.
Fostering Communication and Coii. ah oration
The nihCatalyst A Publication for NIH Intramural Sciintists
National Institutes of Health bOffice of the Director b Volume 16, Issue 2b March-Aprii 2008
Bias Against Women in Science: The problem, policy, history, & fix It’s Still There, and It’s Got to Cleaning Up Cell-Line Go Cross-Contamination by Fran Pollner
by Christopher Wanjek
f only mouse cells had ears, whis- Women in Biome kers, and a tail. These would Practices for I make it much easier to identify Best the type of cross-contamination that Sustaining Career Success for decades has plagued laboratories, invalidated years of research, side- Careers tracked careers, and possibly squan- NIH Working Group on Women in Biomedical dered millions of research dollars. National Center for Research Resources In well-documented cases that Office of Research on Women’s Health highlight both the range and ubiq- uity of the situation, guinea pig cells March 4, 2008 have turned out to be mouse cells, ovarian cancer cells have been dis- guised as breast cancer cells, and, in extreme cases, some cell lines have been unidentifiable. Fran Pollner NIH is not immune, neither in the Agents of Change: Discussing NIH initiatives to correct gender imbalances are (left to research performed here nor in the right) Joan Goldberg, executive director, American Society for Cell Biology’: Jeremy Berg, NIGMS director; Joan Schwariz. assistant director, OIR; Valerie Florance, deputy directorfor products produced. Many cell lines extramural programs, NLNJ Walter Schaffer, senior scientific advisorfor extramural from reputable sources are acciden- research; Raynard Kington, NIH deputy director; and panel chair Kath>yn Zoon, director of tally mischaracterized or masquerad- intramural research, NIAID ing as another kind of cell unbe- knownst to the supplier or user. f there is such a thing today as a post- ognized this long ago” and have devel- At least three lines in the respected feminist world, it’s not to be found oped “innovative practices” to attract and and much utilized NCI-60 cancer cell I just yet in much of the biomedical retain women at the highest levels, lines are mischaracterized—such as research arena, where various obstacles Alving said, presaging several talks on MCF-7/AdrR, which was once thwart the advancement of women sci- the day’s agenda. thought to be a daughter of the breast entists to commanding positions, such as department head at a research uni- Issues: cancer line MCF-7 but in reality is Framing the Numbers Talk lab chief an ovarian cancer cell line. versity or at NIH. 'Women have become 50 percent of rigorous documentation of attri- More than 15 percent of cell lines But medical school applicants and graduates continued on page 11 tion rates for women beyond the and they are 46 percent of assistant postdoctoral level has set the stage for deans and 33 percent of associate PuhMed Central New Rule designing and implementing systematic deans—but only 12 percent of deans of Please remember: All NIH-supported remedies, and large numbers of people U.S. medical schools, said keynoter researchers must submit their peer- in the field are determined to turn things continued on page 4 reviewed articles accepted for around. “This is not something ought to publication on or after April 7, 2008, we CONTENTS 6-10 to the National Library of Medicine’s be doing because it’s nice to do. It’s 1 Research Roundup PubMed Central digital archive. something we have to do” because the Changing the Climate For Women Scientists/ 12 Submissions take about 10 minutes future of biomedical research depends Cell-Line Cleanup Training News/ but do require your NIH e-mail user on it, said NCRR Director Barbara Alving, On Tenure Track name and password. Straightforward opening a daylong conference here on 2-3 A Tribute to Ed Rail 13-15 instructions “Best Practices for Sustaining Career Suc- are posted at Recently Tenured in research.
Kids’ Catalyst: Psst . . tor, as well as successful businesses, “rec- On Small RNAs The NIH Catalyst From the Deputy Director for Intramural Research
A Life Remembered: Joseph Edward Rale, 1920—2008
Joseph “Ed” Rail, one of the lions of NIH who helped to define its modem intramural re- search program and, in the 1950s, to establish a stable academic community within a rap- idly expanding government agency, died on Febmary 28. He was 88 years old. Often in my own role as DDIR, I marvel at the lasting effect Ed had on the style and sub- stance of the IRR I'd like to share my thoughts on his life, as well as the sentiments of those who worked closely with him. Rail was a consummate scientist; a charis- matic mentor, recmiter, and scientific direc- tor; and an engaging Renaissance man. He arrived at NIH in 1955 and built from scratch the Clinical Endocrinology Branch in the newly formed National Institute of Arthritis and Meta- bolic Diseases. He hired a diverse crew of sci- entists with seemingly disparate backgrounds to focus on a single endocrine organ, the thy- roid, a vision that soon produced one of the most productive branches at NIH and helped earn NIAMD international recognition. In 1962, Rail became scientific director of
NIAMD (where I was a research associate from 1971 to 1974) and continued in that position for more than 20 years through the institute’s
various transformations into the National In- /. Edward Rail at a lab in New Zealand stitute of Diabetes and Digestive and Kidney Diseases. From 1981 to 1982, he was also act- to other people,” he said. ing NIH deputy director for science before Under Rail’s guidance, the Clinical Endocri- stepping into that position full time with its nology Branch soon became a Mecca for bright
current title, deputy director for intramural re- endocrinologists from around the world, in- search, from 1983 to 1991. He never left NIH, cluding Rosalind Pitt-Rivers, co-discoverer of transitioning to emeritus status in 1995. triiodothyronine; Nino Salvatore, a Fogarty For more than 40 years. Rail was a major scholar who later helped reform the Italian edu- force at the NIH, first with his groundbreaking cational system; and Jamshed Tata, a develop- research on the thyroid and then with his lead- mental biologist from Britain’s National Insti- ership skills guided by a broad knowledge of tute for Medical Research. multiple scientific disciplines. He lived and “The best people from around the world breathed science and eloquently championed came [to the Clinical Endocrinology Branch] and defended the scientific process. His col- to work,” said Ira Pastan, one of those endo- leagues at NIH and around the world com- crinologists as well as a close friend, who be- prise a veritable Who’s Who in biomedical gan working with Rail in the 1960s and who is and clinical research. now chief of NCI’s Laboratory of Molecular “Ed was remarkable in his drive, his pas- Biology. “Ed’s intelligence and personality at- sion to help other scientists—young scientists tracted them. He was fun to talk science to.” in particular—to foster a sound scientific atti- “Ed had excellent scientific judgment; he was tude,” said Baruch Blumberg, a long-time always interested in the science, always en- friend who won a 1976 Nobel Prize for his couraging,” said Marshall Nirenberg, another work on hepatitis B. friend who, while at NIAMD, performed his Blumberg, whose research on polymor- famed RNA and poly-U experiments, a pre- phisms at NIAMD aided his NIH-funded re- amble to the research on the genetic code that search on hepatitis B later at the Fox Chase matured after his transition to the National Cancer Center in Philadelphia, recalled his Heart Institute in 1962 and which led to his frequent conversations with Rail about the sci- 1968 Nobel Prize. entific process and how much these had in- Rail was in fact involved indirectly in several fluenced his career. “He gave a lot of himself Nobel Prize-winning research efforts, from his
2 - M A u c n A i> R I I. 2 0 0 8
encouragement of Nirenberg—then a junior had high standards. If you were smart, you postdoc at NIAMD before his rapid rise to had his attention.” prominence in 1962—to the remarkable stretch “He was that element at NIH with profound of highly productive research that occurred at respect for basic research,” said Blumberg. NIAMD during his tenure as scientific direc- Socially, Rail was a “warm and inviting tor: namely, that of sailing buddy Christian man” who hosted countless parties at his Anfinsen, who won a 1972 Nobel Prize for house, said Pastan, who remembers bang- protein chemistry; Martin Rodbell, who won ing his head hard during one backyard soc- a 1994 Nobel Prize for GTP-binding and G cer game there. Rail’s favorite sport was ten- proteins; and Blumberg. nis. He, Pastan, David Davies, Cal Baldwin, A member of the National Academy and the Mort Lipsett, Bill Eaton, and others from NIH first person at NIH named to the executive would meet early in the morning before work rank in the Senior Executive Service, Rail him- at the Linden Hill tennis club. self was a man of acute scientific acumen who “Ed was enthusiastic about eveiything he authored more than l60 journal articles. did, including tennis,” Pastan laughed. “We His first major contribution to science came often joked that all the important decisions in the early 1950s, as a graduate student at about the NIH were done at Linden Hill.” the Mayo Clinic in Rochester, Minn., and then Other pastimes included sailing, skiing, postdoc at Memorial Sloan-Kettering in New skating the C&O canal, music, and a love of York, where he was among the first to use literature and words. “He was a superb public radioactive iodine to study thyroid function. It speaker,” Nirenberg said. was here that he met Jacob “Jack” Robbins, a Rail shared a large working farm on the meeting that would blossom into a nearly 60- banks of the Potomac with Robbins, year friendship. Robbins helped build the Blumberg, and Wilfred Rail of NIDDK, a dis- Clinical Endocrinology Branch with Rail, suc- tant cousin. This was the opposite of a time- ceeded him as chief in 1962 for the next quar- share, Robbins said, because the four fami- ter of a century, and remains an active volun- lies would go there not when it was empty teer in the branch today. but rather when everyone could make it. The With Robbins and others. Rail introduced families, now in their second and third gen- hormone treatment to thwart the development erations, still tiy to meet. of thyroid nodules and cancer from radiation “Ed was interested in everything,” Robbins fallout from atomic bomb testing on the Bi- said. Then, pausing to think of all he had kini Atoll. In the landmark I960 paper by just relayed about Rail’s life, he added: “We’ll Robbins and Rail in Physiological Reviews, really miss him.” entitled “Proteins Associated with the Thyroid Hormones,” the two colleagues surveyed ev- eiything known about thyroid hormones in circulation and the effect of the binding pro- teins on their bioactivity. They developed the then-revolutionary, now classic, hypothesis that the free hormone, only a tiny fraction of the total, was the active molecule.
