Fostering Communication and Collaboration
The nihCatalyst A Publication for NIH Intramural Scientists
National Institutes of Health bOffice of the Director' e Volume 11, Issue 6* November-December 2003
CC Celebrates 50th at Research Festival > the Sum of the Parts Giants Standing Copeland and Jenkins On the Shoulders of Giants And the Development Of Mouse Cancer Genetics by Fran Pollner
DeVita it by PeterJ. Kozel ince put this way: “It’s nice V to come home.” And in one way or an- other, each of the speak- ers who took the stage to commemorate the CC’s 50th anniversary ex- pressed an affection for the daily working envi- ronment at NIFI and its research hospital that Bill Branson conjured up the image of CC DirectorJohn Gallin salutes former and current NIH NancyJenkins Neal Copeland home: scientists and a half-century of transforming research t’s hard to say what the NIH sci- The collaborative entific directors were honoring and feisty spirit among colleagues remi- The perseverance, warmth, and mu- I when they picked husband-and- niscent of the best kind of sibling cama- tual regard that characterized the rela- wife cancer genetics investigators raderie—and squabbling tionships between the physician-re- Neal Copeland and Nancy Jenkins searchers and the patients undergoing to present this year’s Mider Lecture. experimental treatments, sometimes ex- Was it their legacy—almost 700 pa- tending through decades of follow-up pers and the reference mouse ge- The culture of NIFf, like that in a nome map? Was it their astonishing nurturing family, that supported the pur- record of training successful scien- suit of new ideas and personal intellec- tists? Was it their innovative “recom- tual expansion bineering” technique that’s revolu- They all saw the past—studded with tionizing the manipulation of DNA? the gems of biomedical research that
Or was it their almost unparalleled, contributed enormously to science and highly productive collaboration, now human health—as prologue to the fu- in its third decade? ture. capsules continue on page 3 The NIH Catalyst spoke with Copeland chief se- and Jenkins— and CONTENTS nior investigator, respectively, of the Bill Branson
1 7 NCI-Freclerick Mouse Cancer Genet- Back in the Day: Former NCI director Giant Shoulders: CC ProtoType: Crafting ics Program shortly before they Vince DeVita displays the senior — faculty Celebrates 50th Clinical Protocols taught a short course on mouse ge- of the NCI Medicine Branch, circa 1975: netics at the Jackson Laboratory in (left to right) George Canellos (now at Copeland & Jenkins 10-15 Research Cornucopia: Bar Harbor, Maine, this past summer. Haward), Bruce Chabner (Massachu- & Recombineering An IRP Year’s Worth setts General Hospital), Phil Schein Jenkins and Copeland met in 1977 2 (University Pennsylvania), DeVita as postdoctoral fellows in Geoffrey of From the DDIR: 16-17 (“with more hair and polyester"), and Cooper’s retrovirus laboratory at the A 50-Year Bonanza Recently Tenured Bob Young (Fox-Chase Cancer Center). Of CC Research Dana Farber Cancer Institute in Bos- 18-19 DeVita 's talk, not only tracked the rise of ton. 4-7 At the time, retroviruses were chemotherapy and the decline in cancer Catalytic Reactions/ Research Festival Relay Revelry/Training at the “very forefront of molecular modality, it was a paean to dozens of The Clever Host biology,” according to Jenkins. “Mo- his NCI colleagues and the Friday Gene Complexities 20 continued on page 8 afternoon Society ofJabbering Idiots A Random Sample At Your Fingertips The NIH Catalyst From the Deputy Director for Intramural Research
Highways and Byways: 50 Years of Research at the Clinical Center
his year we celebrate the 50th anniversary of like driving a car at night. You can only see as far as the opening of the NIH Clinical Center. On the headlights, but you make the whole trip that way.” T October 14, 2003, a symposium was held in The history of the Clinical Center has many ex- Masur Auditorium to recognize the scope and depth amples of circuitous trips without maps that have of research accomplishments that represent some of arrived at unexpected and far-reaching destinations. the history of the Clinical Center. For example, studies of the rare human embryonic Those who attended—whether newcomers to NIH cancer choriocarcinoma, by Roy Hertz and Min Chiu or longtimers who were here when the doors to the Li, led to a need to follow success of treatment by Clinical Center first opened—could not help but be measuring human chorionic gonadotropin. Judy impressed by the enormous impact the Clinical Cen- Vaitukaitus developed the first radioimmunoassay for Michael Gottesman ter has had on the practice of medicine, from devel- this hormone—-and this assay became the basis for oping the current paradigm for the chemotherapy of the home pregnancy test, which, needless to say, cancer, to changing the way in which ischemic heart has had profound social consequences. disease is treated, to creating new approaches to the Tom Waldmann, in searching for a way to diag- treatment of multiple sclerosis. nose and treat a rare form of T-cell leukemia, devel- This kind of occasion also inspires reflection on oped an anti-TAC antibody to the a-chain of the the constellation of causes of past success to assist interleukin-2 receptor. This antibody blocks T-cell us in imagining how best to ensure continued suc- activation and has found important use in the treat- cess in the future. ment of several autoimmune dis- In listening to the presentations orders at the Clinical Center, includ- and reviewing other contributions To paraphrase the ing multiple sclerosis and autoim- made at the Clinical Center, I was mune uveitis. struck by the fact that some of the NOVELIST E.L. Finally, our courageous patient major paradigm-shifting research Doctorow: Re- volunteers and the observations was accomplished in the face of made by astute clinicians have led great resistance and with enormous search ‘is like driv- to new pathways to discovery. The investment of time, staff, and re- ing a CAR AT NIGHT. combined observations of Isaac sources. Asimov and Dr. Seuss summarize In keeping with the current road You CAN ONLY SEE AS the NIH research terrain. Asimov map metaphor, Clinical Center re- FAR AS THE HEAD- put it this way: "The most exciting search built the major highways, phrase to hear in science, the one bridges, and tunnels that have LIGHTS, BUT YOU that heralds new discoveries, is not transformed the face of medicine. Eureka!, but Hmm, that's funny." MAKE THE WHOLE TRIP Vince DeVita’s recounting of the And from Dr. Seuss, we append a need for protracted persuasion of THAT WAY.’ key road map legend: "From there influential skeptics in the develop- to here, and here to there, funny ment of multiagent chemotherapy things are everywhere." We need of cancer—and the involvement of so many physi- to continue to be accessible to patients with a large cians and patients over so many years—illustrates variety of disorders, and observe them carefully as the kind of major effort to which I am referring. we care for them, to learn more about human health Similarly huge efforts informed NIH contributions and disease. to cardiac surgery (the first implantation of an artifi- We are awaiting the imminent recommendations cial mitral valve), to the treatment of manic-depres- of a Blue Ribbon Panel on Clinical Research at the sive illness (demonstration of the dramatic effect of NIH, co-chaired by Ed Benz, president of the Dana- lithium), and to identification and control of HIV in- Farber Cancer Center in Boston, and Joe Goldstein, fection. professor at the University of Texas Southwestern So, too, will current and future undertakings re- Medical Center, Dallas, on how best to ensure that lated to major public-health problems require a large the new Clinical Research Center has as much im- commitment of resources and energy. The payoff, pact as the Clinical Center has had in the past.
however, is certainly larger. We are now in the pro- I am confident that NIH will be asked to continue cess of planning a major initiative to better under- to take on important public health issues—but not stand the physiological causes and consequences of eschew the rare diseases that have led to so many obesity, an effort that will require a substantial trans- important insights about human pathophysiology. NIH commitment. If you are interested in watching and listening to But the success of clinical research at NIH is as the many outstanding presentations given at the Clini- much written in the shortcuts and scenic byways as cal Center 50th anniversary symposium, they are in its major highways. When we study rare diseases, archived at
photos by Bill Branson CC Celebrates 50th at Research Festival Giants Standing on the Shoulders of Giants text by Fran Pollner
Francis Collins, director, NHGR1 (at NIH since 1993) What’s next after you 've mapped the human genome? a human haplotype map to chart the variants that contribute to common diseases—an international project involving six countries and support from 18 NIH institutes
Harvey Alter, chief CC Infectious Diseases Section (at NIH since 1969); Co-discoverer of the Australia antigen, Elizabeth Nabel, scien- eradicator ofposttransfusion hepatitis, tific directorfor clinical and poet: “When I came to NIH as a Eugene Braunwald, Hersey research, NHLBI (at NIH lowly fellow, 1 saw that patients were distinguished professor medicine. of since 1999): Genomics turning yellow ..." Harvard Medical School (NIH: 1955- and stem cells are involved 1968; hangout: CC, 7th floor, in much of cardiovascular Elizabeth Neufeld, professor and cardiovascularphysiology lab): disease research at the CC chairman, biological chemistry, UCLA Thanks to the disobedience of a today. Researchers are David Geffen School ofMedicine (at patient on self-activated carotid coirelating gene polymor- NIH 1963-1984)) devoted to the study sinus nerve stimulation, it was phisms with drug sensitiv- of lysosomal enzyme deficiencies, learned that ST segment elevation ity and with the propensity recalled the “ inadvertent mix in the decreases in the midst of an ongoing for restenosis, and Petri dish ofHurler and Hunter cells, infarct—and the concept of myocar- injecting endothelial which together produced a normal pattern proving that two wrongs can dial salvage was born. With 13- progenitor cells into — " right blockade and fibrinolysis, acute MI ischemic scar tissue to make a mortality droppedfrom 18 to 7 repair vascular damage percent Tony Fauci, NIA1D director (at NIH since 1 968). Seeing AIDS patientsfor the first time on the CC’s 11th floor, “I Vincent DeVita, professor of clidn 't fully appreciate this was a new medicine, epidemiology, and public disease, but I was anxious because I
health, Yale University (at NIH couldn ’t understand it. I turned 1963-1988, as NCI directorfrom over my (host immune defense) lab to 1980): Lead author of the 1970 the study ofHIV" Annals of Internal Medicine report Dennis Chantey, chief Mood and establishing that some advanced Anxiety Disorders Research Program, cancers could be cured by combi- NIMH (at NIH since 2000): Collabora- nation chemotherapy, a strategy tive proof-of-concept trials are that launched the era of cancer underway that aim at new targets to survival, with rates going 0 to from fight depression, an underappreciated, cancers 80 percent todayfor some crippling disorder that can potentiate conditions like heart disease, diabetes, Thomas Waldmann, chief. Metabo- and osteoporosis lism Branch, NCI (at NIH since 1956, when, according to the textbook in the Allen Spiegel, NIDDK director (at background, “thefunction of the NIH since 1973), world-renowned lymphocyte [was] still obscure ”): for his research in G-protein Developer anti-TAC, the of first dynamics and hormone disorders, antibody to a cytokine receptor (IL- paid homage to his NIH mentor G.D 2Ra)— used clinically in the manage- Aurbach, who purified parathyroid ment of cancer, transplant rejection, hormone and launched the study of and autoimmune disease and in signal transduction disorders studies underway at six NIH institutes. The IL-2/IL-15 interface now com- Henry McFarland, director, Clinical Neurosciences Program, NINDS (at NIH mands much of his attention. The T since 1976): “[Early on], multiple cell, Waldmann says, “is the sun of the sclerosis later it's immunological system ” is inflammatory;
degenerative. . . . There are both Steven Rosenberg, chief, Surgery upregulated and downregulated genes.
