR5. Their offspring showed few symptoms of fragile mGluR5 plays a role in weakening X, despite the mutation in FMRP they had inherited. neural connections, by increasing Since mGluR5 and FMRP do not directly interact, but influ- the amount of proteins made at ence neural protein synthesis in opposite directions, the results the synapses between neurons. suggest that it is the increased protein synthesis in fragile X patients Most recently, Bear discovered that leads to the syndrome. The brains of fragile X–affected mice that fragile X mental retardation typically have an excess of particularly weak neural connections. protein (FMRP), which is Bear hypothesizes that the excess protein synthesis could be mutated in fragile X syndrome, leading to this high density of connections. counterbalances mGluR5. “The “Now we have a lot of work ahead of us to figure out which BVSQ]\\SQbW]\aPSbeSS\\Sc`]\a fragile X protein is normally proteins are producing the pathology,” says Bear, who is also now W\bVSP`OW\V]ZROac`^`WaW\UQZcS putting a brake on the protein studying whether blocking mGluR5 receptors in humans can b]T`OUWZSFag\R`][S synthesis stimulated by mGluR5,” counter fragile X syndrome. . —SARAH C.P. WILLIAMS 7<0@734 ^S]^ZSeWbV]cb[S\bOZ`SbO`RObW]\T]c\R QO\OTTSQbeVSbVS`bVSUS\SWaSf^`SaaSR AB@C1BC@3=4A>/AB7< \]W\abO\QSa]TbVSRSZSbW]\ BVS`SacZba OaO^`]bSW\ 3 May 2oo8 | HHMI BULLETIN "' lab book A New Clarity />>:G7<5/<3E;71@=A1=>GB316<7?C3B=23B31B 7<27D72C/:;=:31C:3A7<B6@3327;3 The intricate molecular insides of cells are coming into focus, featureless dot,” says Zhuang. Multiple fluorescent molecules blur thanks to HHMI investigator Xiaowei Zhuang at Harvard University. together. So she and her colleagues came up with a trick. Zhuang has developed a three-dimensional version of her high- Zhuang’s STORM technique, first described in 2006, had been resolution stochastic optical reconstruction microscopy (STORM) used only for two-dimensional imaging until now. STORM technique, allowing scientists to find the location of cellular mole- involves tagging molecules with a fluorescent label, or fluorophore, cules with better resolution than conventional light microscopy. that can be switched on and off. To get a glimpse of cells’ inner workings, scientists typically tag Her team avoids the problem of overlapping fluorescence by using molecules with proteins or dyes that give off fluorescence. But low amounts of light to switch on only a small percentage of fluoro- images of this fluorescence have a resolution that’s limited to a few phores at once. Through the microscope, researchers can pinpoint a hundred nanometers by the diffraction of the light in all directions. molecule’s location by calculating where the center of each dot is. With this conventional method, “if you have a very interesting Now, Zhuang has also developed a way to determine where the structure but it’s smaller than the resolution, it just looks like a molecule is in the third dimension—by analyzing the size and shape, or blurriness, of each dot. Repeating the process many times, randomly turning on fluorophores during each iteration, can reveal the precise location of all the tagged molecules in a cell. “These cellular images are now 10 times sharper in all three dimensions,” says Zhuang, who described the technique in the February 8, 2008, issue of Science and has used it to look at the proteins that help viruses enter cells—a process involving minis- cule complexes of molecules that had never before been resolved by light microscopy. “We can solve many problems that were previously beyond our reach, but there are