Fostering Communication and Collaboration
The nihCatalyst A Publication for NIH Intramural Scientists
National Institutes of Health ^Office of the Director* Volume 14, Issue 3b May - June 200 6
Building i i Dedicated May 2 VRC Celebrates 5th Biodefense and Emerging Infectious Diseases Moving Vaccinology Research Building Readied for Prime Time From Basic Science To Global Human Trials
by Fran Pollner
VRC Director Gary Nabel Ernie Branson
y the tender age of five, the On Deck: (left to right) Rep. C.W. Bill Young (R -Fla.), for whom the new building is VRC had launched 14 clinical named, is joined by NIH Director Elias Zerhouni and NIAID Director Anthony Fauci B vaccine trials and generated 14 alongside the Building 33 commemorative plaque, which reads: clinical-grade vaccines that entailed “By Act of Congress This Building is Dedicated as the 31 vaccine runs, one for each of the C.W. Bill Young Center Hoe C. Bill Center Emerging Infectious Diseases is thefirst individual components of the tested W. Young for Biodefense and NIHfacility to focus exclusively on the challenge biodefense and research on new or re- vaccines. of emerging infectious diseases that pose significant public health risks. Representative Eight of the vaccines were anti-HIV Young’s service in the U.S. Congressfor more than 35 years includes six years as Chair- candidates, and the other six were man of the House Comm ittee on Appropriations, two separate terms as chairman of the targeted against the likes of the Subcommittee on Defense, eight years as Chairman of the Health Appropriations Subcom- Ebola, West Nile, and SARS viruses, mittee, and 14 years on the House Permanent Select Committee on Intelligence. Founder VRC Director Gary Nabel recounted of the national registry of bone marrow donors, Representative Young has been tenacious as he took stock of the VRC’s ac- in his support ofpatients and scientists, the biomedical research enterprise, and all those complishments and the road ahead who defend the Nation. Dedicated 2006" on the occasion of the center’s fifth May anniversary. he vision of the building dedicated The science does not turn on whether That disease breakdown reflects on the NIH campus in May 2006 the involved pathogens “are naturally the VRC’s original and continuing T started taking shape in the fall of continued on page 3 focus on HIV and AIDS, as well as 2001—it rose from incinerated buildings CONTENTS its early, logical expansion into re- and powdery envelopes in the New York lated emerging challenges. and Washington, D.C., areas. 1 8-9 Commemoratives: GPP Posters: The scope of VRC activities also Accelerating research to defend against NIAID’s Building 33 Lung Cancer reflects the concept behind its cre- bioterrorism was a driving force behind a VRC’s 5th Chemoprevention? ation—to house in one facility the the concept of Building 33- is Alcohol & the Brain 4-5 and physical resources to But its development like that the human — of NCCAM Fellows 10-11 develop vaccines from start to fin- NIAID biodefense research agenda and Building Bridges Recently Tenured/ ish, from basic research to vaccine strategic plan, issued in early 2002—was Performance Ratings 6-7 production and clinical trials, ob- firmly grounded in the context of emerg- Bench-to-Bedside: 12 continued on page 2 ing and re-emerging infectious diseases. b Pain Vanquisher Spring Break VRC’s Fifth continuedfrom page 1
served NIAID Director Anthony Fauci, who triggered the memories of the assembled cel- ebrants with a bit of VRC history. Homing in on AIDS vaccinology, Nabel dis- cussed the details of the VRC’s recent ad-
vance into Phase II clinical testing of its multigene, multiclade DNA-prime/adenovi- rus-boost AIDS vaccine. The six-plasmid construct contains versions of HIV genes gag, pol and as well as , nef three modified env genes, one from each of clades A, B, and C. Designed to cover the major subtypes found throughout the world, the vaccine will be tested at sites in the United States, Brazil, Haiti, Jamaica, Botswana, and South Africa.* Each component underwent testing alone and in combination in the DNA construct, in the adenovirus vector, and then in the prime- boost sequence. “The DNA-adenovirus plat-
Bill Branson The Dawn of Creation: NIAID Director Anthony Fauci (right) traces the beginnings of the VRC to December 1996, when he and then-NlH Director Harold Varmus were invited to the Oval Office to explain HIV science to President Bill Clinton and Vice President Al Gore Hoe historical photo shows Fauci describing the CCR5 receptor to Clinton (right) and Gore (left), with Varmus (far left) looking on. By the end of the session, Fauci quipped, “Vice President Gore was wondering whether he had " actually discovered the CCR5 receptor —and Clinton was convinced of the need to create a center that would encompass all aspects ofdeveloping an AIDS vaccine, from basic research through vaccine production. It wasfive months later, in May 1997, that Clinton announced that the \7RC was on the drawing board. Bill Branson Engineering Immunity: Two of the guest speakers—Stephen Harrison (left), Howard Hughes investigator and Harvard structural biologist, and David Baltimore, president of the Californ ia Institute of Technology in Pasadena, discussed strategies to bring neutralizing antibodies to bear against HIV,
a quest \ RC Director Gary Nabel called the Holy Grail" ofAIDS vaccine development
form proved to be an effective immunogen in humans, which we did not know before,” Nabel said, noting that the prime-boost re- sponse is “greater than the sum of its parts.” Eliciting broadly neutralizing antibodies
remains a challenge, which is being addressed in ever more sophisticated ways, he said. Another global priority, Fauci noted, is to develop a vaccine that would obviate the need to reconstruct the flu vaccine each year. Such a universal vaccine for seasonal, or stan- dard, flu would also obviate the need to re- spond in a crisis manner to potential pan- demic flu, he observed.