Branch, NCI (at NIH at this post . . . The key is to conduct small trials of ” since 1974): A 30-year odyssey to innovative therapies develop cancer immunotherapy French Anderson, director, Gene has established that this approach Therapy Laboratories, USC Keck School can achieve cures; tumor-infiltrat- ofMedicine (at NIH 1965-1992), shown ing lymphocytes and tumor-specific with thefirst gene therapy patient—age antigens are central to a strategy 4 in 1990—whose adenosine deaminase whose latest development involves levels are still normal. He asks: “ Why is
nonmyeloablative conditioning it that she has been able to develop a T- followed by adoptive transfer of cell response to new antigens? Did some antitumor lymphocytes targeting stem cells get in there? Can T cells de- ?" specific tumor antigens differentiate and be reeducated
3 — The NIH Catalyst Research Festival
Host Response to Infectious Diseases: text and photos Scientists Use New Tools, Tricks to Block Infection by Peterj.Kozei
ew animal models for SARS, the sponses to different cytokines and de- immune cells play in infection by intra-
role of T cells in SIV infection, termined that by blocking I L- fibrosis cellular 1 3 , pathogens could have important N and new vaccine targets were was reduced. Mouse knockouts and IL- long-term consequences for the treatment some of the intramural research high- 13 receptor agonists confirmed this ob- of these diseases. lights at the “Host Response to Infectious servation. For example, IFN-y is often suggested Diseases” minisymposium on October 15. Using additional knockout models, as both an additional treatment for intra- Wynn and his colleagues also demon- cellular pathogens (in combination with SARS Model strated that when the decoy receptor for antibiotics), and as a marker or “corre- Kanta Subbarao IL-13 was knocked out, fibrosis increased, late” of protection for vaccine studies. kicked off the ses- arguing that there are both stimulatory and But these data, Elkins observed, suggest sion with a descrip- inhibitory receptors for this cytokine. Ani- that IFN-y, while important, is far from tion of work by mals treated with a soluble form of the the only T-cell function needed for pro-
NIAID’s Laboratory IL-13 receptor reversed the phenotype tection against these bacteria. In fact, it of Infectious Dis- in the knockout mice, confirming that may actually be a rather minor player; eases, which is the IL-13Ra2 is acting as a "decoy recep- another cytokine, TNF-a, may be key. evaluating animal tor system,” inhibiting fibrosis. Wynn's Further research is necessary to better models for severe work is applicable to other chronic in- define those other players, improving acute respiratory flammatory diseases, including asthma treatment options and aiding vaccine de- syndrome (SARS). and kidney conditions, that exhibit a "ter- velopment. Subbarao delivered the virus into the minal stage of inflammation" comparable noses of mice and observed that the vi- to the scarring in schistosomiasis. New Vaccines Could Foil the Flu rus replicated efficiently, although the And Other Viruses animals didn't become ill and displayed Cytokine Keys and Intracellular Bugs Against a background of colorful au- only mild histopathology. SARS vims was Intracellular patho- tumn leaves that coincided with the re- detected in lungs, and virus-specific gens pose special turn of flu season, Suzanne Epstein, chief hyperimmune sera from infected mice problems for treat- of FDA-CBER’s Laboratory of Immunol- could be used to block infection in other ment. Karen Elkins ogy and Developmental Biology, de- animals. These results are similar to those from CBER/FDA’s scribed new mechanisms to protect for influenza and respiratory syncytial vi- Laboratory of Myco- against the flu. ruses in mice. bacteria demon- Epstein ascribed “lots of excess deaths” Subbarao also described her work with strated that B-cell to this highly transmissible virus. Current primates, including rhesus and African knockout mice re- vaccines provide a measure of protec- green monkeys and cynomolgus spond differently to tion, but would not stop pandemics such macaques. The vims replicated in the res- infections of tubercu- as those in 1918, 1957, and 1968. She piratory tract of all three monkey spe- losis and Francisella, cited the basic biology of influenza as cies without causing illness. All species offering new insight the reason. The high developed neutralizing antibodies, but into the basic biology of the diseases. mutation rate of this African green monkeys were protected During aerosol tuberculosis infection, negative-strand RNA from a second infection with SARS and lung histopathology showed less-severe vims ensures that the proved to be the best model. Subbarao damage in B-cell knockout mice, and outer coat proteins, said both the primate and the mouse there was less dissemination of bacteria to which many vac- models would be useful in screening out of lungs to spleens and livers com- cines are directed, future SARS vaccines and antivirals. pared with wild-type controls. But lung are constantly chang- tissues were more damaged, and dissemi- ing. Also, entire seg- Reducing Cytokine Scarring nation restored, when B cells were added ments of the viral ge- Up to 600 million people in 74 coun- back to the mice. In contrast, secondary nome can be tries suffer from chronic schistosomiasis immunity to Francisella was impaired, not swapped between infections. The improved, in the absence of B cells. strains (genetic reassortment), bringing schistosome para- Elkins was able to tease out a “com- in new coat proteins. sites cause spleen mon thread” in how infected macroph- In contrast, Epstein said, the proteins and liver enlarge- ages control these kinds of bacteria. Mac- inside the viral particle are fairly con- ment and the for- rophages and dendritic cells secrete IL- served, making them excellent vaccine mation of fibrous 12 when infected; this cytokine helps ac- targets. The broad cross-protection they scars. Thomas tivate production of interferon gamma can induce, so-called “heterosubtypic im- Wynn, a senior (IFN-y), which increases nitric oxide pro- munity,” can be achieved in animals by investigator in duction in macrophages. IFN-y is a nec- immunization with live virus and also NLAID's Immuno- essary but not sufficient component of with DNA vaccines. These new vaccines pathogenesis adaptive protective immunity; in fact, can deliver a conserved antigen, confer- Section in the Laboratory of Parasitic dis- macrophages from mice lacking the in- ring immunity to many different viral eases, says cytokines are responsible for terferon receptor eliminated up to 95 per- strains and even across subtype differ- the scarring. cent of bacteria. ences, which occur in pandemics. Wynn’s group looked at T-cell re- Elkins’ elucidation of the varied roles DNA vaccines have another advantage:
4 — . November — December 2003
Through a Glass Darkly: Strategies To Probe Complex Genetics
by PeterJ. Kozel
he tools of molecular genetics with investigators have given scientists powerful in- trained in different T sights into cellular processes and fields to interpret the diseases that result when pathways data. break down. Kenneth Buetow, But currently, that vision is limited. chief of NCI’s Labo- Although hundreds of genes have ratory of Population been associated with diseases, many of Genetics, fleshed out Peter Kozel Embracing the Complexities: to right) Colleen McBride, these diseases are rarely seen. Mean- this approach. He (left Kenneth Kathleen Merikangas Buetow, , andJohn Hardy while, major public health problems, urged the audience to such as diabetes, neurological diseases, “embrace the complexity” of disease and models. and lung cancer, resist molecular illustrated how bioinformatics can clarify Testing that pathway in animal mod- deconstruction. “Bringing Genetics to disparate observations. By putting ex- els would identify additional candidate the Public” sought to update investiga- perimental results in the context of path- genes. Population genetics would asso- tors on the status of complex genetic ways and ontogeny, Buetow is creating ciate risk factors with mutant alleles to disease research and strategies to peer a “User’s Guide to the Human Genome” those genes. This integrated approach through the fog to find causative genes. that will allow researchers to look across would also identify new opportunities Kathleen Merikangas, chief of the Sec- gene families and understand disease for therapy. Hardy concluded by illus- tion on Developmental Genetic Epide- from a systems perspective. trating how this “bench and bedside and miology at NIMH, summarized why Buetow’s Cancer Genome Anatomy back” model was applied in Alzheimer’s complex diseases are so recalcitrant. Project links genes and genetic infor- disease to generate new treatment strat- Most known disease genes confer a mation with mapping and expression egies. high risk of disease, but such diseases data, ontogenies, and biochemical and Approaching patients and the public, are relatively rare in the population. On signaling pathways to help scientists especially about diseases with behav- the other hand, common diseases are “begin to construct models at different ioral risk factors, introduces another often associated with combinations of levels.” layer of complexity. Colleen McBride, multiple disease alleles—at least 10 are Noting that useful models for many chief of NHGRI’s Social and Behavioral associated with type 1 diabetes, for ex- diseases and processes existed well be- Research Branch, showed how genet- ample. Thus, Merikangas said, the risk fore genes—or even DNA—had been ics can be combined with public-health attributable to a single gene may be so described, Buetow said he believes that initiatives to reach large numbers of at-
small that it may be missed. In addition, bioinformatics will allow scientists to risk individuals. But motivating specific many complex diseases lack narrow, “connect the dots” to develop a deeper behaviors can entail even more mysti- precise clinical definitions, further cloud- understanding of complex disease. fying forces than the most complex cel- ing the interpretation of whole-genome NIA’s John Hardy, chief of the Labo- lular pathways (see “Recently Tenured,” scans. ratory of Neurogenetics, addressed the page 1 6)
Merikangas proposed a new model for genetic complexities of neurodegener- Despite the murkiness, it seemed that complex disease research—analytical ative diseases. He laid out his path to NIH investigators left the workshop with genetic epidemiology. Combining tradi- the study of complex disease: Starting a sense of challenge, not despair—remi- tional family studies with biologically with familial diseases and positional niscent of Michael Gottesman’s para- validated phenotypes and disease patho- cloning to identify early disease features phrase of Doctorow (see page 2) about genesis, this model espouses that inves- and rare causes of disease, respectively, night driving and being able to see only tigators share kindreds, pool positive scientists can develop an understand- so far as the headlights—all the way to and negative—results, and collaborate ing of disease pathogenesis in cellular the destination.
they do not have to be kept cool, allow- the VRC, and his colleagues are T cells were lost, the investiga- ing millions of people to be immunized using a rhesus macaque model tors initiated a second study, in places lacking adequate refrigeration. in an attempt to gain insight into which revealed that there was Epstein concluded by noting that influ- the extensive early loss of CD4 an extensive loss of CD4 enza is not the only virus for which vac- T cells in HIV infection. memory T cells in the mesen- cines inducing broad cross-protection Initial findings in rhesus mon- teric lymph nodes within two might be useful. The knowledge gained keys infected with SIV showed weeks of infection. The loss in the influenza system can suggest strat- that loss of memory CD4 T cells was deemed due to direct in- egies for partial protection to other fami- from the peripheral blood was fection, since more than 90 per- lies of highly variable viruses, such as preceded by a severe loss of B cent of these cells carried a Hantaviruses and HIV. cells within a week of infection; single copy of SIV. this loss could not be accounted Whether this mechanism re- Tracking Memory Cell Loss for by the expression of CCR5 (a SIV flects the kind of depletion of memory In SlV-infected Macaques coreceptor) or the mucosal homing re- CD4 T cells that occurs in human infec- Joseph Mattapallil, a research fellow ceptor CD103. tion remains to be determined, Mattapallil in the flow cytometry core laboratory of To determine how these memory CD4 said.