Robbins joked of how he stuck it out in bench work while Rail moved into the lead- ership role of scientific director and deputy director, which naturally suited him. “He was a polymath; every field was easy for him,” Robbins said. Nirenberg added that Ed followed in the footsteps of his father, who was president of North Central College, a small liberal arts school outside of Chicago. Rail in essence be- came the dean of NIH. ‘“Ed surfed through life, riding the crests of the waves, recognizing where they began and where they were headed,” said Robbins at Rail’s memorial service on March 4. This keen insight that embraced mathematics, physics, chemistry, biology, and clinical studies enabled Baruch S. Blumberg Rail to grease the wheels and “make things Ed Rail at Antietam Meadowsfarm in Shatpsburg, happen” at NIH, Robbins later recalled. “He Ma}yland. fall 1968
3 — The N[H Catalyst
Bus Against Women in Science
continuedfrom page 1
Nancy Andrews, dean of the Duke Uni- K23 and K08 levels, versity School of Medicine, Durham, N.C., when about half of the who upon her appointment published a women applicants are piece in the November 2007 issue of the lost; when the first ROl New EnglattdJournal ofMedicine, “Climb- application level is ing Through Medicine’s Glass Ceiling.” reached, the ratio of Deans, Andrews obsei-ved, emerge not male to female appli- from the pool of associate deans but from cants is 2-3:1, he said. Fran Pollner department chairs, a far elusive in- more “Among those who do Camaraderie : (left to right) Katbiyn Zoon. NIAID scientific ner circle for women, who hold 8.5 per- apply, the success rates director; Barbara Airing, NCRR director and conference chair,
cent of these positions. Although junior are identical . . . but and Naomi Liiba)i, chief of laboratoiy medicine. Department of
women tend to downplay gender bias as women are leaving the Pediatrics. Children 's National Medical Center. Washington a major problem for women in academic academic medical career medicine, citing work-family balance as path at double and triple the rate of men.” the results of a survey of 58 institutions the greatest challenge, marginalization Ley observed that that path “was created that in November 2007 had advertised fac- rooted in gender bias is felt increasingly by men for men." ulty positions in these fields. Far fewer by senior women as they move up in the “The objective evidence,” Leboy con- women applied than would be expected ranks, she said. curred, “is that women score very well on based on the percentage of women in the Andrews advocated relentless “nagging” grant applications.” In 2006, there were potential Ph.D. applicant pool. to change the facts on the ground—like more women than men in the top 10 per- For instance, although women hold 43 upping the numbers of women on speak- cent fundable NIH grant applications, she percent of Ph.D.s in biochemistry, they ers’ lists and search committees and re- said, but the other side of that story is that were only 17 percent of applicants for jun- moving administrators with poor track there are fewer ior faculty posi- records in hiring and retaining women. grants per PI among tions in biochem- More numbers—documenting just how women, fewer dol- istiy departments; few women do move up in the ranks lars per grant the statistics for were offered by Timothy Ley, associate awarded women, a cell and develop- director of basic science and professor of lower reapplication mental biology medicine at the Washington Liniversity success rate for were closer to 30 Medical School in St. Louis, and Phoebe women, and a near- percent but well Leboy, president of the Association for ly complete absence under the ex- Women in Science and professor of bio- of women on the pected 48 and 52 chemistry at the University of Pennsylva- "really big and in- percent. “Women
nia School of Dental Medicine in Phila- creasingly popular Fran Pollner are avoiding ten- delphia. center grants.” The Data miners: Timothy Ley and Phoebe Leboy ure-track faculty At each step on the NIH grant-funding last item, she noted, jobs,” Leboy said, ladder, fewer women apply—and not be- reflects the nearly exclusive selection of noting that this study did not address how cause they are less successful at being se- men as Pis by the participating institutions. many women were actually hired. lected, Ley reported. There is little differ- Tracking the progress of women with She noted that the “proportion of ten- ence among the three groups of degree- Ph.D.s in biochemistiy, molecular biology, ure-track and tenured women has reached holders—Ph.D, M.D., and M.D.-Ph.D. cell biology, developmental Iriology, and a plateau of less than 60 percent of ex- with the most dramatic falloff occuring at neuroscience at academic health centers pectations and is now declining.” These the late postdoctoral stage between the and research universities, Leboy reported data, she said, support the finding that women are more likely to opt out at the How Does Industry Do It? point of transitioning beyond the postdoc stage, reported in the November 2007 is- nticipating a serious shortage of skilled they are in. sue of EMBO Reports.* Aemployees, private sector companies Flexibility is also the key in keeping The question of why, however, remains, in the late 1980s and early 1990s decided women in the workforce at Ernst & Young. she added, noting that although the EMBO that hiring more women and, especially, Flexible work hours, mentoring, and net- — report suggests that women have less con- retaining them—would be a solution and working are essential, and such items as fidence, the “chilly climate” for women in key to future success, according to Asif longer maternity leave have greatly added academia may go further in explaining Dhar, biomedical informatics practice to the satisfaction of women, Helmer said. why “smart young women” are disinclined leader at Deloitte Consulting in McLean, In fact, the models originally developed for to pursue biomedical careers there. There Va., and Jo Ellen Helmer, a partner at Ernst women have been adopted for the are no data, she added, on how many of & Young LLP in Chicago. workforce in general and have proved to enter the private workforce. Deloitte .started the Women’s Initiative increase overall productivity. these women in 1993, focusing on two main aspects: Both speakers emphasized the impor- In all arenas, it was mentioned through- providing a network and mentorship for tance of measuring the success of the pro- out the conference, there are next to no women throughout their careers and al- gram and making senior staff accountable. data on minority women in science.
lowing for a nonlinear progression of ca- At Ernst & Young, it is impossible to reach continued on next page reers. Employees can customize and ad- maximum points (and therefore maximum ‘“Falling Off the Academic Bandwagon,” by just the pace, workload, location sched- pay bonuses) if the “inclusiveness” goals members of the NIH Postdoctoral Fellows Sub- ule, and role they would like to play in have not been achieved, committee of the Second Task Force on the the company according to the stage of life Christianejost — Status of NIH Intramural Women Scientists 4 . .
