Vol. 13 / No. 3 / March 2014
The member magazine of The American Society For Biochemistry And Molecular Biology CONTENTS
NEWS FEATURES PERSPECTIVES
2 24 35 PRESIDENT’S MESSAGE WHY SO BLUE? ESSAY e impact of the sequester: 1,000 A scienti c look at seasonal An open letter to my younger self, an fewer funded investigators a ective disorder aspiring graduate student in the sciences 5 28 37 NEWS FROM THE HILL Q&A WITH JONATHAN WEISSMAN OUTREACH When agreement isn’t enough Annual meeting plenary speaker Teaching science and social justice 6 32 40 MEMBER UPDATE MEET JOHN DENU A new associate editor of the OPEN CHANNELS 7 Journal of Biological Chemistry Reader comments JOURNAL NEWS • Effects of follistatin on brown fat 13 • Channeling pain 8 • A broader look at the proteins involved in learning and memory 10 LIPID NEWS Identi cation of ceramide-1-phosphate transport proteins 13 NEWS 37 NSF funds $25 million center for X-ray bioimaging 14 ANNUAL AWARDS
24 14 In our cover story, contributor Diedre Ribbens explores what we know about the underpinnings of seasonal a ective disorder.
MARCH 2014 ASBMB TODAY 1 PRESIDENT’S MESSAGE
$1.2 billion (compared with the $1.5 show any R funding in FY13. Given the sequester may have resulted in the billion cut across the entire NIH that there have been about 180 K99/ loss of about 200 new investigators THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY appropriation and $1 billion for all R00 awards per year, this indicates who normally would have received FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY The impact of research project grants). is drop that more than half of the K99/R00 their rst major NIH funding and has two components: e number of awardees are not transitioning to may have interrupted funding for OFFICERS COUNCIL MEMBERS investigators decreased by 1,001, or other R funding, at least in the rst more than 400 more established Jeremy M. Berg Squire J. Booker the sequester: 3.8 percent, and the average fund- year after the completion of their investigators. President Brenda Schulman ing per investigator dropped by 5 R00 awards. Steven McKnight David Sabatini President-Elect Melissa Starovasnik percent. • Nearly 900 investigators had R series versus Karen Allen Wesley I. Sundquist 1,000 fewer funded R21 funding in FY12 but did not research project grants Secretary Gregory Gatto Jr. Year-to-year dynamics show any R funding in FY13. Given Toni Antalis Natalie Ahn that there have been about 1,800 R21 In her post, Rockey notes that the Treasurer Anjana Rao of the investigator pool awards per year, this indicates that total funding for all research proj- Daniel Leahy investigators ese trends can be analyzed further about half of the R21 awardees are ect grants, or RPGs, dropped from EX-OFFICIO MEMBERS by examining the dynamics of inves- not transitioning to other R funding $15.92 billion in FY12 to $14.92 Geeta Narlikar ASBMB TODAY By Jeremy Berg Enrique de la Cruz EDITORIAL ADVISORY tigators into and out of the system as in the next year. billion in FY13, a decrease of 6.3 Co-chairs, 2014 Annual shown in the gure. What about the more than 600 percent. e total funding going to Meeting Program BOARD Committee Charlie Brenner Of the 26,513 investigators investigators who would have been the R series awards that I examined Chair Peter J. Kennelly he Rock Talk blog recently fea- I analyzed data from NIH funded by these mechanisms in expected to be funded without the (which makes up about 85 percent Chair, Education and Carol Shoulders tured a post titled “FY2013 by RePORTER for R-series grants (2). FY11, 5,287 were no longer funded sequester but who weren’t funded? Of of the RPG pool) dropped by 8.9 Shiladitya Sengupta Professional Development the numbers: research applica- ese included all funding mecha- by these mechanisms in FY12. How- course, we do not know who these percent. Committee Yolanda Sanchez T Daniel Raben Floyd “Ski” Chilton tions, funding and awards” (1) in nisms from R01s to R56s (including ever, 5,136 investigators who were investigators are. However, based What accounts for this di erence? Chair, Meetings Committee Cristy Gelling which National Institutes of Health SBIR and STTR, or R41 to R44, not funded in FY11 were awarded on the data recently posted on Rock U01 awards comprise the largest Fred Max eld Peter J. Kennelly Deputy Director for Extramural grants) but excluded R13 (confer- grants in FY12, with the di erence Talk, we can estimate that about remaining portion of the RPG pool Chair, Mentorship Committee Michael Bradley Research Sally Rockey noted that the ence awards) for FY11, FY12 and accounting for the small decrease 50,000 investigators competed for (4). ese are cooperative agreements Takita Felder Sumter Rajini Rao number of competing R01 awards of 151 investigators. e number these mechanisms in FY13. rather than grants for which NIH Chair, Minority A airs FY13. Data for other mechanisms, dropped from 5,436 in scal year of investigators for whom funding Also, based on previous years (3), sta members are involved in guiding Committee ASBMB TODAY such as P01s, DP1s (Pioneer awards) 2012 to 4,902 in FY13 and that the omas Baldwin Angela Hopp and larger mechanisms, were not ended and was not renewed in FY12 we can reason that about 30 per- the research. e funds devoted to Chair, Outreach Committee Editor, [email protected] number of competing R21 awards fell included. grew by 219 to 5,506. More strik- cent of those who would have been U01 awards remained essentially con- Bob Matthews Rajendrani Mukhopadhyay from 1,932 to 1,771. ese results For each year, data for about ingly, the number of investigators funded without the sequester would stant from FY12 to FY13 at $1.57 Chair, Public Affairs Sr. Science Writer, re ect the impact of the sequester, 35,000 awards were downloaded. who were not funded in FY12 but have been new investigators. us, billion. Advisory Committee [email protected] which resulted in a $1.5 billion, or who were awarded grants in FY13 Je rey Benovic Marnay Harris e number of awards is made up of Chair, Publications Designer, [email protected] 5 percent, decrease in the NIH about 75 percent R01s, 10 percent dropped by more than 600 to 4,505, Committee Characteristics of funding through R mechanisms Andrew Harmon appropriation. R21s, 5 percent SBIR/STTR awards a decrease of more than 12 percent Martha J. Fedor Science and Technology While these data capture one and all research project grants (RPGs) for FY11 through FY13 Editor-in-chief, JBC and 10 percent other mechanisms, from the previous year. Publishing Manager, important aspect of the sequester’s Herbert Tabor [email protected] with R01s accounting for approxi- impact, they do not re ect a more Co-editor, JBC Nancy J. Rodnan mately 80 percent of the funds. e Who are the unfunded FY11 FY12 FY13 Sources A. L. Burlingame Director of Publications, integrated evaluation of the e ect on awards for each investigator were Editor, MCP [email protected] investigators? investigators. As I detail below, such aggregated for each year. Some of the Total funding for R mechanisms $13.38B $13.51B $12.31B This study Edward A. Dennis Barbara Gordon an evaluation reveals that the number key parameters from this analysis, Examination of the parameters for Joseph L. Witztum Executive Director, Number of investigators with R [email protected] of funded investigators dropped by the applicants who received funding 26,513 26,362 Co-editors, JLR together with those reported on Rock funding 25,361 This study about 1,000 from FY12 to FY13, Talk, are summarized in the table. in FY12 but not in FY13 revealed the substantially more than the drop of Average R mechanism funding Examination of these data reveals following: $505K $512K $486K This study 150 from FY11 to FY12. Given the per investigator that from FY11 to FY12 the total • More than 2,900 investigators investments these investigators and Total funding for all research amount of funding going to the of the 5,506 who lost R funding had $15.82B $15.92B $14.92B (1) and (2) society have made in developing their project grants (RPGs) For information on advertising, contact Fox Associates Inc. R mechanisms increased slightly R01 grants in FY12. e median scienti c skills, these data provide a Average size of a research project at 800-440-0231 or [email protected]. while the number of investigators duration of these R01 grants was ve $450K $455K $441K (1) and (2) quantitative measure of the inecien- grant decreased by 151, resulting in a slight years, with more than 750 having cies created by erratic support for increase in the average funding per durations of eight years or more and Number of research project grants 35,173 35,029 33,796 (1) and (2) biomedical research. investigator. with more than 180 with durations www.asbmb.org/asbmbtoday of 20 years or more. Examining R grants held In contrast, from FY12 to FY13 SOURCES: 1. HTTP://1.USA.GOV/1HT40KY 2. HTTP://1.USA.GOV/1ET5MQQ the total amount of funding going • More than 110 investigators had CONTINUED ON PAGE 4 by each investigator to these mechanisms decreased by R00 funding in FY12 but did not
2 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 3 NEWS FROM THE HILL
INVESTIGATOR POOL DYMANICS When agreement isn’t enough now unfunded now unfunded investigators 5,287 investigators 5,506 By Benjamin Corb
5,136 newly funded newly funded he U.S. Congress is now enter- was championed successfully by con- grams, such as the nonpro t Planned investigators investigators 4,505 ing appropriations season — servative House members. In addition Parenthood and President Obama’s T that exciting time of the year to discretionary appropriations caps, A ordable Care Act. One side of the when the House and the Senate dole the act established automatic, across- debate will argue for increased fund- out funding to federal departments, the-board budget cuts, commonly ing for the NIH by taking money 151 1,001 agencies and pet projects for scal known as sequestration, which have away from other programs under this 26,513 26,362 25,361 2015. is time of year has advocates so negatively impacted research. particular appropriations umbrella, funded investigators funded investigators funded investigators like me scheduling meeting after Advocacy e orts like those by the but the other side will oppose bitterly meeting to ght for funding for our American Society for Biochemis- the reduction of funding for the other constituencies. On one hand, this try and Molecular Biology’s Public programs. As such, NIH funding kind of dialogue with members of A airs Advisory Committee were ends up in a political quagmire. Congress represents democracy at its a part of the reason a bipartisan Finally, there are the issues of 2011 2012 2013 best. On the other hand, this dia- accord was reached last December history and optics. Regarding his- logue can be one of the most frustrat- that relieved the cuts of sequestration tory, the NIH budget doubled from Shrinking pool of R-series-funded investigators: Of the 26,513 investigators funded by R-series mechanisms in fiscal 2011, 5,287 were no longer funded by those mechanisms in FY12. At the same time, 5,136 investigators who had not been funded by these mechanisms in FY11 ended up being funded in FY12. As a result of ing aspects of science advocacy. for FY14 and FY15. e Bipartisan the late 1990s to the early 2000s, this give-and-take, 151 fewer investigators were in the pool. This downward trend continued in FY13, when 5,506 investigators did not receive funding and only 4,505 e case for increased federal Budget Agreement last December which was a blessing and curse. is investigators were added to the mix. Ultimately, 1,001 fewer investigators than in FY12 were in the pool. investments in research and develop- delayed some spending cuts and budget growth led most members of ment is, on its face, an easy argu- raised some fees to an extent that Congress to develop a “you already CONTINUED FROM PAGE 3 investigators who lost this funding with the reduced appropriation ment to make. You’d be hard-pressed relieved the majority of budget cuts got yours” attitude toward the NIH. from FY11 to FY12 and a 3.8 percent associated with the sequester. e to nd a member of Congress who slated for these scal years. However, Regarding optics, the NIH receives What does it all mean? drop in the R-mechanism-funded results described, wherein R series doesn’t see value in investing in the budget caps remain. As a result, the second-largest appropriation First, let me o er a disclaimer. While I investigator cohort. awards absorbed a disproportion- research on diseases like cancer, appropriators are still limited in the in the entire government, after the have done my best to ensure accuracy e NIH took steps to reduce the ate amount of the sequester, do not Alzheimer’s and diabetes. Likewise, amount of money they can disperse, Department of Defense. Signi cantly in this analysis, these are not ocial drop in the number of grants awarded appear to be a matter of clearly articu- the economic argument in support including funds for research funding increasing NIH funding, when that NIH data and some minor di er- in FY13. is can be seen in the cut in lated policy decisions but rather the of investments in research is clear, agencies. money could fund dozens of other ences likely would be observed with a the average level of R funding going accumulated impact of a large number concise and widely accepted. If the e second issue is politics. e programs, is politically very dicult. more detailed analysis due to a range to each funded investigator by 5.2 of individual decisions. Only through argument is that clear, and support is National Institutes of Health is But change is possible. As a result of technical issues. Furthermore, I percent. is gure re ects both the analyses like the rst-pass analysis bipartisan, then why are increases so funded in the appropriations bill for of our e orts and other factors, the have focused on R-series awards and e ect of cutting noncompeting grants, that I have described here can the real hard to come by? Labor, Health and Human Services, NIH received a $1 billion increase in have not included other mechanisms estimated to average 4.7 percent across e ects of the sequester be appreciated. is answer has many parts. e Education and related agencies. FY14 over FY13. is boost didn’t that also contribute to the support of NIH (5), and the limited number of e results of this analysis highlight rst is legal. In 2011, Congress passed Sadly, while supporting biomedical make up for sequestration entirely, speci c investigators. new grants going to already-funded the ineciency associated with having the Budget Control Act, which research at the NIH is easy regardless but it again demonstrates Congress’ With that said, the analysis does investigators. e 5.2 percent decrease a large number of individuals, both established hard caps on how much of political party, this bill has been understanding that biomedical place the impact of the sequester in in R funding going to each investiga- productive established investigators money Uncle Sam can appropriate for arguably one of the most politically research is a worthy investment of relatively sharp focus: ere were tor can be compared with the increase and talented young scientists at the discretionary programs between 2011 charged bills in the appropriations the taxpayers’ money. ese suc- about a thousand fewer investigators of 1.5 percent of funds going to each dawn of their careers, struggling to and 2021. is statute was an e ort process because it includes funding cesses ensure that the PAAC and the funded by these mechanisms in FY13 investigator from FY11 to FY12. obtain even modest resources to real- to curb growing debt and de cits and for controversial groups and pro- ASBMB Public A airs Oce will compared with FY12. is represents e NIH leadership and sta had ize their contributions to science and continue to strongly advocate for increases in the budgets of federal more than six times the number of a great challenge in trying to operate to the health of the nation. Advocacy efforts like those by the American Society science funding agencies, even in the face of the obstacles listed above. REFERENCES Jeremy Berg ([email protected]) is for Biochemistry and Molecular Biology’s Public the associate senior vice-chancel- 1. http://nexus.od.nih.gov/all/2014/01/10/fy2013-by-the-numbers/ lor for science strategy and plan- A airs Advisory Committee were a part of the reason Benjamin Corb (bcorb@asbmb. 2. http://projectreporter.nih.gov/reporter.cfm ning in the health sciences and org) is director of public affairs 3. http://report.nih.gov/FileLink.aspx?rid=826 a professor in the computational a bipartisan accord was reached last December that at ASBMB. 4. http://grants.nih.gov/grants/funding/funding_program.htm and systems biology department at the University of Pittsburgh. relieved the cuts of sequestration for FY14 and FY15. 5. http://www.nih.gov/news/health/jun2013/nih-03.htm