still things that we can’t reveal,” she says. “And ;WQ`]bcPcZSadWacOZWhSReWbVO\Se[WQ`]aQ]^gbSQV\W_cS`WUVbO^^SO` the closer the resolution gets to true molecular scale, the more aVO`^S`bVO\eVS\dWSeSRcaW\UQ]\dS\bW]\OZ[WQ`]aQ]^gZSTb questions arise.” . —SARAH C.P. WILLIAMS 7<0@734 ^`]QSaaWaVW\RS`SRPg[cbObW]\aW\a^OabW\ [O`YS`eOa\]ba^SQW¿Qb]QO\QS`QSZZa GSb bVObPSUW\aObO`]c\ROUS! <]e66;7 bVS[WQ`]bcPcZSaW\\Sc`]\a´eVS`Sa^OabW\ W\ZWdW\U[WQSBQSZZaQO``gW\UbVS`SQS^b]` W\dSabWUOb]`6cROH]UVPW]T0OgZ]`1]ZZSUS [OgPSSa^SQWOZZgOQbWdS´QO\¸b`SO``O\US ]TW\bS`SabObbOQYSRXcab^`]abObSbc[]`a ]T;SRWQW\SVOaaV]e\eVgbVWaSf^O\aW]\ bVS[aSZdSa B]QZSO`c^bVWaRWaQ`S^O\QgbVSaQWS\ Waa]b]fWQb]QSZZa bWabaaSO`QVSRT]`bVS[]ZSQcZSbVObbVSB H]UVPWO\RVS`Q]ZZSOUcSaeO\bSRb] 231=27<5B63;=:31C:/@ QSZZa`SQ]U\WhS BVSg^W\^]W\bSRVWab]\S Sf^Z]`SO`SQS\b]PaS`dObW]\bVObOaS^O A75@=AB/B31/<13@ 6"O^`]bSW\T]c\RcPW_cWb]caZgW\aWRSbVS `ObSaW\UZS[cbObW]\W\/BF< QO\QO\QSZ >`]abObSQO\QS`aRWa^ZOgO[]ZSQcZO`aWU\ \cQZSW]TQSZZa´Sf^ZOW\W\UeVgOZZU`]c\R ]cb bVS RWaSOaSQOcaW\U STTSQba ]T bVS ^]abbVObOZS`babVSP]Rgb]bVSW`^`SaS\QS c^bWaacSaOQbWdObSbVSBQSZZa 7\^`]abObS Sf^O\aW]\ A]bVSgaQ`SS\SR^`]bSW\ab] 66;7 `SaSO`QVS`a VOdS RWaQ]dS`SR bc[]`QSZZabVSgRSbS`[W\SRVWab]\S6" ¿\R]\SabVObW\bS`OQbSR^`STS`S\bWOZZgeWbV C\RS`abO\RW\U V]e bVWa TZOU aWU\OZa bVS ZSOdSabVS\cQZScaO\RWaRWa^ZOgSR]\bVS ]\ST]`[]T/BF< ]`bVS]bVS` W[[c\SagabS[b]`Sa^]\Rb]bc[]`QSZZa ac`TOQS]TbVSQSZZa BVS`SaSO`QVS`aT]c\Rbe]^`]bSW\a´ [OgVSZ^`SaSO`QVS`aRSdSZ]^\SeeOgab] BVSbSO[\SfbV]^Sab]ZSO`\SfOQbZg @0; % O\R 171 BVS RWaSOaSQOcaW\U ¿UVbQO\QS` V]eVWab]\S6"U]SaT`][PSW\UW\aWRSQSZZ dS`aW]\]T/BF< ^`STS`ab]PW\Rb]@0; % AQWS\bWaba ZSR Pg 66;7 W\dSabWUOb]` \cQZSW b] PSW\U O TZOU T]` bVS W[[c\S ZSOdW\U171eWbVZSaa/BF< b]PW\Rb] 8O[Sa> /ZZWa]\]T;S[]`WOZAZ]O\9SbbS`W\U agabS[OaeSZZOaeVSbVS`bVS^`]bSW\VOa @0; %O\R171O`SQ]\abO\bZgab`cUUZW\U 1O\QS` 1S\bS` QV]^^SR c^ bc[]`a O\R dOZcSW\^`SRWQbW\U^`]abObSQO\QS` b]a^S\RbW[SeWbV/BF< aOgaH]UVPW Sf^]aSRbVSbWaacSb]O[Wfbc`S]TW[[c\S BVSW\VS`WbSRSf^O\aW]\aVWTbabVWaPOZO\QS BQSZZaOZZQO``gW\URWTTS`S\b`O\R][`SQS^ 2/ # HHMI BULLETIN | May 2oo8 ask a scientist ? / Do only the Most of the bones with growth plates also decrease (but not to zero). As are indeed the long bones—those that that happens, this type of lengthwise “long bones” make up your arms, legs, fingers, and growth in the long bones stops and of the arms and toes. If you think about it, this makes you are as tall as you will ever be. sense: most of an individual’s growth, Does this mean the long bones are legs contain especially during the spurt that occurs done growing or that other bones never in adolescence, involves the length- grow? Absolutely not. All bones grow growth plates? ening of his or her limbs. constantly, even after maturity, but And if so, how Growth plates, found at both ends they are constantly being reabsorbed of the long bones, consist of cartilage, as well. As cells called osteoclasts do all of the which is made by special cells called destroy the older bone tissue, the chondrocytes that inhabit the growth osteoblasts make new bone to replace body’s bones plate zone. During adolescence, it. During childhood and adolescence, stop growing at chondrocytes make cartilage at a very signals are being released throughout fast pace in growth plate zones at both your body that tip this balance toward maturity? ends of the long bones, adding length the positive, so that all your bones and creating a scaffold upon which generally do grow. In healthy adults, Bret, a curious adult from Illinois specialized cells called osteoblasts can who have all the bone they need, the form bone. The process, which results