March — April 2008
Anita B. Roberts Lecture Series: Distinguished Women Scientists at NIH Susan Gottesman: Small RNAs and Adaptevg to Stress by Gail Seabold
RNA. By base-pairing with messenger Starring Roles RNA, small RNAs can influence the trans- usan Gottesman grew up on Long Is- lation of messenger RNA in a positive or land and became interested in micro- negative manner, depending on the envi- S biology after reading Microbe Hunters by ronment of the cell. Gottesman’s sug- work Paul de Kmif, a “historical fiction” about gests that small RNAs are important com- such early microbiologists as Antonie van ponents of regulatory circuits and play a Leeuwenhoek and Louis Pasteur. Gottes- role in regulating stress responses to con- man received her B.A. in biochemical sci- ditions such as low iron or the accumula- ences from Radcliffe College (Cambridge, tion of toxic glucose phosphate. Mass.), magna cum laude, and her Ph.D. For example, small RNAs can limit the in microbiology and molecular genetics production of nonessential iron-binding from the Graduate School of Arts and Sci- proteins, making iron more available to ences, Harvard University, Cambridge. She essential proteins, and cause the degrada- came to NIH in 1971 to pursue postdoc- Holly Dimitropoulos tion of niRNA for the glucose transporter toral training with Max Gottesman (for- Susan Gottesma)! of the phosphotransferase system, thereby merly at NCI, now at Columbia Univer- usan Gottesman, co-chief of NCI’s reducing the uptake of glucose and pro- sity), then went back to Boston as a re- search associate in the laboratory Laboratory of Molecular Biology and duction of glucose phosphate. MIT of David Botstein, and returned to NIH in S chief of its Biochemical Genetics Sec- Gottesman’s collaborations with other 1976 as a senior investigator in the Labo- tion, presented the fourth lecture in the NIH investigators include the identifica- ratory of Molecular Biology, NCI, where “Anita B. Roberts Lecture Series: Distin- tion with Gisela Storz, NICHD, of some she continues today. She is married to guished "Women Scientists at NIH” on small noncoding RNAs in bacteria and with Michael Gottesman, deputy director for in- March 4. Michael Maurizi and Sue 'Wickner, both of tramural research, and they have two chil- Gottesman’s seminar, entitled “Stress NCI, previous that on work focused on dren and two granddaughters. Adaptation via Regulatory RNAs,” focused the role of energy-dependent proteases in on her recent work examining the role of regulation of the degradation of abnor- small noncoding RNAs in regulating trans- mal and iTiisfolded proteins, as well as their The Roberts Legacy lation, and messenger RNA stability. Her involvement in setting critical levels for he “Anita B. Roberts Lecture Series: laboratory is interested in novel mecha- regulatory proteins. This work led to T Distinguished 'Women Scientists at nisms for gene regulation and how these Gottesman’s election to the American NIH” honors the memory of its namesake, mechanisms contribute to global control Academy of Microbiology, the National who was chief of the Laboratory of Cell circuits in Escherichia coli. Academy of Sciences, and the American Regulation and Carcinogenesis at NCI Conducting a genome-wide collabora- Academy of Arts and Sciences. from 1995 until her death May 26, 2006. A research leader at for years, tive study, Gottesman identified 17 novel Gottesman has also served as an editor NIH 30 Rob- erts was a pioneer in the field of carcino- small RNAs and six new short mRNAs. of the Joiinial of Bacteriology, Genetics, genesis, autoimmune disease, and wound Study of the function of these new small and Annual Review of Microbiology and healing, with special contributions to cur- RNAs is ongoing, but many of them ap- as an editorial board member of Genes & rent knowledge of transforming growth pear to be involved in translational regu- Development and MolecularMicrobiology factor-p. She was among the top 50 most- lation. She has had leadership positions in the cited authors for her published work from Another genome-wide search identified ASM, ASBMB, Genetics Society, and AAAS 1982 to 2002 (see “The Shining Legacy of small that bind to the chaper- is currently the council. RNAs RNA and on NAS Anita Roberts, Tlje NIH Catalyst, Sept.- one Hfq, a protein that facilitates the in- Among her many awards are an NIH Oct. 2007). teraction of small RNAs with messenger Director’s Award and NIH Merit Award. continuedfrom page 4 targeting women for awards but by mak- ing times of needed extended leave Climate Change ing the process fairer, he said. recrtiitment of dual-career couples, Early last year, in response to a National His subcommittee is canvassing pro- facilitated through a regional consortium, Academies report on bias and barriers fac- grams across the country aimed at “trans- of which NIH is a founding member ing women in academic science and en- forming the culture” and has found that encouraging teleworking gineering, NIH Director Elias Zerhouni most of them are small, under five years creation of a trans-NIH mentoring established the NIH "Working Group on old, and unevaluated for impact. NIGMS, committee; training Pis in mentoring skills 'Women in Biomedical Careers. This con- he said, has issued an REA to study inter- and senior investigators, postdocs, and ference was the objective of one of the ventions to promote biomedical research graduate students in leadership skills group’s 11 subcommittees. careers and their effectiveness. conducting focus groups among NIH NIH Deputy Director Raynard Kington, Addressing the climate at home, Joan women to learn how to promote taking chair of the subcommittee on research on Schwartz, assistant director, OIR, and a the first step beyond the postdoc level the efficacy of programs to reduce gen- member of several subcommittees aimed Asked for some statistics on women lab der bias, observed that with the will to at recruiting, retaining, and advancing chiefs at NIH, Schwartz noted that the change, things can happen quickly, as was women at NIH, outlined some of the pro- percent has increased over the last 10 the case with the Director’s Pioneer grams under consideration or undeiway: years—from 4 to l6 percent. Awards, part of the NIH Roadmap: None expanding access to childcare both She issued an oft-repeated invitation that of the first-year awardees were women, on and off campus attendees “please send in any thoughts you but 46 percent of the second-year cohort providing a tenure-track investigator have.” To do so, write to: were. The change was effected not by or PI with a temporary lab manager dur-
Annual Review Selected NIH Intramural Research Accomplishments 2007
Discoveries that add to the body of presymptomatically (NIA, NINDS, Demonstration in mice of a potential knowledge about normal and abnor- NICHD) new route to prevention of salivary, mal biological functions and behavior Identification of a new gene, FANCN, gland damage—by protecting the mi- that is defective in Eanconia anemia pa- crovascular endothelial cells in the Identification of disease genes tients of complementation group N and gland—in patients undergoing irradia-
Detection in a genome-wide associa- also resembles PALB2, suggesting it is tion for head and neck cancer (NIDCR, tion study of new genetic variants in a also a breast cancer susceptibility gene NCI) previously unsuspected region on chro- (NLA) Demonstration for the first time that mosome 8q24 associated with increased Identification of a single ancient al- siRNA as expressed by a lentiviral vec- risk of prostate cancer in men of Euro- lele of the insulin-like growth factor gene tor is both safe and efficacious in a large- pean ancestry (NCI-DCEG, NCI-CCR) as the major contributor to small size animal model in a study that achieved Identification in a genome-wide as- across dog breeds, shedding light on the downregulation of CCR5 expression in sociation study of breast cancer of four evolution of complex traits (NHGRI) nonhuman primates, with evidence of single-nucleotide polymorphisms in the Identification of at least four new ge- continuing SIV resistance to simian im- FGFR2 gene that are highly associated netic variants associated with increased munodeficiency virus in transduced ceOs with sporadic postmenopausal breast risk of diabetes UGF2BP2, CDKALl, for at least two years (NHLBI) cancer in women of European ancestry CDKN2A, and CDKN2B), bringing to at Identification in animal models of in- (NCI-DCEG, NCI-CCR, NCI-DCP) least 10 the number of genetic variants fection that the production of high con- Discovery of HAXl mutations in some confidently associated with increased centrations of the novel phenol-soluble cases of autosomal recessive severe con- susceptibility to type 2 diabetes (NHGRI) modulins is key to the severity of com- genital neutropenia (NCBI/NLM) Identification of a common variant of munity-associated methicillin-resistant Identification of a homozygous point the STAT4 gene, which encodes a pro- staph infections (NIAID) mutation in the 3^ untranslated region tein involved in immune cell activation Study in mouse models of neurode- of the pf4 gene (also known as the and differentiation, as a contributor to generation of the newly identified pro- MAPBPIPgene) as the cause of a newly susceptibility to two autoimmune dis- tective pathway—called preemptive characterized syndrome combining se- eases, rheumatoid arthritis and systemic quality control—that attenuates the ad- vere congenital neutropenia, hypopig- lupus erythematosus (NLAMS) verse consequences of protein misfold- mentation, B-cell defects, and short stat- Identification in a genome-wide as- ing in the endoplasmic reticulum ure (NCBI/NLM) sociation study of a locus on chromo- (NICHD) Identification of mutations in the some 9 that includes two rheumatoid Demonstration of a potential role of STAT3 (signal transducer and activator arthritis susceptibility genes, TRAFl (TNE glutamate-dopamine interactions in a of transcription 3) gene as the cause of receptor-associated factor 1) and C5 mouse model of schizophrenia lacking hyper-IgE syndrome, also known as (complement component 5) (NIAMS) functional GluRl (AMPA) glutamate re- Job’s syndrome (NIAID, NHGRI, NCI, The finding on EMRI scans that two ceptors (NIAAA) NCBI, CDER) gene variants implicated in schizophre- Description of a novel, brain-pen- Discovery using retrovirus-mediated nia interact to degrade the brain's abil- etrant, orally active corticotropin-releas- RNA interference of several unexpected ity to process infomiation and conse- ing factor receptor antagonist with effi- roles of the DISCI (dismpted-in-schizo- cjuently impair working memory in oth- cacy in animal models of alcoholism in (NIAAA) phrenia-1 ) gene the development of eiwise normal adults (NIMLI) new neurons in the adult hippocampus Demonstration in a rat model of hu- (NICHD) Important new animal models man metabolic syndrome that the green Identification of the genes