5 ^ The NIH Catalyst
~ ~~ Research Festival^^ ^^ A Random Sample of Festival Fare text andphotos by PeterJ. Kozel
Sun, Genes, risk of other cancers, unrelated to radia- cal microscopy, using specific wave- And Melanoma tion exposure, in children inheriting a lengths to exploit the auto-fluorescence The sun- mutation in RB-1. characteristics of aldehydes. drenched Italian Campos 1 technique opens up reposi- Presenting climate is good for tories of eye and other tissues—col- growing both ol- Cancer E-mice lected for decades—to study via con- ives and skin can- And More... temporary imaging techniques. cer. Melanomas A favorite model have been linked for studying dis- Tracking MS to mutations in ease, mutant mice With MRI two genes in- have now been cre- Being able volved in cell ated and examined to track im- by the hundreds of cycle regulation, CDKN2A (protein pl6) mune cells in and CDK4. thousands. NCI’s vivo would These genes, however, are not mu- Mouse Models of improve un- tated in the population of Northeastern Human Cancer derstanding Italian melanoma patients studied by Consortium created of autoim- a new website to help scientists navi- NCI’s Monica Ter-Minassian. mune disease. Ter-Minassian and her NCI colleagues gate the sea of mouse models for can- Early-stage cers. his in the Genetic Epidemiology Branch, In poster, NCI's Fei Xu, of NCI’s multiple scle- Center for Bioinformatics, pointed out DCEG, have now begun whole-genome rosis (MS) is thought to involve a reac- of the site
Prototype: According to Protocol
ccording to Bob Nussenblatt, it’s a these findings and also ensure that the A “very smart” package. wording is right. “The goal,” Nussenblatt was added to mes- “It knows the format to use for the says, “is that required adverse event re- enchymal stem various institutional review boards. ports go directly to the relevant agen- “It asks you what kind of study you’re cies, such as the FDA if an IND is in- cells. Mesenchy- doing, and if you click on to volved, and in the right time frame, which mal progenitor ‘interventional,’ it will ask a series of varies depending on the severity” of the cells have the po- questions to determine if you need an adverse event. tential to differen- IND [investigational new drug]. Using ProtoType is not now viewed tiate into chondro- “In most cases, you will—and when as a prerequisite for conducting clinical cytes. that occurs, there will be another mod- trials at the CC. “It’s not mandatory, but
Miyoshi and her ule with a form to fill out for the IND we’re hoping that investigators will see colleagues added submission [to the FDA], And much of it as counterproductive not to use glucosamine to that form will be prepopulated with the ProtoType. There are just so many posi- high-density mes- information you already put into the tives, it’s hard to guess why someone enchymal stem clinical protocol. would choose not to,” Nussenblatt ob- cell cultures un- “It has links to impor- serves. tant regulations. And you The prototype for dergoing chondrogenesis and saw an in- won’t have to worry that ProtoType had been ger- hibition of collagen and proteoglycan you’re doing something minating for about two expression. In contrast, collagen and with rules that expired years, beginning with dis- proteoglycan levels rose in primary three years ago, or that cussions between Nuss- chondrocytes, which were prepared you’re missing some form enblatt and CC director from normal and osteoarthritic cartilage that is now necessary. John Gallin and gradually taken from human knee replacement “Everything we could including other clinical in- surgeries. think of is under one vestigators at NIH whose The next step will be to test mesen- roof.” experiences in writing chymal stem cells and chondrocytes That roof is ProtoType, clinical protocols and con- growing on a synthetic matrix in order a web-based software ducting clinical trials at the to mimic an in vivo environment. It may program that standardizes CC informed their opin- be, she speculated, that glucosamine the framework for writing a clinical pro- ions on how the protocol-writing pro- works to maintain a correct balance be- tocol but does not box the PI in to rigid cess could be improved. “The product is descriptions of the nature of the research. definitely a reflection of what clinicians tween mesenchymal stem cells and ex- Among the menu items is IC selection, wanted,” Nussenblatt says, “and as it isting condrocytes. so that if there are any institute-specific turned out, it also harmonizes very well protocol requirements, the appropriate with the international committee on har- Sniper Attacks format will be offered. ProtoType will monization of all aspects of clinical pro- And Stress be available to the intramural commu- tocols and clinical trials.” Completing ev- nity by year’s end—at: For ProtoType’s journey from vision eryday errands,
7 The NIH Catalyst Research Festival
Mouse Cancer Genetics continued from page 1 lecular biology was just flourishing,” They saw it as a unique opportunity' to meated Jenkins’ and Copeland’s work Copeland continues. “They lifted the conduct mouse genetic research on an in both development and cancer biol- cloning ban shortly after we arrived in unprecedented scale. "We really wanted ogy and the intergrading and interact- Boston and Boston became a hotbed of to fuse molecular biology and develop- ing zones of these fields. Copeland molecular research. I think we probably mental biology on a large scale in mice notes that the coat color mutations, for did the first Southern blot at Harvard .... this was the only place we could example, led to a deeper understand- Medical School, with David Livingston's really do it," says Copeland. ing of deafness disorders, such as help,” he recalls. Waardenburg syndrome type 2A. By 1980, Jenkins and Copeland had The Royal Beginnings Jenkins says the goal of their work decided to marry and began to look for Of Mouse Genetics “has always been to manipulate genes institutions that would hire them both. “The first geneticists were the Japa- and understand their biology, their One offer, from the Jackson Laboratory, nese emperors,” Jenkins notes. “They physiology, [and] their interaction path- was an intriguing, albeit curious, choice. collected the unusu- “We didn’t know mouse biology at all,” ally colored mice and Copeland recounts. The pair quickly the neurological mu- realized that “JAX” and its mouse mu- tants, the waltzers. tants were a gold mine—“models for When trade finally human cancer and a lot of developmen- opened between Eu- tal disorders in people. We could apply rope and Japan, the molecular biology to mouse genetics and mice were given as the combination of the two would hope- pets or presents to fully be better than each of the parts,” Europeans. Copeland says. When Mendel's “It was a very unique time at JAX,” laws were rediscov- Jenkins continues. “There were no other ered at the beginning molecular biologists. We were the first of the 20th century, [at JAX], and they were very excited all they had for re- about learning molecular biology, and agents were these they reciprocated by teaching us formal funny colored mice genetics.” and ones that had “A lot of the projects we worked on neurological pheno- for the last 20 years, and what we work types.” Peter Kozel on today, got their start when we were Copeland says the Neal Copeland and NancyJenkins backlit by theirfamous map at The Jackson Lab,” Copeland remi- mouse fanciers bred of the mouse genome nisces. “It was a magical time to be coat color mutants “ ,” “ “ there. It set the tone for our whole ca- such as dilute brown," and non- ways in mouse and [to] try to translate reer.” agouti .” These mutations were incorpo- that back into human.” After three years of learning, teach- rated into early inbred strains, such as She sees the mouse as an excellent ing, and groundbreaking publications, “DBA,” which had all three traits. model for human diseases—about 80 Jenkins and Copeland were getting rest- “Dilute” has a special significance for percent of human genes have mouse less. As much as they loved the research the lab, Copeland says. “The first paper orthologs. environment, “we were just going stir we ever published together at JAX was The human-murine genetic similarity crazy,” says Copeland. Jenkins found Bar a 1981 article in Nature that showed that has led to some amazing genetic feats. Harbor “a little too isolated” by 1983, dilute was caused by the integration of Shyam Sharan, an investigator in the and the pair moved to the University of a retrovirus into the mouse genome that Mouse Cancer Genetics Program, has Cincinnati, the only place to which they happened hundreds of years ago. That "rescued the embryonic lethality of the applied. was the first insertional mutation ever loss of a mouse BRCA gene with a hu-
It wasn’t long before they started to described in mammals.” This mutation man ortholog.” Copeland notes that this be recruited by, and interested in, other could be traced back to a mouse fan- is even more astonishing because “the programs. Jenkins remembers, “We cier in the 1700s, and from there to the regulatory sequences are not conserved weren’t looking for jobs, but the draw Japanese emperors. “We’ve been study- at all” between the two species. of having a really large animal colony ing that mutation ever since.” Copeland says his more than 20 years that we could devote to our numerous Dilute was just the beginning. In the of experience has forged his impression interests—we think the whole genome ensuing years, Jenkins says, “there’s al- that, as a model of human disease, the is interesting—was just too strong to let most no area of biology that we haven’t mouse is “much better than we ex- go-” touched on.” The overall theme has re- pected." Noting that it’s not perfect, George Vande Woude offered the mained constant, however. Copeland Jenkins says, “the mouse has three very couple the chance to pursue their inter- says, “We specifically tried to work on strong advantages: it s a mammal; you ests as he was setting up the NCI- mutations that were models of human can manipulate its germline . . . and you Frederick Applied BioSciences Labora- disease." have veiy good genetics.” As if tossing tories-Basic Research Program in 1985. The translational emphasis has per- down a latex glove, Copeland adds, “I 8 — — November — December 2003
challenge you to find a better one.” an excited postdoc returning from a their research program at a university, One way that Jenkins and Copeland meeting. Developed in collaboration they still “really like training and teach- linked their mouse mutants to human with Donald Court’s bacterial genetics ing.” Speaking like a proud parent, disease was by mapping and cloning the lab across the hall, recombineering “has Jenkins credits much of the success of genes responsible for the spontaneous widespread implications for mouse func- their lab to their “incredibly talented mutations in JAX mice. The pair learned tional genomics,” according to Copeland. postdocs.” She says they tiy to encour- about interspecific backcrossing needed “Everybody’s using it,” lie adds. “As far age creativity and then send the
for this linkage at a conference shortly as I can tell, it’s not limited to any spe- postdocs on their way only when “their after arriving in Frederick. cies, prokaryotic or eukaryotic.” creativity is fully in bloom.” Realizing its potential, Copeland re- Recombineering takes advantage of The postdocs usually don’t leave calls, “when we came back, we an- enzymes from bacteriophage X to pre- empty-handed, but take with them the nounced to the postdocs, ‘we’ve decided cisely manipulate DNA cloned in plas- research projects and mutant mice to make a map of the mouse genome. mids, BACs, or PACs, or even the Es- they’ve developed. “We’ve trained, Would you like to participate?”’ cherichia coli chromosome. frankly, some of the best people in The project quickly took on a life of For example, Copeland explains that mouse genetics,” Copeland says.