4 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 5 MEMBER UPDATE JOURNAL NEWS
capping o the ends of chromosomes. Agre won the 2003 Nobel in chem- Effects of follistatin on brown fat Zuk tapped to oversee division focused istry for his discovery of aquaporins, on policy and communications at NCATS which move water molecules through By Mary L. Chang Dorit Zuk in January became director the cell membrane. Nary a week goes by without a new of the National Center for Advancing fad diet limiting or directing the Translational Sciences’ Oce of Policy, AAAS recognizes Tsin intake of sugars, fats or proteins — Communications and Strategic Alli- for his dedication or a combination of any or all three. ances. In this position, Zuk oversees So it’s rather interesting that a study the development of policy solutions to mentoring in the March issue of the Journal of intended to hasten the delivery of throughout his career Lipid Research seems to indicate new drugs, diagnostics and devices to Andrew Tsin of that a glycoprotein known to be patients. She also oversees the oce’s the University of involved with promoting growth of communication arm, which serves the Texas at San muscle mass may have an unexpected general public and scienti c com- Antonio received relationship with brown adipose munity by disseminating information the 2013 Lifetime tissue, more commonly known as ZUK about NCATS programs, policies and Mentor Award brown fat. partnerships. “I am very excited to be joining NCATS, the newest center TSIN from the Ameri- Brown fat generates and main- at NIH,” Zuk said. “I look forward to helping transform the translational can Association for the Advancement tains body heat in warm-blooded science process so that new treatments and cures for disease can be deliv- of Science at the organization’s annual animals, and its activity a ects energy ered to patients faster.” Before joining NCATS, Zuk spent four years as a meeting in February in Chicago. metabolism and therefore could be a science policy adviser to the National Institutes of Health’s deputy direc- determinant in predicting obesity and AAAS ocials cited Tsin’s dedication tor for extramural research, Sally Rockey. Before that, she was a science metabolic syndrome. In an article by to “facilitating dramatic education policy fellow at the American Academy of Arts and Sciences and at the Melissa Braga of the Charles R. Drew and research changes at his institu- American Association for the Advancement of Science. Zuk, who earned University of Medicine and Science tion, leading to a signi cant produc- her Ph.D. in cell biology at the Weizmann Institute, is a member of the and colleagues, the activity of a glyco- tion of Hispanic American doctorates American Society for Biochemistry and Molecular Biology’s Education protein called follistatin in brown fat in the biological sciences.” Tsin has and Professional Development Committee and chairs the advisory com- was examined. been described as going above and mittee on AAAS Science and Technology fellowships. Braga et al. had noted that fol- beyond in support of his students, listatin expression levels are signi - many of whom are rst-generation Tissue distribution of follistatin and its induction during adipogenic differentiation of mouse brown pre- cant in some brown adipose tissue college attendees. George Perry, a adipocyte cells. (A) Real-time quantitative PCR analysis of follistatin gene expression in mouse tissue and wanted to know its functions business magnate Michael R. Bloom- dean at UTSA, pointed to an panel (n=3). (B) Photomicrographs of mouse brown pre-adipocyte cells grown either in regular growth Greider and Agre among there. So rst, they examined mouse medium (undifferentiated) or in BAT-specific adipogenic medium (differentiated) for 8 days. berg. e program is intended to pro- undeniably powerful statistic: brown pre-adipocytes allowed first at Hopkins to secure mote interdisciplinary research in line “ e signi cant contribution of Dr. to di erentiate under controlled tiation of brown adipocytes and that with the university’s initiatives. “ is Tsin’s mentoring is evidenced in the out broblasts compared with the Bloomberg professorships conditions; follistatin levels went severe metabolic defects may occur university is committed, as much or successes of his mentees: 100 percent wild-type cells and indicated that from undetectable from baseline to without normal follistatin function, more than any other, to assembling of his undergraduate and graduate follistatin is a key modulator of lipid substantial levels once the adipocytes including defects that could prove and energy metabolism. experts from divergent disciplines students completed their degrees and di erentiated. fatal. e researchers say more detailed to attack humanity’s most impor- have continued in their educational From there, the team looked By treating both kinds of cells with studies of follistatin’s functional role tant problems from every angle,” track or have entered successful at adipogenesis in vitro in mouse follistatin, the researchers con rmed in vivo are the next logical step. e explained Hopkins’ president, Ronald scienti c careers.” In a statement, embryonic broblasts, comparing the it was the lack of the glycoprotein development of in vivo models hope- GREIDER AGRE J. Daniels, announcing the appoint- the university noted that during his di erences between those isolated that was causing the decreased levels fully will help identify potential tissue Two members of the American Soci- ments. Hopkins’ provost, Robert C. tenure at UTSA, Tsin has helped from wild-type embryos or embryos of key brown adipocyte proteins. targets of follistatin and therefore ety for Biochemistry and Molecular Lieberman, added: “ ere is already a bring in $68.5 million in funding in which the follistatin gene had been Addition of the glycoprotein to provide novel therapeutic approaches Biology are among the rst faculty tremendous spirit of collaboration at for programs for underrepresented knocked out. e levels of key brown follistatin-de cient broblasts also for treating obesity, diabetes and members at Johns Hopkins Univer- Hopkins. at is one of our hall- minorities. Tsin previously received adipocyte proteins, including uncou- increased cellular respiration. metabolic syndrome. sity granted appointments under the marks. I think this program institu- the Presidential Award for Excellence pling protein 1, or UCP1, were found Global gene-expression pro ling Bloomberg Distinguished Professor- tionalizes it all in a way that nothing in Science, Engineering and Math- to be much lower in the knockout also was conducted on broblasts of ships program. Carol Grieder and else could.” Greider won the 2009 ematics Mentoring from President Mary L. Chang (mchang@asbmb. mouse broblasts compared with wild both types during the early stages of Peter Agre, both Nobel laureates, Nobel in physiology or medicine for Obama and is a fellow of the org) is publications manager for type. e decrease in the amounts of brown adipocyte induction. Expres- the Journal of Lipid Research. secured the endowed chairs funded the discovery of telomerase, which Association for Research in Vision these proteins suggests that follistatin sion levels of genes were reduced last year by Hopkins alumnus and safeguards genetic information by & Ophthalmology. in uences adipogenesis and di eren- by 3.5-fold or more in the knock-
6 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 7 ey observed that resurgent cur- e results are signi cant, because ing particle that gives rise to resurgent Channeling pain rents do, indeed, increase in A1632E they o er insights into the key di er- currents could be developed. e role of resurgent currents in inherited pain syndromes mutation but not in A1632T muta- ence between the electrophysiology tions. us they concluded that IEM of IEM and PEPD, both of which By Sapeckshita Agrawal Sapeck Agrawal (sapeck.sriv- results from increased inactivation of are debilitating conditions that cause [email protected]) earned her Nav1.7 without an increase in resur- episodic pain. ese ndings provide Ph.D. in molecular microbiology Nociceptors are nerve cells that sense gent currents, while PEPD results a novel target area for the develop- and immunology from the Johns potentially harmful stimuli and from increased inactivation with ment of therapeutic strategies; drugs Hopkins University. For more report to the brain and the spinal increased resurgent currents. counteracting the action of the block- stories, visit sapeckagrawal.wordpress.com cord to e ect an appropriate defense response. e reporting is relayed in the form of action potentials trans- mitted by voltage-gated sodium chan- nels on these nerve cells. Interest- A broader look at the proteins ingly, the nerve cells can be rendered hyper-excitable by various mutations involved in learning and memory in the SCN9A gene that encode the By Rajendrani Mukhopadhyay sodium channel subtype Nav1.7. As a result, two distinct types of inherited Learning is complicated business. type of experiment, mice are put in been reported in brains of Alzheimer’s pain syndromes can arise: inherited or But typical research studies into a new cage and given a small electri- patients. “One surprise was that primary erythromelalgia, called IEM the molecular basis of learning and cal shock. Researchers can tell when many proteins that increased in level for short, and paroxysmal extreme memory measure only one or a few a mouse has learned to be fearful of with normal learning also increased, pain disorder, or PEPD. proteins. In a study just reported in the same cage when the mouse freezes although not as much, with treatment To date, IEM has been linked to the journal Molecular & Cellu- when put back in the cage. is with memantine alone,” says Gar- at least 20 mutations of the SCN9A lar Proteomics, researchers cast a approach “has the advantage that it diner. “Memantine induces responses gene, all of which reduce the depo- wider net and looked at 80 proteins requires only a single trial, lasting less in a substantial number of proteins larizing potential needed to activate in the brain of mice. By looking at than ve minutes, for mice to learn,” that we measured, and it does this the mutant channel, thus facilitating more proteins, the study’s leader, explains Gardiner. “ is means that without impairing or enhancing hyperexcitability of the nerve cell. IEM. Sequencing her SCN9A gene team determined that the di er- Katheleen Gardiner at the University we have a clear window in time where learning. is indicates that there is Consequently, seemingly innocuous identi ed the responsible mutation, ence in electrophysiology between of Colorado in Denver, says research- we know molecular events associated considerable exibility in the timing activities such as exercise can trigger A1632T. However, instead of a ect- A1632E and A1632T was in the ers can get a better appreciation of with successful learning occur.” and extent of protein responses that episodes of excruciating pain. ing activation of Nav1.7 as expected, decay time constants of the current. “the greater complexity of molecu- Context fear conditioning demands still result in successful learning.” PEPD, on the other hand, has the mutation, when tested in While A1632T and wild type had lar events underlying learning and that the hippocampus, a region of the In particular, Gardiner’s group been linked to 10 (and potentially transfected human embryonic kidney similar decay constants, A1632E had memory, how components of a single brain important for memory forma- identi ed the MAPK and MTOR more) separate mutations, also on the cells, shifted steady-state fast inactiva- a slower current decay. Based on this pathway change in concert, and tion, be functional. e hippocampus pathways to be a ected in their SCN9A gene, all of which obstruct tion to depolarizing potentials – a observation, the team hypothesized how many pathways and processes is also a part of the brain that degener- experiments as well as subunits of channel closure by inducing a depo- phenomenon expected from PEPD that the slower current decay also respond.” ates in Alzheimer’s disease. glutamate receptors and the NOTCH larizing shift of steady-state inactiva- mutations. would lead to resurgent currents in Gardiner’s research focus is on e investigators gave the mice pathway modulator called NUMB. tion. e result is, again, a hyperac- is surprising result led Eber- the system. Down syndrome, two characteristics a drug called memantine, which is NUMB is known to be essential for tive nerve cell causing debilitating hardt and her team to determine Resurgent currents, an unusual of which are that patients su er from used to treat moderate to severe cases some aspects of brain development. pain. what bifurcates pain syndrome phenomenon in which sodium chan- some level of intellectual disability of Alzheimer’s disease. e drug has Gardiner says her group is now e apparent dichotomy between from SCN9A mutations into IEM nels brie y open during depolarizing and that they eventually develop been shown to correct for learning looking at data from a similar experi- IEM mutations a ecting activa- or PEPD. To do so, the team took currents in the decaying phase of an Alzheimer’s disease. Gardiner’s group impairment in a mouse model of ment done with a mouse model of tion and PEPD mutations a ecting advantage of a previously charac- action potential, arise as a result of aims to nd drugs that can lessen the Down syndrome. Down syndrome. ose mice were inactivation of the sodium channels terized mutation of SCN9A gene, occlusion of the sodium channel dur- learning disability. But in order to do Gardiner’s group used proteins unsuccessful with context fear condi- recently has been challenged after the A1632E. Interestingly, that mutation ing inactivation by a blocking parti- that, researchers need to better under- arrays to see how protein expression tioning, but they did as well as wild- characterization of a new mutation gives rise to overlapping symptoms of cle, which is di erent from the intra- stand the molecular events associated changed in the brains of mice that type mice when they were treated of the SCN9A gene published in the IEM and PEPD, displaying shift of cellular loop responsible for routine with learning, memory and neurode- underwent context fear conditioning with memantine. Journal of Biological Chemistry voltage-dependence for both activa- channel inactivation. us, to test the generation. and were given memantine com- by Mirjam Eberhardt and collabora- tion and fast inactivation. hypothesis that A1632E mutation led Rajendrani Mukhopadhyay (rmuk- To get a grasp of the proteins pared with control mice. ey found [email protected]) is the tors in Germany. Using whole-cell voltage-clamp to an increase in resurgent currents, involved in a particular learning pro- levels of 37 proteins changed in the senior science writer and blogger e study highlights the case recordings of human embryonic the team added a peptide with the cess, the investigators studied context nuclear fraction of the hippocampus. for ASBMB. Follow her on Twitter of a 22-year-old female su er- kidney cells transfected with mutant sequence of the blocking particle to fear conditioning in mice. In this Abnormalities in 13 proteins had at www.twitter.com/rajmukhop. ing from canonical symptoms of versions of the SCN9A gene, the the transfected cells.