rates of destruction and of creation of in a very rapid lengthwise growth of the bone net out to zero. The bones grow bones in your limbs, is jump-started only as fast as they are destroyed and during adolescence by a growth factor so stay the same length and thickness. in the body called insulin-like growth Amazingly, 30 percent of bone in any factor (IGF). human is generally destroyed and re- However, this process doesn’t created every year. last forever. The osteoblasts replace cartilage with bone faster than new cartilage is created at the far end of ANSWER RESEARCHED BY STEPHEN PAN, the growth plate. As this happens, the M.D., former HHMI-NIH research scholar, growth plates gradually thin, until now a resident in internal medicine at eventually they disappear. At the same Stanford University Hospital & Clinics, time, IGF concentrations in the body Stanford, California. FOR MORE INFORMATION on bone growth, visit http://www.endotext.org/parathyroid/parathyroid1/parathyroidframe1.htm (Baron, R. “Anatomy and Ultrastructure of Bone – Histogenesis, Growth, and Remodeling,” 2006). AQWS\QSWaOZZOP]cbOaYW\U_cSabW]\aSf^Z]`W\UbVS^`]PZS[abVObQ]\T]c\R]`W\b`WUcSca 0cb O\aeS`aQO\¸bOZeOgaPST]c\RW\OQZOaa`]][]`bSfbP]]Y /b66;7¸a/aYOAQWS\bWabESPaWbS e]`YW\UaQWS\bWababOQYZSg]c`b]cUV_cSabW]\aOP]cbVc[O\PW]Z]UgRWaSOaSaSd]ZcbW]\O\W[OZa O\RUS\SbWQa DWaWbeee VV[W ]`U OaYOaQWS\bWabb]P`]eaSO\O`QVWdS]T_cSabW]\aO\RO\aeS`a ¿\RVSZ^TcZESPZW\Ya]`b]aag]c`_cSabW]\W\b]bVS[Wf EVOb¸aPSS\^chhZW\Ug]cZObSZg- May 2oo8 | HHMI BULLETIN # up close Hearing Through the Din Receptors embedded in the ear’s hair cells might explain mammals’ selective hearing. a chicken waiting to cross a noisy road can’t be concentrate on relevant sounds such as hearing a knock at the blamed if it doesn’t hear the fox sneaking up behind it. door over the sound of music. The efferent system also may Chickens—and a host of other vertebrates—don’t have as dampen loud sounds to protect ears from injury. sophisticated hearing systems as mammals. The efferent system’s neurons control outer hair cells by One protein makes the difference, says HHMI international launching bursts of the neurotransmitter acetylcholine at recep- research scholar A. Belén Elgoyhen. It’s a component of a tors embedded in the surface of these hair cells. These receptors receptor in a part of the auditory system of mammals, called the latch onto the acetylcholine, which triggers a gush of calcium efferent pathway, that modulates whether sounds reach the into the outer hair cell, inhibiting the cells’ ability to modulate brain or are fi ltered out. auditory output and dampen sound signals. So by adjusting the Basic sound detection is a one-way process that begins amount of acetylcholine it pumps out, the efferent system can when sound waves strike the eardrum and jiggle hair cells in change how the outer hair cells function, and how much they the cochlea of the inner ear. That jiggling generates neural dampen sound. signals that speed to the brain’s auditory center, where they In earlier work, Elgoyhen discovered that these “nicotinic register as sound. acetylcholine receptors” are built of two basic protein compo- But really sophisticated sound processing in mammals also nents, the alpha-9 subunit and the alpha-10 subunit, which depends on efferent signals that travel in reverse, from the brain differ subtly in structure. back to the cochlea. These signals control specialized, adjust- “We know these receptor subunits exist in all vertebrates; able outer hair cells that can modulate sound signals traveling to however, only the mammalian cochlea has this fi