its own. Copeland and Jenkins spoke they use recombineering to “make con- “They’ve been successful because they about their map at meetings, and it ditional targeting vectors in less than two have projects that are great for grants, quickly attracted the appreciation and weeks,” a process that takes months and they didn’t have to compete with contributions of other scientists. using conventional cloning techniques. us." Copeland recalls, “People would say, this Epitope tags can also be introduced Copeland andJenkins also avoid com- is really cool! And so we had more and “to the nucleotide, anyplace you want peting with one another. Although ad- more people contacting us, and pretty in cloned DNA, and it does not depend ministratively separate, their labs func- soon we were overwhelmed.” on the location of convenient restriction tion as a single entity, as they have since Although other groups also made enzyme sites,” Jenkins adds. “It’s almost they began work at JAX, where they maps of the mouse genome, it was the like PCR was in its infancy,” Copeland shared an office, research projects, and Jenkins-Copeland map that was the stan- continues. “There are so many uses. The publications. “It was never clear to us dard in the field for several years. They more we give it out, the more people what you gain by splitting everything note that there are several reasons for think about what you can do with it.” up,” Jenkins says. this success. Their map was gene-based, The method is extremely popular “A lot of fairly well known scientists and human gene-hunters could use their “most every system that has a BAC li- have looked at our careers and have mouse map to predict locations—and brary at some stage of development has said that we’re better working together proximity to disease genes—on human requested this,” Jenkins notes. than we would be on our own,” chromosomes. As new genes were In addition to the conditional target- Copeland says. mapped, the resolution of the map im- ing vectors they are making for their own After more than 20 years and nearly proved. mouse research, Copeland and Jenkins 700 co-authored papers, the couple of- Another key advantage of the pair’s are setting up a recombineering core to ten finishes each other’s sentences, but map was that it focused on the markers make targeting vectors for NCI’s Mouse can’t precisely explain how the symbio- and repeated questionable results until Models of Human Cancer Consortium. sis of their careers evolved. they “disappeared.” Finally, all the map- Even before developing the revolu- “It just happened that way,” Jenkins ping experiments were carried out in- tionary recombineering technique, the reflects. “Each one of us has strengths house—making for “extremely high Copeland-Jenkins lab had generated and weaknesses that the other one quality,” according to Copeland. such powerful new tools, data, and strat- complements. People who know us say The map eventually became an inter- egies that in 1999 it was given an ex- that the sum is better than the parts.' H national resource that Jenkins, Copeland, panded mission and renamed the Mouse and their collaborators used to localize Cancer Genetics Program. and clone entire families of new and The team could now offer to other Copeland & Jenkins important genes. early-career investigators the lure that To Deliver Mider Lecture brought to Frederick. In addi- had them eal Copeland and Nancy Technology for the Future: tion to tenure-track investigators Sharan, N Jenkins are this year’s Mider in breast cancer, and Lino Tessarollo, a Recombineering Lecture honorees, a recognition of With the neurogeneticist, Jenkins and Copeland mouse genome nearly com- their significant contributions to the plete, Jenkins and Copeland have moved have successfully recruited another two biomedical research eminence of beyond mapping. “Technology has al- “spectacular" tenure-track investigators: NIH. ways a real interest," Karlyne Reilly, works on brain can- been says Jenkins. who They will deliver their lecture In modifier genes, and angiogenesis 2001, they described a groundbreak- cer “Retroviral insertional mutagenesis ing researcher Brad St. Croix. “They were new method for precisely manipu- provides a road map for navigating lating re- two candidates,” remembers cloned DNA by homologous our top the cancer genome”—on Wednes- combination, alleviating the need for re- Copeland. They are now about to begin day, January 14, 2004, at 3:00 striction search for the program’s next recruits. enzymes and DNA ligases. a p.m., in Masur Auditorium, Build- this While Copeland and Jenkins recog- Dubbed “recombineering,” tech- ing 10. nology sprang from the brainstorm of nize it would be impossible to support 9 — ; The NIH Catalyst
Selected NIH Intramural Research Accomplishments 2002—2003 Organized According to Government Performance and Results Act Goals
Goal A: Add to the body of knowledge ponent, as a tumor-suppressor gene in mice model demonstrated the mutation’s effect about normal and abnormal biological that works in concert with p53 the absence on the development of atherosclerosis functions and behavior of even one allele increases tumor formation (NIAID, NHLBI, NICHD) in the absence of p53 (NCI) 9 A new mouse model for S-Ag-induced Identification of disease genes Identification of the human chromosomal uveitis supports an etiological role for reti- Identification of Vang 12 as a gene impor- regions that contain allelic variants that pre- nal antigens and facilitates development of tant for the correct organization of stereo- dispose to addiction vulnerability (NIDA) antigen-specific therapies tailored to particu- cilia within the sensory cells of the inner ear, Mutation in a gene that encodes the larg- lar HLA haplotypes; the model presents a the appropriate movement of which is the est subunit of the axonal transport protein vehicle to engineer the development of au- first step in the detection of sound (NIDCD, dynactin found to cause motor neuron dis- toimmunity (NEI) NCI) ease characterized by muscle weakness and Discovery that the regulation of epider- Identification of the gene responsible for vocal fold paralysis (NINDS, NIDCD) mal factors controlling the skin’s permeabil- the ability to taste phenylthiocar bamide con- Identification of a novel ubiquitin ligase as ity barrier depends on a kruppel-like tran- tributes to understanding phenotypic varia- a new Fanconi anemia gene—the first of the scription factor leads to the development tions in bitter taste sensitivities, with impli- Fanconia anemia genes found to encode a of a mouse model for studying how to ac- cations for clinical interventions related to product, PHF9, with catalytic activity that celerate the process of barrier acquisition diet and behaviors such as smoking (NIDCD) might serve as a target for new therapeutic in premature infants (NHGRI) Identification of a novel mutation of modalities (NIA) PCDH15 that accounts for a large propor- Correlation of an amino-acid-altering poly- Basic discoveries in cell molecular, and tion of cases of type 1 Usher syndrome morphism in the BDNF (brain-derived neu- structural biology with implicationsfor among Ashkenazi Jews (NIDCD) rotrophic factor) gene with ability to remem- the treatment of human disease Identification of genetic defects in two ber past experiences, measures of hippo- Study of the interaction of cadherin 23, drug-metabolizing enzymes, CYP2C9 and campal neuronal activity, and hippocampal and accelerating alleles in mice, sheds more CYP2C19, offering the prospect of genetic activation patterns (as seen on functional light on predisposition to age-related hear- testing to customize drug prescriptions; MRI), findings that advance the study of ing loss and noise-induced hearing loss in among drugs metabolized by these enzymes Alzheimer’s disease, depression, and normal humans and informs the exploration of stem are anticoagulant, anticonvulsant, antidia- aging (NIMH, NIAAA, NCI, NICHD) cell treatment strategies (NIDCD) betic, antihypertensive, antiinflammatory, First demonstration in humans of a genetic The actin cytoskeletal core that supports
antiulcer, and antianxiety agents (NIEHS) basis ( COMT gene variations) for individual the stereocilia within the inner ear sensory Discovery of a gene involved in congeni- differences in the brain’s response to amphet- cells is not rigid, as previously thought, but tal hydrocephalus in mice Rfx4—which amine, suggesting that COMT genotype be undergoes dynamic renewal in about the
establishes a model system to study genetic taken into consideration in managing such same time it takes to recover from tempo- and environmental causes of hydrocephalus disorders as depression, schizophrenia, rary noise-induced hearing loss (NIDCD) in humans and lays the groundwork for de- Parkinson’s disease, attention deficit disorder, Single-cell mutational analysis of the c- veloping screening assays for defects in the and traumatic brain injury (NIMH) kit gene demonstrates that systemic masto- Rfx4 human gene (also cloned) (NIEHS) cytosis is a clonal disorder of a pluripotential Identification of the gene HRPT2, whose Important new animal models hematopoietic progenitor cell; the study inactivation predisposes to hyperparathyroid- Claudin 14 knockout mice, a model for establishes the precision of the single-cell ism-jaw tumor (HPT-JT) syndrome (NHGRI, autosomal recessive deafness DFNB29, tracks PCR technique and also suggests that the NIDDK) the rapid degeneration of cochlear hair cells development of mastocytosis may require Identification of SUFU as a susceptibility during the second and third weeks of life, two lesions of the c-k.it gene (NIAID, gene for medulloblastoma (NCI) when hearing function in mice is being es- NIAMS) Discovery of mutations in a novel kidney tablished (NIDCD, VRP) The finding that cell-free hemoglobin lim- cancer gene (BHD) that lead to kidney tu- Mouse models of mutations in the A-type its nitric oxide availability in sickle cell dis- mors, lung wall defects, and benign tumors lamins—structural proteins in the nucleus ease suggests the potential benefit of thera- of the hair follicle in patients with Birt-Hogg- associated with congenital forms of muscu- pies that accelerate cell-free ferrous hemo- Dube syndrome (NCI) lar dystrophy, cardiomyopathy, peripheral globin oxidation (NIDDK, CC, NHLBI) H Identification of the genetic basis for motor neuropathy, lipodystrophy, and pre- Individuals with risk factors for coronary Hutchinson-Gilford progeria syndrome, mature aging—cast light on how nuclear or- artery disease have reduced numbers of cir- which may shed light on the general phe- ganization relates to cell function in devel- culating endothelial progenitor cells, which nomenon of human aging (NHGRI) opmental and disease processes (NCI) may contribute to impaired angiogenesis in myocardial H I dentification of the genetic basis for Char- A pyrin-truncation mouse model of famil- and ventricular remodeling cot-Marie-Tooth disease type 2D and distal ial Mediterranean fever exhibits heightened ischemia (NHLBI) spinal muscular atrophy type V, a finding sensitivity to endotoxin, suggesting that in af- Reduction of nitrite to nitric oxide by that could have implications for other inher- fected humans, transient bacteremias might deoxyhemoglobin in the circulation leads ited neuropathies and motor neuron diseases provoke systemic inflammatory response and to vasodilation of blood vessels (NHLBI) as well (NHGRI, NINDS) pointing to potential treatments involving re- A novel cytokine-receptor-binding ami- Identification of de novo CIAS1 mutations combinant IL-1 receptor antagonist and phar- nopeptidase (ARTS-1) may regulate inflam- in about 50 percent of clinically recognized macologically manipulated pyrin (NIAMS, mation by promoting release of three fami- neonatal-onset multisystem inflammatory dis- NHGRI) lies of soluble cytokine receptors: type I ease, a pyrin-associated autoinflammatory A chemokine receptor mutant that resulted tumor necrosis factor, type II interleukin- 1, disease, with implications for IL-1 receptor in impaired adhesive function is found to be and interleukin-6 receptor-a (NHLBI) blockade treatment (NIAMS, NIAID) associated with reduced risk of atheroslerotic The chromatin-binding protein HMGb3 9 Identification of H2AX, a core histone com- cardiovascular disease in humans; a mouse is required to prevent differentiation of he-