8 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 9 LIPID NEWS Identification of ceramide-1-phosphate transport proteins By Robert V. Stahelin
ecently, investigators have ceramide. At the trans-Golgi network, Structural details for CPTP identi ed the protein that car- C1P has been shown to activate the R ries the important sphingolipid pro-in ammatory enzyme cytosolic e authors went on to solve the α α structure of CPTP bound to several ceramide-1-phosphate in humans. phospholipase A2 , or cPLA2 (6). is nding helps us understand More recently, C1P has been shown lipids, including C1P, with varying how C1P is transported inside cells to regulate other proteins (7, 8); acyl chains. e structure revealed α 60 106 110 to carry out its critical signaling however, the cellular mechanisms and an -helical topology and a fold Crystal structure of CPTP in complex with 16:0-C1P (PDB ID: 4K84). Cationic residues (Lys , Arg and Arg ) that bind the phosphate headgroup of C1P are shown in blue. The C1P acyl chains are ensheathed in the deep hydrophobic pocket beneath the surface cationic residues that interact with the phosphate headgroup. functions for processes such as cell localizations are not well understood. homologous to that of GLTP proliferation and migration. C1P may be transported via vesicular ( gure 1C). Sphingolipids play key roles in transport from the trans-Golgi net- CPTP has one surface enriched ally, the lack of the acyl amide moiety network, endosomal and nuclear While metabolism of C1P back fractions but were decreased in the to another sphingolipid (ceramide or cellular signaling and membrane traf- work (9), but for the most part, how in cationic residues, which contains on phosphatidic acid precluded the 60 106 interaction with residues in CPTP plasma membrane. CPTP overexpres- S1P) is still a controversial subject, cking — with sphingosine, sphingo- speci cally C1P is disseminated from three amino acids (Lys , Arg and 110 that bound the acyl amide of C1P. sion could rescue these e ects. this new study suggests that perhaps sine-1-phosphate, ceramide and C1P the trans-Golgi network to other Arg ) critical for binding to the C1P us, phosphatidic acid had altered CPTP involvement in C1P e ec- deacylation of C1P may occur as acting as the main players (1). cellular membranes, where it interacts phosphate headgroup. Mutation of these residues greatly diminished the headgroup and acyl chain positions tor cPLA α activity was also assessed. silencing of CPTP reduces cellular C1P is an anionic sphingolipid with e ector proteins, remained 2 compared with C1P, which was When CPTP was silenced, arachi- levels of S1P and sphingosine. containing a phosphomonoester unknown until recently. ability of CPTP to transport C1P. determined to loosen the phospha- donic acid levels increased, consistent CPTP does not appear to be headgroup (see Figure 1A) and in Last year, a multidisciplinary team Below this surface cationic patch tidic acid binding. is distorted with C1P accumulation and therefore limited to mammalian cells. A CPTP mammalian cells is synthesized from reported in the journal Nature that it lies a portal to a deep hydrophobic cavity that can accommodate both orientation likely dampens transfer of increased cPLA α activation at the was found in Arabidopsis (14). In ceramide by the enzyme ceramide had identi ed a putative C1P transfer 2 acyl chains of the C1P molecule. is phosphatidic acid. trans-Golgi network. Metabolites that model, cell death 11 mutant, or kinase. CerK was discovered more protein, or CPTP, in humans (10). hydrophobic pocket is highly exible of cyclooxygenase, lipoxygenase ACD11, is able to transfer C1P or than 20 years ago by a team that co- e team screened the National and can expand to accommodate and CYP450 pathways also were phyto-C1P, the major component of puri ed it with brain synaptic vesicles Center for Biotechnology Informa- Cellular studies the sphingosine and acyl chains of increased. Conversely, eicosanoid plant cells. (2); to date, it remains the only kinase tion’s human genome and identi ed a 16:0- and 18:1-C1P. e authors of C1P transport levels decreased upon overexpression e structure of ACD11, like that known in mammalian cells to convert predicted transcript with 17 percent demonstrate that this pocket wasn’t as In cells, CPTP visualized by antibody of wild-type CPTP but not dominant of CPTP, revealed a surface cationic ceramide to C1P. sequence identity with glycolipid adaptable to accommodating longer or enhanced green uorescent protein negative mutations. patch for C1P headgroup recogni- In 2002, CerK was cloned and transfer protein, or GLTP. acyl chains (such as lignoceryl) and tag was found in the cytosol but also e authors suggest that CPTP tion and a hydrophobic pocket that found to be expressed in the brain, e authors demonstrated that thus propose that CPTP may serve to associated with the trans-Golgi net- acts as a C1P sensor, transferring C1P can accommodate the lipid chains. In heart, kidney, lung and hematopoi- the mRNA for this construct was transfer 16:0- and 18:1-C1P selec- work, endosomes, nuclei and plasma from the trans-Golgi network to the null ACD11 cells, normally low levels etic cells (3). Since then, the many found in most tissues and that the tively in cells. membrane. us, the authors propose plasma membrane as levels increase of phyto-C1P greatly rise, leading to bioactive roles for C1P have been recombinant protein can transfer e structure of CPTP with phos- a C1P-sensing role for CPTP at the such that C1P does not build up in an increase in phyto-ceramides and elucidated. ese include macrophage C1P selectively between phosphati- phatidic acid bound ( gure 1B) also trans-Golgi network during CERK the trans-Golgi network. is would programmed cell death. migration, cell proliferation, stem dylcholine vesicles. is is an exciting was solved to investigate why a di er- signaling. also allow for ne-tuning of cPLA2α cell mobilization and regulation of nding for the lipid research com- ent anionic phosphomonoester was Silencing of CPTP in human cells activity and the ability to regulate eicosanoid production (4, 5). munity, as lipid-transport proteins What’s to come? for sterols, ceramide, glycolipids and not transferred eciently by CPTP. resulted in elevated cellular 16:0-C1P arachidonic acid generation. CPTP Many questions about C1P-mediated glycerophospholipids have been stud- Phosphatidic acid interacts with and 24:1-C1P as well as fragmented depletion also had e ects on other signaling and cellular transport ‘An exciting finding’ the same residues as the C1P head- Golgi cisternal stacks. Subcellular sphingolipids, namely decreased cel- ied intensely (11 – 13), and yet those remain unanswered. CerK is localized to the trans-Golgi for lipids such as C1P had remained group but with a slightly di erent fractionation showed that C1P levels lular levels of sphingosine, sphingo- network, where it generates C1P from unexplored. H-bonding arrangement. Addition- were increased in the trans-Golgi sine-1-phosphate and sphingomyelin. CONTINUED ON PAGE 12
10 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 11 NEWS
CONTINUED FROM PAGE 11 plasma membrane is unknown, and brane is not understood. However, For instance, which lipids CPTP how speci cally it transports C1P these represent exciting questions for binds at the trans-Golgi network and from the Golgi to the plasma mem- future studies. NSF funds $25 million center C1P also has unique biophysi- cal properties that may play roles in REFERENCES its signaling and transport (15). In 1. Hannun, Y.A. and Obeid, L.M. J. Biol. Chem. 32, 27855 – 27862 (2011). closing, these new studies identifying for X-ray bioimaging 2. Bajjalieh, S.M. et al. J. Biol. Chem. 24, 14354 – 14360 (1989). the existence of CPTPs will gener- 3. Sugiura, M. et al. J. Biol. Chem. 26, 23294 – 23300 (2002). ate much excitement toward further By Aditi Iyengar 4. Hoeferlin, L.A. et al. Handb. Exp. Pharmacol. 215, 153 – 166 (2013). unraveling the mechanism and role of 5. Gomez-Munoz, A. et al. Biochim. Biophys. Acta. 1831, 1060-1066 (2013). C1P signaling in normal and patho- 6. Lamour, L. et al. J. Biol. Chem. 39, 26897 – 26907 (2009). logical processes. 7. Lamour, L. et al. J. Biol. Chem. 50, 42808 – 42817 (2011). 8. Hankins, J. et al. J. Biol. Chem. 27, 19726 – 19738 (2013). 9. Boath, A. et al. J. Biol. Chem. 13, 8517 – 8526 (2008). Robert V. Stahelin (rstaheli@ iu.edu) is an associate professor 10. Simanshu, D.K. et al. Nature 500, 463 – 467 (2013). of biochemistry and molecular 11. Schaaf, G. et al. Mol. Cell 29, 191 – 206 (2008). biology at the Indiana University 12. Villasmil, M.L. et al. Biochem. Soc. Trans. 40, 469 – 473 (2012). School of Medicine-South Bend. 13. Prinz, W.A. Nat. Rev. Mol. Cell Biol. 15, 79 (2014). He also is a Showalter scholar, a designation 14. Simanshu, D.K. et al. Cell Reports 6, 388 – 399 (2014). reflecting his support from the Ralph W. and Grace M. Showalter Research Trust Fund. 15. Kooijman, E.E. et al. Biophys. J. 94, 4320 – 4330 (2008).