ne-tuning of the brain. The exact function of this feedback system largely outer hair cells,” says Elgoyhen, who is at the Institute for remains a mystery. But researchers believe it enables mammals, Research on Genetic Engineering and Molecular Biology, including humans, to filter background noise so they can CONICET, in Buenos Aires, Argentina. “We believe that Aidan O’Rourke Blobel: Matthew Septimus Frauenkirche: Alex Robbins # HHMI BULLETIN | May 2008 mammals and nonmammals may have slightly different alpha- mice lacking the alpha-10 subunit were not fully functional at 10 subunits that enables this tuning in mammals.” the electrophysiological level. The outer hair cells in those In their latest study, Elgoyhen and her colleagues tackled the mice did not respond normally to bursts of acetylcholine from key question of whether the alpha-10 subunit is really critical to efferent neurons. the receptor’s function. To their puzzlement, earlier test-tube Establishing the physiological role of the alpha-10 subunit studies had revealed the opposite—that even without the alpha- represents only the beginning of their explorations into its func- 10 subunit, the receptor appeared to function normally. tion, says Elgoyhen. Her lab has already started cloning the So the researchers explored what would happen when they chicken versions of the alpha-10 and alpha-9 subunits. created “knockout” mice that had no alpha-10 subunit. They “We are comparing the properties of the chicken receptor reported their fi ndings in the December 18, 2007, Proceedings to the mammalian receptor,” she says, “to see if there is some of the National Academy of Sciences. functional difference between them that can tell us why this Their fi rst measurements of the physiological functioning of alpha-10 subunit uniquely evolved a special role in mammals the basic machinery of the animals’ auditory system indicated compared with nonmammalian vertebrates.” What’s more, that it functioned perfectly well. Then they conducted more Elgoyhen and her colleagues plan to explore the more subtle subtle physiological tests that specifi cally measured whether the hearing consequences of loss of the alpha-10 subunit and thus a animals’ efferent auditory systems were working properly. To fully functional efferent system. determine how the ears of the mice responded to different “So far, we only know that without the subunit, the efferent sound frequencies, the researchers inserted electrodes into the system does not work,” she says. “Now, we are investigating the auditory nerves of the mice and placed delicate microphones consequences at the level of behavior—whether the knockout next to the outer hair cells. Those tests revealed that, although mice show a difference in protection from sound injury or in Blobel: Matthew Septimus Frauenkirche: Aidan O’Rourke Blobel: Matthew Septimus Frauenkirche: the animals’ basic hearing was intact, the efferent systems in the attentional behavior.” . —DENNIS MEREDITH May 2008 | HHMI BULLETIN #! nota bene groundbreaking work on the bacterium that A>=B:756B causes listeriosis and her coordination of a European consortium that decrypted the Lifton Wins Wiley Prize bacterium’s genome. 