that Demonstration in a mouse model that tea polyphenol epigallocatechin gallate cause—and elucidation of the pathways anthrax lethal toxin produces shock that lowers blood pressure, improves endo- insulin leading to—recessive osteogenesis is insensitive to fluid administration and thelial dysfunction, increases sen- imperfecta (OI), a relatively rare form that the anthrax edema toxin produces sitivity, and protects against myocardial of OI at the most severe end of the clini- much greater decreases in blood pres- ischemia and reperfusion injury as well cal spectrum (NICHD) sure than lethal toxin, suggesting that as conventional therapy with the ACE Identification in a genome-wide as- both the pathogenesis and the response inhibitor enalapril (NCCAM) sociation scan of genetic variants in the to conventional therapy for anthrax-in- Eindings in mouse studies that neu- FTO gene associated with obesity-re- duced shock differ substantially from rons express several Toll-like receptors lated traits in BMI, hip circumference, conventional septic shock and require (TLRs), whose levels increase and pro- and body weight, providing a novel new management approaches (CC, mote cell death in response to stroke- entree to corresponding pathways and NIAID) induced energy, establishing an adverse a target for possible therapeutic ap- Development of an experimental uvei- effect of TLR activation in neurons and proaches (NIA) tis model by exposing mice to the same inflammatory immune cells that may Identification of a deletion mutation retinal antigen but under different in- worsen the outcome of a stroke and pro- of ITPRl as the cause of spinocerebral ductive conditions, eliciting a disease viding a rationale for therapeutic stroke ataxia 15, an inherited adult-onset neu- that differs from the currently used interventions that target TLR-signaling rological disease, further implicating cal- model clinically, histologically, and im- pathways (NLA) cium regulation in the pathobiology of munologically and shedding light on the The finding that resveratrol, a this disorder and enabling an accurate heterogeneous nature of uveitis in hu- polyphenolic compound found in red molecular diagnosis that can be applied mans (NED grapes, improves health and survival in 6 March — Apr II, 2008
middle-aged ovei'weight male mice on cal model of acute inflammation that in- phorylation is a regulatory mechanism a high-calorie diet, the first demonstra- hibition of cyclooxygenase-2 (COX-2) by of MnSOD activity (NFILBI) tion of health and sui'vival effects of drugs such as ibuprofen modulates gene Elucidation of the catalytic process by resveratrol in mammals (NIA) expression besides the COX-2 cascade; which hemoglobin converts nitrite to ni- The finding in a rat-reinstatement these changes in gene expression may tric oxide, with implications for the un- model that injections of peptide YY3- be associated with both the analgesic derstanding of normal physiology and a gastrointestinal-derived hormone, and the toxic effects of these widely used the therapeutic application of this 36 , “new decreased typical cue-induced high-fat di-ugs (NINR, NIDCR) chemistiy” (NHLBI) food seeking behavior, suggesting a role Finding that acetaminophen, widely Discovery of a novel immunogenic for this peptide in preventing relapse of used for pain management as an alter- antigen encoded by human endogenous poor eating habits among people on a native to drugs like ibuprofen and COX- retrovirus type E that is selectively ex- diet (NIDA) 2 inhibitors, alters the release of inflam- pressed in the majority of clear-cell kid- matory mediators and expression pat- ney cancers but not in normal tissues Basic discoveries in cell molecular, terns of genes related to COX-2 much and elicits immune responses resulting and structural biolog}’ with impli- as drugs like ibuprofen and COX-2 in- in regression of metastatic kidney can- cations for the treatment of human hibitors do, raising the possibility of simi- cer after allogeneic hematopoietic cell disease lar adverse effects as well (NIDCR, transplantation (NHLBI) Determination of the molecular com- NINR) Discoveiy of a regulatory role for position of tip links, which connect the Elucidation of novel mechanisms by CD40 ligand in loss of bone mass, re- tops of stereocilia found on sensory cells which omega-3 long-chain polyunsatu- vealed in a study involving patients with in the inner ear and are thought to con- rated fatty acids and macular xantho- X-linked hyper-IgM syndrome (NIAID, vey the force to gates in mechanoelec- phylls influence angiogenic, inflamma- CC, NCI) trical transduction channels (NIDCD) tory, and cell-sui'vival pathways impli- New insight into potential cellular and 'I'vvin study evidence that dichotic lis- cated in the pathogenesis of age-related molecular mechanisms underlying the tening—the ability to identify and dis- macular degeneration, diabetic retinopa- genetic link between CX3CLI and tinguish different stimuli presented si- thy, and retinopathy of prematurity (NEI, CX3CRI and atherosclerosis, suggesting multaneously to each ear, which is re- NIAAA, ODS) that this chemokine-chemokine recep- lated to normal interhemisperic informa- Discovery that expansion of Thl7 cells tor pair may be considered a pro-inflam- tion processing—is a highly heritable in normal human blood by IL-2 is a matoiy target in the prevention and treat- trait (NIDCD) cause of human inflammatoiy and au- ment of atherosclerosis (NIAID) Enhanced understanding of ABC trans- toimmune diseases and that antagonism Discovery of the first component, porters with the finding that “silent” mu- of Thl7 by IFN-y and IL-27 could be called TRC40, of a novel membrane pro- tations in a multidrug-resistance gene used for treatment of two human chronic tein insertion pathway for tail-anchored affect cancer diagnosis and treatment ocular inflammatory diseases, uveitis or proteins, adding to the knowledge of (NCI-CCR) scleritis (NEI) normal cellular function (NICHD) Keener insight into DNA damage with Identification of progenitor cells re- Findings related to the role of brain- the visualization of DNA breaks in liv- siding in a unique extracellular niche in derived neurotrophic factor in depres- ing cells and the finding that ATM human and mouse tendon that have uni- sion and anxiety that suggest that BDNF (ataxia-telangiectasia mutated kinase) versal stem-cell characteristics, includ- is a target of antidepressants (NICHD, prevents the persistence and propaga- ing clonogenicity, multipotency, and NIMH) tion of DNA breaks (NCI-CCR) self-renewal capacity, thereby opening Findings that several amino acid de- Elucidation of the role of chaperones up new approaches to help mend torn rivatives of P-cyclodextrin block ion con- in the identification of an acetylation site or degenerating tendons (NIDCR) ductance through pores formed by both in the middle domain of Hsp90 that regu- Establishment of the existence of a anthrax lethal toxin and Staphylococcus lates its function, coupled with the find- dysregulated signaling network in head aureus a-hemolysin, raising the pros- ing that asymmetric deceleration of ClpB and neck cancer, thereby identifying pect of new effective therapies against or Hspl04 ATPase activity unleashes pro- novel molecular targets for the preven- various pathogens that use pore-form- tein-remodeling activity (NCI-CCR) tion and treatment of these malignan- ing proteins (NICHD) Finding that junctional adhesion mol- cies (NIDCR, NCI) Characterization of mammalian genes ecule-C regulates the vascular endothe- Discoveiy of random cell migration involved in iron-cluster synthesis and de- lial barrier, advancing the understand- and self-organization during gland de- velopment of methods to assess cluster ing of angiogenesis (NCI-CCR) velopment that lead to tissue engineer- biogenesis, with implications for treat- Discovery of nonhistone Scm3 as a ing of three-dimensional salivary gland ment of neurodegenerative and hema- crucial component of the core of yeast precursors by self-assembly of dissoci- tologic conditions such as Parkinson’s centromere, advancing knowledge of ated cells (NIDCR) disease and refractory anemias (NICHD) chromosome biology (NCI-CCR) Identification of a much more exten- Discovery that cannabinoids mediate Finding that frequent engagement of sive mitochondrial phosphoproteome analgesia largely via peripheral CBl re- the classical and alternative NF-kB path- signaling pathway than previously rec- ceptors, which may help guide the de- ways by diverse genetic abnormalities ognized, including the identification of velopment of peripherally restricted CBl promotes cell survival in multiple my- specific phosphorylation sites within the agonists as analgesics without any cen- eloma (NCI-CCR) entire oxidative phosphoiylation pro- tral side effects (NIAAA) Discovery in a well-characterized clini- cesses and the demonstration that phos- Finding of excessive telomere loss and
7 — The NIH Catalyst
Annual Review Selected NIH Intramural Research Accomplishments 2007
reduced T-cell immune function among ing via the transcription factor StatS, pro- to the whole ER to promote cell sur-
| caregivers of Alzheimer's patients, es- motes the differentiation of immunosup- vival by preventing protein aggrega- i tablishing a link between chronic stress, pressive regulatoiy T cells but inhibits tions—with implications for diseases in lymphocyte lifespan, and aging (NIA) the generation of proinflammatoiy T which sigma- 1 receptors have a role, | Further elucidation of the DNA repair cells that produce IL-17 (NIAMS, NIAID, such as addiction, depression, amnesia, | functions of FANCJ, the Fanconi anemia NIDDK) stroke, and cancer (NIDA) protein associated with FA complemen- Eirst demonstration that the “master” Einding that blockade of brain tation group J, based on studies dem- regulator MyoD requires an RNA endocannabinoid CBl receptors by • onstrating its interactions with proteins helicase and a noncoding RNA to pro- AM251, a novel CBl receptor antago- ^ associated with breast and colon can- mote muscle gene expression and dif- nist, alters the breakpoint for intrave-
|
cer; and the identification of replication ferentiation of skeletal muscle cells nous cocaine self-administration and at- 1 protein A as the first regulatory partner (NIAMS) tenuates cocaine-enhanced electrical of FANCJ in DNA repair and the main- Identification of the sphingolipid sph- brain-stimulation reward, suggesting that