The first high-resolution diffraction pattern results from the X-ray free electron laser at LCLS in February 2011. NSF BIOXFEL SCIENCE AND TECHNOLOGY CENTER
he University of Bu alo won a systems that are currently inaccessible understanding of drug design. prestigious science and technol- by current X-ray methods,” says NSF e University at Bu alo and T ogy center grant conferred every Chemistry of Life Processes Program Hauptman-Woodward Medical four years by the National Science Manager David Rockcli e. “Once Research Institute will host this cen- Foundation for the establishment the center develops the measurement ter in partnership with Arizona State of innovative and interdisciplinary tools to fully utilize the XFEL source, University; the University of Wiscon- research centers across the country. the scienti c payo s are expected to sin, Milwaukee; Cornell University; is $25 million grant will go toward be extraordinary.” Rice University; Stanford University; launching the Center for Biology e use of XFEL technology could the University of California, San A conference ASBMB members should not miss! with X-ray Laser, or BioXFEL, which enable scientists to develop advanced Francisco; and UC, Davis. will focus on developing new bioim- forms of X-ray bioimaging, including Eaton E. Lattman, a professor in aging techniques using the immensely the serial femtosecond crystallography Bu alo’s structural biology depart- Protein Folding in the Cell powerful X-ray free-electron laser method for the characterization of ment and medical school and chief technology. biological structures. is particular executive ocer of the Hauptman- July 20 - 25, 2014 Researchers aliated with the technique, with its ability to predict Woodward Medical Research Insti- BioXFEL center anticipate new the structure and motion of extremely tute, will be director of the BioXFEL Vermont Academy breakthroughs in the eld of biomo- small and previously uncrystallizable center. Saxtons River, VT lecular crystallography using this kind molecules, could provide structural For more information on this of X-ray beam, originally developed biologists with a valuable tool to center and its research, visit www.bioxfel.org. Conference Co-organizers: Je rey Brodsky, Ph.D., University of Pittsburgh at the SLAC National Accelerator analyze accurately biological func- Laboratory at Stanford University. tion of proteins and their dysregula- Patricia Clark, Ph.D., University of Notre Dame Aditi Iyengar ([email protected]. “With this (technology), the center tion in disease. Such research would harvard.edu) is a postdoctoral will provide the biology research boost current methods employed to fellow at Massachusetts General For more information, please visit us at www.faseb.org/SRC community with tools to study an identify molecular targets for drug Hospital. enormous number of biological development and improve the current
12 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 13 ANNUAL AWARDS
ALICE AND C.C. WANG AWARD IN MOLECULAR PARASITOLOGY Stuart recognized for his work with trypanosomes By Sarah Perdue
Ken Stuart, founder and president Research at the National Institute of emeritus of the Seattle Biomedical Allergy and Infectious Diseases. “His Research Institute and an aliate lab determined the crystal structures professor of global health at the Uni- of some of the editosome proteins versity of Washington, is the recipient and is testing compounds as potential of the American Society for Biochem- leads for drug development.” istry and Molecular Biology’s Alice Stuart’s editing work has led others and C.C. Wang Award in Molecular to nd additional types of editing Parasitology. in such diverse organisms as plants e award is given to researchers and humans, said Stefan Kappe, the who are making signi cant con- Seattle Biomedical Research Institute’s tributions to the eld. Stuart was malaria program director. Kappe I am honored to receive this award nominated for his work on post- noted that in humans, for example, from the Wang’s, who have made transcriptional mRNA editing in try- post-transcriptional editing has been pioneering contributions to molecular panosomes as well as the sequencing shown to function in resistance to parasitology and are committed to and annotation of their genomes. HIV infection as well as in the regula- improving global health. Trypanosomes include the caus- tion of channel receptors in the brain. – KEN STUART ative agents of African sleeping sick- Stuart was also a leading force in ness, Chagas disease and Leishmani- the sequencing and annotation of and detoxi es heme, and he is using asis. More recently, Stuart has begun the so-called “TriTryp” genomes, RNAseq to characterize lympho- to study the interactions between the and he has since used genetic and cyte gene expression in response to malaria parasite and its human host. biochemical approaches to character- malarial infection and immunization His work has led to a broad under- ize and assign function to more than against the parasite. standing of trypanosome biology as 1,000 mitochondrial proteins as well “In the late 1970s, ‘global health’ well as the identi cation of hundreds as many of the cellular proteins in was not a term in common use, and of potential drug targets to combat Trypanosome brucei. His character- there was almost no research in the the diseases. ization of the proteome, including U.S. on neglected diseases,” said In this issue: In the April issue: Stuart showed that some tran- structural prediction and enzymatic Wellems. “(Stuart) had the vision scripts in trypanosomes are edited by analysis, has helped identify inhibi- to build a new organization (Seattle 15 Alice and C.C. Wang Award in Molecular Parasitology Bert and Natalie Vallee Award in Biomedical Science the addition or removal of a nucleo- tors that could lead to the develop- BioMed) and partnerships that would winner Ken Stuart winner Michael M. Gottesman tide and that that process alters how ment of anti-trypanosome drugs. attract leading principal investigators the pathogen regulates energy genera- “Now that many genes of these 16 ASBMB/Merck Award winner Benjamin Cravatt William C. Rose Award winner Lynne E. Maquat to this research.” tion. He also found that this editing parasites are mapped, researchers 17 Walter A. Shaw Young Investigator in Lipid Research Stuart will receive his award dur- is di erentially regulated throughout can more easily identify genes that winner Mary Kraft ASBMB-Howard K. Schachman Public Service Award ing the Experimental Biology 2014 the organism’s life cycle and that this are critical for parasite survival, and conference in San Diego, where he 18 Mildred Cohn Award in Biological Chemistry Herbert A. Sober Lectureship winner Dana Carroll editing is essential during the disease new knowledge about the similarities winner Lila Gierasch will deliver an award lecture. e pre- Herbert Tabor Research Award winner Bruce W. Stillman stage, making the so-called “edito- between each trypanosome suggests sentation will take place from 3:45 to 19 Avanti Award in Lipids winner Sandra Hofmann some” an ideal target for therapies. the potential to develop a class of 6 p.m. Monday, April 28, in the San Ruth Kirschstein Diversity in Science Award winners 20 ASBMB Young Investigator Award winner Samie R. Jaffrey “Dr. Stuart’s RNA editing discov- drugs that can target all three para- Deigo Convention Center Room 1A. Freeman A. Hrabowski III and Michael F. Summers eries expanded the central dogma sitic diseases,” said Wellems. 21 DeLano Award for Computational Biosciences of molecular biology by showing In addition to Stuart’s work on try- Sarah Perdue (sp366@cornell. ASBMB Award for Exemplary Contributions to Education winner Michael Levitt that the protein-coding sequence of panosome pathogenesis, he is study- edu) received her Ph.D. in micro- winner Harold B. White III biology from Cornell University, 22 Earl and Thressa Stadtman Scholar Award mRNAs can be precisely changed ing the malaria parasite Plasmodium spent two years teaching at winner Aviv Regev after their transcription from DNA,” falciparum. He recently characterized different colleges as a visiting said omas Wellems, chief of the a protein complex in that organ- professor and now is a postdoctoral researcher at Laboratory of Malaria and Vector ism that metabolizes hemoglobin the University of Minnesota.
14 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 15 ASBMB/MERCK AWARD WALTER A. SHAW YOUNG INVESTIGATOR AWARD IN LIPID RESEARCH Cravatt lauded as ‘gem of the scientific community’ Kraft ‘has changed our understanding for his work on activity-based protein profiling of lipid organization’ By Mark Stewart By Shaila Kotadia
Benjamin Cravatt of e Scripps matabolizing enzyme. ABPP revealed Mary Kraft, assistant professor of supported Kraft’s nomination for the Research Institute in La Jolla, Calif., important roles for endocannabinoid- chemical and biomolecular engi- award: “I cannot think of anyone who has been named the winner of the metabolizing enzymes in pain, neering at the University of Illinois is better suited to this award, aimed American Society for Biochemistry in ammation and neuropsychiatric Urbana-Champaign, is the winner as it is at young researchers who have and Molecular Biology/Merck disorders. In collaboration with the of this year’s American Society for not only attained prominence but also Award. pharmaceutical company P zer, a Biochemistry and Molecular Biology hold considerable promise for future Cravatt, professor and chair of the highly potent and selective FAAH Walter A. Shaw Young Investigator in work.” chemical physiology department at inhibitor was developed and today Lipid Research award. Kraft started her career as a coop- Scripps, received this award based is in human clinical trials. is Established by the ASBMB’s Lipid erative education student at the Nalco on his groundbreaking contributions FAAH inhibitor represents a poten- Research Division and named after Chemical Company and completed to the development and application tial new class of analgesics and a the founder of Avanti Polar Lipids, her graduate work at UIUC. She took of post-genomic methods for the novel treatment for nervous system the award recognizes outstanding a four-year hiatus from the Midwest functional annotation of mammalian disorders. research contributions by investigators to do her postdoctoral fellowship I am tremendously honored to receive I’m honored to receive the Walter enzymes. “Cravatt pioneered the use James Wells of the University of with 10 or fewer years of experience. at Stanford University, where she the 2014 ASBMB-Merck Award, A. Shaw Young Investigator Award of the now widely practiced activity- California, San Diego, describes Cra- Kraft’s colleague at UIUC, Jona- was willing to try what many other which is a tribute to the many in Lipid Research for my lab’s work based protein pro ling technology, vatt as “a star at the chemistry-biology than Sweedler, said that Kraft’s work researchers could not achieve. talented and hardworking graduate on lipid organization in the plasma “has changed our understanding of Her postdoctoral adviser, Steven which utilizes site-directed chemical interface and a worthy recipient of students, postdoctoral fellows and membrane. I’m especially grateful to lipid organization within the cellular Boxer, explained: “Everything she was probes to pro le active enzymes in this important award.” collaborators with whom I have had my students, collaborators, colleagues, plasma membrane and the mecha- doing was new. ere is little prece- complex proteomes,” said Chaitan Cravatt attended Stanford Uni- the pleasure of working during my the ASBMB and Walter A. Shaw for nisms that produce it.” dent for the application of the method Khosla of Stanford University, who versity, earning a B.A. in history career at TSRI. making this possible. Kraft devised a novel method to any soft material, let alone biologi- nominated Cravatt for the award. and a B.S. in biological sciences. He – BENJAMIN CRAVATT – MARY KRAFT Most proteomic technologies mea- then pursued a Ph.D. at e Scripps for imaging using high-resolution cal membranes, and the consensus was sure protein abundance and therefore Research Institute under the men- secondary ion mass spectrometry in that it would be impossible to pull provide only an indirect estimate of torship of Dale Boger and Richard Cravatt will receive his award at conjunction with metabolic isotope o .” Kraft overcame those obstacles 2014 ASBMB annual meeting in San protein activity. Cravatt’s work has Lerner. At Scripps, he became an the Experiment Biology 2014 confer- labeling, which opened an unexpected and established the high-resolution Diego, where she will give a presenta- led to the development of a chemical assistant professor in 1996 and rose ence in San Diego. He will present new view of lipid composition in the SIMS technique for lipid membranes. tion. e presentation will take place strategy to pro le the functional state through the ranks to become profes- his award lecture at 2:55 p.m. Tues- cellular plasma membrane. One key Kraft soon returned to UIUC for an at 3:45 p.m. Sunday, April 27, in of enzymes through the development sor and chair in 2007. day, April 29, in Room 6A of the San nding demonstrated that choles- assistant professor position. Room 6C of the San Diego Conven- of active site directed probes, known “His love of science is over owing Diego Convention Center. terol is not enriched in sphingolipid Kraft not only has excelled in the tion Center. domains but rather evenly distributed laboratory but also in the classroom as activity-based protein pro ling, or and contagious. If you haven’t had the Mark Stewart ([email protected]) Shaila Kotadia (skotadia@asbmb. ABPP. chance to hear him speak about his is a Ph.D. student in the Univer- throughout the cell membrane. and in advising, receiving multiple org) is an ASBMB science policy During his graduate work, Cravatt work, there’s nothing I’d recommend sity of Alabama at Birmingham’s Kraft is continuing her excellent awards from her institution for her fellow. discovered fatty acid amide hydrolase, more highly,” says Daniel Herschlag cancer biology program and works e orts, said Bill Bement at the Uni- attentiveness to student needs. in the pathology department. or FAAH, an endocannabinoid- of Stanford University. versity of Wisconsin-Madison, who She will receive her award at the
16 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 17 MILDRED COHN AWARD IN BIOLOGICAL CHEMISTRY AVANTI AWARD IN LIPIDS Gierasch lauded as ‘phenomenal mentor’ Hofmann honored for her contributions and ‘rigorous biophysical chemist’ to the field of protein lipidation By Anna Shipman By Mark Stewart
e American Society of Biochemistry Some of Gierasch’s more recent e American Society for Biochemis- PPT1 has led to modest improve- and Molecular Biology has awarded work has been focused on developing try and Molecular Biology has named ments in mice and provides the basis Lila Gierasch the 2014 Mildred Cohn and testing experimentally a com- Sandra Hofmann at the University of for further studies. Award in Biological Chemistry for putational model of cellular protein Texas Southwestern Medical Center Robert Deschenes of the Uni- her extensive work in protein folding, homeostasis in E. coli in collaboration at Dallas the winner of the Avanti versity of South Florida says that structure and function. is award with Evan Powers of e Scripps Insti- Award in Lipids. “Hofmann’s work is a model of trans- recognizes scientists who have made tute. is collaboration has resulted in Hofmann, a professor in the lational science at its best” and that substantial advances in the eld of FoldEco, an online modeling program internal medicine department at UT- he even uses her work as an example biological chemistry through the use used to examine how protein folding Southwestern, focuses her research when teaching graduate and medical of innovative physical methods. in the cell is facilitated by chaperone on fundamental questions in lipid students. Gierasch’s early research into the and degradation networks. Gierasch’s metabolism and protein lipidation, Hofmann earned her B.A. in relationship between amino-acid lab also uses uorescent reporters to which has led to novel insights into chemistry with the highest distinc- sequence and peptide and protein study how protein sequence may a ect I am thrilled to be chosen to receive the treatment of human diseases. tion at the University of Virginia in I am honored to have received structure resulted in the development protein aggregation and folding. the Mildred Cohn Award from When Hofmann set up her own Charlottesville. She proceeded to earn this award and am grateful to my of fundamental principles for reverse- Gierasch earned her A.B. in chem- ASBMB. She was one of my heroes; lab at UT-Southwestern, the enzy- an M.D. and Ph.D. at Washington colleagues for the nomination and turn conformation features as well as istry in 1970 from Mount Holyoke her contributions reflect her deep mology of palmitoylation, which University School of Medicine in to Avanti Polar Lipids for their the establishment of several biophysi- College in South Hadley, Mass., and physical understanding, her experi- is the attachment of fatty acids to St. Louis under the mentorship of support of this award. Lipid enzy- cal methods commonly used today earned a Ph.D in biophysics from mental boldness and her willingness proteins, was unknown. Hofmann’s Philip Majerus. In the Majerus lab, mology is a di cult and rewarding to characterize protein turns, such as Harvard University in Cambridge, to deploy any biophysical approach research led to the puri cation of pal- she made seminal contributions to field pioneered by a number of cou- nuclear magnetic resonance, quan- Mass., from the lab of Elkan R. Blout that would answer the key questions mitoyl protein thioesterase, or PPT1, the enzymology of phosphatidylino- rageous individuals and it has been titative nuclear Overhauser e ects, in 1975. underlying a biological system. an enzyme that removes these fatty sitol hydrolysis. at work provided a privilege to continue to work in circular dichroism and computational Today Gierasch is a distinguished My laboratory’s contributions acids from proteins. is was the rst her experience in the isolation and this great tradition. It is particularly modeling. is research was also the professor at the University of Mas- reflect the energy, creativity, enthu- enzyme identi ed with a role in pro- characterization of novel enzymes. exciting to see protein lipidation basis for Gierasch’s later research with sachusetts Amherst. She has mentored siasm, hard work and dedication of tein palmitoylation. e PPT1 gene She left Washington University to being recognized. The potential GnRH analogs and the use of peptide many undergraduate and graduate the wonderful students and postdocs eventually was mapped to a region in pursue postdoctoral training in the for new discovery in this area is fragments to examine protein recogni- students and postdoctoral fellows; I have worked with through the chromosome 1p, which also had been laboratory of Nobel laureates Michael enormous. It would not surprise me tion motifs. Gierasch also has studied served on many editorial advisory years. I thank them! In addition, linked to infantile neuronal ceroid Brown and Joseph Goldstein at UT- to be treating future patients with how protein folding occurs within boards; and played leadership roles in thanks to many collaborators who lipofuscinosis, or INCL, a devastating Southwestern. Hofmann has since cancer or neurological disorders with the cell, using transferred nuclear several scienti c societies. worked with us to tackle daunting neurodegenerative disease in children. remained at UT-Southwestern, where protein palmitoylation inhibitors Overhauser e ect, or trNOE, meth- “To me, Lila is not only an problems, who elevated our science Her training as a clinician-scientist she has risen through the ranks to in the same way that protein kinase ods to show how chaperone proteins outstanding scientist who has made and who shared the pleasures of helped her make this link and dis- professor. inhibitors are used today. recognize the folded state of a protein milestone and unique contributions garnering meaningful results. cover that de ciencies in PPT1 cause In recognition of her research, – SANDRA HOFMANN substrate. to her own research eld but also a – LILA GIERASCH INCL. Hofmann was inducted as a member “Lila is a rigorous biophysical phenomenal mentor who never ceases “Hofmann’s research is a superb of the American Society for Clinical chemist, but unlike most chemists to inspire and help many of her men- example of how tackling a fundamen- Investigation and the American presentation. e presentation will deliver an award lecture. Her lecture who avoid complexity and prefer tees to launch success in their careers,” tal basic science question can lead to Association of Physicians. She also take place at 8:30 a.m. Monday, April will be at 8:30 a.m. Wednesday, April reductionist type studies, Lila’s whole says Ning Zheng, Professor at Univer- discoveries of great clinical signi - chairs the Scienti c Advisory Board 28, in Room 6A of the San Diego 30, in Room 6A of the San Diego career has been focused on applying sity of Washington and an Howard cance,” explains Maurine Linder of for the Batten Disease Support and Convention Center. Convention Center. chemistry and biophysical methods Hughes Medical Institute Investiga- Cornell University, who nominated Research Association, which allows to the study of peptides and their role tor. “Her achievements as a scholar, a Anna Shipman (alsnpc@mail. Hofmann for the award. her to have a sustained in uence on in biology as well as protein folding leader and a mentor are extraordinary umkc.edu) received her B.S. in Hofmann later developed the the eld of disorders of the nervous biology–biotechnology from Mis- Mark Stewart ([email protected]) and tracking in vivo,” says Je rey W. at every level.” souri Western State University and rst mouse model of INCL. at system. is a Ph.D. student in the Univer- Kelly at e Scripps Research Insti- Gierasch will receive the award at is a Ph.D. student in the School of mouse model allowed her to develop Hofmann will receive her award sity of Alabama at Birmingham’s tute. “Her work is insightful, revealing the 2014 ASBMB annual meeting Biological Sciences at the University of Missouri– enzyme-replacement therapy. e in San Diego at the Experimental cancer biology program and works and is well ahead of its time.” in San Diego, where she will give a Kansas City. addition of intravenous recombinant Biology 2014 meeting, where she will in the pathology department.