10 ) — ) November — December 2003
matopoietic stem cells and must be down- 81 HuR, an RNA-binding protein whose deple- toxin suppresses normal protective anti-in- regulated to enable differentiation of my- tion via AMP-activateci protein kinase activ- flammatory response—by repressing certain eloid and B cells; HMGb3 deficiency causes ity is associated with cell senescence, is found nuclear hormone receptors—can aid in the a functional loss in stem cell activity to play a major role in enhancing p53 trans- development of new treatments and preven- (NHGRI) lation in response to ultraviolet irradiation, tion of the toxic effects of anthrax (NIMH, 1 Elucidation of the aggregation of a- -pro- suggesting that it has a broad role in cellular NIAID, NIDDK) teinase inhibitor (PI) deficiency and associ- response to toxic agents (NIA) H Elucidation of the mechanism by which ated liver disease may improve the manu- 9 Ovarian cancer cells engineer resistance IL-2 adjunctive therapy expands peripheral facture of a-l-PI augmentation products to cisplatin by remodeling the extracellular CD4+ T cells in HIV-infected patients is elu- (CBER, NIDDK) matrix through upregulation of COL6A3, in- cidated (CC, NIAID 9 A new type of prion, based on autoacti- creasing tumor cell collagen VI expression; 9 The DNA polymerase, DnaE2, is found to vation in trans rather than amyloid forma- strategies to inhibit ECM-tumor interactions contribute to the survival and emergence of tion, is discovered (NIDDK) may enhance chemotherapy (NIA, NHGRI) drug resistance in Mycobacterium tubercu- 9 Continuing studies of the pathogenesis The role of receptor channels in mediat- losis, suggesting a potential new target for of HIV infection suggest that integrin avb3 ing calcium signaling leading to the secre- therapeutic intervention (NIAID) (the vibronectin receptor) plays a role in tion of pituitary hormones essential for nor- U Intravenous immunoglobulins are found HIV infection of peripheral blood mono- mal breast development, lactation, and re- to neutralize the pro-inflammatory effects of cyte-derived macrophages and may be a productive function is elucidated (NICHD) complement fragments C3a and C5a—po- CD4 cofactor in promoting viral entry into H Demonstration of a physical association tent anaphylatoxins—in a mouse model of cells (CBER, NIDCR) between anaphylatoxins and the constant re- asthma and a pig model of cardiopulmonary 9 Recognition that the synuclein gene lo- gion of immunoglobulin (F9ab)2 fragment distress, suggesting a possible expansion of cus is triplicated in Parkinson’s disease, with suggests a strategy for interference with the the clinical applications of therapeutic doses a concomitant increase in the production inflammatory process (NINDS, NICHD, of immunoglobulins (NINDS, NICHD, NIAID, of synuclein mRNA and protein, advances NIAID, NHLBI, CBER) NHLBI, CBER) understanding of Parkinson’s mechanisms Discovery of a mechanism for the devel- H Animal studies of scrapie transmission into and informs treatment strategies (NIA, opment of AIDS-related lipodystrophy and a resistant species produces subclinical in- NINDS, NHGRI insulin resistance in successfully treated AIDS fection with underlying persistence, replica- 9 A single treatment of recombinant hu- patients—two small proteins encoded by HIV tion, and adaptation of infectivity, suggest- manized erythropoietin after coronary ar- that are produced by the patient’s cells and ing that subclinical infection of humans ex- tery ligation in rats dramatically reduces the usurp the normal proteins that regulate hor- posed to bovine spongiform encephalophy extent of myocardial infarction (MI) and left mone actions and gene transcription—sug- ( mad cow disease) could lead to dangerous ventricular functional decline that occurs in gests a therapeutic role for antagonists to transmission in the future INLAID) untreated animals, a finding that supports these two viral proteins (NICHD, NCI) 9 Discovery of elevated levels of IL-6 in pa- the initiation of clinical studies in MI pa- 9 Glial cell-line-derived neurotrophic factor tients with mastocytosis has implications for tients (NIA) and neurturin are demonstrated to be new therapy (NIAID) 9 Animal studies show that nitric oxide sig- neuromodulators that regulate the develop- 8 Studies in yeast and human cell extracts naling and brain-derived neurotrophic fac- ment of the neuromuscular synapse through demonstrate that cadmium acts as an envi- tor (BDNF) together regulate neurogenesis both pre- and postsynaptic mechanisms ronmental mutagen and carcinogen by in- in the mammalian brain and that dietary re- (NICHD, NCI) hibiting the DNA mismatch repair system, striction increases neurogenesis, apparently H Elucidation of the immune-suppressing rather than by direct DNA damage (NIEHS) by stimulating production of BDNF; drug mechanisms of human herpesvirus 6, a HIV S Elucidation of the molecular mechanism and dietary strategies to prevent or treat hu- co-pathogen, provides the first evidence in a by which chelation therapy effects methyl- man neurodegenerative disorders might be physiologically relevant model (human lym- mercury excretion after mercury-induced re- entertained (NIA) phoid tissue) that HHV-6 can severely affect nal damage suggests that variations in or- 9 Dietary restriction (intermittent fasting) the physiology of secondary lymphoid or- ganic anion transporters may explain indi- in huntingtin mutant mice, an animal model gans through direct infection of T lympho- vidual susceptibility to methylmercury tox- for Huntington’s disease, increases levels of cytes and modulation of key membrane re- icity (NIEHS) BDNF and the protein chaperone heat- ceptors and chemokines (NICHD) 8 Mesoamerican Mestizos and North Ameri- shock protein-70, slows the progression of 9 Structural and functional studies of can Caucasians with idiopathic inflammatory neuropathological, motor, and metabolic ab- glutamate receptors, including high-resolu- myopathy display differing patterns of clini- normalities, and extends lifespan, suggest- tion X-ray structures of glutamate receptor cal manifestations, autoantibodies, and im- ing that dietary intervention may suppress agonists, provide detailed insight into the mo- munoglobulins, suggesting that expression the disease process in humans who carry lecular basis of ligand-receptor subtype speci- of this condition is modulated by different the mutant huntingtin gene (NIA) ficity that may aid in the design of selective genes and environmental exposures around 9 In a study for the first time linking two agonists to manage stroke damage and other the world (NIEHS) signaling pathways—p-1 adrenergic recep- CNS disorders associated with dysfunctional 8 Postpartum uterine tissue remodeling ap- 2+ tor (AR) and the Ca /calmodulin kinase II glutamate receptor activity (NICHD) pears to be the mechanism by which parity sustained |3lAR stimulation precipitates car- 9 Development of a new method for cultur- confers protection from uterine fibroids diac myocyte apoptosis, suggesting signal- ing Plasmodiumfalciparum at high erythro- (NIEHS) ing-selective receptor stimulation in the cyte concentrations demonstrates that P. U A polymorphism in the COMT (catechol- management of cardiovascular disease—for falciparum can replicate at packed densities O-methyltransferase) gene affects opioid g- example, selective (3lAR blockade with con- and offers a new approach to studying the receptor mediated responses to pain and was current (32AR activation as a potential ap- pathogenesis of cerebral malaria (NICHD) found to be associated with anxiety disor- proach to chronic heart failure (NIA) 8 The mechanism by which anthrax lethal der among Caucasian and Plains American
11 The NIH Catalyst
Selected NIH Intramural Research Accomplishments 2002—2003 continued
Indian women (NIAAA) tissue (VAT) volume, which refutes findings the blood flow in the cardiac chambers en- 19 Demonstration of impaired synaptic plas- in other studies that sex differences docu- ables evaluation of pressure differences in ticity in the brain and well-defined functional mented in other racial groups do not apply different locations in the heart and great consequences of prolonged marijuana use to African Americans (NIDDK, NICHD, CC) vessels and assessment of the severity of (NIDA) Design and manufacture of a unique acu- certain types of cardiovascular disease Description of the ascending pathway from puncture needle with a microdialysis probe (NHLBI) the primate brainstem to the cortex sets the that enables the recovery of biological agents Combining electron tomography with en- stage for tracking other ascending pathways, from the tissue surrounding the needle tip ergy-filtered electron microscopy yields high- and the impaired feedback is thought to con- (DBEPS, CC) resolution images of 3-D distributions of spe- tribute to such conditions as acquired nys- Development of fine-bore immunoaffinity cific chemical elements in cells; this tech- tagmus, spasmodic torticollis, Parkinson’s dis- capillary electrophoresis enabling multiple nique will be useful for elucidating the or- ease, and schizophrenia (NEI) analyte analysis on collected samples ganization of DNA in the nucleus because K Identification of a cellular phenotype char- (DBEPS, NINDS, NICHD) the intrinsic image contrast mechanism acteristic of Lowe syndrome provides a Development of a 3-D anatomically cor- clearly distinguishes between protein and model system to test possible interventions rect computational model of the human spi- nucleic acid (DBEPS) in the disease process (NHGRI) nal cord to model drug delivery and tissue The use of semiconductor-based nano- The results of a 10-year imaging study distribution, with the aim of studying this sys- crystals as a nontoxic angiographic contrast show that although children and adolescents tem to treat chronic pain (DBEPS, NIDCR, agent is explored (DBEPS, NICHD, NCI) with attention deficit hyperactivity disorder NINDS) The first radiolabeled nonpeptide ligand have smaller brain volumes than healthy Development of a variant of green fluo- for the corticotropin releasing hormone type controls (whether previously medicated or rescent protein that allows selective mark- 1 receptor that can be used for PET scan- not), their brain development throughout ing of proteins through photoactivation (PA- ning is designed and synthesized (NIDDK) childhood and adolescence is similar to con- GFP ), a labeling method preferable to photo- Stem cells labeled with magnetic particles trols, evidence that stimulant drugs do not bleaching for studying temporal and spatial are amenable to magnetic resonance imag- disturb brain development (NIMH, NINDS) dynamics of proteins and addressing funda- ing, which has been used to track mesen- Elucidation of the process by which in- mental questions in cell and developmental chymal stem cells injected directly into the hibitory synaptic neuronal endings absorb biology (NICHD) left ventricle (NHLBI, NINDS) glutamate, which leads to the production of Measurement of the kinetics of folding of GABA and may prevent seizures resulting a single protein molecule (NIDDK) Advances in bioinformatics from excess glutamate, advances understand- Delineation of a molecular structural model Launching of the Cohort Consortium—an ing and control of epilepsy (NINDS) of amyloid fibrils formed by the 40-residue interdisciplinary public-private, intramural- Neurocognitive effects of chronic mari- (i-amyloid peptide associated with extramural collaboration—to facilitate sub- juana, cocaine, and alcohol use are found Alzheimer’s disease (NIDDK) set data analysis and the examination of to persist after 28 days of abstinence, with High-resolution microscopy, high-through- gene-gene and gene-environment interac- severity related to dose; multiple drug use put imaging, and computer simulations to tions in cancer, diabetes, and cardiovascu- produces additive negative effects (NIDA) study the positioning of entire chromosomes lar, neurological, and other complex diseases The finding that T cells reactive to myelin and gene loci within the nucleus and their (NCI) basic protein contribute to disease activity rearrangements during differentiation and in multiple sclerosis points to a more spe- tumorigenesis, which enhances understand- Advances in biotechnology cific target in future therapeutic