Bill Branson
* Harmonic Convergence: (left to right): VRC Director Gary Nabel; Pontiano Kaleebu, The VRC vaccine is also being tested by the Interna- tional AIDS Vaccine Initiative in Phase I studies in Kenya assistant director of the Uganda Virus Research Institute, Entebbe, and president of the and Rwanda and by the U.S. Military HIV Research WHO AIDS vaccine program Viral Pathogenesis Laboratory ; Barney Graham, chief. Program in Phase I and II studies in Uganda, Kenya, and Clinical Trials Core, VRC; and Stanley Plotkin, world-renowned vaccinologist and Tanzania. 2 May — June 2006
Building 33 Dedication
continuedfrom page 1
occurring or deliberately perpetrated,” NIAID Director Anthony Fauci observed in a speech during the cer- emony to dedicate the brick, glass, and steel structure where that research will now be concentrated. The new facility, Fauci noted, will enable the “gather- ing under one roof of a critical mass of researchers cur- rently scattered in many buildings around this campus,” whose work with a variety of respiratory viruses and bacteria will benefit from the “creative synergies” fos- tered by the new infrastructure. The building houses animal care-areas, conference rooms, offices, and biosafety level 2 and 3 laborato- ries—adding another 14,300 square foot of BSL-3 lab space to NIAID’s current 4,700 square feet. Researchers
Fran Pollner
The latest addition to the NIH research complex, Building 33 will house about 250 laboratory, administrative, and support staff within its four Ernie Branson stories and 12 intramural research laboratories. Construction was begun Building 33, NIH Director Elias Zerhouni in November 2003 and completed in December 2005: move-in is antici-
noted with pride, emerged “on time, on pated throughout the summer of2006. budget ” but obstacles to , had overcome, not the least of wh ich was the concern of the surrounding Bethesda community about potential environmental risks. Detailed explanations of the building's design, security, and safeguards were not quite convincing enough, Zerhouni recalled. "But then I told them that I guarantee that Tony Fauci will have his office right in the middle of that building—and that won the clay!" working in the BSL-3 labs will wear special protective equipment and receive specialized training in state-of- the-art techniques for handling BSL-3 pathogens. The new center will consolidate and expand NIAID’s existing research programs on Respiratory viruses (such as influenza and avian flu) Respiratory bacteria, such as multidrug-resistant TB and anthrax) a Insect-borne viruses (such as West Nile and dengue) B Immunology of infectious diseases
B Development of vaccines for infectious diseases Bill Branson program focusing innate immunity will also A new on Flanked by NIAID Director Anthony Fauci and NIH Director Elias be established in Building Fauci noted that patho- 33. Zerhouni, Rep. C.W. Bill Young receives gifts ofgratitudefor his “unwa- gens requiring BSL-4 facilities will not be studied in the vering supportfor biomedical research’’-—an artist’s rendering ofBuilding new center. 33 and a certificate commemorating the day’s event —Fran Pollner 3 The NIH Catalyst
New NCCAM Fellows To Create Bridge Between CAM and Conventional Research by LeiknyJohnson, NCCAM
Fran Pollner The Upside of Three on a Match: NCCAMfellow Marni Silverman (center) and her two mentors, NIMH's Esther Sternberg and NCCAM’s ” Patrick Mansky. “Marni, ’’says Sternberg, “is the glue between us.
he first two winners of the NCCAM research projects: One explores the re- (GR); the other explores the effects of Director’s Fellowship have been lationship of glucocorticoid resistance tai chi on the quality of life of cancer Tnamed: Marni Silverman, whose and inflammation vulnerability to genetic survivors. doctorate is in neuroscience, has already variants in the glucocorticoid receptor Glucocorticoids such as cortisol are arrived at NIH, and Patrick McCue, whose degree is in molecular and cel- lular biology, is due in July. Fellowship Promotes Silverman began work at NIH in Feb- Evidence-based CAMaraderie ruary after receiving her Ph.D. in neu- roscience from Emory University in omplementary and alternative medicine (CAM ) is used by 36 percent Atlanta. C of American adults to treat a spectrum of diseases and conditions. Her motivation in applying for the Because of the breadth of health conditions for which CAM is used, fellowship, NCCAM she says, was to ex- NCCAM has collaborated in its research efforts with many of the NIH amine the “physiological and molecular institutes and centers (ICs). mechanisms by which CAM therapies, Recently, NCCAM created a new collaborative program—the NCCAM or mind-body interventions, are effec- Director's Fellowship—to promote the training