18 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 19 ASBMB YOUNG INVESTIGATOR AWARD DELANO AWARD FOR COMPUTATIONAL BIOSCIENCES Jaffrey called ‘a tremendously gifted thinker’ Nobel laureate Levitt: ‘an intellectual leader’ for having accomplished so much so quickly By Preethi Chander By Anna Shipman Michael Levitt of the Stanford In other work done at the same time University School of Medicine is the with Warshel, Levitt introduced Samie R. Ja rey of Weill Medical that cannot be detected by Förster recipient of the DeLano Award in coarse-grained models of the poly- College of Cornell University has Resonance Energy Transfer and the Computational Biosciences awarded peptide chain for rapid simulation of been awarded the American Society detection of signaling molecules by the American Society for Bio- protein folding. As a sta scientist at for Biochemistry and Molecular within cells. rough the use of these chemistry and Molecular Biology. the MRC Laboratory of Molecular Biology’s 2014 Young Investigator uorescent-tagged RNA molecules, e award recognizes scientists for Biology, he worked with Tony Jack Award for his advancements in RNA Ja rey’s lab has identi ed novel RNA their innovative development of com- and laid the groundwork for modern technology and mRNA regulation. mechanisms that may control protein putational technologies that enable approaches to crystallographic e award seeks to recognize out- expression. life-science research at the molecular re nement. standing research done in the eld of e recent focus of his lab has level. Levitt’s work on protein model- biochemistry and molecular biology been the role of adenosine meth- Levitt, who won the Nobel Prize ing combining segments of known in chemistry in 2013, is well known protein was adapted and extended by by scientists with fewer than 15 years ylation in mRNA regulation and is is the only prize I received in the for his pioneering work in modern David Baker’s group at University of of postdoctoral experience. modi cation using a novel sequenc- decades preceding the Nobel Prize. computational biosciences – work Washington, leading to the develop- e Ja rey lab researches how ing approach that targets N6-methyl It’s a great honor to be included in Warren DeLano showed exceptional that embodies the key elements of the ment of Rosetta, software widely used RNA regulation a ects neuronal adenosine residues to target their the company of the previous recipients foresight in his pioneering use of DeLano award: the productive use of by the protein-modeling community. growth and development – and espe- presence in the transcriptome. ASBMB Young Investigator Award. Python, a trend adopted by much computers to accelerate research and Many of the fundamental architec- cially how novel functions of RNA “I know of few individuals who This award would not have been modern scienti c software. His is ready access to these programs for the tural principles of protein structure are involved in intracellular signal- combine Samie’s level of understand- possible without the remarkable a remarkable legacy I am proud to scienti c community. and protein-classi cation schemes ing pathways needed for growth and ing of chemistry, molecular biology students and fellows who have been honor. Raised in South Africa and later in taught in protein biochemistry development. and biochemistry and have been able members of my laboratory. – MICHAEL LEVITT England, Levitt earned his bachelor’s courses stem from classic papers that One point of interest is how RNA to leverage deep understanding in – SAMIE R. JAFFREY localization to speci c regions of all of these areas to transform our degree in physics from King’s College Levitt authored in the 1970s along a cell may in uence the pattern of understanding of RNA biology,” says London. He studied at the Medi- with Cyrus Chothia while he was at are combined.” protein expression; however, there Rajiv R. Ratan of Weill Medical Col- currently a tenured professor of phar- cal Research Council Laboratory of the MRC. Past recipients of the DeLano previously were no simple methods lege of Cornell University and Burke macology at Weill Medical College in Molecular Biology, Cambridge (a part Barry Honig of Columbia Univer- award include Helen Berman and available to visualize RNA in live Medical Research Institute. “Samie New York City. of Cambridge University), where he sity, a past recipient of the DeLano Axel Brunger. cells. Ja rey’s lab developed uores- is a tremendously gifted thinker who Ja rey will receive his award at earned his Ph.D. in computational award, described Levitt as “an Levitt will receive the award at the cent-tagged RNA molecules to deter- has accomplished as much in the rst the ASBMB annual meeting in San biology. He then did his postdoc at intellectual leader in computational ASBMB annual meeting in April in mine the location of RNA within 10 years of his laboratory’s existence Diego. e presentation will be at the Weizmann Institute of Science in structural biology.” It is notable that, San Diego. His award lecture, tenta- live cells. ese RNA- uorophore as many of us endeavor to achieve in 9:05 a.m. April 29 in Room 6A of the Israel, where he later became a citizen apart from a an award in 1985 from tively titled “Solving large and di- complexes are composed of an RNA a lifetime.” San Diego Convention Center. and did a few weeks of basic service the Federation of European Biochem- cult structures with less experimental aptamer that binds to a target ligand Ja rey earned his B.S. in biology in the Israeli Defense Forces. ical Societies, the DeLano Award in data,” will be on Tuesday, April 29, in and an RNA aptamer that binds and from the Massachusetts Institute of Anna Shipman (alsnpc@mail. In the year that he spent in Israel Computational Biosciences was the Room 6A of the San Diego Conven- activates a uorophore. Technology in 1992 and then his umkc.edu) received her B.S. in before starting his Ph.D., Levitt only prize awarded to Levitt before he tion Center. biology–biotechnology from Mis- published the rst protein simulation was recognized in Stockholm. ese complexes could aid in the Ph.D. in neuroscience and M.D. souri Western State University and study of splicing, RNA editing and from the Johns Hopkins University is a Ph.D. student in the School of using Cartesian coordinates. at Honig said of Levitt: “(He) has Preethi Chander (chander. degradation, as well as visualization School of Medicine in 1999 in the Biological Sciences at the University of Missouri– revolutionary paper laid the ground- taught the practitioners new ways [email protected]) earned a Kansas City. work for molecular simulations. to apply computational tools to Ph.D. in structural biology from of metabolite levels and interactions lab of Solomon H. Snyder. Ja rey is Purdue University and completed Later, with Arieh Warshel, Levitt structural biology and that it is pos- a postdoctoral fellowship at the described a framework for simulation sible to have impact if theoretical National Institutes of Health. She works at the studies combining quantum mechan- rigor, algorithmic novelty and deep National Institutes of Health, Bethesda, MD, as a ical and classic mechanical methods. understanding of experimental reality health science program administrator.
20 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 21 EARL AND THRESSA STADTMAN SCHOLAR AWARD Regev recognized for rigorous integration of experimental and computational approaches By Sarah Perdue
Aviv Regev of the Broad Institute at model for other impulse responses the Massachusetts Institute for Tech- to environmental challenges that are nology and Harvard University won ubiquitous in biology. Second, the the American Society for Biochemis- well-characterized stimuli provide try and Molecular Biology’s Earl and unique handles with which to resolve ressa Stadtman Scholar Award. regulatory relations computationally.” e award is given to researchers It is this rigorous integration of with outstanding achievement in the experimental and computational elds of biochemistry and molecular approaches that Regev’s nominators biology who have fewer than 10 years emphasize. “Her strategy starts by of postdoctoral experience. monitoring the transition in exqui- Regev, a Howard Hughes Medical site detail. She then uses these data Institute early career scientist, was to drive her model-building e orts. I am tremendously honored to nominated for her insightful work on And nally she perturbs the system receive the award, highlighting the evolution of regulatory networks in a manner designed to test and the importance of the interface in cells and for her development of challenge her models,” Weissman between genomic and more focused cutting-edge techniques that have said. “When applied iteratively, this approaches to biological circuits. broad implications in diverse elds of approach leads to robust models that – AVIV REGEV molecular biology. explain the observed data and have “At the conceptual level, Aviv is true predictive value.” interested in one of the deepest and Lander added, “Aviv was an early one more example of Regev’s com- most general of biological questions: pioneer in the reconstruction of mitment to staying at the forefront of how biological circuits function and networks using probabilistic models, cutting-edge technologies. rewire – from the rapid responses of and her work has de ned the eld Regev and her colleagues had to immune cells within hours, to devel- today. In the past few years, she develop algorithms to handle these opmental commitments by cells in has expanded these models to the novel types of data sets, writing pro- the blood system, to genetic changes dynamic setting, where the network grams (such as Trinity) that allow for in cancer, to long-term evolutionary components and connectivity change data analysis without prior knowl- changes over millions of years,” said with time, a very dicult computa- edge of an organism’s genes or even a Eric Lander, president and director of tional problem.” sequenced genome. Trinity today has the Broad Institute, who nominated Regev also has been a pioneer more than 20,000 users. Regev for the award. in RNA sequencing to elucidate Regev will receive her award dur- e bulk of Regev’s work focuses these complex changes in regula- ing the Experimental Biology 2014 on the short timescale responses of tory networks. She noted that the conference in San Diego, where she dendritic cells to pathogen chal- bulk responses she observed in her will deliver an award lecture. Her pre- lenge. “Dendritic cells were a superb dendritic cell work may be concealing sentation will take place at 9:05 a.m. choice for deciphering cell circuits,” important changes at the single-cell Sunday, April 27, in Room 6A of the says Jonathan Weissman, an HHMI level; thus, she and her colleagues San Diego Convention Center. investigator and professor at the adapted a single-cell RNA sequenc- University of California, San Fran- ing approach and found that, even Sarah Perdue (sp366@cornell. cisco, School of Medicine, who within a homogeneous population of edu) received her Ph.D. in micro- biology from Cornell University, also nominated Regev. “First, the cells, there were subpopulations that spent two years teaching at dendritic cell response is physiologi- responded at di erent times and in different colleges as a visiting cally and clinically important its own di erent manners. professor and now is a postdoctoral researcher at right and more broadly serves as a Weissman said this work is just the University of Minnesota.