trials (NINDS) ing of how spatial organization affects ge- The finding that over a lifetime the mito- Discovery of second-site, function-restor- nome expression and could lead to new di- chondrial DNA of single bone-marrow pro- ing mutations in Wiskott-Aldrich syndrome agnostic and analytic cytogenetic tests based genitor cells accumulates multiple mutations suggests that such genetic reversions may on interphase genome organization (NCI) has implications for the aging process, fo- take place more frequently than generally Human lymphoid tissue studies to eluci- rensic identifications, and anthropological believed and that identification and charac- date the dynamics of HIV-1 variants, which conclusions based on mitochondrial DNA terization of the mechanisms underlying back show that the later-stage CXCR4-utilizing sequence (NHLBI) mutations can aid in the development of new variant upregulates CC-chemokines that sup- The finding of sequence-based bias in the therapeutic strategies for genetic disorders press the replication of early-stage CCR5, ush- integration of murine leukemia virus and hu- (NHGRI, NCI) ering in accelerated progression to AIDS; de- man immunodeficiency virus-1 into the hu- The potential for blood-cell-associated velopment of a real-time PCR-based assay to man genome has ramifications for gene prion proteins to transmit transmissible evaluate the replication of HIV variants and therapy (NHGRI) spongiform encephalopathies through blood the R5-to-X4 switch (NICHD) Generation and analysis of a phylogeneti- transfusion is elucidated (NHLBI, CBER) cally diverse set of genomic sequences from Embryonic epithelial branching in the mor- Advances in imaging 12 vertebrate species is accomplished, as phogenesis of salivary glands depends on A novel real-time MRI system for guiding well as the demonstration of how compara- regulation by the extracellular matrix pro- intramyocardial injections of therapeutic tive sequence analysis can be used to iden- tein fibronectin, just as do lung and kidney agents affords better visualization of the tar- tify small genomic regions that are highly development (NIDCR) get tissue than traditional X-ray fluoroscopy conserved across multiple species (NHGRI) and the ability to monitor drug effects im- A new, highly specific molecular tracking Goal B: Develop new or improved instru- mediately (NHLBI) technique—T-cell clonotype tracking—al- ments and technologies for use in re- An MRI system that allows physicians the lows ex vivo determination of clonal fre- search and medicine ability to visualize 3-D volumes inside a pa- quency without prior in vitro expansion that tient in real-time, rather than individual slices, can aid in the study of pathogenesis of neu-
Use of more relevant computed tomogra- is particularly useful for tracking interven- rological immune disorders and in design- phy measures to determine visceral adipose tional devices; a method to obtain maps of ing therapeutic interventions in such condi-
12 — November — December 2003
tions as multiple sclerosis, HTLV-1 -associ- treatment for Hodgkin’s disease increases nary infection, proved safe and immunogenic
ated myelopathy/tropical spastic parapare- with radiation dosage to the breast and is in adults and is now being planned for evalu-
sis, and chronic Lyme neuroborreliosis ameliorated by the degree of damage to ova- ation in a phase II trial in children (NIDCD) (NINDS) rian function from radiation or alkylating A single injection of a conjugate vaccine Description for the first time of the global agents; the risk of lung cancer is associated containing Staphylococcus aureus type 5 and
differences between expression profiles of with both radiation exposure and alkylating type 8 capsular polysaccharides is safe and the two stem cell lineages—embryonic and agents; these risks persist for decades, sup- immunogenic and provides some protection trophoblastic—derived from the early em- porting the need for long-term follow-up of for approximately 40 weeks against S. aureus bryo, and identification of genes expressed these patients (NCI) bacteremia in patients with end-stage renal specifically in TS and ES cells, sets the stage Data generated from the ALTS Cervical disease, an immunocompromised population for further study of the differences between Cancer Screening Study demonstrate that hu- at especially high risk for S. aureus bacter- the lineage-committed and pluripotent stem man papilloma vims testing helps distinguish emia; testing of booster doses is suggested cells and their genes (NIA) women with equivocal cytological findings (NICHD) Buccal epithelial cells collected from who have potentially precancerous lesions Isolation and characterization of two gly- women who had received male-to-female from those whose abnormalities are not life colipid surface antigens of Borrelia bone marrow transplant show the Y pheno- threatening (NCI) burgdorferi advances the study of immunity type in the overwhelming majority of cells Circulating free testosterone levels corre- to this pathogen and the quest for an effec- with no evidence of fusion—supporting the lates with specific measures of cognitive per- tive vaccine against Lyme disease (NICHD) idea that adult stem cells retain plasticity and formance among men 50-90 years old in the Persistence of antibodies and efficacy have a role in regenerative medicine (NIDCR, Baltimore Longitudinal Study of Aging, a find- against typhoid fever is documented for up NHGRI. NHLBI, NIMH, NINDS) ing that could lead to study of the safety and to four years follow-up in children 2 to 5 Engineering of an anthrax toxin activated efficacy of testosterone supplementation to years old vaccinated with conjugate Salmo- by urokinase plasminogen activator trans- prevent or attenuate cognitive loss in healthy nella typhi vaccine (Vi capsular polysaccha- forms this toxin into a potent suppressor of aging men (NIA, NCCAM) ride bound to a recombinant mutant Pseudo- a broad array of malignant tumors, eradicat- Differences in characteristics of African monas exotoxin) (NICHD, NIDDIO ing established tumors without damaging American and non-African American teen- Development and testing of conjugate normal cells (NIDCR) agers suggest the need for ethnoculturally shigella and cholera vaccines and purifica- sensitive treatment strategies for smoking ces- tion of Campylobacterjejuni and Mycobac- Goal C: sation in adolescents—and the need to be terium tuberculosis polysaccharides contin- Develop new or improved approaches mindful that the number of cigarettes smoked ues (NICHD, NIDDK) for preventing or delaying the onset or daily may reflect nicotine clearance rate rather An improved anthrax vaccine that induced progression of disease and disability than degree of dependence and addiction capsular antibodies in mice expands the (NIDA) immunity conferred by available anthrax Neither estrogen nor prolactin exposure Skipping meals (without calorie reduction vaccines and could prove to provide more is found to be related to the risk of develop- or weight loss) was found to have beneficial protection against the greater number of ing systemic lupus erythematosus, but effects on resistance to diabetes, cardiovas- spores that might be released in a deliber- breastfeeding is associated with reduced risk cular risk factors and response to stress, and ate anthrax attack (NICHD, NIDDK, NIAID) in a population-based, case-control study neive cell integrity in mice; a controlled trial Studies showing that Brucella abortus in- (NIEHS) to test the effect of reducing meal frequency teracts with two different toll-like receptors Continuing post-trial follow-up of the Finn- in humans is in development (NLA) to trigger the release of both TNF and IL-12 ish ATBC (a-tocopherol, (3-carotene cancer Synthetic p53 inhibitors improves behav- inform the use of bacteria in designing ad- prevention) trial reveals no new findings that ioral outcome in a mouse model of Parkin- juvants and/or carriers for vaccines and im- would alter the recommendation that smok- son’s disease and may have clinical implica- munotherapy (CBER, NIAID, NCI) ers should not take supplemental (3-carotene tions (NIA) (NCI) Goal D: Continuing very long-term follow-up of Vaccine development Develop new or improved methods for sibling patients with gyrate atrophy show that A recombinant hepatitis E vaccine is highly diagnosing disease and disability the earlier in life an arginine-restricted diet immunogenic and efficacious in preventing is begun, the greater the protection against hepatitis and even infection in rhesus A computer-aided detection algorithm retinal lesions that ultimately lead to blind- macaques after I.V. challenge with three dif- identifies large polyps missed by CT in pa- ness (NEI) ferent genotypes of hepatitis E virus, strongly tients at risk for colorectal cancer (CC)
Epidemiologic studies indicate that DDT suggesting it will prove highly efficacious in Establishment of the best predictors of fi- use for malaria control in sub-Saharan Af- preventing hepatitis E in an ongoing field brosis progression in chronic hepatitis en- rica is accompanied by an increase in infant trial in Nepal (NIAID) ables the safe deferral of treatment for pa- mortality from DDT toxicity equal to a de- A phase I multiclade HIV-1 DNA plasmid tients with normal aminotransferase levels crease in infant mortality attributable to ma- vaccine trial is underway (VRC) and mild liver histology (NIDDK, NCI, CC) laria prevention, suggesting that other means A phase I/II clinical trial of modified vac- The uncovering of three immunogenetic to control malaria be used (NIEHS) cinia virus Ankara is being tested against markers provides additional evidence for Analysis of data from the Breast Cancer Dryvax challenge in vaccinia-na'ive individu- linkage disequilibrium in familial Hodgkin's Detection Demonstration Trial shows that the als (VRC) disease (NCI) risk of ovarian cancer is increased in women A phase I study of a lipooligosaccharide- High-throughput microarray genetic test- who use estrogen-only replacement therapy based conjugate vaccine against nontypeable ing and novel imaging techniques with im- increases especially Haemophilus the cause of about age-analysis software improves early identi- and with duration, be- influenzae , yond 10 years (NCI) one-third of cases of purulent pediatric otitis fication of neovascularization in patients with The risk of breast cancer after successful media and a common cause of adult pulmo- age-related macular degeneration (NEI, CIT)
13 ) The NIH Catalyst
Selected NIH Intrametral Research Accomplishments 2002—2003 continued