of promising young CAM tive in alleviating depressive symptoma- investigators by supporting their work in the intramural laboratories of tology in the medically ill.” senior scientists in other ICs. Ultimately, the fellows will serve as a bridge She is based in the lab of Esther between their mentor’s laboratory and NCCAM. Sternberg, head of the Section on Neu- The fellowship, says NCCAM Director Stephen Straus, “exemplifies our roendocrine Immunology and Behavior, approach to promoting the integration of evidence-based CAM practices NIMH. Her selection in the NCCAM com- into conventional biomedicine.” petition based not only her was on own It also provides an innovative means through which NCCAM can re- qualifications and the nature of the pro- cruit and train the next generation of CAM researchers, he observes, posed research but also on the noting that the program has gained wide support throughout NIH. That capabilites and relevance of the lab she support has been rewarded, he observes, by the “excellence” of the designated as her desired base. “There program’s inaugural awardees— Marni Silverman and Patrick McCue. had to be a good match between the The fellowship provides full research support for two years of clinical, postdoctoral fellow and the lab,” translational, and/or laboratory research. It is funded by NCCAM in part- Sternberg notes. nership with the Prince of Wales Foundation through the Foundation for the NIH. The Cortisol Connection —Leikny Johnso n Silverman’s fellowship comprises two
4 — May — June 2006
the brain’s messen- studying the efficacy of Tai Chi versus gers in mediating the moderate exercise to reduce stress and body’s stress re- improve metabolic parameters and sponse and are po- physical and psychological well-being tent modulators of in adult cancer survivors. the immune system, The NCCAM Director’s Fellowship Silverman notes. served as the vehicle for the first col- “Intriguingly,” she laborative contact between Mansky and says, “we can study Sternberg. Without that vehicle, Stern- both ends of the berg observes, this valuable exploration workings of cortisol, might have been viewed as a diversion from the [mecha- of lab resources. nisms by which] cells receive the cortisol Botanical Extracts signal to the effect of And Cancer Prevention tai chi on cortisol lev- McCue received his Ph.D. in molecu- els.” lar and cellular biology from the Uni- Noting that her dis- versity of Massachusetts at Amherst and sertation centered on neuroendocrine- lated diseases, such as asthma and rheu- is currently at the Genome Research Fa- immune interactions—cytokine activa- matoid arthritis. cility at the NASA Ames Research Cen- tion of glucocorticoid responses This research might also shed light on ter, Moffett Field, Calif., where he is in- Silverman says she is eager to piece to- reasons for individual differences in re- vestigating herbal antioxidants as coun- gether the genetic component of this dy- sponsiveness to CAM therapies, Silver- termeasures for radiation injury. namic and the related behavioral inter- man says. In July, he will be joining the Labora- ventions that can have a clinical effect. tory of Comparative Carcinogenesis, The project, observes Sternberg, “ful- A Step Beyond Cancer Survival: NCI-FCRDC, where he will work with fills both objectives” of the NCCAM Comparing Tai Chi James Phang, who heads the Metabo- director’s fellowship—“basic research And Physical Exercise lism and Cancer Susceptibility Section. relevant to the [patient-care] issue and In her second project, Silverman plans When asked what attracted him to clinical research central to the issue.” to explore changes in neuroimmune CAM research, McCue pointed to the In the basic-research project, markers in cancer survivors practicing a “challenge of applying cutting-edge re- Silverman is hoping to substantiate a role mind-body intervention such as tai chi search techniques to the study of CAM for genetic variants of GR in the sus- compared to physical exercise. modalities” and contributing to a science- ceptibility to inflammatory syndromes For this project, she is collaborating based perspective that generates a bet- that could be extended to immune-re- with NCCAM’s Patrick Mansky, who is ter understanding of how such thera- pies work. He plans to investigate the chemopre- ventive mechanisms of action of botani- cal extracts against cancer cells using a functional genomic approach. The underlying hypothesis is that phe- nolic antioxidants in the extracts may promote apoptosis by modulating the link between the proline and pentose phosphate pathways. He will enlist high-throughput tech- nologies, high-density DNA microarrays, computational biology, and bioinfor- matics in the investigation of this hy- pothesis.