22 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 23 FEATURE
ach year, many people experi- “ e SCN is the master oscilla- rhythms in the lab of Doug McMa- is only one component of a larger ence the “winter blues,” the tor, and it can be considered to be hon at Vanderbilt University during picture, and other components of the E layman’s term for a particular the conductor of a symphony,” says his graduate work and retains an circadian clock (such as enzyme mood disorder called seasonal a ec- David Klein, chief of the neuroen- interest in the intersection of neurobi- activity and hormone production) tive disorder, or SAD. ere’s a lot docrinology section at the National ology, circadian rhythms and mood also contribute to this mood disorder. of information swirling around in Institutes of Health. “You can imag- disorders. In a 2011 study, the group popular media about the cause of ine what happens if you go to the looked at the e ects of light exposure The rhythmic hormone SAD, but what does science have to symphony and the conductor walks during development on epigenetic say about it? o stage: e music falls apart. e changes that a ect circadian rhythms. melatonin Researchers have been looking into same thing happens when you travel “What we were focusing on in the SAD research also has focused on SAD since it was rst de ned in the and get jet-lagged. e conductor lost 2011 Nature Neuroscience paper was melatonin, a hormone primarily 1980s. Early studies were focused on control of all the separate rhythms in the connection between season of synthesized by the pineal gland in nding treatment options, because your body.” Klein adds that keeping birth and subsequent circadian func- the brain. Melatonin levels uctuate alleviating the symptoms of SAD was tight control of the circadian clock tion, with the view that any imprint- throughout the day, with increased a top priority. Since the early 2000s, is a contributing factor to mental ing from the environment that might synthesis at night. In organisms like scientists have been looking at the health. happen during your development humans, who are diurnal and thus genetic, epigenetic and biochemical It is known that disruption of the might impact your subsequent awake and more active during the causes that underlie SAD, along with circadian rhythm is associated with circadian and/or other functions,” he day, melatonin helps to trigger the other mood disorders, and they’ve mood disorders, including SAD and explained. onset of sleep. been nding some pretty interesting bipolar disorder, and this is thought Other researchers have pinpointed e production of this hormone stu . to be due to the body’s inability to speci c genes in the circadian rhythm is tightly linked to the amount of adapt its internal clock to match the pathway that have polymorphisms daylight exposure an animal receives, Genetic studies external environment. In the winter, linked to patients with SAD that are so in the winter, when daylight hours especially in more northern climates, not present in healthy controls. ese wane, melatonin synthesis begins of the circadian clock the body is exposed to substantially genes include CLOCK, Period 2, earlier and lasts longer, allowing for One of the earliest suspects linked less sunlight than in the summer. e Period 3 and NPAS2, among others. a greater uctuation in the overall to SAD was dysregulation of the SCN can sense this change in light Whether polymorphisms in these amount of melatonin produced. circadian clock. e circadian clock is and, subsequently, alter the timing of genes are causative in the case of SAD Klein describes the changes in housed in a part of the hypothalamus the body’s natural rhythm in response remains to be shown, but current melatonin synthesis, which he learned called the suprachiasmatic nucleus, or to this change. studies suggest they may contribute to from his studies of the enzyme that SCN. e SCN controls many func- Chris Ciarleglio, a postdoctoral a predisposition to developing SAD produces the hormone: “ e pattern tions of the body that uctuate over fellow at Brown University, believes and that epigenetic changes induced of activity looks like a hill, because it our natural circadian period, which there are strong genetic and epigen- by light exposure during development goes up, then down during the course is about 24 hours long, including etic components to the body’s ability may tip the balance toward or away of the night. When we look at (the sleeping and waking cycles, body tem- to alter circadian rhythms. from the development of SAD. perature, appetite, and many others. Ciarleglio studied circadian However, genetic predisposition CONTINUED ON PAGE 26
24 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 25 CONTINUED FROM PAGE 25 that shows that dysregulation of your common factors that are used in the that all three of these diurnal spe- melatonin rhythm, how much mela- studies of SAD and other mood disor- cies develop SAD-like symptoms pattern of activity) more closely, we tonin your pineal gland produces over ders. Research by Serge Daan argues when exposed to shorter periods of see that this one hill that goes up and the course of the day, will in uence that the nocturnal nature of lab mice daylight, indicating that they make down is actually two hills of activity your mood,” says Ciarleglio. is due to polymorphisms in their appropriate models for seasonal mood that overlap.” e extent that melatonin pro- circadian clock genes and that their disorder studies. Klein explains that in the summer, duction contributes to SAD is still counterparts in the wild are more e study of SAD and other mood when the nights are short, these two debated, and studies using animal diurnal. Both of these opinions point disorders has seen great progress in overlapping hills get closer together, models are one way researchers are to the need for other animal models the past 20 years, and recent genetic, so the activity of the enzyme is starting to address this question. to study SAD. epigenetic and biochemical studies highest at only one point during the Haim Einat, a behavioral scientist indicate that there is still much to be night. In the winter, when nights Challenges in using animal at Tel Aviv-Ya o Academic College, learned. e increased knowledge and are longer, the peaks of the two hills has begun vetting several species of detailed understanding hopefully will separate, meaning the enzyme activity models to study SAD diurnal rodents for use in the study of lead to more speci c and varied treat- uctuates more and reaches the high- Some scientists question the use of SAD. Einat has studied fat sand rats, ments — right now the most popular est point for a longer period of time. mice as models for SAD, because Nile grass rats and, most recently, treatment for SAD is bright light As a result, the period of melatonin lab mice are nocturnal and therefore small rodents called degus as candi- therapy — and ultimately will be a production is longer. respond di erently to light-dark date model organisms. boon to those who live with mood “ ere’s a lot of research in SAD cycles, melatonin secretion and other Einat and colleagues have shown disorders.
the retina, but melatonin produc- Studying the Timezyme tion occurs primarily in the pineal gland. In this way, the high levels of and ancient melatonin production serotonin required to make melatonin are separated from retinaldehyde, David Klein, director of circadian mostly in the pineal gland, where it preventing destruction of this vision biology research at the National produces the melatonin precursor molecule in the eye. Institute of Child Health and Human N-acetylserotonin from serotonin “ e Timezyme evolved just to Development, studies the enzyme via the addition of an acetyl group. make melatonin. Pineal melatonin that produces melatonin. Nonvertebrate AANAT enzymes are synthesis also requires a very high Although the technical name generally similar and are thought to capacity to synthesize serotonin. Elephant shark PHOTO COURTESY OF: WIKIMEDIA COMMONS USEER FIR0002/FLAGSTAFFOTOS of the enzyme is arylalkylamine add acetyl groups to a broad range of Although serotonin synthesis occurs N-acetyltransferase, or AANAT, Klein potentially harmful, serotonin-related in other tissues, the concentration Klein and a group of international refers to the enzyme colloquially compounds. is is in contrast to in the pineal gland is much higher, collaborators tracked down an organ- as “the Timezyme.” is nickname vertebrate AANAT, which acts more consistent with the knowledge that it ism with both forms present to help comes from the role of melatonin in selectively, adding acetyl groups to is a melatonin factory. For example, con rm the idea and put a timeline regulating the body’s internal clock, one speci c compound. serotonin concentrations in the pineal on the Timezyme’s evolution. e and because AANAT manufactures “Many enzymes that are involved gland are more than 100-fold higher team eventually located both forms melatonin, it is crucial to maintain- in neurochemical signaling were origi- than those in the retina.” in the genome of the elephant shark. ing proper control of the body’s daily nally detoxifying enzymes,” explains Klein’s study bridges the gap Using samples from the elephant rhythm. Klein. Nonvertebrate AANAT was between nonvertebrate and vertebrate shark and related aquatic species, Klein recently led a study, pub- “sort of a shield,” he says, part of a AANAT, showing how a gene- Klein’s team used RNA sequencing, lished earlier this year in the Pro- group of proteins that evolved to pro- duplication event of nonvertebrate 3-D structure modeling and other ceedings of the National Academy tect the light-absorbing vision mol- AANAT that occurred 500 mil- tools to show that the vertebrate form of Sciences, that showed the form of ecule retinaldehyde. AANAT acted as lion years ago led to the branching of AANAT was derived from the AANAT in vertebrates originated 500 a shield by acetylating serotonin and and evolution of the two separate nonvertebrate form. Diedre Ribbens (diedre.johnson@ million years ago. Other studies have related compounds, thereby prevent- enzymes. Before the PNAS paper, Klein’s work has implications for gmail.com) is a freelance science shown that vertebrates and nonverte- ing them from inactivating retinalde- the gene duplication event was only a the study of melatonin-related disor- writer based out of Minneapolis. brates have distinctly di erent forms hyde via Schi base formation. hypothesis due to lack of evidence. ders, such as SAD, and also for vision Visit her website, dribbens.com, of AANAT. Today, vertebrate AANAT is At some point, vertebrates stopped disorders in which harmful chemicals to contact her or learn more about her writing. Vertebrate AANAT is found still expressed in small amounts in making the nonvertebrate form, so are accumulating in the retina.
26 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 27 FEATURE
prion phenomenon called [PSI+]. e To put your work in a larger phenotype of [PSI+] is that when the context, what do you think Q&A with cell contains this prion, or self-propa- gating infectious protein, it increases are some of the big-picture the rate of translation read-through. questions in biochemistry We wanted to develop an assay that let Jonathan Weissman us watch where ribosomes were read- and molecular biology? ing through stop codons in vivo. But One of the things is: How do cells By Rajendrani Mukhopadhyay then, once we developed ribosome maintain integrity of their proteome pro ling, it was clear it was a much and detect misfolded proteins? How broader tool. do the di erent quality-control sys- e plenary speaker for this tems work together in a coherent way to allow cells to function, and when year’s American Society for What are some of the technical challenges with and why do they break down? Biochemistry and Molecular I think there’s another, broader ribosomal profiling? question of how we de ne the func- Biology annual meeting is e biggest challenge is interpreta- tion of a protein. What do we mean Jonathan Weissman of the tion and data analysis. We get huge when we identify protein X to do job amounts of data. It takes longer for Y? A lot of this has been classically University of California, San us to analyze the data and ask the done, arguably, in an ad hoc way Francisco. An investigator with right questions than it does to actually where you look for some activity in a collect the data. e other technical cell and you try to nd the proteins the Howard Hughes Medical Institute, Weissman is a challenge is working with relatively that are responsible for it. biochemist whose laboratory focuses on protein folding, small amounts of cells. We’d really like is type of reductionist, top-down to optimize the amount of sample we approach has been incredibly success- amyloid formation and next-generation genomic use in our system. ful, but it has some inherent aws and sequencing. ASBMB’s science writer, Rajendrani biases to it. We’re trying to develop Mukhopadhyay, spoke with Weissman to learn more How do you balance your more systematic and less ad hoc, more scientific efforts between principled and faster approaches to about his scientific interests and influences. The interview nding gene function. asking fundamental e other general area, which is has been edited for length and clarity. biological questions and related, is that we have built tools with which we can sequence any individual developing techniques? or organism’s genome rapidly and at What does your research techniques to de ne the information For my lab, it’s very important that low cost. ere’s now a huge challenge encoded with these genomes and the techniques we develop be driven to de ne the information encoded focus on? to watch it being expressed in space by fundamental questions that in genomes and how it’s expressed in We’re interested in how proteins fold and time is really exciting. Ribosome we want to answer. My lab is very time. Ribosomal pro ling is a part in cells, especially how chaperones pro ling is one example of these tech- interested in seeing what happens to of that e ort. It lets you know what assist protein quality control and how niques. We get to watch, with exqui- a protein as it’s synthesized and how proteins are being encoded for in a a cell distinguishes between correct site precision, the ribosome get in the it is recognized by the cell’s quality- cell in an objective way and see how and incorrect proteins both in the act of converting an informational control systems and doing this in an much is made at a given time. If we cytosol and endoplasmic reticulum. molecule, the RNA, into a functional in vivo setting. Although the ribo- really want to test our ideas and try We also have a broad interest in devel- molecule, the protein. some pro ling is an -omics tool and to use this information to design new oping general approaches for querying I’ll be talking about our ribosome- it broadly looks at protein translation, systems, we have to have much better biological systems, especially around pro ling work during my plenary I’m personally most excited about its ways of turning on and o genes and next-generation sequencing. e most lecture. value as a high-precision tool for look- to engineer genomes. I’m very excited mature of those e orts is an approach ing at mechanisms of how proteins about approaches that we and others we call ribosome pro ling. It allows us What was the genesis are synthesized and folded. I see the are working on using the CRISPR to globally monitor translation in cells methods development as something system. at single-nucleotide resolution. for ribosome profiling? that drives our ability to ask questions is idea of using deep sequencing Our original interest was on the yeast that we want to ask. CONTINUED ON PAGE 30