tenance of genomic stability (NIA) ingosine-1 -phosphate as an important AM251 or other more selective and po- ! Finding, in a genome-wide search for regulator of allergic responses and the tent CBl receptor antagonists deserve genes with RNA polymerase II stalled discovery of its possible role as a deter- further study as potentially effective anti- within the promoter-proximal region, minant of anaphylaxis (NIAMS, NIDDK) cocaine medications (NIDA) that regulated stalling of polymerase The finding of reduced occurrence of Demonstration by pharmacologic MRI elongation occurs at hundreds of genes post-traumatic stress disorder among that a novel dopamine Dj receptor an- that respond to stimuli and developmen- combat veterans who sustain damage tagonist blocks the targeted receptors in tal signals, establishing that polymerase to either of two brain areas—the ven- the nucleus accumbens, the likely stalling is an important mechanism in tromedial prefrontal cortex or an ante- mechanism by which it produces anti- the regulation of gene transcriptional re- rior temporal area that includes the cocaine-like effects in vivo, suggesting sponses to dynamic environmental and amygdala—suggesting that these two that such compounds may be used to developmental cues (NIEHS) areas are critically involved in PTSD further elucidate the role of dopamine Solving the ciystal structure of DNA (NINDS) D3 receptors in drug abuse and may polymerase |l, providing new insights The finding that GABAergic circuits serve as leads for therapeutic agents to into the repair of potentially cytotoxic are not engaged by thalamocortical in- treat addiction (NIDA) double-strand DNA breaks that can be put in the neonate, but are poised for a Demonstration on MRI that in youth induced by chemotherapeutic agents remarkably coordinated development of with attention deficit hyperactivity dis- and by physical and chemical agents in feedfoiward inhibition at the end of the order, the brain matures in a normal the environment (NIEHS) first postnatal week, a critical event in pattern but is delayed three years in Derivation of a detailed molecular the development of a functional circuit some regions, on average, compared model of the retromer cargo-recognition in the mammalian brain (NINDS) with that of youth without the disorder, subcomplex by combining X-ray ciys- Demonstration that voltage-sensor suggesting that ADHD may be a disor- tallography, computer-enhanced elec- paddle motifs are modular structural der of brain-maturational delay (NIMH) tron microscopy, and bioinformatic motifs in ion channels and in other volt- Completion of the first prospective analysis, elucidating many of the cellu- age-sensitive membrane proteins and study of cortical brain development be- lar functions performed by the retromer that they are important pharmacologi- fore and after the onset of pediatric bi- complex, such as iron-transporter recy- cal targets (NINDS) polar disorder, revealing a distinct pat- cling and processing of the amyloid pre- Einding that new cell lines from mouse tern of developmental change—asym- cursor protein (NIDDK, NIAMS, NICHD) epiblast share defining features with hu- metric gains and losses of gray matter Demonstration of a new function for man embiyonic stem cells and can en- compared with that of healthy youth and RNA: playing a direct role in the repair hance understanding of how pluripo- of those with childhood-onset schizo- of double-strand breaks in chromosomal tent cells generate distinct fates during phrenia (NIMH) DNA by sei"ving as a template at the early development (NINDS, NCI) The finding that a variation in a gene break site, potentially leacling to new Elucidation of biochemical mecha- called GRIK4, which codes for a kainic directions in gene targeting given that nisms underlying the ability of the green acid-type glutamate receptor, appears RNA can be amplified at will within cells tea polyphenol epigallocatechin gallate to make people with depression more (NIEHS) to stimulate production of nitric oxide likely to respond to the medication Discovery that the high-mobility group from vascular endothelial cells and to citalopram than are people without the box 1 protein specifically interacts with inhibit hepatic gluconeogenesis, findings variation, suggesting that the glutamate the base excision-repair intermediate relevant to potential cardiovascular and system plays a role in modulating re- and accumulates at sites of oxidative metabolic health benefits of drinking sponse to selective serotonin reuptake DNA damage in living cells, suggesting green tea (NCCAM) inhibitors (NIMH, NHGRI, NIAAA) that it serves as a novel base excision- Identification of a new endoplasmic H Identification of a key step in the si- repair cofactor (NIEHS) reticulum chaperone protein, called the lencing of the FMRl gene that causes
Identification of an enzymatic path- sigma- 1 receptor, which under normal fragile-X mental retardation syndrome way that freezes the chromatin environ- physiological conditions, senses and SIRTl deacetylation, a late event in gene ment to ensure that DNA lesions are transmits the ER calcium level to mito- silencing—suggesting that SIRTl inhibi- properly repaired (NIAMS, NCI) chondria to increase bioenergetics and tion and reactivation of FMRl in neu- Demonstration that interleukin-2, act- in deteriorating conditions translocates rons may be possible (NIDDK) 8 )
March — April 2008
Development of new or improved man mitochondria-focused cDNA pathway of aiteiy specification, estab- instruments and technologies for microarray (hMitChip3) and its bioinfor- lishing a role for neuronal guidance fac- use in research and medicine matics tools: the chip consists of the 37 tors in vascular patternings, illuminat- mitochondrial DNA-encoded genes, ing vascular tube formation in vivo, and Development of novel techniques to 1,098 nuclear DNA-encoded and mito- identifying a lymphatic vascular system map human histone methylations that chondria-related genes, and 225 con- in zebrafish (NICHD) showed correlations between chromo- trols, each in triplicate; the bioinformatic Improved MRI contrast and resolu- some banding patterns and unique his- software includes data-analysis proce- tion that allows visualization of laminar tone modifications, as well as associa- dures and a customized database for in- cortical architecture of human brain tions with chromosome breakpoints terpretation of results (NCCAM) based on magnetic properties of tissue detected in TY cell cancers, providing (NINDS) new insights into the function of his- Advances in imaging Development of a method to com- tone methylation and chromatin orga- Development of a real-time system bine measurements of intensities and nization in genome function (NHLBD for intraoperative visualization of fluores- photon trajectories with theory and Development of an ultrasensitive, cently labeled tissue, demonstrated on simulations to rigorously determine dis- faster method for detecting infectious surgical resection in metastatic murine tances in single-molecule FRET (fluores- prions using seeded conversion of re- ovarian cancer (NIBIB, NCI, CIT) cence resonance energy transfer) experi- combinant prion protein, which should Demonstration that MRI can be used ments (NIDDK) facilitate improvements in the practical- to guide X-ray procedures using con- Improvement on matrix-assisted la- ity of diagnostic prion assays as well as ventional equipment to test cell thera- ser desorption/ionization mass spec- in fundamental studies of structure and pies for heart disease (NHLBD trometry (MALDI-MS) with MALDI-ion formation of the scrapie prion protein Development of an easily imple- mobility orthogonal time-of-flight MS isoform (NLAID) mented imaging technique in the spa- (MALDI-IM-TOFMS) as a means to di- Development of an automated lab- tial frequency domain capable of acquir- rectly probe tissue to map and image on-a-chip immunoassay for inflamma- ing both the scattering and the absorption distribution of analytes and elucidate tory biomarkers in newborns (NIBIB) distributions in a single exposure, which molecular stnicture with minimal prepa- Development of a microcalorimetric should help broaden the imaging appli- ration (NIDA) method to determine the thermodynam- cations of X-ray scattering (NHLBD ics of multiprotein complex assembly, Development of a new fluorescence Advances in bioinformatics with applications to signaling complexes collection device—total emission detec- Introduction of dbGaP (database of important in T-cell activation (NIBIB, tion—that greatly increases fluorescence genotypes and phenotypes) to archive NCI) light collection in a two-photon micro- and distribute genome-wide association Use of a combination of solid-state scope, with the potential for decreasing studies and other data that explore the nuclear magnetic resonance data and photodamage and allowing for deeper connection between phenotype and electron microscopy data to develop a imaging in thick tissue and faster imag- genotype, with the aim of facilitating re- search into the genetic causes of dis- full model of the molecular structure of ing for dynamic studies ( NHLBI amylin fibrils, a pancreatic peptide that Development and demonstration of ease and accelerating the advance of may contribute to the destruction of in- scanning transmission electron tomog- personalized medicine (NCBI/NLM) sulin-producing cells in patients with raphy for imaging cellular proteins la- Publication by the ENCODE Consor- type 2 diabetes, elucidating the generic beled with heavy-atom cluster tium of landmark papers that advance propensity of peptides and proteins to nanoparticles (NIBIB, NIDDK) the collective knowledge of human ge- form amyloid fibrils and potentially fa- The use of novel fluorescence imag- nome organization, functioji, and evo- cilitating the development of therapeu- ing approaches combined with quanti- lution, including elaboration of transcrip- tic agents (NIDDK, NIBIB) tative analysis and mathematical mod- tional regulation and chromatin struc- Development of a novel procedure eling to further elucidate cellular pro- ture (NHGRI, NCI) that allows rapid and accurate determi- cesses, such as membrane partitioning nation of a protein's three-dimensional and its role in protein sorting and trans- Development of new or improved structure using only chemical shifts as port in the Golgi apparatus, biogenesis approaches for preventing or delay- input data, applicable to proteins of up and turnover of peroxisomes, mitochon- ing the onset or progression of dis- to 130 residues, but can be extended to drial morphology and its regulation of ease and disability larger sizes when supplemented with a cell-cycle progression, control of primaiy small fraction of the commonly used cilia dynamics, intercellular transfer be- Identification of rapamycin as an ef- regular NOE restraints (NIDDK) tween stem and niche cells, origin of fective agent for the prevention of to- Development of a new equation to autophagosomes, and PALM (live-cell bacco carcinogen-induced lung tumors determine the cumulative energy defi- photoactivation localization microscopy) (NCI-CCR) cit required to lose a pound of body for single-particle tracking (NICHD) Demonstration that complications of weight that includes initial body fat in Further elucidation of blood and lym- sickle cell disease, such as pulmonaiy the calculation and accounts for why in- phatic vessel formation during vertebrate hypertension, priapism, leg ulceration, dividuals with lower initial body fat re- embryogenesis through the develop- and stroke, are directly linked to the quire less than the 3,500-kcal deficit per ment of confocal microangiography and intensity of hemolysis, providing new pound of weight loss (NIDDK) high-resolution in vivo imaging of insights into treatments (CC, NHLBI) Development of a third-generation hu- zebrafish blood vessels, elucidating a Development of a risk-assessment P The NIH Catalyst