8 MRI proves more accurate than cardiac 8 Gene expression profiling demonstrates with lower incidence of necroinflammatory risk factors, ECG, and troponin assays in de- for the first time that the transcription de- changes in the liver (NIDDK, NCI) tecting acute coronary syndrome in patients fect in Werner’s syndrome (WS) is specific H Safety is established for nonmyeloablative arriving at the emergency room with chest to certain genes and that transcription al- allotransplantation in HIV patients with he- pain (NHLBI) terations in WS are strikingly similar to those matologic malignancies (NIDDK, NIAID, 8 Only one-third of children with Smith- in normal aging, identifying which genes NHGRI, CC, NHLBI, NCI) Magenis syndrome are found to have a nor- are important in the aging process and sup- 8 Melanoma patients offered nonmyeloab- mal lipid profile, suggesting that hypercho- porting the use of WS as an aging model lative conditioning followed by adoptive lesterolemia can be an early marker of the (NIA) transfer of antitumor lymphocytes specific for syndrome in children younger than 4 or 5, Gene expression patterns in the postmor- the MART-1 melanocyte differentiation anti- the age when the disease is usually diag- tem cortex of cocaine abusers reveals co- gen experience both the destruction of meta- nosed (NHGRI) caine-regulated transcripts associated with static tumors and an autoimmune attack on H New hepatitis B surface antigen assays an array of signaling mechanisms, neuronal normal tissues that express the MART-1 anti- proves superior to currently licensed tests plasticity, and oligodendrocyte function, gen; these results support the efficacy of this for detecting hepatitis B virus in blood do- including alteration in the extracellular new approach in melanoma treatment and nations; two of the newer tests were subse- signal-regulated kinase (MEK/ERK) path- suggest that normally expressed “self-anti- quently licensed; work continues on devel- way (NIDA) gens” can be useful as targets for human tu- oping nucleic acid tests to assay for HBV Ex vivo gene expression profiles differ mor immunotherapy in other settings if the DNA (CBER, NHLBI) among multiple sclerosis patients accord- autoimmune consequences of such treatment 8 Sequential evaluation of changes in visual ing to responsiveness to interferon-(3, a find- are acceptable, as may be the case in pros- memory test scores are predictive of Alz- ing that can elucidate the mechanism of tate, breast, ovaiy, or thyroid cancer (NCI, heimer’s disease up to 15 years later in a action of IFN-(3 in relation to different dis- NEI) study involving more than 1,400 people en- ease patterns and lead to optimized therapy; 8 A Phase I trial involving patients with a rolled in the Baltimore Longitudinal Study profiling after short-term treatment may variety of solid tumors at advanced stages of Aging, providing a tool for early identifi- enable prediction of long-term treatment and prior treatment histories establishes a safe cation of increased risk and lengthening the response (NINDS, NCI, CC) dose for further clinical trials of an epothilone window of opportunity for preventive mea- B analog—a member of a novel class of sures (NIA) Goal E: nontaxane microtubule-stabilizing agents that 8 Cerebrospinal fluid levels of |3-amyloid and Develop new or improved approaches has shown promise in vitro (NCI) tau proteins appear to be early biomarkers for treating disease and disability 8 Bevacizumab (anti-VEGF antibody) pro- of Alzheimer’s disease that offer a tool more longs time to progression in patients with reliable than current methods to prospec- 8 Cyclophosphamide and glucocorticoids metastatic renal cancer in a randomized con- tively track changes in people at risk for the for induction and methotrexate for main- trolled trial (NCI) disease; long-term studies to evaluate this taining remission prove an effective and B In the most favorable outcome yet docu- potential are now underway (NIMH) well-tolerated regimen in patients with ac- mented for this incurable disease, treatment tive Wegener’s granulomatosis (NIAID) of aplastic anemia with immunosuppression Gene expression patterns 8 Itraconazole proves effective in prevent- results in remission and a favorable long-term 8 Gene expression profiling proves to be ing fungal infection in patients with chronic response (NHLBI) the most precise prognostic index yet de- granulomatous disease; recurrent infections 8 Autologous lymphocyte-depleted periph- scribed for mantle cell lymphoma and sug- in patients with CGD are most likely eral blood stem cells mitigates the myelosup- that therapeutic modulation of the cell reinfections not relapses (NIAID, CC, NCI) pressive effects of high-dose cyclophospha- gests , cycle has the potential to significantly pro- 8 Pretreatment of fatty donor livers with mide in the treatment of refractory chronic long life (NCI IL-6 in vitro dramatically improves the take autoimmune thrombocytopenia (NHLBI, CC) 8 The Clinical Proteomics Program pioneers of such livers in liver transplantation, a find- 8 Different “trajectories of dying” and degrees the use of serum proteomic patterns to de- ing with major clinical implications because of dependency during what turned out to be tect early-stage ovarian cancer, achieving 100 one-third of all donor livers are fatty and at the last year of life are observed in elderly percent sensitivity in identifying all stages of high risk of transplantation failure (NLAAA) individuals who died of cancer, of organ fail- ovarian cancer—including stage 1 —and 95 8 Endocannabinoids acting on cannabinoid ure, suddenly, or in a frail state, underscor- percent specificity; serum proteomic patterns receptor 1 (CB1) in the brain have a major ing the need to create more-tailored programs also correctly predict 95 percent of prostate role in regulating alcohol preference in mice of care for elderly patients (NIA) cancers and 78 percent of benign prostatic and also in the age-dependent decline in 8 A short course of humanized anti-CD40 conditions; specificity for men with margin- alcohol preference, findings that support the ligand antibody improves serologic activity ally elevated PSA levels is 71 percent, sug- planned use of CB1 antagonists in the treat- and decreased hematuria in a pilot study in- gesting that this assay become an adjunct to ment of alcoholism (NIAAA) volving patients with proliferative lupus glom- PSA in deciding whether to biopsy men with 8 Recombinant leptin-replacement therapy erulonephritis, but the potential for increased marginally elevated PSA levels (NCI, CBER) improves glycemic control and decreases risk of thrombotic events needs study (NIAMS, The Clinical Proteomics Program has pro- triglyceride levels in patients with lipodys- NIDDK) duced more than 20 publications in the past trophy and severe insulin resistance 8 A new clinical program for the study of year elaborating on signal pathway analysis (NIDDK, CC) allograft tolerance introduces four novel of metastasis models and human cancers and 8 Maintenance therapy with ribavirin alone immunomodulation regimens, including proteomic pattern diagnostics, with particu- in patients with chronic hepatitis C main- Campath-IH, a humanized CD52-specific lar reference to prostate, ovarian, and colon tains biochemical improvements obtained monoclonal antibody (alemtuzumab) cancers (CBER, NCI) with combination interferon-ribavirin but (NIDDK, NCI)
14 . November — December 2003
High daily doses of sublingual buprenor- ising candidate for immunomodulatory treat- drugs in humans with a wide array of phine significantly reduces both cocaine and ment of MS (NINDS, NCI) neurodegenerative diseases (NIA) opiate use in outpatients dependent on both H Primate studies showing that adenovirus- 9 A potential therapeutic agent for spinal substances—the first direct demonstration of induced thrombocytopenia is the result of a muscular atrophy is identified (NINDS) this agent’s efficacy in treating dual depen- reversible increase in platelet clearance M Deacetylase inhibitors reduce the toxicity dence (NIDA) rather than bone marrow suppression may associated with the mutant polyglutamine Immunological tolerization to E-selectin, inform the design of safer gene-therapy de- that underlies many hereditary neurodegen- an adhesion molecule on endothelial cells, livery methods (CBER, OAR) erative disorders and are being considered
provides protection against development of ifi Small clinical srtidies in which exendin-4, for clinical trials in Huntington’s disease, ischemic and hemorrhagic strokes in animal an amino acid found in the saliva of the spinal muscular atrophy, and other diseases studies; plans for human trials using this ap- Gila monster and an agonist of glucagon- associated with polyglutamate expansion and proach are underway under a CRADA with like peptide-1 (GLP-1) receptor in humans, aberrant histone acetylation (NINDS) industry (NINDS) is well tolerated and a potent, long-acting 9 Identification of a drug that drastically re- Dopamine D3 receptor antagonists show insulin-releasing agent in patients with type duces the toxic homogentisic acid produced promise as anti-addiction and anti-relapse 2 diabetes, setting the stage for larger phase by alkaptonuria patients suggests moving agents (NIDA) III clinical trials (NIA) toward long-term safety and efficacy studies Methadone treatment induces attenuation GLP-1 agonists are shown to be neu- (NHGRI, NICHD, CC) of cerebrovascular deficits associated with rotrophic and neuroprotective in cell cul- E3 Generated under a CRADA with industry, prolonged cocaine and heroine abuse (NIDA) tures subjected to toxic insults emulating a new class of immunosuppressive drugs that Enzyme replacement therapy improves pe- stroke and Alzheimer’s disease and to be inhibit JAK3 proves effective against allograft
ripheral nervous system function, corrects effective in well-established animal models rejection in nonhuman primates and is of abnormal cerebral perfusion, and improves of neurodegenerative conditions; novel GLP- likely use in the treatment of autoimmune quality of life in a controlled clinical trial in- 1 analogs ai'e synthesized and patented and and inflammatory disorders as well; human volving patients with Fabiy disease (NINDS, are being assessed for use as experimental trials are anticipated (NLAMS) 9 NHLBI) Long-term follow-up of patients in the Early Treatment Diabetic Retinopathy Study shows Coming Soon: Next Class ofPRATS that 15 to 20 years after laser photocoagula- he NIGMS Pharmacology Research Associate ( PRAT) program is now accept- tion therapy and despite progression of other Ting applications for positions to begin in October 2004. This program sup- diabetic complications, retinopathy remains ports two years of training in NIH or FDA laboratories for postdoctoral candidates largely stabilized, with 80 percent still hav- in the pharmacological sciences and related research areas. These may include, ing good vision and no patient becoming but are not limited to, molecular pharmacology, signal-transduction mechanisms, blind. (NEI) drug metabolism, immunopharmacology, chemistry and drug design, structural Elucidation of the role of ocular surface biology, endocrinology, bioinformatics, and neuroscience. PRAT fellows receive inflammation in Sjogren’s syndrome helps competitive salaries as well as supply and travel funds to support research in their secure the approval of cyclosporine-A eye preceptors' laboratories. Candidates apply in conjunction with an identified pre- drops in the treatment of dry eye (NEI) ceptor, who may be any tenured or tenure-track scientist at NIH or FDA. Applica- In vitro studies demonstrated that acceler- tions must be received by January 5, 2004. For more information or application ated programmed cell death of the retinal materials, contact the PRAT program assistant at 301-594-3583 or pigment epithelial cells, a major cause of
Daclizumab is not only well tolerated in Individuals seeking academic credit may register with FAES. Those not seeking multiple sclerosis patients unresponsive to academic credit should register through the course e-mail list. To subscribe, for standard therapy but also dramatically inhib- more information on registration, and to see the class schedule, go to:
its inflammatory activity in a phase II clini- http:/ /wwwl.od.nih.gov/oir/DemystifyingMed/index.html>
cal trial that establishes the drug as a prom- 15 The NIH Catalyst
People Recently Tenured
Crystal Mackall received her M.D .from factors that regulate T-cell regeneration to direct the regenerating immune sys-
Northeastern Ohio Universities ofMedi- that could potentially be used to en- tem to react against tumor antigens. I cine, Rootstown, Ohio, in 1984 and hance immune reconstitution. We iden- believe that through this approach, im- completed a combined internal medi- tified IL-7 as a potent therapeutic ca- mune therapy will be effectively inte- cine/pediatrics residency in Akron, pable of enhancing T-cell regeneration grated into the oncologic armamen- Ohio, in 1988. In 1989, she joined NCI in mouse models. tarium and yield the greatest benefit. in the Pediatric Oncology’ Branch as a More recently, my laboratory demon- clinical associate. She was a postdoc in strated that endogenous IL-7 levels rise Colleen McBride received her Ph D the Transplantation Biology Section of in response to CD4 depletion in a vari- from the University of Minnesota, Min- the Experimental Immunology Branch, ety of clinical settings. These observa- neapolis, in 1990 and did her postdoc- NCI, from 1990 to 1996 and is currently tions, as well as the demonstration by toral training at Group Health Coopera- a senior investigator in the Pediatric On- other groups that IL-7 is required for tive ofPuget Sound in Seattle. She came cology Branch, NCI. thymic-independent homeo- to NIH in October of this year as a ten- Dramatic advances in the static expansion, led to the ured senior investigator to lead NHGRI’s basic understanding of cel- paradigm that IL-7 is a "mas- newlyformed Social and Behavioral Re- lular immunity over the past ter regulator of T-cell homeo- search Branch.