28 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 29 CONTINUED FROM PAGE 29 blueprint itself. I think it may even be I published four papers from that time fewer good tools, but they understood a competitor to RNAi approaches. that, in many ways, cemented the the concepts. (Editor’s note: Nirenberg Tell me more about the I will also mention the CRISPR standard model for GroEL and how had married Weissman’s mother, who CRISPR system. work during my talk. proteins fold inside the central cavity was divorced from Sherman Weissman.) of GroEL. It was a wonderful time CRISPR is an adaptive-immunity Your undergraduate degree because the structures were coming What is your guiding system from bacteria that’s been and Ph.D. were in physics out from Art’s lab so we were able to principle in science? known for some time. It’s turned out exploit the structural information. to be a very useful system for engi- from the Massachusetts Tr y to nd new questions that are neering genomes. e CRISPR system Institute of Technology. How I read in Horwich’s fundamental and important, but they that has become particularly popular should be ones we can answer in a now is the CAS9-based system. In a did you make the switch “Reflections” in the Journal clean and crisp way. I really like prob- nutshell, when a cell becomes infected from physics to biology? of Biological Chemistry that lems that lend themselves to very clear, with a phage, it grabs part of the To be honest, I did get my Ph.D. in you kept chameleons in the de nitive answers rather than prob- phage’s DNA and inserts it into its physics, but what really happened is lab. He described them as lems where one ends up going back own genome in these special cluster that, after a year of doing hardcore and forth with arguments because it’s repeat regions. It then later transcribes physics in phase transitions and all even more finicky eaters hard to resolve anything. e GroEL that copy of the phage DNA as that, I decided I was much more inter- than children. work illustrated that nicely: When RNA and uses that RNA to guide an I was a postdoc in Art’s lab, a big ested in biological questions. I found I did indeed have a Jackson’s chame- endonuclease (called) CAS9. Now, if Peter Kim, who was then a professor question, and it was quite controver- the bacterium is ever infected with the leon, Lance. It required taking crickets sial at that time, was if proteins fold at MIT in the Whitehead Institute of and coating them with vitamin D and same phage, the CAS9 plus this guide Biomedical Research. I rotated and inside the GroEL/GroES cavity or on RNA will speci cally cut up that calcium and holding them in front of the outside. It was an incredible idea then joined his lab. I did all my quali- it every day. (Chameleons) appar- phage DNA by hybridization. fying exams in physics, but I did my that a protein could get encapsulated What revolutionized things is that ently don’t get much vitamin D and in another protein and fold in this research in a mainstream biological calcium when they are in captivity, so Emmanuelle Charpentier (at Molecu- laboratory. at meant I had to take a protected environment. But I liked lar Infection Medicine Sweden) and you have to give them vitamin D and the problem, because it was easy to lot of courses and spend a lot of time calcium. Jennifer Doudna (at University of catching up, because I had very little explain to anyone and it was going to California, Berkeley) showed that a be one way or the other. I was quite biology (training). But, by the time Who are your scientific single protein, CAS9, and a single I had graduated (with my Ph.D.), I con dent that we, or other people, engineered guide RNA are sucient was pretty well immersed in modern influences? would be clever enough to gure it to guide the CAS9 endonuclease to out. I also like developing approaches, molecular biology. But fast-forward 15 Obviously, my Ph.D. adviser, Peter a given sequence. So if you give me especially when they let you ask ques- years later, all the quantitative tools, Kim, and my postdoctoral adviser, Art a piece of DNA, I can design the tions in a deeper and more de ned like deep sequencing, are incredibly Horwich. Also, I used to go to group complementary guide RNA. If you way and much more rapidly. I always valuable. ere has been this con- meetings of Ari Helenius’ laboratory then express that guide RNA plus worry about spending our time doing vergence where biology has become (at Yale University). I really learned CAS9, the CAS9-guide-RNA complex hard work on something when, if we an information-rich science. All that a lot about how cell biologists think. will cleave that piece of DNA. had a new approach, it would make training I had in physics and math My father, who is a molecular biolo- what we do obsolete. At UCSF, working with Stanley Qi actually ended up being extremely gist, is a huge in uence. He’s Sherman and Wendell Lim, among others, we useful. Weissman, and he’s at Yale. We talked have made a catalytically dead version a lot about science when I was grow- What are your hobbies? of CAS9, the so-called dCAS9. Now You did your postdoctoral ing up. We still do. Here (at UCSF), Since I spend pretty much no time the guide RNA guides the dCAS9 fellowship with Arthur I’ve had many mentors and collabora- now doing experiments, I really love to a speci c place on the DNA, but tors. Marshall Nirenberg (who worked to cook, especially things that are instead of cutting it, it just sits there. Horwich at Yale University. at the National Institutes of Health) based around techniques. I’ve been You can then use this (dCAS9) to How did that experience was certainly a big in uence as well. perfecting using my grill as a pizza fuse gene-activator domains to turn influence you? We talked a lot about translation. I oven, getting the temperature up to on genes; if you fuse repressors, it will came into translation independently about 700 degrees and making the turn o genes. If you fuse GFP, it will Enormously. We did great work on and then had the good fortune of perfect dough. My lab just gave me Rajendrani Mukhopadhyay (rmuk- mark that part of the chromosome. the biochemistry of GroEL and really being able to talk with Marshall about a 40-pound slab of steel for my pizza [email protected]) is the It lets us turn on and o genes and got into the structure-function aspect. it. I learned that many of the ribo- stone because it conducts heat much senior science writer and blogger mark chromosomes without actu- It was a terri c time. I wasn’t there all some experiments we were doing were better. But it’s also great at inducing for ASBMB. Follow her on Twitter at www.twitter.com/rajmukhop. ally causing any changes in the DNA that much time, about 2 ½ years, but done back in the 1960s. ey had back pain.
30 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 31 FEATURE
Accumulating evidence suggests that function, particularly for improved reversible lysine acetylation is a major metabolism, anti-in ammation and Meet John Denu regulatory mechanism that controls decreased tumorigenesis. protein function. A new associate editor of Sirtuins are a conserved family of Tell us about your + NAD -dependent protein deacetylases academic background the Journal of Biological Chemistry that have emerged as important play- and research training. By Rajendrani Mukhopadhyay ers in modulating protein acetylation. Compelling genetic evidence impli- My (bachelor’s) was in biochemistry cates sirtuins in genome maintenance, from the UW–Madison, where it metabolism, cell survival and lifespan. became clear that I wanted to grow John Denu at the University We are examining the central hypoth- up and be a biochemist. My Ph.D. esis that reversible protein acetylation with Paul Fitzpatrick at Texas A&M of Wisconsin−Madison joined is a major regulatory mechanism for University provided training as a the ranks of the Journal of controlling diverse metabolic pro- classical enzymologist. Postdoctoral cesses and that, at the molecular level, training at the University of Michigan Biological Chemistry associate site-speci c acetylation alters the with Jack Dixon allowed me to use editors in July. His laboratory intrinsic activity of targeted proteins. those skills to tackle new enzymologi- We are exploring sirtuin function as cal questions in the signaling eld. In focuses on the roles of reversible a means to tackle these questions and Jack’s lab, I became enamored with protein modi cations that are uncover their role in these processes. protein modi cations and the idea that PTMs communicate critical cel- involved in modulating signal transduction, chromatin You recently had a JBC paper lular information. dynamics and gene activation. In particular, the group selected as a Paper of the studies histone modi cations. e American Society for Week. It was about SIRT6’s What does it mean to you, Biochemistry and Molecular Biology’s science writer, activation by long-chain on a personal level, to be an associate editor for the JBC? Rajendrani Mukhopadhyay, interviewed Denu to learn fatty acids. What is the significance of the work? It was a tremendous honor to be more about his scientific interests, career and hobbies. asked to serve the JBC in this capac- The interview has been edited for length and clarity. We are very excited about this dis- ity. In addition to previously serving covery and the impact it might have as an editorial board member, I have on human health. SIRT6 is linked authored JBC papers throughout with aging, cancer and metabolism. every stage of my career, so the JBC Briefly explain what your Also, we are investigating the links e protein is an extremely inef- occupies a very special place in my cient histone deacetylase in vitro, research group is studying? between metabolism and epigen- life. To me, the JBC represents a com- etic mechanisms that regulate gene suggesting that there is an activating munity, and now I get to contribute We are broadly interested in the expression. Chromatin-modifying mechanism in cells. In this paper, we to this community in a new way as an mechanisms and functions of revers- enzymes rely on coenzymes and demonstrated that SIRT6 is directly associate editor. ible protein modi cations that substrates derived from metabolic activated by free long-chain fatty control signal transduction, chro- pathways, suggesting coordination acids, including ones linked to the How is the new role going so matin dynamics and metabolism. between nuclear events and metabolic health bene ts of dietary polyun- More speci cally, one major goal is networks. We are testing the hypoth- saturated fatty acids. ese results far? Have you been surprised to understand the basic biochemi- esis that certain chromatin-modifying suggest the SIRT6 is stimulated to by anything during your cal principles that govern epigenetic complexes have evolved to exquisitely downregulate carbohydrate and lipid tenure with the JBC? information written onto histones. sense metabolite levels and respond metabolism during conditions that is information dictates gene-expres- accordingly, modifying speci c chro- increase levels of particular omega-3 So far so good, but the rst two sion programs and takes the form of a matin loci for altered gene expression. and omega-6 fatty acids, such as fast- months were a very steep learning diverse array of histone post-transla- Another major e ort involves ing and dietary supplement intake. curve. One of the best aspects of tional modi cations, which are added understanding the mechanisms e discovery of these endogenous, being an AE is the ability to tap into and removed by chromatin enzyme and functions of sirtuin deacylases small-molecule activators of SIRT6 the collective wisdom of the other complexes. and reversible protein acetylation. suggests the therapeutic potential of compounds that promote SIRT6 CONTINUED ON PAGE 34
32 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 33 JOHN DENU An open letter (Left) Denu with his brother after a half-marathon. (Above) Denu before a Warrior Dash with his son and daughter-in-law. to my younger self, When I’m not in lab, I’m still think- ing about the lab. Obviously, this can be a problem if you want to have an aspiring graduate a so-called normal life. But there is nothing very normal about the life of a scientist. It is important to try and press pause routinely. I try to pick student in the sciences nonscience activities that force me to refocus my attention on something completely di erent. I do this one of Dear Paul, immediately, it’s to immerse yourself just one more experimental replicate several ways: go for a vigorous run, in the academic and scienti c com- to show that your amazing results play basketball or work on mechani- know what you’re thinking: “ is munity. ese people are not only are reproducible. But don’t forget to cal problems like xing or modify- will be a snap. I’ll be out in four your colleagues and friends but also engage your peers and attend social ing cars. It’s worked for me: I’m still years!” your potential collaborators. e gatherings or even just take co ee CONTINUED FROM PAGE 33 married to the same understanding I You can brush up on your class scienti c community is a tight-knit breaks to catch up. Many people woman after 25 years, and the two AEs. e board is an amazing group schedule, ll up your book bag with collective. But its members will be struggle with separating work life and boys turned out ne. of scientists, and our discussions shiny new notebooks and highlight- there for you when you are feeling social life. Why can’t it be combined? on JBC matters are enjoyable with ers with more colors than a Skittles down on your luck or need advice After all, we are all here, presumably, plenty of give-and-take. Perhaps most For scientists in training, packet, and march into your new (which will happen often!) or even because we want to be, so why not surprising to me is how we handle do you have any words of endeavor with determination. How- help you procure jobs. Networking, make it productive and enjoyable manuscripts. Of course, there are wisdom or a favorite motto? ever, there are a few words of wisdom networking, networking. Do it now now and for the rest of your career? important policies and guidelines that I would like to share with you or else learn the hard way why it isn’t Diversify and volunteer. Many Enjoy the work. is is an awesome to follow, but it’s not an impersonal before you take this long, strenuous just a buzzword. times the research problems you are career, but not everyone is cut out for operation where a computer weighs and, yes, sometimes crazy journey as Balance work and play. It’s easy trying to solve are so speci c and it. At di erent stages of your career, the reviews and spits out a decision. a graduate student. to be sucked into lab life — slaving narrow that it becomes easy to lose do the 50-percent test. If you’re miser- Each of us can bring our own unique If there’s one thing you should do away at the bench, trying to nish track of the bigger picture. Even more perspective to the editorial process. able more than 50 percent of the time, tragic: You might lose the ambition to it’s time to change your line of work. develop skills outside your eld. Pub- If you enjoy your work most of the Many times the research problems you are trying lic speaking, presentations, scienti c What do you do outside time, keep doing it. I prefer to operate writing and networking are crucial of the lab? Do you have near 90-percent job satisfaction, where to solve are so specific and narrow that it becomes easy Rajendrani Mukhopadhyay (rmuk- skills that can be helpful not only in the missing 10 percent represents time [email protected]) is the any advice for balancing life to lose track of the bigger picture. Even more tragic: your research but in your social life as senior science writer and blogger spent trying to keep the lab funded. well. You can develop these skills by for ASBMB. Follow her on Twitter in the lab with life outside Congressional sequester can greatly You might lose the ambition to develop skills outside at www.twitter.com/rajmukhop. helping others with projects, listening of the lab? a ect that percentage. your eld. CONTINUED ON PAGE 36
34 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 35 OUTREACH