Annual Review Selected NIH Intramural Research Accomplishments 2007
tool, called the CARE model, that pro- Identification of mutations in influ- festations of children with Hutchinson- vides a more accurate assessment of in- enza A subtype H5N1 (avian) hemag- Gilford progeria syndrome, including
vasive breast cancer risk in African glutinin ( HA) that alter its specificity for sclerotic skin changes, joint contractures, American women than the currently sialic acid (SA) either by decreasing a- bone abnormalities, alopecia, growth available NCI Breast Cancer Risk Assess- 2,3-SA or increasing a-2,6-SA recogni- impairment, elevated blood pressure, ment Tool (NCI-DCEG, NICHD) tion, a finding that can guide the devel- reduced vascular compliance, low-fre- Identification of two new components opment of preemptive vaccines and quency conductive hearing loss, ftinc- of the Fanconi anemia (FA) core com- therapeutic monoclonal antibodies that tional oral deficits, abnormal prothrom- plex: FAAP 24 and FAAP 100, with im- can be evaluated before the emergence bin times, and elevated platelet counts, plications for further understanding of of human-adapted H5N1 strains (VRC/ setting the stage for the evaluation of the FA-breast cancer-associated DNA NIAID) interventional therapies (NHGRI, CC, damage repair pathway and for screen- Identification in patient sera of a po- NHLBI, NIDCD, NIDCR, NICHD, NEI, ing potential anticancer claigs that fa- tent and broad HIV-1 neutralization ca- | NCI, OD) cilitate or block interactions between the ! pacity mapped to the primary receptor The finding that gene-expression pat- FA core complex and DNA (NIA) CD4 binding region of HIV-1 Env gpl20 terns derived from blood cells are a near- The finding that gynecomastia in three glycoprotein, a finding that could lead match to liver gene-expression patterns otherwise healthy prepubertal boys with to improved vaccine immunogens and predict acute acetaminophen expo- normal seaim concentrations of endog- (VRC/NIAID) sure in rats more reliably than traditional enous steroids was associated with the Finding that preserved central clinical parameters, suggesting a means topical application of products that con- memory CD4+ T lymphocytes are asso- to ascertain exposure levels well before tained lavender and tea tree oils, both ciated with prolonged survival in patho- liver damage is detected by classical pa- of which were found to have estrogenic genic SIV-challenged monkeys immu- rameters and supporting the potential and antiandrogenic activities in human nized with plasmid DNA and replica- use of genomic markers in the blood as cell-line studies (NIEHS) tion-defective adenoviral vectors encod- surrogates for clinical markers of poten- The finding that patients with rheu- ing SIV proteins, with implications for tial acute liver damage (NIEHS) matoid arthritis who were treated with immune correlates of vaccine efficacy hydroxychloroquine were much less in humans (VRC/NIAID) Development of new or improved likely to develop diabetes mellitus than Finding in a mouse model that the ways to treat disease and disability those not treated with hydroxychloro- highly lethal 1918 pandemic influenza quine, suggesting this medication may virus is susceptible to immune protec- Blood levels of NF-KB-related serum
be useful to prevent development of ! tion by a preventive hemagglutinin DNA factors found to be biomarkers of thera- diabetes in those at risk (NIAMS) vaccine (VRC/NIAID) survival | peutic response and in patients Completion of recmitment for the first Identification of new antigens that treated for advanced oropharyngeal can- phase I study of a whole-plant mistle- may be potential targets for new thera- cer (NIDCD, NCI) j toe extract given together with chemo- peutics or vaccines to help control ma- Development of damnavir (approved
therapy in patients with advanced solid laria (NIAID) ! by the FDA) and other protease inhibi- tumors (NCCAM) Development of a vectored vaccine tors that block the dimerization process
| Launch of an exploratory study to delivered nasally that protected rhesus of HIV-1 protease (NCI-CCR) | evaluate the ability of the green tea monkeys against El^ola vims challenge, New data from adult nephropathic polyphenol epigallocatechin gallate to in the first study in which topical im- cystinosis patients seen at the NIH Clini- simultaneously improve metabolic and munization through the respiratory tract cal Center from 1986 to 2006 showing cardiovascular actions of insulin in achieved prevention of a viral hemor- that chronic oral cysteamine therapy re- healthy, obese, hypertensive, or diabetic rhagic fever infection in a primate model sults in taller and heavier individuals with subjects (NCCAM) (NIAID) lower cholesterol levels and lower fre- Conduct of a clinical study of the role Demonstration of the immunogenic- quencies of myopathy, diabetes, pulmo- of endocrine-immune dysfunction in pa- ity and induction of protective immu- nary dysfunction, hypothyroidism, and tients with active rheumatoid arthritis, nity by recombinant hepatitis C virus- death, pointing to cysteamine as the aimed at gathering data that may pro- like particles (HCV-LP) in chimpanzees; treatment of choice for cystinosis patients vide further support for investigating immunized animals developed HCV-spe- of all ages (NHGRI) selected CAM interventions, such as cific cellular immune responses (NIDDK) Improvement in the rate of gene trans- DHEA and stress-reduction techniques fer in patients with adenosine deami- in similar populations of RA patients Development of new or improved nase deficiency by using chemotherapy (NCCAM, NIAMS, NCI, CC) ways to diagnose disease and dis- to reduce the number of patient mar- ability row cells to make room for the corrected
Vaccine development \ ones, with subsequent marked improve- Identification and stmctural definition Gene expression patterns T-cell j ment in numbers and immune
of a site of vulnerability on the HIV-1 i Expression profiling to develop new function (NHGRI, NCI, NHLBI, NIDDK) Env gpl20 glycoprotein that is recog- biomarkers for liver cancer and to re- High-dose idebenone shown to im- nized by the broadly neutralizing anti- veal a signature of high cancer risk in prove neurological outcome in patients body bl2 and is involved in the attach- benign tumor (NCI-CCR) with Friedreich’s ataxia in a randomized
ment of gpl20 to CD4 ( VRC/NIAID, NCI) Characterization of the clinical mani- controlled trial (NINDS)
10 - .
March — April 2008
Coming Clean on Cell Line Contamination
continuedfrom page 1
might be cross-contaminated or improp- “The NIH notice Obtaining cell erly characterized, according to peer-re- strongly suggests that lines from the origina- viewed papers published in recent years. peer reviewers of grants tor should not be The issue has been addressed in the pages and manuscripts could construed as sufficient of Science, Nature, and other prominent be the key to compli- evidence of their iden- journals and has prompted position state- ance,” said Nardone. “I tity. ments from professional organizations. Yet do not subscribe to that Whenever pos- the problem lumbers on largely unabated. view because the pool sible, cell lines should Cell-line cross-contamination com- of reviewers lacks the be obtained from a monly refers to when a foreign cell, background knowledge major repository that usually mammalian, is introduced inad- and it will be some has a rigorous pro- veitently into a culttire of living cells and time—if ever—before gram of cell-line au- becomes a resident of that culture, either that hole in the fence thentication. Doing so coexisting or entirely replacing the original gets closed.” trom the Cel! Line Authentication Global Awareness Initiative does not absolve the website: 4ittp://cellid.cua.edu> line. Contamination from bacteria, yeast, He noted that the investigator, however, and other invaders is also problematic, FDA has a requirement for cell-line au- of the responsibility to confirm indepen- but for the most part researchers know thentication as a condition for drug ap- dently and monitor authenticity as experi- how to identify or prevent this kind of proval. NIH, he said, has a different cul- mental use of the cells continues. contamination. ture and feels such an approach would Nardone lists various techniques for au- “We are fundamentally in agreement be dogmatic. thentication, such as karyotyping, iso- that misidentified and contaminated cul- NIH Director Elias Zerhouni has since enzyme profiling (developed by Stephen tures constitute a serious, ongoing prob- tasked Nardone with bringing together a O’Brien of NCI), and DNA fingeiprinting, lem,” said Michael Gottesman, deputy diverse group of scientists, scientific soci- in his white paper entitled “Eradication director for intramural research. “What is eties, grant reviewers, and scientific pub- of Cross-Contaminated Cell Lines: A Call debated is how to best eliminate it.” lishers to establish a consensus policy. for Action,” now published in Cell Biol- The NIH intramural and extramural pro- Nardone leads a campaign started in the ogy and Toxicology and posted at grams have stopped short of mandating 1960s by Walter Nelson-Rees, a biologist
11 The NIH Catalyst
From OITE patent and grant directors, scientific consult- Career Symposium on Tap ants, medical directors of pharmaceutical companies, and university professors. On Tenure Track '^he First Annual NIH Career Symposium Skills workshops will address networking, X will be held Wednesday, April 9, 2008, leadership, and work-life balance. There will from 7:30 a.m. to 5:00 p.m. in the Natcher be ample time during lunch and at a recep- Conference Center. tion after the event to interact with speakers Organized by the Office of Intramural (and practice networking skills). Training and Education (OITE), in collabo- The career symposium also marks the of- ration with the Graduate Student Council, ficial opening of the Career Services Center NIH Fellows Committee, and the Founda- in the OITE. The center has been in opera- tion for Advanced Education in the Sci- tion for several months (see Tlje NIH Cata- ences, the symposium aims to provide NIH lyst, Jan.-Feb. 2008) and is staffed by pro-