or more information about the F NCCAM Director’s Fellowship, Fran Pollner see Good Fellowship: (left to right): Patrick Mansky, NCCAM clinician: Marni 5 The NIH Catalyst Bench-to-Bedside Journey to Morocco Novel Strategy to Vanquish Intractable Cancer Pain: Resiniferatoxin At Threshold of Clinical Trial by Karen Ross out of the equation,” says intracellular storage compartments. Mannes. Within an hour of exposure to RTX, Opioids work by binding to neurons expressing TRPV1 die, and they receptors on pain-sensitive do not grow back. Cells that do not ex- neurons and inhibiting trans- press TRPV1 are unaffected. Only a few mission of pain signals to the types of neurons in the body express brain. However, animals have TRPV1, so the effects of RTX treatment evolved to remain sensitive to are quite specific. pain as long as the tissue in- The cell bodies of TRPVI -positive neu- jury remains and the pain- rons are found in the dorsal root gan- sensing neurons are intact. “If glion, and their nerve endings are in the [the painful stimulus] is still skin, where they respond to sensations happening at the periphery, it’s of moderate heat, and in the internal going to get through the spi- organs, where, importantly, they appear nal cord and up to the brain to be the main mediators of cancer and one way or another,” says inflammatory pain. Iadarola. With long-term use, opioids Early Findings gradually lose their effective- Iadarola and his colleagues have long ness and patients need pro- been interested in clinical treatments for gressively higher doses to get severe pain and in the basic science pain relief. behind the sensory detection of painful Karen Ross stimuli (nociception) and the transmis- Michael Iadarola Killing the Messenger sion of pain signals to the brain. (Pain In contrast, RTX is a non- in humans is a combination of ichael Iadarola, chief of the Neu- opioid, nonaddictive analgesic that nociception and higher-order sensory, robiology and Pain Therapeu- works by selectively killing the neurons psychological, and emotional re- M tics Section, NIDCR, and anes- that are responsible for cancer pain sponses.) Their experience in both of thesiologist Andrew Mannes, who works while leaving other neurons intact. RTX, these areas put them in an ideal posi- both in Iadarola’s laboratory and in the explains Iadarola, “is like a molecular tion to recognize the potential of RTX Clinical Center, are leading an effort to scalpel.” for pain relief. bring a new pain-relieving drug, called RTX is a naturally occurring substance On the clinical side, they were already resiniferatoxin or RTX, to the clinic. found in a species of a Moroccan cac- testing strategies for specifically killing RTX is intended for patients with ad- tus-like succulant plant. People have pain neurons. On the basic-science side, vanced cancer whose pain is not allevi- used latex from this cactus for topical they were interested in TRPVl’s role in ated by morphine or other currently pain relief and other medicinal purposes the early stages of nociception. available drugs. It is almost ready for a for thousands of years. Phase I clinical trial, thanks in part to The molecular structure of Iadarola’s 2001 Bench-to-Bedside Award RTX resembles that of capsai- that funded critical parts of the transla- cin, the active ingredient in tional work. 1 hot peppers. 2 RTX and cap- saicin both bind to the same Opioids and Cancer Pain neuronal receptor, an ion Patients with advanced cancer often channel called TRPV1 or the experience severe pain. Many, but not vanilloid receptor-1, but RTX all, patients can control their pain with binds 500 to 1,000 times as high doses of morphine and other opio- tightly. ids—but at the cost of a host of debili- Capsaicin binding causes tating side effects, including impaired the TRPV1 channel to open consciousness, nausea, vomiting, and briefly, allowing a limited constipation. And for patients who do amount of calcium and so- not get relief from morphine, there are dium ions to flow into the cell not a lot of options. and generating the burning Iadarola estimates that there are cur- sensation associated with eat- rently 50,000-100,000 cancer patients ing hot peppers. RTX, in con- who either cannot control their pain or trast, holds the channel wide have a dismal quality of life because of open for a long time, flood- the side effects of their pain medication. ing the cell with a toxic level Iadarola and Mannes hope that their of calcium ions. It can also Fran Pollner novel strategy for pain relief can help cross the plasma membrane A ndrew Mamies this population. “We want to take pain and release calcium ions from 6 May— June 2006 In an effort to better understand sig- macotherapies and Medical Conse- tion—informs their very best guess that naling through the TRPV1 receptor, quences of Drug Abuse at NIDA, who the drug will also be safe and effective Zoltan Olah and Laszlo Karai, scientists has extensive experience with the FDA’s in patients with heretofore severe intrac- then in Iadarola’s lab, treated cells that procedures and requirements for new table pain. 51 expressed a fluorescently labeled form drugs, says Iadarola. In this realm “defi- of TRPV1 with RTX and examined them nitions of words [such as “impurity"] are Footnotes under the microscope. To their amaze- a little bit different from the way we 1 . The Bench-to-Bedside program ment, the cells underwent a dramatic normally think of them,” he says. funded some of the initial animal death. These studies “gave us the in- After some false starts, the group now work, the purchase of the initial Eu- sight” into how RTX could work as a has a batch of RTX that qualifies for use phorbia resinifera latex from Mo- painkiller, says Iadarola. in humans. Their clinical protocol is also rocco, and the costs of drug purifi- After completing studies in rats that well on its way, awaiting final approval cation to meet FDA regulatory suggested that RTX was effective at re- from the NCI’s Institutional Review guidelines. Additional funding came ducing pain, Iadarola’s lab teamed up Board. front Iadarola’s laboratory budget with Dorothy Cimino-Brown, a veteri- They expect to begin toxicology stud- and, importantly, from the NIDA