CONTINUED FROM PAGE 35 you, and being in an unfamiliar and procrastinate. You’ll nd your way. disorienting new setting only adds to Life can be dicult at times, but it to your peers’ presentations, or even the initial struggle. While it’s normal also can be rewarding and wondrous! Teaching science proofreading essays and papers. ese to doubt yourself and wonder why So make the most of your time and skills will be even more important you are putting yourself through such enjoy the ride. if you decide to search for a career hardships when things consistently Oh, and your geek T-shirt collec- outside of basic research. don’t go as planned, your failures are tion is getting out of hand, so try to and social justice Before I close, I want to talk really what make you a better and save your money for something more about something that may seem more informed person. Perseverence, useful, like a house. Project seeks to promote social consciousness in the classroom unfathomable at this moment. Your determination, patience and a sense experiments that you thought were of humor will help you get out of any Sincerely, By Morgan ompson, Jon Beckwith and Regina Stevens-Truss foolproof will sometimes fail and may mishaps unscathed and will make you Your older and wiser postdoctoral even cause you to doubt yourself. It a stronger person. fellow self will be discouraging, time and time Graduate school, and much of life hen did you rst learn about again, having one positive result for from here on out, is much less struc- Paul Sirajuddin (psiraju1@jhmi. the American eugenics every ve failures. Or there may be a edu) is a first-year radiation movement and the Tuskegee tured than you have experienced previ- oncology postdoctoral fellow W time when you get some questionable ously. But it can be summed up with at The Johns Hopkins School of syphilis studies? How long were you results that will have you stumped for brevity: You get out what you put in. Medicine. A native of Michigan, he culturing HeLa cells in the lab before ventured to the East Coast for a postbaccalaurate weeks on what to do next. Having If there’s disorganization, then you heard of Henrietta Lacks? What fellowship at the National Cancer Institute in do you say to a family member who only three classmates in your Ph.D. take the initiative to make sense of 2008 and then earned his Ph.D. from the George- program to ask questions can be dif- things, even if it’s a little extra work. town University Lombardi Comprehensive Cancer has chosen not to vaccinate his or her cult when no one has an answer for Be con dent, take action and don’t Center in 2013. child after nding extensive pseu- doscience masquerading as evidence online? Most scientists gain their rst Enjoying the Open Letters series? research experiences as undergradu- We’ve extended the submission deadline to Oct. 1, 2014. Send yours to [email protected]. ates, prior to any formal training in ethics or social justice in science. ough we train scientists to be technically and theoretically critical of their own work and that of others, critical examination of the societal
The Robert A. Welch Distinguished Chair in Chemistry context of research or active engage- Department of Biochemistry ment in public discourse rarely is The University of Texas Health Science Center at San Antonio encouraged. e Science and Social Justice We are seeking outstanding candidates at the Professor or senior Associate Professor level who employ biochemical and bio- physical approaches to the study of molecular structures and biochemical mechanisms. Areas of interest include, but are not Project — a joint e ort of faculty restricted to, cancer, neuroscience, aging, metabolic disorders and drug discovery. In addition to the Welch Chair endowment and members at the Arcus Center for Actors in “Edge of the Map” portray Alice Wexler and her father, Milton Wexler, discussing whether she should its associated newly renovated space, significant resources from the Institution, UT System (UT STARS) and State agencies such Social Justice Leadership at Kalama- have children, given that her mother suffered from Huntington’s disease. as the Cancer Prevention and Research Institute of Texas (CPRIT) are available to outstanding candidates. zoo College and at Harvard Medical The selected candidate will be expected to play a leadership role, including involvement in the hiring of several junior faculty able, those courses continue to vary highlighting stellar exemplars of inte- within the department in the coming years. Currently, the Department has 19 primary faculty covering a broad range of research School — seeks to remedy the segre- interests (http://www.biochem.uthscsa.edu/). There is a significant structural biology focus, which is supported by uniquely gation of science from its value-laden widely in quality and depth and are grating science and social justice that integrated core facilities in X-ray crystallography, NMR spectroscopy, Mass Spectrometry, AUC, SPR, ITC, and a new Center for historical, social and political context diminished in importance by being often go undetected and uncovering Innovative Drug Discovery (CIDD), including High Content/ High Throughput Screening and Medicinal Chemistry, established in in undergraduate and graduate tacked onto, rather than woven best practices that can ultimately collaboration with the University of Texas at San Antonio. into, curricula. It is our belief that bolster mandatory ethics training UTHSCSA is located northwest of downtown San Antonio in the South Texas Medical Center, gateway to the scenic Texas Hill classrooms. Together, we are building Country, with its many recreational opportunities. UTHSCSA consists of five schools: Medical, Graduate, Dental, Nursing and a Web-based repository of curricula substantial experience with relevant and make substantial exposure to the Health Professions. San Antonio is the 7th largest city in the U.S. with a beautiful, historical downtown area featuring the River- and activities that integrate science materials from the social sciences and social sciences standard throughout walk with its diverse entertainment, and fine restaurants. and social justice topics into scienti c humanities must be incorporated science curricula. e Science and Please submit a Curriculum Vita, description of research interests, list of four referees and a cover letter to Dr. Bruce J. Nich- into the scienti c curriculum. Yet, to Social Justice Project will present a olson, Chair of Biochemistry, MSC 7760, UTHSCSA, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, or by E-mail to Esther training programs. James at [email protected]. While continued e orts to expand date, incorporation of these topics in compendium of curated models that and improve the mandatory eth- science courses is left exclusively to span the sciences and o er a range of The University of Texas Health Science Center at San Antonio is an Equal Employment Opportunity/Affirmative Action Employer. All faculty appointments are designated as security-sensitive positions. ics training and guidelines of the the personal motivations of indi- depth so that you, the user, can easily National Institutes of Health Oce vidual educators. We hope to raise of Research Integrity are laud- the pro le of these individual e orts, CONTINUED ON PAGE 38
36 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 37 CONTINUED FROM PAGE 37 extract, adapt and integrate social Principles of practicing social justice in science justice components in your science • Develop awareness of current and historical injustices and injuries classroom. promoted or perpetrated by science and scientists. Courses with science and social • Use science as a tool to improve the human condition and create justice content: more just communities. • include science-communication • Speak out in defense of sound science and against scientific abuses training to improve the public dis- and unreasoned attacks on science. course about science, • Challenge the work of scientists that entrenches inequities in power • bring relevant examples of social and resources or harms, divides or discriminates against people. justice issues into introductory sci- ence survey courses and advanced • Involve those who are the subjects or stakeholders of scientific study topics courses, in the design and implementation of solutions. • incorporate social justice issues • Foster discourse between those in the natural sciences and those into laboratories, class activities, or in the social sciences to promote a critical examination of scienti c eld trips, and/or endeavors, broader accountability, the communication of science and • focus on scientific ethics. solidarity. At the University of Minnesota, Sehoya Cotner has incorporated social justice issues into her introduc- materials were publicly exhibited in take place Sept. 25−28. Conference tory biology course, “Evolution and conjunction with the nal produc- participants will contribute to work- Biology of Sex.” In the course, Cotner tion. e course and performance shops and have broader conversations moves beyond the basic biological also incorporated a Twitter campaign about scienti c culture, interdisci- de nition of sex to what science can to engage audiences in discussions plinary boundaries and globalization. and cannot tell us about such things about the social implications of Embedding social responsibil- as gender identity, mating prefer- science. ity and engagement in the science ences and kin selection. By pushing “ e Edge of the Map” focused classroom will create a community to the boundaries of what is cur- on genetics, interweaving four stories of scientists who are able to distill rently known, Cotner introduces her that tackled questions about what and present nuanced perspectives on students to discovery science. As she genetics can and cannot tell us about how science can and cannot inform states, “It’s an opportunity for me to identity using present-day and near- decisions in our daily lives and public say that science isn’t about answers; future innovations in genetic testing policy. Together we can rmly inte- it’s about questions and about re n- and engineering. “Connecting a grate social consciousness within the ing your hypotheses and guring out theater production with a course on scienti c culture. what data you really need.” social issues in biology energized the To read more about the Science e “Social Issues in Biology” class in its discussions of the social and Social Justice Project and nd out course taught by Jon Beckwith implications of genetics and of how how you can get involved, visit at Harvard Medical School also theater could communicate these www.kzoo.edu/praxis/category/science. incorporates societal factors within issues to the public,” Beckwith says. a science setting. Last spring, the You can help us gather and enlarge Morgan Thompson is a geneticist course allowed students to partici- and consultant of the Science the community of scholars devoted and Social Justice Project. Jon pate in a collaborative, multimedia to making social science training an Beckwith is a microbiologist and theater production called “ e Edge explicit and desegregated part of sci- longtime social activist in science of the Map.” Calla Videt, a writer and ence teaching and research in one of who has taught the “Social Issues director of the SIGHTLINE theater in Biology” course at Harvard two ways: Medical School for three decades. company in New York, developed • by contributing syllabi and other Regina Stevens−Truss is a an experimental production with the course materials that you have devel- chemistry professor at Kalamazoo input of students and Beckwith. oped and/or College and a member of the During a ve-week residency, ASBMB Minority Affairs Committee • by participating in the Science and Educational and Professional Videt and the course teaching assis- and Social Justice ink Tank, as part Development Committee, as tant led students in art-making activi- of the Kalamazoo College Arcus Cen- well as the faculty adviser of the ties to produce content, such as audio ter’s upcoming conference, WITH/ Kalamazoo ASBMB Undergraduate recordings and visual artwork. ese OUT – ¿BORDERS?, which will Affiliate Network chapter.
38 ASBMB TODAY MARCH 2014 MARCH 2014 ASBMB TODAY 39 OPEN CHANNELS Reader comments Re: “ e promise vs. the payo of the NIH intramural program” by Jeremy Berg, President’s Message, February issue
As usual, Jeremy, so well-framed. How Second, I would question 350 can we ensure that intramural inves- whether they are indeed directly tigators are evaluated with the same comparable to extramural grants. 300 rigor as (Howard Hughes Medical Are they expected to pay for the 250 Institute) investigators or (National same supplies, services, sala- Institutes of Health) Pioneer Award- ries, etc.? Universities subsidize 200 ees? Should they be reviewed in extramural grants in ways that do parallel with extramural applications? not show up in grants and that 150
Is the intramural program on par with cannot be done intramurally. Yes, 100 the well-funded science going on at some of the numbers are stag-
Janelia Farm? We need to demand gering and insupportable. But Number of IRP Investigators 50 uniform excellence, as the program I simply urge caution in their $0-0.5 >$5 0 $0.5-1.0 $1.0-1.5 $1.5-2.0 $2.0-2.5 $2.5-3.0 $3.0-3.5 $3.5-4.0 $4.0-4.5 $4.5-5.0 represents a major investment and interpretation and, again, strongly M
a signi cant proportion of NIH encourage the use of the same M research expenditures. level and type of peer review for M M M M M M M M M − SUZANNE PFEFFER internal and external funding. Annual Funding (Total Costs) ere are simply too many I agree wholeheartedly with the argu- outstanding investigators in the Figure from President’s Message, February issue ment that peer review of intramural intramural program to paint labs needs to be at a comparable level them all with one brush. I urge pare due to di erences in accounting to extramurally funded labs. And the moving quickly to the use of (the practices. Indeed, comparing one inclusion of budgets for intramural Center for Scienti c Review) to extramural grant and other (or likely labs in the NIH RePORTER is a review internal funding. e internal one intramural budget and another) great step toward more transparency review system at the NIH is simply requires care. My purpose in this col- in how funds are distributed inter- too tarnished by a long history of umn was to put the best available data nally. However, as a former section abuse and politics. to which I had access out to stimulate chief in the intramural program, I − RICHARD A. KAHN discussion and the gathering of more also urge caution in how those num- and better data. I know from my own bers are interpreted. I have several comments at this point. time in the IRP that there are many It is far too easy to look at the First, the apparent growth in the outstanding and productive scientists budgets of a laboratory and take (NIH Intramural Research Program) in the IRP. anks, Rick, for sharing o ense at the number of “R01 equiva- between 2003 and the present is due, your insights. lents” spent in one lab at the NIH. in part, to an accounting change With regard to Dr. Pfe er’s com- However, I would rst question their regarding the National Library of ments, I do not pretend to know the accuracy. Do the RePORTER num- Medicine that occurred in 2006- answers about how best to review the bers agree with internal budgets that 2007. is accounts for some, but not intramural program. Simply impos- each (principal investigator) may have all, of the growth that I noted. e ing the CSR-based extramural review access to, or do miscellaneous items IRP grew from 9.6 (percent) of the system is, in my opinion, likely to be (some quite substantial) get lumped overall NIH appropriation in 2006 to problematic. I am simply trying to into those budgets at the discretion 10.5 (percent) in 2007 due, in large encourage transparency and rigor- of administrators or those higher up part, to this accounting change. ous processes for all (intramural and the food chain? Although I left the Second, with regard to Dr. Kahn’s extramural) research investments for intramural program >15 years ago, comments, I realize and agree that the good of our national scienti c this was commonplace when I was intramural and extramural budgets for enterprise. there. a given laboratory are hard to com- − JEREMY BERG
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