trainees with solid information about ca- fessional career counselors. It provides guid- reer options across science and medicine ance on career directions, options, and self- and the opportunity to network with es- evaluation, as well as assistance with inter- tablished professionals in these fields. viewing, networking, and CV and resume Christopher Wanjek There will be 15 panel sessions—on sci- development. Rajat Varma entific writing, education, grants adminis- All trainees and mentors are encouraged Rajat Varma, head of the new T-Cell tration, public policy, clinical job options, to attend the symposium. For more infor- Biophysics Unit in NIAID’s of research-intensive careers, and careers mation or to register, visit the OITE website: Laboratory away from the bench. Panel speakers in-
Recently Tenured
Sanjay A. Desai received M.D. and pore, must also contribute to Na^ ex- Lmmunoepidemiology Branch. NCI. Ph.D. degreesfrom Wasbingto)! Univer- clusion. As an epidemiologist in NCI’s Division sity Medical School in St. Louis in 1992. PSAC’s strict conservation in all plas- of Cancer Epidemiology and Genetics,
After an internal medicine residency modia suggests it may be a target for my research focuses on the role of in- and infectious diseases fellowship at antimalarial development. To test this fection, immunity, and inflammation in Duke U)iiversity Medical Center, in hypothesis, we found high-affinity PSAC the etiology of cancer. This work is Durham, N.C., hejoined the Laboratory antagonists through high-throughput grounded in my long-standing clinical ofMalaria and Vector Research, NLALD, screening with a quantitative transmit- interest in HIV and other infectious dis- in 1998. He is currejitly a senior i)ivesti- tance-based assay developed by my eases and in a keen appreciation for gator and chief of the Molecular Ph ysi- group. These antagonists sterilize in quantitative approaches to epidemio- ology Section. LLVIVR, NLALD. vitro parasite cultures. logic questions. My laboratoiy has focused There is also a good cor- A major component of my research on the cell biology and relation between these an- aims at improving our understanding of physiology of the malaria tagonists’ affinity for PSAC cancer among people with HIV/AIDS. parasite, Plasmodium falci- and their parasite growth in- This research uses data from my HIV/ parum. We are particularly hibitoiy concentrations, ful- AIDS Cancer Match (HACM) Study, interested in how malaria filling a classical test of tar- which links HIV/AIDS and cancer regis- parasites acquire nutrients get validation in dnig devel- tiy data from 13 U.S. regions to identify and other essential solutes opment. The Medicines for cancers arising in more than 630,000 from the human blood- Malaria Venture, a Geneva- HIV-infected people. stream. based public-private part- The HACM Study allows me to exam- While growth inside host nership that seeks to dis- ine patterns of cancer incidence that
erythrocytes facilitates eva- cover and develop new an- have direct public health relevance. I
sion of immune responses, it complicates timalarial drugs, has recognized PSAC recently used this resource to describe acquisition of nutrients from serum. as an important target and has accepted trends in cancer risk among people with Many essential nutrients are not present our project into their portfolio. AIDS over the course of the AIDS epi-
in red cell cytosol and have inadequate The second ion channel demic from 1980 to 2002. I host cell permeability to sustain para- we identified is a large con- documented substantial de- site demand. This problem had been rec- ductance channel on a spe- clines in Kaposi sarcoma and ognized for decades, but the molecular cialized membrane, the non-Hodgkin lymphoma
mechanisms used to overcome it were parasitophorous vacuolar (NHL) over time, and a steep unknown. My laboratoiy identified two membrane, surrounding the unexpected rise in Hodgkin unusual ion channels that appear to re- intraerythrocytic parasite. lymphoma risk. solve this dilemma. This channel appears to pro- My interest in cancers in One channel, the plasmodial surface vide the parasite with direct transplant recipients, another anion channel (PSAC), is present on the access to metabolic precur- immunosuppressed popula- infected eiythrocyte membrane but ab- sors in RBC cytosol and may tion, evolved from my work
sent from uninfected cells. Its unique also be a good drug target. on HIV/AIDS. I lead a major functional properties along with two Major ongoing areas of collaboration with the Health mutants we generated through in vitro investigation in the laboratoiy include Resources and Services Administration, selection strongly suggest PSAC is en- 1) identification of the genes respon- which oversees the U.S. transplant net- coded by the parasite and trafficked out sible for these and other parasite trans- work. Together we are conducting a to the host membrane. port mechanisms with molecular, ge- computerized match of U.S. transplant Striking among PSAC’s functional netic, and biochemical approaches, 2) and cancer registries.
properties is that it permits negligible functional characterization of these Our Transplant Cancer Match Study Na"' uptake despite broad permeability transport proteins with the goal of un- will obtain population-based cancer data to needed sugars, amino acids, purines, derstanding their structures and physi- on approximately half of the U.S. trans- organic cations, and some vitamins. ological roles, and 3) antimalarial drug plant population. The coupling of data This selectivity profile is unprec- discoveiy and development using novel, in the transplant registiy regarding de- edented among other ion channels; it is high-affinity PSAC antagonists. mographics, cancer-related exposures also important for parasite survival be- (for example, viral infections), and medi- cause Na* exclusion is required to main- Eric Engels received his M.D. degree cations, with detailed information from tain infected eiythrocyte osmotic stabil- from Haward Medical School in Bos- the cancer registries, will create a unique ity in plasma. ton in 1991. He trained in internal research resource. Having a We determined that a major contribu- medicine at Brigham and Women 's observed remarkably high tor to PSAC’s solute selectivity is elec- Hospital, Boston, and in infectious dis- risk for lung cancer among HIV-infected trostatic repulsion of Na’’ by cationic resi- eases at Tufts University School ofMedi- people in the United States, I questioned dues situated at the extracellular pore cine, Boston, beforejoining NCL in 1998 the common assumption that frequent mouth. The significant permeability of as a senior staffj'ellow in the Viral Epi- tobacco use entirely explains the eleva- organic cations indicates tion. I have now conducted several ret- that additional demiology Branch . He is currently a se- features, presumably acting via an as- nior investigator in that branch, re- rospective cohort studies of lung cancer yet-unidentified selectivity filter in the cently renamed the Infections and among HIV-infected persons.
13 . The NIH Catalyst People
Recently Tenured continuedfrom page 13
Using various statistical methods to Charles Rotimi received his Ph.D. de- graphical origin of most African Ameri- adjust for the effects of tobacco, each gree in epidemiology from the Univer- cans. It has expanded to include sites in I study has demonstrated that lung can- sity ofAlabama, Birmingham, in 1991. East Africa and China. j cer risk is higher in HIV-infected people He did his postdoctoral work at Loma The AADM project has enrolled more than predicted from the effects of smok- Linda (Calif) University and Loyola Uni- than 4,800 persons with diabetes and [ ing alone. We are now developing epi- versity Chicago-Stritch School of Medi- control subjects, and it is contributing j demiologic approaches to test the hy- cine in Maywood, LlL, and in 2004 be- significant data to the global effort to i pothesis that other processes, such as came the director of the National Hu- understand the genetic basis of T2D. ! inflammation, play a role in promoting man Genome Center at Howard Univer- In collaboration with colleagues in Ice- j lung damage among HIV-infected indi- sity College ofMedicine in Washington. land (deCODE Genetics), we recently |
viduals. In several other studies, I am Hejoined NHGLU in late November 2007 identified three genes that are likely to i currently evaluating chronic Chlamydia as the first director of the new NLH In- play a major role in the risk of getting i pneumoniae infection, pulmonary scar- tramural Center for Genomics and diabetes. I ring, and pneumonia and tuberculosis Health Disparities. The first gene, j as risk factors for lung cancer. Research activities called TCF7L2, is j My interest in NHL also stems from in my laboratory are arguably the most \ the high risk seen in people with HIV/ directed at under- important gene i AIDS, as well as my belief that other standing the patterns identified for diabe- | infections and immune-related condi- and determinants of tes to date and was tions are important. Building on my prior common diseases in identified using the ! work on the epidemiology of human populations of the genome-wide asso-
j herpesvirus 8 (HHV8), I described the African Diaspora, ciation strategy in- ; first volving thousands case of an HHV8-positive NHL in with particular focus |
Africa. I also conducted a large retro- on the triangular re- of persons with dia-
j spective cohort study of hepatitis C vi- lationship between betes and control rus (HCV) and risk of lymphopro- obesity, hyperten- subjects. I liferative malignancies in U.S. militaiy sion, and type 2 dia- The second gene,
| veterans. This study showed an asso- betes (T2D). Charles Rotirni called CDKALl. in- j ciation with NHL and, for the first time, Recent African-ori- tluences insulin re- j an increased risk for the related malig- gin populations provide unique oppor- sponse. Persons who have two copies j nancy Waldenstrom macroglobulinemia. tunities to study how “old” genes inter- of this gene have a blunted insulin re- | Finally, my official duties include work act with “new” environments in the evo- sponse compared with those who carry | as a physician in the Johns Hopkins Hos- lution of common complex diseases. only one copy or are noncarriers. ! pital HIV clinic in Baltimore, where I Taking advantage of the huge contrast The third gene, TCF2 (HNFlb), asso- j attend for one full day eveiy two weeks. in the distribution of risk factors at the ciated with increased prostate cancer l
Most of my patients there have com- genetic and environmental levels in con- risk, may confer protection against ! plex medical problems, such as HCV- temporary African populations, my lab T2D—an important finding that may ! help us understand the inverse relation- related liver disease and tobacco-in- uses genetic epidemiology and popula- j duced lung disease, compounded by tion genetics models to study the cleter- ship previously observed between the '
‘ such social problems as substance minants of obesity, hypertension, dia- risk of diabetes and prostate cancer and treatment abuse, poverty, and homelessness. betes, and associated complications. that may have prevention and !