2735=23;3<2=H/, an HHMI interna- tional research scholar at the Institute of Molecular and Cellular Biology of Rosario, received a Bernardo Houssay prize from Argentinean President Nestor Kirchner. The Argentine Secretariat awards the prize for Science, Technology, and Innovation annu- ally for outstanding work in one of six scientific fields. HHMI investigator 2/D72 37A3<03@5, @716/@2:74B=< University of California, Los Angeles, received the 2008 Emily Gray Award from 66;7W\dSabWUOb]`@WQVO`R> :WTb]\]TGOZSC\WdS`aWbgAQV]]Z]T ;SRWQW\S`SQSWdSRbVS &EWZSg>`WhSW\0W][SRWQOZAQWS\QSa the Biophysical Society for significant contri- /eO`RSRPgbVSEWZSg4]c\RObW]\bVSO\\cOZ^`WhS`SQ]U\WhSaO butions to education in biophysics. aQWS\bWabeV]aSQ]\b`WPcbW]\aVOdS]^S\SR\Se¿SZRa]T`SaSO`QV ]`ORdO\QSR\SeQ]\QS^baeWbVW\PW][SRWQW\S :WTb]\eOaQV]aS\ 3::3<6 4/<<7<5, an HHMI professor at T]`VWaRWaQ]dS`g]TbVSUS\SabVObQOcaS[O\gT]`[a]TVWUVO\R Vanderbilt University, was elected to the Z]ePZ]]R^`Saac`SW\Vc[O\a BVSUS\SaW\d]ZdSRW\`SUcZObW]\ ]TaOZbPOZO\QSPgbVSYWR\SgVWUVZWUVbbVSZW\YPSbeSS\RWSbO`g German National Academy of Science aOZbO\RVg^S`bS\aW]\ (Deutsche Akademie der Naturforscher Leopoldina). Fanning studies how DNA tumor viruses take advantage of cells to replicate. HHMI investigator /<53:79/ /;=<, received the Distinguished Service Award from Massachusetts Institute of Technology, the National Association of Biology Teachers. HHMI investigator @716/@2/ 4:/D3::, received the 2008 National Academy of Presented annually, the award honors a nation- Yale University School of Medicine, received Sciences Award in Molecular Biology, ally recognized scientist who has made major the 2008 Invitrogen Meritorious Career awarded annually for a recent notable contributions to biology education through Award from the American Association of discovery in molecular biology by a young research, writing, and teaching. Immunologists. The award recognizes his scientist. Amon was recognized for her numerous contributions to the field of immu- groundbreaking studies on the mechanism of HHMI investigator /@C:; 167 at the University of Wisconsin-Madison, a European researcher, recognizes Cossart’s diseases, including childhood cancers. Fetters Paul #" HHMI BULLETIN | May 2oo8 HHMI investigator 8C27B6 97;0:3, A>=B:756B University of Wisconsin–Madison, was elected to serve a three-year term on the Council of the National Academy of Sciences. Hynes Awarded Wilson Medal HHMI investigator ACA/<: :7<2?C7AB, Massachusetts Institute of Technology, received the 2008 Otto Warburg Prize from the German Society for Biochemistry and Molecular Biology. She also received the Protein Society’s 2008 Stein and Moore Award, which recognizes her groundbreaking discoveries in understanding the wide array of biological processes governed by protein folding, and the 2008 Genetics Society of America Medal. HHMI investigator A3/<8 ;=@@7A=<of @716/@26G<3A the University of Michigan Medical School received the 2008 Harland Winfield Mossman BVS %3 0 EWZa]\;SROZeS\bb]66;7W\dSabWUOb]`@WQVO`R= Award from the American Association of 6g\Sa]TbVS;OaaOQVcaSbba7\abWbcbS]TBSQV\]Z]Ug BVS[SROZbVS Anatomists. The award, presented annually to VWUVSabaQWS\QSV]\]`]TbVS/[S`WQO\A]QWSbgT]`1SZZ0W]Z]UgWa a young investigator who has made important OeO`RSRT]`ZWTSbW[SQ]\b`WPcbW]\ab]QSZZPW]Z]Ug 6g\SaabcRWSabVS []ZSQcZSabVObU]dS`\V]eQSZZaORVS`Sb]]\SO\]bVS`O\RV]e contributions in the field of developmental bVSg`SOQVbVSW`^`]^S`Z]QObW]\aW\bVSP]Rg biology, recognizes Morrison’s research on 6g\SaO\ObWdS]T5`SOb0`WbOW\eOaOZa]`SQS\bZgO^^]W\bSROa stem cell biology. ]\S]TbS\U]dS`\]`a]TbVSESZZQ][SB`cabbVSC\WbSR9W\UR][¸a ZO`USab\]\U]dS`\[S\bOZa]c`QS]TTc\RaT]`PW][SRWQOZ`SaSO`QV HHMI international research scholar :ÈAH:Ï hormone Donna Coveney / MIT of Medicine, received the 2008 K.S. Cole May 2oo8 | HHMI BULLETIN ## 1= 1= BVWa^O^S`WaQS`bW¿SRPgA[O`bE]]RT]`4A1abO\RO`RaeVWQV^`][]bS S\dW`]\[S\bOZZgO^^`]^`WObSa]QWOZZgPS\S¿QWOZO\RSQ]\][WQOZZgdWOPZS [O\OUS[S\b]TbVSe]`ZR¸aT]`Saba #$ HHMI BULLETIN | May 2oo8