narian at the University of Pennsylvania ies in the animals this summer, and if all division headed by Frank Vocci, with in Philadelphia, to try RTX as a pain re- goes well they will to a Phase move on which the Iadarola lab collaborated liever in dogs with naturally occurring I clinical trial in humans. Mannes is the in preparing the drug for toxicologic bone cancer. PI and Iadarola the associate PI on the studies. protocol, entitled “A Phase 1 study of 2. The fact that RTX is a capsaicin Preempting Euthanasia in Dogs the intrathecal administration of resin- analog was discovered in unrelated The dogs enrolled in the study had iferatoxin for treating severe refractory research by NCI’s Peter Blumberg severe pain that was not well controlled pain associated with advanced cancer.” (see The NIH Catalyst, March-April by available analgesic medications, and They plan to enroll patients at NIH 1997, “The Capsaicin Story: Some their owners were considering euthaniz- who have advanced cancer and are no Like It Hot”). Blumberg was work- ing them. They received a single injec- longer seeking curative therapy. Al- ing with tumor-promoting phorbol tion of RTX into the fluid around the though the purpose of the Phase I trial esters and found that the non-cap- spinal cord so the drug would bathe the is to establish the safety and optimal saicin part of RTX has structural simi- dorsal root ganglia. RTX is very painful dose of RTX, they hope that some of larity to phorbols, though it does not for the first hour or so after administra- the patients in the study will also get have tumor-promoting actions. tion, so the dogs were placed under relief from their pain. 3. In addition to the Bench-to- general anesthesia for treatment. Bedside program, the primary facili- The results were impressive. All of the A Fine Translation tator of the research, and their NIDA dogs experienced significant pain relief Iadarola emphasized the importance collaborators, Iadarola and Mannes that lasted for the rest of their lives. One of having a supportive environment in cite the Pharmaceutical Develop- dog that had only walked on three legs which to do translational research. 3 Stud- ment Section of the NIH Pharmacy, due to pain a large his ies that are essential to preparing a drug from tumor on run by George Grimes, and the NCI foreleg the clinic are not the of re- trotted almost normally through for types Protocol Review and Monitoring the clinic with his tail wagging several search that are rewarded by the basic- Committee and the NCI IRB for their weeks after treatment. Moreover, science community, he says. Iadarola RTX help with issues related to cere- did not negatively affect locomotion, co- praised the members of his laboratory brospinal fluid volume in humans, ordination, bowel and bladder function, for their independence and their ability starting-dose justification in extrapo- or behavior in any of the animals. to advance the lab’s basic-science lating from animals, and dose esca- Encouraged by the results in dogs, projects while he was busy with tasks lation. Iadarola and Mannes are currently de- such as importing 40 liters of cactus resin 4. The team worked with Ahmed veloping for testing in humans, from Morocco’s Atlas Mountains. 4 RTX Benharref, of the Laboratory of Natu- which has immersed them in the com- Iadarola and Mannes are cautiously ral Chemical Products at the plex and sometimes frustrating world of optimistic about RTX’s future. “There’s Universite Cadi Ayyad in Marrakech, the that if there translational medicine. a [saying] around NIH and Charles Dahan, of the United was ever a mouse or a rat that had can- States and Morocco, who handled Going the cer or pain, we’d be able to treat it,” by Book international coordination and ex- Before a drug can be used in says Mannes. While many of these seem- new port licensing. Although the plant humans, researchers must obtain a very ingly successful therapies do not live up is not endangered and the latex-col- high batch of the drug con- to their promise in humans, the investi- quality and lection procedure involves a gentle duct formal toxicology studies that meet gators observe they have reason to hope scoring of the skin surface that does the FDA’s specifications, and they must that the therapeutic effects of RTX will not damage the plant, the investi- clinical for be extrapolatable. design a protocol adminis- more gators had to secure phytosanitary tering it. The dramatic relief it afforded dogs clearances in accordance with the the first requirement, the with naturally occurring cancer the To meet team — Cooperative International Treaty on has of clinical correlate of what could be ex- relied heavily on the assistance Endangered Species. H James Terrill, of the Division of Phar- pected based on its mechanism of ac- 7 " 1 The NIH Catalyst On the Road to Doctoral Degrees: NIH Graduate Students Emerge from Their Labs To Reveal Their Recent Findings The Graduate Partnerships Program (GPP) is NIH's contribution to the training ofgraduate students who are working toward a degree in the biomedical sciences at accredited universities in the United States and abroad. The university partners provide the the degree , research advisors; provides the labs, research mentors, coursework in cases , and and, some NIH NIH and hands- on research training. Tloere are now about 3 70 students in the GPP, and that number will top 400 when the new students arrive this summer. The students come from more than 100 universities—about 62 percent based in the United States and 38 percent elsewhere. Tlje third annual GPPgraduate student research symposium tookplace May 5. Seventy-six ofthe studentspresentedposters; 1 gave talks on their research. on the basis “organization clarity, and scientific significance, ” 20 the posters were designated “finalists. "From Judged of , of this cohort, three were selected as winners (seefootnote, nextpage). Following are brief reports on two of the 76posters. Harnessing the Antitumor Effect of an Immunosuppressant For Lung Cancer Prevention “Rapamycin, an inhibitor of mTOR, decreases tobacco car- Now a fourth-year student in the cinogen-induced lung tumori- graduate genetics progra m at genesis” George Washington