It has been rewarding to follow these We are particularly interested in gen- implications. ! patients over an extended period of time erating data to explain phenomena such Research resources available through and to see the beneficial effects of HIV as the “thrifty genotype” hypothesis, the AADM project have facilitated mul- therapy advances. This work provides which postulates that some genes in tiple international collaborations, includ- the opportunity to use my clinical skills humans have evolved to maximize ing; 1) an ongoing project in Joan to help an undersei-ved population, and metabolic efficiency—as reflected, for Marini's lab at NICHD on the genetic it motivates and grounds my research instance, in lipid storage and food- basis of osteogenesis imperfecta caused activities. searching behavior—and that in times by mutation in the LEFLLEl gene; 2) a of abundance, these genes predispose genome-wide association study of hy- Patent Law/Tech Transfer IG their carriers to diseases caused by ex- pertension in African populations in Ri- chard Cooper’s lab at Loyola University new interest group focused on patent law cess nutritional intake, such as obesity in Chicago; a study of the genetics of Aand technology transfer is hoping to attract and T2D. 3) individuals currently at the NIH Office of Tech- My lab is leading an international team Bardet-Biedl syndrome in African pa- nology Transfer, bench scientists with interests of investigators to understand how in- tients—the role of novel mutations in in intellectual property, and former fellows who herited factors in combination with the BBSS gene; and 4) the population have transitioned into related careers in local lifestyle increase the risk of or resistance genetics of the hypeiwariable region of companies. The group will hold seminars with project the mtDNA. invitees from the U.S. Patent and Trademark to T2D. The name of this novel Office, law firms, and biotechnology and phar- is “Africa America Diabetes Mellitus In collaboration with investigators at maceutical companies. Contact Cameron Good (AADM, pronounced Adam) Study.” It the Coriell Institute for Medical Research
14 a March — April 2008
Array 6.0 with 1.8 million genetic mark- to engage African researchers, and other lab and attract minority and African stu- ers to perform the first genome-wide as- researchers interested in Africa, in ge- dents and investigators to multiple labs sociation scan of an African American nomic research. at NIH.
cohort to search for genes associated Since its inception the society has pro- Finally, I believe that scientific activi- with obesity, hypertension, diabetes, and vided a forum for African scientists and ties operate within the larger context of the metabolic syndrome. students to interact and exchange infor- societies and that the junction of soci- The more than 2,000 related and un- mation in the field of genomic research. ety and science constantly has to be related African Americans included in In collaboration with scientists from managed so as not to trample on the this study were enrolled and examined Ethiopia, the United Kingdom, and the independence required for good schol- by my lab. United States, my lab is in- arly investigation or to In collaboration with Julie Palmer of volved in a Wellcome Trust- alienate members of soci- Boston University, my lab is participat- funded project to understand eties from the scientific pro- ing in the Black Women Heart Study— the genetic basis of cess. national longitudinal cohort of women podoconiosis. In this regard, my lab is assembled in 1995 to study causes of A model for gene-environ- interested in how scientists illness in black women. It includes ment interactions, podocon- document and describe the 59,000 women aged 21-69 at baseline. iosis (endemic nonfilarial el- nonrandom pattern of hu- My lab has been responsible for receiv- ephantiasis) is a geochemi- man genetic variation and ing, isolating, and tracking DNA samples cal disease occurring in indi- its link to disease risks in Lower legs ofpatient from more than 25,000 women. This is different populations. For viduals exposed to red clay with podoconiosis in bis a national resource that is making sig- soil derived from alkalic vol- 20s, showing asymmet- example, how does human nificant contribution to our understand- canic rock. One of the strik- ric nodular disease genetic variation inform our ing of major health outcomes (for ex- ing features of podoconiosis understanding of self and ample, diabetes and lupus) in women, is that only a small proportion of indi- group identity and differential distribu- with special focus on African American viduals who are exposed to red clay de- tion of diseases? We are directly involved women. velop disease. Investigators involved in in these debates and hope to inform the
I am the founding and current presi- this project met under the umbrella of interpretation of human genetic varia- dent of the African Society of Human the AfSHG, and I anticipate that AfSHG tion within the context of health dispari- Genetics (AfSHG), which was formed will provide a wonderful forum for my ties and group identity.
Visiting Fellows Expo NIHVFC presents he fifth international exposition for NIH visiting fellows will be held T Thursday, May 15, 2008, at the Natcher Auditorium. The expo is organized by the NIH Visiting Fellows Committee, which International Opportunities has sent invitations to 38 embassies and 12 companies and welcomes the attendance of the 2,821 visiting fellows currently on campus. Expo 2008 Steven Buchsbaum, senior technology strategy officer for global health discoveries, of the Bill & Melinda Gates Foundation, will speak from 11 a.m. to noon, after which the expo will follow from noon to 4:00 p.m. For more info, visit the Visiting Fellows Committee website:
Foreign Scientists at NIH by Country*
Algeria, 1 Cyprus, 1 Iran, 4 Norway, 9 Argentina, 34 Czech Republic, 17 Ireland, 19 Pakistan, 3 Armenia, 2 Denmark, 14 Israel, 75 Panama, 1 Australia 28 Dominican Republic, 1 Italy, 145 Peru, 8 Austria, 13 Ecuador, 2 Japan, 319 Philippines, 6 Azerbaijan, 1 Egypt, 5 Jordan, 3 Poland, 33 Date: May 2008 Bangladesh, 9 Estonia, 1 Kazakhastan, 1 Portugal, 5 Barbados, 1 Ethiopia, 3 Kenya, 3 Romania, 14 Time: 12:00 noon-4:00 p.m. Belams, 2 Fiji, 1 Korea, 260 Russia, 85 Venue: Natcher Belgium, 11 Serbia and Finland, 6 Kyrgizstan, 1 Bethesda campus Bldg. 45 Bolivia, 1 France, 116 Lebanon, 7 Montenegro, 1 Brazil, 40 Georgia, 1 Madagascar, 1 Singapore, 6 Bulgaria, 6 Germany, Federal Malaysia, 4 Slovak Republic, Burkina Faso, 2 Republic of, 109 Mali, 2 14 Cameroon, 1 Ghana, 2 Mexico, 23 Slovenia, 2 Taiwan, 43 Venezuela, 3 Canada, 101 Greece, 28 Mongolia, 6 South Africa, 7 Thailand, 17 Vietnam, 2 Chile, 15 Hong Kong SAR, 22 Morocco, 2 Spain, 45 Tunisia, 4 West Bank, 1 Sri Lanka, China (People’s Hungary, 27 Nepal, 2 5 Turkey, 18 Total active = 2,821 Republic), Sweden, 27 495 Iceland, 1 Netherlands, 22 Ukraine, 12 * as of September 24, 2007 Colombia, 7 India, 303 New Zealand, 8 Switzerland, 11 United Kingdom, 91 Source: Division of International Cuba, 1 Indonesia, 4 Nigeria, 3 Syria, 1 Uruguay, 2 Services, NIH
15 The NIH Catalyst
Catalytic • • • Want to hear sot^e^hlf)^* Reactions? ey! Hey!! Please put those headphones down for just a minute and lis- H ten. Thank you. What? You can't hear me so well because the music was loud and your ears are ringing? Just give it a few minutes and read a f you have a photo or — little bit about the ear in the meantime. I other graphic that Our ears are complex, sensitive, and capable (in theory, if in practice) reflects an aspect of life at not NIH (including, laboratory of detecting sound signals that are very low or very high in both tone and life) or a quotation that intensity. scientists might appreciate The terms “tone,” “frequency,” and even “pitch” are sometimes used interchangeably. Someone that would be fit to print in like your little sister most likely has a high voice—a high-frequency voice. Your dad's is usually the space to the right, why much, much lower. If you ask someone to play 440 hertz (or Hz, the unit frequencies are not send it to us via e- measured in), they'll stroll over to a piano and hit the A above middle C—the audio frequency mail: [email protected]>; reference. Your sister's voice is much higher than that. fax:402-4303; or maU: “Intensity” is how loud something is, measured in decibels. The intensity of parents quietly Budding 2, Room 2E26. plotting where to hide your present is about 20 decibels (or clB, the unit used to measure loudness). That music you were just listening to is 80-100 dB—or more. No wonder your ears Also, we welcome hurt. “letters to the editor” for As a side note, how much louder is 80 dB than 20 clB? You get to look that one up yourself, publication and your but a hint for you is that it's probably not what you think. Then you can also look up dB “sound reactions to anything on intensity levels” versus "clB sound power levels”—and teach me about it! the Catalyst pages. The normal tone range of the human ear is 20-20,000 Hz. Actually, we're exposed to more
than 20,000 Hz all of the time, we just don't hear it (so that's okay). Not so with decibels: If
In Future Issues... you're listening to something louder than 85 dB for a long time, it can cause gradual hearing loss, and more than 110 dB for more than a minute may bring permanent hearing loss. H Framingham’s New Home So if you want to keep on enjoying the ability to hear soft conversations about where gifts for you are hidden, you might want to turn the music down. It's good for your snooping future. I know it's not so easy. After all, headphones are great because you hear what no one else hears Copyright Issues and no one is asking you to turn the noise down in the middle of the night.. But though others may not be bothered by your loud music, you will be when you just can't quite make out what ^ Seciuencing people are whispering about. The Microbiome For more information about the ear, how to protect it, and much more, go to
Managing Editor
77?e NIH Catalyst is pub- Publisher Fran Pollner Editorial Advisory Board lished bimonthly for and by Michael Gottesman David Davies, NIDDK the intramural scientists at Depury Director Wriitr-Editor Dale Graham, CIT NIH. Address correspon- for Intramural Research, OD Christopher Wanjek Elise Kohn, NCI dence to Building 2, Room Director of Communications, OIR Susan Leitman, CC 2E26, NIH, Bethesda, MD Editor,s Bernard Moss, NIAID
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