University in Courtney Granville, George Washington and already the holder Washington University, Wash- of a master's degree in public ington, D.C., Graduate Program health, Courtney Granville has in Genetics been working in the NCI lab of NIH research advisor: Phillip Phillip Dennis for three years, Dennis, investigator, Medical drawn there, she says, by the lab s Oncology Branch, NCI-CCR “emphasis on tobacco-related lung cancer and the environmental ranville’s research project, causes of disease in general. which was one of 14 se- Equally important is the “transla- lected for oral presentation ” G tional nature of the lab's research. at the GPP Research Symposium, Tloe science, Granville says, “is very explored further the role of tobacco- real and very applicable. ” She activated mTOR in the induction of wants to focus her career on lung cancer, as well as the inhibi- chemoprevention and can envision tion of mTOR in the prevention of working in academia or a regula- lung cancer and the amelioration tory agency. of existing tumors. The Dennis lab had previously Fran Pollner that tobacco components ac- shown Courtney Granville great caution in considering it as a tivate the Akt/mTOR pathway. preventive agent, even in heavy In the current project, the team bacco carcinogen-induced lung tumori- smokers. treated mice that had been exposed genesis depends on mTOR and that That rapamycin might be useful as to a specific tobacco carcinogen rapamycin-mediated inhibition of mTOR a cancer preventive was suggested, with rapamycin, an mTOR inhibi- prevented the development of lung le- however, in a study reported last tor that is also an immunosuppres- sions in carcinogen-exposed mice. The year: Transplant patients who re- sant approved by the FDA to pre- action of rapamycin before the emer- ceived rapamycin exhibited a de- vent post-transplantation graft re- gence of observable lesions had not pre- creased incidence of de novo ma- jection and to coat arterial stents. viously been demonstrated, Granville lignancies, compared with transplant Rapamycin works as an immu- noted. patients who had received other im- nosuppressant by squelching T-cell This ability to suppress tumorigenesis munosuppressive drugs. proliferation and function, Granville “provides a rationale to test mTOR in- Figuring out how to maximize noted; it has been studied in tumor hibitors in smokers at high risk for lung rapamycin’s antitumor effect while models and found to shrink exist- cancer,” Granville wrote in her abstract. minimizing its immunosuppressive ing tumors. She noted in an interview, however, that effect would be a worthy pursuit for In the current study, Granville the immunosuppressive action of future studies, Granville said. and her colleagues showed that to- rapamycin would necessarily inspire —Fran Pollner 8 — ) May— June 2006 Parental Alcohol Use Reflected In Brain Measurements of Adult Alcoholics “Influence of parental alcohol- unaffected parents, a find- Bel < ing not previously demon- (Rosso f 990. De volumes in alco- fiervcuj system -Mveiopmwt ism on brain «rtnrt Wefch-Carra 2005.1 «aM999: Orvy) <* a) 2001. tomHal ataWoCcs strated. Resejrcf'.ers haw suggested ihJl holics” alcoholic ejpewee 3 more severe form of alcolioSsm than aiokuI a positive Stmty hsiory Studies have shown (dal Jodi Gilman, Brown Univer- Unlike the cerebral cor- *iato>3 rave smaller train yrXi/nes than non-atayiolic cohorts oof an effect of family tefoiy on wain volumes Iras not teen oemcrsuafed Furthermore, (fic direction of causatil tex, which is subject to al- remans sity, Providence, R.I. Graduate uncertain. Toe neu/otoxic effects of alcohol on We WM1 are iSverse, causing atrophy of We cerebral cortex, wtirti mader. We toss) toreOran in cohol-induced atrophy, regions and We hmtwc system Program Neuroscience Ashman 1990. Oscar- Berman 2000, Hammer el al 2001 1 **”"*“”»*' urn. nun, m, n in „J, or is a particularly intrigu- i possible NIH research advisor: Daniel ICV pre-e»isiing volume Hommer, chief, Brain Electro- ing measure, Gilman said, (ICV) and soil Nrena ami*, (HP0) ''*eW-«r ^avy physiology and Imaging, Labo- because it reaches its per- w,a '*wfyh ratory of Clinical and Transla- manent size by about age 1s(oryof Hp0 tional Studies, NIAAA 12 to 16. Factors operating during the time between mages of the brains of alcohol- conception and puberty, ics pose general questions re- therefore—not the I garding cause and effect and individual’s alcoholism Me, hods particular questions regarding ge- would be in play. MR) lev netic versus environmental causes. “We have a lot to ral more JSS?™ *a2S**««S* vow Jodi Gilman and her NIAAA co- study,” Gilman noted, list- to ef- ing studies; workers aimed tease out the functional MRI ^ SS&a*al * cs o enis ^SM.// -"lero, fQ, l p fects of alcoholism and the influ- looking at the influence of ence of parental history on brain family history on the size structure and function in adult al- of different parts of the coholics. brain, such as the frontal Jodi Gilman Study volunteers were alcoholics lobe; looking more deeply seeking inpatient treatment at the at the cogitive and emo- Thefield of neuroscience, Gilman says, is “awe- NIH Clinical Center. Sixty-four men tional impact of family his- some. ” One of the 20 or so finalists among the 76 and 27 women had no family his- tory; analyzing the impact graduate students ivho presented posters at the GPP tory of parental alcoholism; 96 men of age at drinking onset on Graduate Student Research Symposium, Gilman is and 60 women had at least one measures; and, of course, in her second year of doctoral training at Brown heavy-drinking or alcoholic parent. “everyone is still looking University in Providence. Eventually, she says, she Using MRI, the team measured in- for genetic factors." would like to work at NIH or in academia. tracranial volume (ICV), cerebral The fact, however, that brain volume, and white and gray people have been looking for genetic too, for the physical brain findings, matter volume. factors for decades inclines Gilman to she remarked. Consistent with reported findings accord a greater role to environmental Not only does stress affect brain in previous studies, the entire co- reasons to account for why children of growth and development in animals, hort of alcoholics had smaller-than- alcoholics are at a fivefold increased risk she observed, but there are studies average brain volumes. Beyond of becoming alcoholics themselves. showing that children subjected to that, however, the alcoholics with The stress of growing up in an envi- abuse and other experiences associ- a positive family history had signifi- ronment where heavy alcohol consump- ated with post-traumatic stress disor- cantly smaller ICVs than those with tion is a fact of daily life might account, der have reduced ICVs. —Fran Pollner *At the end of the GPP poster day, three of the 76 graduate student poster presenters were declared winners. In alphabetical order, they are: m Kristina Buac, George Washington University graduateprogram in genetics, Washington, DC., “Wireless, a novel ENU- induced allele of ErbB3 gene exhibiting neural crest defects distinct from the null allele.” NIH research advisor, Bill Pavan, senior investigator, Genetic Disease Research Branch, NHGRI. » Daniel Spellman, New York University School of Medicine graduate program in structural biology, “Stable isotopic labeling of amino acids in cultured primary neuronsfor the study ofprotein turnover and neuronal signal trans- duction. ” NIH research advisor, Alfred Yergey, Head, Section on Mass Spectrometry and Metabolism, N1CHD. m Hopkins University School Public Health graduate department epidemiology), Baltimore, “Sec- Honghong Zhu , Johns of of ondhand smoke and breast cancer risk: a population-based prospective cohort study. ” NIH research advisor, Ken- neth Cantor, senior investigator, NCI-DCEG. 9 . The NIH Catalyst People Recently Tenured tion of new therapeutic approaches. portant mediator of endothelial cell Steven Libutti received his M.D. from The use of angiogenesis inhibitors in apoptosis and a common link between the College of Physicians and Surgeons the clinic has faced several challenges. the effects of several different angiogen- of Columbia University in New York, in Although the anti-VEGF antibody esis inhibitors. 1990 and completed a residency in gen- Avastin (bevacizumab) has recently been Recently, our laboratory became a part eral surgery at the Presbyterian Hospi- approved by the FDA for the treatment of the new Tumor Angiogenesis Section tal in New York in 1995. He then joined of colon cancer, many other antiangio- in the Surgery Branch, opening up new the Surgery Branch. NCI. as a clinical genic agents have shown mixed results. opportunities to better translate our find- associate and after completing his sur- This may be due, in part, to the need to ings to the clinic. We believe the next gical oncologyfellowship in 1996joined deliver such agents directly to the tu- one to two years will bring the transla- the senior staff. In 2001. he became a mor microenvironment to exert sus- tion of several new vascular-targeted tenure-track, investigator with afocus on tained paracrine effects. therapies to our patients with cancer. tumor angiogenesis and the tumor mi- We have therefore explored the use croenvironment. He is currently a senior of targeted gene therapy to deliver Xinzhuan Su received his Ph.D. in investigator and the chief of the Tumor antiangiogenic gene products to tumor parasitology from the University ofGeor- > Angiogenesis Section in the Surgery vessels. In collaboration with investiga- gia in Athens, Ga.. in 1990. He did Branch. Center for Cancer Research. tors at the University of Texas M.D. postdoctoral training at the University of NCI. Anderson Cancer Center, Georgia before coming to the Laboratory In order for a tumor to Houston, we have been de- ofParasitic Diseases. NIA1D, in 1992. He grow larger than a few milli- veloping a phage-based vec- is currently the head of the Malaria meters, it must develop a tor system that is capable of Genomics Section and a senior investi- blood supply. This process targeting tumor vessels selec- gator in the Laboratory> ofMalaria and of new vessel growth from tively. Vector Research pre-existing vessels is termed We are now testing this Lack of an effective vaccine and wide- “angiogenesis,” and it is im- vector in animals within the spread parasite resistance to multiple an- portant not only for the NCI Comparative Oncology timalarial drugs have led to a resurgence growth of the primary tumor Program by delivering vas- of malaria worldwide. Indeed, after de- but also for tumor invasion cular-targeted, TNF-express- cades of research and much progress in and spread to distant sites. Fran Pollner ing phage to dogs with spon- molecular biology, we are not much Steven Libutti Aiming to identify novel taneous cancers. Data from better off in treating and controlling targets for cancer therapy, this study will be malaria than we were 50 my laboratory has focused on under- submitted to the FDA to sup- years ago. Dynamic and standing the tumor microenvironment, port an IND (investigational rapidly evolving parasite the molecular processes involved in the new drug application) to con- populations present tremen- development of new vessels, and the duct the first clinical trial of dous problems for develop- complex interactions between the tumor this vector. ing effective control mea- and host cells. Along with others in the an- sures. We have developed some new tech- giogenesis field, we have pur- Under the guidance of niques and assays to help us model and sued the identification of Thomas Wellems, my initial measure these processes. unique targets in the tumor research as a postdoctoral We contributed to the creation of a vasculature. fellow at NIH involved ge- technique for isolating endothelial cells Utilizing genomic and Xinzhuan Su netic mapping of a gene from tissues that have been fixed or fro- proteomic approaches, we linked to chloroquine resis- zen. This adaptation of a novel laser have attempted to elucidate common tance in Plasmodium falciparum para- capture approach termed expression pathways involved in the response of site. microdissection, or xMD, has allowed endothelial cells to angiogenesis inhibi- I developed various tools and meth- us to study DNA, RNA, and protein tors. ods, including a high-density microsat- changes in tumor-associated endothe- This work has enabled us to charac- ellite map, and mapped the locus of re- lial cells in situ. terize more completely the activity of sistance to a 36-kb region. I realized then We were able to demonstrate that tu- two important mediators of endothelial how much remained to be discovered mor endothelial cells exhibit differen- cell apoptosis. in malaria genetics and genomics and tial patterns of promoter methylation We recently elucidated the mechanism decided these were areas I wanted to compared with endothelial cells in ad- by which EMAP-II (endothelial cell explore for years to come. jacent normal tissues. monocyte-activating polypeptide-II) My laboratory applies genome-wide This provided the first definitive evi- gets into endothelial cells and exerts its approaches to fundamental problems of dence in vivo of epigenetic alterations effects via an HIFl-a-mediated pathway. parasite biology and evolution. in tumor neovasculature. We hope this By enhancing HIFl-a degradation, Current goals are to develop observation will lead to a better under- EMAP-II induces endothelial cell apop- genome-wide single-nucleotide poly- standing of the mechanisms that result tosis. morphism (SNP) and microsatellite ge- in phenotypic alteration of endothelial We have also identified the putative netic maps and to use these maps to cells and thus facilitate the identifica- tumor-suppressor gene DOC1 as an im- identify genes affecting such phenotypes 10 as parasite drug resistance, red blood ment. drug-resistant parasites from one or two cell invasion, and sexual development. Malaria parasites can be grouped into foci. Collections of genome-wide polymor- populations according to their continen- Malaria parasites have a complex life phisms from malaria parasites world- tal origins, yet no obvious population cycle, with asexual replication in the wide will also provide a useful database structure exists in Africa due to high human host and mandatory sexual re- for studies of parasite origin, transmis- transmission and recombination rates. combination in the mosquito host. The sion, and evolution. We have collected thousands of SNPs sexual stages are vital phases in malaria Using malaria parasite lines adapted from geographically diverse parasite iso- parasite transmission and are the targets to in vitro culture and large numbers of lates and are in the process of develop- of various interventions such as genotypes obtained from both nuclear ing a microarray chip to genotype addi- transmission-blocking vaccines. and mitochondrial genomes, we stud- tional isolates from field sites, including Malaria parasites have a haploid ge- ied parasite population structure, recom- a new field site in Cambodia. Our plan nome in the human host. The switch bination rate variation, linkage disequi- is to perform association studies with from asexual replication to sexual dif- librium, and evolutionary history. We well-characterized parasite phenotypes. ferentiation is therefore likely to involve have shown that P. falciparum probably For example, to map important signal transduction and gene regulation. migrated with humans out of Africa to drug-resistance genes, we will look for Recently, we used genetic mapping other parts of the world about 50,000- loci with signatures of selection such as to identify a candidate gene that plays 100,000 years ago. chromosomal regions with reduced an important role in parasite sexual de- Our studies also found that parasite polymorphism. velopment. We are now using genetic population expansions probably oc- Indeed, we have already shown re- mapping, microarrays, and other ap- curred in Africa 5,000-10,000 years ago, duced diversity in a large chromosomal proaches to study the regulation of this along with changes in mosquito ecol- region surrounding a gene for a complicated process and gain knowl- ogy and species distribution from agri- chloroquine-resistance transporter on edge to inform the development of strat- culture and its impact on the environ- chromosome 7, suggesting spread of egies for malaria control. HI New Performance Management Appraisal Program New Vision Research by Sue Fishbein Lecture Series/Award orientation provided are What is the PMAP? by OHR and now he first Sayer Vision Research Who Will Be Affected? helping to train supervisors and employ- — ees in their respective ICs, assist with the T Lecture “Stemming Vision Loss Efforts are underway at NIH to imple- with Stem Ceils” took place ment the new HHS-wide performance development of employee performance — May 2006 . It can be viewed at management appraisal program (PMAP). plans, and track PMAP progress. They are 25 , the first point of contact for questions about 11 2 The NIH Catalyst Ks^f 5 Catalyst: Catalytic Spring B reafc — Enjoy Nature Reactions? f you have a photo or I other graphic that reflects an aspect of life at NIH (including laboratory life) or a quotation that scientists might appreciate that would be fit to print in the space to the right, why not send it to us via e- mail: [email protected]>; fax:402-4303; or mail: Building 2, Room 2E26. Also, we welcome “letters to the editor” for publication and your reactions to anything on the Catalyst pages. In Future Issues... a More Bench To Bedside H Nobel Experience For GPP Students Jennifer White B IG Directory Kids’ Catalyst creator and writerJennifer White was so enchanted by the spring sights on the NIH campus that she took time out to capture some of them in her digital camera. You can- see a few more of her NIH nature photos (in color, including the one above) in the online edition ofThe NIH Catalyst at Publisher Managing Editor Editorial Advisory Board The Catalyst is pub- NIH Michael Gottesman Fran Pollner Jorge Carrasquillo, CC lished bi-monthly for and by Deputy Director David Davies, NIDDK the intramural scientists at for Intramural Research, OD Copy Editor Dale Graham, CIT NIH. Address correspon- Shauna Roberts Elise Kohn, NCI dence to Building 2, Room Editors Susan Leitman, CC 2E26, NIH, Bethesda, MD John I. Gallin Contributing Writers Bernard Moss, NIAID 20892. Ph: (301) 402-1449; Director, NIH Clinical Center Karen Ross Paul Plotz. 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