several decades have stasis.” On this basis, we have Before coming to NHGRI, I spent 15 opened up the real possibil- worked to develop early years developing innovative public- ity that clinically relevant im- clinical trials of recombinant health interventions to promote behav- mune-based therapies for human IL-7. The first such ior change to reduce health risks. In a
many human cancers will trial recently opened in the series of randomized controlled trials, I soon emerge. Translating Clinical Center. developed and evaluated a broad range these basic insights into In addition to T-cell regen- behavior interventions includ- Fran Pollner of change clinical gains requires a fun- eration, the immunobiology Ctystal Mackall ing: damental understanding of of pediatric cancer is another smoking prevention and cessation both sides of the host-tumor interface. area my lab pursues. We have focused treatment decision-making The major long-term goal of my lab is primarily on Ewing’s sarcoma, an ag- dietaiy change the development of immune-based gressive, poorly differentiated bone and physical activity therapies for pediatric cancers. My re- soft tissue tumor that afflicts children and sexually transmitted disease preven- search focuses heavily on the study of young adults. We have iden- tion the immune system in cancer patients, tified Ewing’s sarcoma as The common aim of these especially those who have undergone highly responsive to both trials was to design and standard cancer therapies. Fas-based and TRAIL-based evaluate low-cost, self-di- After completing clinical training in the apoptosis. Recently, we pub- rected behavior change in-
Pediatric Oncology Branch, I undertook lished the first evidence that terventions for large and postdoctoral work in transplantation endogenous immune re- geographically dispersed
biology in Ron Gress’ lab. There, I fo- sponses exist in patients with populations at risk for cused on basic questions related to the Ewing’s sarcoma. Work is chronic diseases and cancer. regeneration of T-cell populations after underway to find the best In particular, my research T-cell depletion due to therapy and/or way to immunize patients maximized the potency of
disease. Using mouse models, I identi- against Ewing’s sarcoma and/ brief interventions by taking fied markers to distinguish T cells re- or adoptively transfer T cells advantage of “teachable mo- generated via thymic-dependent vs. reactive to it. ments”—health-related events that natu- thymic-independent pathways and iden- My long-term goal is to use the dis- rally increase motivation for making tified differences in levels of immune coveries we have made in immune re- lifestyle changes. competence depending upon which constitution to develop immune-based My early research in smoking and pathway was utilized. therapies for patients with minimal re- pregnancy suggested that feedback of Translating these findings to the clinic, sidual disease. This is particularly perti- test results could yield teachable mo- we then undertook studies of T-cell re- nent to pediatric tumors, where inten- ments. For example, learning they are generation in children and young adults sive multimodality therapy is the rule in pregnant prompts up to half of women treated with intensive chemotherapy for treatment regimens. As a means toward to stop smoking spontaneously. Unfor-
cancer. I identified reduced thymic func- this end, we are currently conducting tunately, without formal behavioral in- tion as the primary cause of slow im- clinical trials of tumor vaccines, alloge- terventions, most women return to mune recoveiy in these patients. Dimin- neic bone marrow transplants, and smoking after giving birth.
ished thymic function as a primary cause adoptive transfer of autologous lympho- I also tested annual Pap screening and of slow immune recovery was subse- cytes, after chemotherapy for pediatric receiving test results showing low-grade quently confirmed in other states of T- sarcomas. cervical abnormalities as a possible cell deficiency, including those attribut- Ultimately through this work, I hope teachable moment for quitting smoking. able to HIV infection and bone marrow to develop clinical trials that integrate Generally, women were unaware of the transplantation. immune restoration with state-of-the-art link between cigarette smoking and cer-
I then began to focus on identifying adoptive therapy and/or tumor vaccines vical cancer and did not understand the
16 November — December 2003
mechanisms through which their risk Peter Apian received his M.D degree used Cre-lox technology to generate in- might be increased. from Pennsylvania State University at ducible rearrangement and expression
My colleagues and I developed and University Park, in 1983 . He was a pedi- of the SCL transgene. evaluated a quit-smoking intervention atric intern, resident, and chiefresident More recently, we have begun experi- for women receiving Pap smear results. at the Children s Hospital ofBuffalo, New ments aimed at modeling leukemia in Unfortunately, this intervention resulted York, from 1983 to 1987. He was a pe- zebrafish. Zebrafish offer several advan- in no greater smoking quit rates among diatric hematology-oncologyfellow and tages to the cancer biologist: Adult fish women with an abnormal Pap test than then a biotechnologyfellow at NIHfrom are approximately one inch long, and among women with normal results. 1987-1992. He moved to Roswell Park many fish can be housed in a small These results piqued my interest in ex- Cancer Institute in Buffalo, where he space. They have large, easily manipu- ploring how to communicate “normal” was an assistant professor and then as- lated eggs. These can be microinjected and “abnormal” results or to explain sociate professor ofpediatrics and mi- to generate transgenic fish. Because the biological mechanisms in ways that crobiology before joining the Genetics fish are transparent for the first weeks could be understood by lay audiences Branch at NCI in 1999. He is now a se- of life, we can track development using and would motivate behavior change. nior investigator and bead ofthe Leuke- fluorescent proteins. This led to the idea of using feedback mia Biology section in that Over the past several from genetic susceptibility testing as a branch. years, my lab has cloned and motivator for behavior change. With My laboratory studies non- characterized several chro-
funding from NCI, my colleagues and I random chromosomal trans- mosomal translocations that evaluated feedback on genetic suscep- locations associated with he- are seen in patients with tibility to lung cancer to motivate smok- matologic malignancy. Trans- acute myelogenous leuke- ing cessation among African Americans. locations have proven to be mia and produce NUP98 fu- For this campaign, we developed a car- a rich source of insights into sion genes. NUP98 is nor- wash metaphor and graphical images to cancer biology as well as mally a component of the communicate what the genetic marker many fundamental biologic nuclear pore complex, glutathione S transferase enzyme could processes. For instance, the which mediates transport of and could not tell a smoker. anti-apoptotic bcl2 gene was RNA out of, and protein into, The study showed that smokers could initially identified due to its the nucleus. We have devel- understand genetic results they got in involvement in a recurrent chromosomal oped lines of transgenic mice that the mail—with follow-up counseling on translocation. overexpress an NUP98-F10XD13 fusion the telephone—just as well as results Our studies begin with a clinical ob- gene. These mice develop pancytope- and counseling received in person. But servation, namely, a chromosomal ab- nia and a myelodysplastic syndrome that we also found that learning that one was normality associated with hematologic progresses to acute myeloid leukemia. genetically susceptible to lung cancer malignancy. Our general approach is to The experiments I described above was not associated with higher rates of clone the translocation and identify the focused on demonstrating that genes smoking cessation. The data indicated gene(s) involved, determine a mecha- activated by chromosomal translocations only about half of the smokers fully un- nism by which the translocation might lead to leukemia. This is just the begin- derstood the meaning of the test result. have occurred, and develop animal ning for us. If the chromosomal translo-
Results also showed that smokers may models of leukemia using the genes cation does cause leukemia, it becomes have been biased in remembering the identified. Our ultimate goal is to iden- important to determine what caused the result: Those with results indicating the tify causes of these oncogenic translo- chromosomal translocation. Therefore, greatest health risk, who got the most cations (so that they might be avoided), in addition to studies aimed at charac- threatening message, were most likely and to identify pathways activated by terizing the downstream effects of leu- to recall their results incorrectly. these translocations, so that these path- kemic chromosomal translocations, we Looking ahead, in my next five years ways might be targeted for therapeutic are also quite interested in learning the at the NHGRI Social and Behavioral intervention. mechanisms by which chromosomal
Research Branch, my goal is to work As a postdoctoral fellow, I identified translocations (and other gross chromo- with colleagues to build a leading-edge, and characterized several chromosomal somal rearrangements) occur. collaborative research program using rearrangements involving the SCL gene, We showed that we can reproducibly diverse scientific perspectives and ge- which is activated by chromosomal re- cleave genomic DNA at or near sites of nomic discoveries to develop public- arrangements in approximately 30 per- known translocation breakpoints within health interventions with the promise of cent of patients with T-cell acute lym- the MLL (mixed lineage leukemia) gene
real-world dissemination. I also want to phoblastic leukemia. Our laboratory has using known genotoxic agents. Im- continue to explore psychological pro- developed a mouse model for this type proper repair of these breaks could re- cesses that might help explain misun- of leukemia using SCL transgenic mice. sult in chromosomal translocation. We derstanding of biomarker feedback. Almost 100 percent of the mice develop are now developing a system in which Another goal is to develop tools to as- a fatal leukemia that resembles the hu- we can use the rare-cutting restriction sess key elements of teachable moments man disease in clinical presentation, enzyme I-Scel to induce a single double- so that we might capitalize on these pattern of spread, invasion, morphology, strand break in cells and determine events to increase the efficacy of health and immunophenotype. To mimic the whether improper repair of this break promotion efforts. human disease more closely, we have leads to chromosomal translocation, i®
17 The NIH Catalyst
Catalytic Reactions
On Review of Intramural Research details of the type requested in the re- Response Joram Piatigorsky’s recent commen- view of R01 proposals at study sections. Dr. Stetler-Stevenson has clearly described tary (Tide NIH Catalyst, March-April 2003) In both extramural review of grant pro- some of the similarities and differences in raised concerns about acquiescence to posals and BSC review of intramural re- intramural and extramural review ofscience the Board of Scientific Counselors (BSCs) search, the past research accomplish- and argues that we underutilize intramural expertise on our revieiv groups. for determination of the direction of the ments of the investigator under review There is, in fact, no prohibition against NIH Intramural Research Program (IRP). are usually used as a measure of ability the inclusion ofsuch scientists as ad hoc re- In conversations with friends and col- to carry out the proposed studies and viewers, and several institutes use intramu- leagues, it is clear that many agree with not as a basis for a final recommenda- ral scientists from other institutes as part of Dr. Piatigorsky that the changing role tion. their review groups. In addition, I routinely of the BSC may “threaten the most im- The blurring of the subtle difference assign intramural scientists to attend reviews portant features of the IRP." between a retrospective review based of all tenure-track investigators (approxi- His commentary also raises an addi- on quality of total work and a prospec- mately one-quarter of all of our principal tional dilemma—the disenfranchisement tive review has resulted in BSC reviews investigators), and they provide reports that help determine the response the to the of intramural investigators from the re- becoming as prospective as they are ret- of NIH BSC reviews. view process. The BSC was established rospective and “substitutes for NIH R01 Critical career decisions, such as appoint- in 1956 to assist the scientific directors grant applications.” ment of tenure-track investigators, promo- in evaluating the quality of the intramu- Perhaps the most difficult problem tions to tenure, and other intramural pro- ral research programs for which they are with BSC review of the IRP is interin- motions, are all made using internal com- responsible. stitute inconsistency. As pointed out in mittees of intramural scientific experts. I be- The IRP now has more than 1,250 in- Dr. Gottesman’s reply to Dr. Piatigorsky’s lieve that we makegood use ofthe enormous tramural investigators, many of whom comments, only three institutes conduct scientific talent in the intramural program, are internationally recognized experts, site visits led by at least two BSC mem- but also strive to avoid the conflict of interest yet these scientists are systematically bers. Other institutes have other ap- that may resultfrom using reviewers who are close to the people being reviewed. excluded from the scientific review pro- proaches. Quality assessment mecha- There is both real and perceived value of cess that determines the fate of their nisms are therefore inconsistent, and ex- outside review as one way to exercise good research projects. Is it not time that the pectations may also be. stewardship of taxpayerfunds. collective expertise of senior investiga- How can an equitable review for all —Michael Gottesman, DDIR tors in the IRP be utilized in evaluating members of the IRP be ensured and re- the scientific direction of the IRP? flect the unique aspects of the IRP re- On Tenure and Tuition: A Proposal In his response to Dr. Piatigorsky, Dr. search environment? Members of the IRP Recently tenured researchers at NIH Gottesman, DDIR, points out several research community ought to be in- have been encouraged to consider them- details of the BSC review process. He cluded in the BSC process. Intramural selves faculty, and that reminds me of notes that three institutes utilize site-visit investigators have outstanding scientific one of the most important privileges of teams, led by at least two BCS mem- credentials and are committed to pro- faculty members at most public and pri- bers, but consisting principally of extra- viding rigorous, objective reviews. They vate universities that we haven’t been mural “expert" investigators. These “sub- would bring a sensitivity to issues spe- awarded as NIH faculty. ject matter experts” from the extramural cific to intramural research that would That privilege is the opportunity for research program conduct the initial re- complement the perspective of extramu- dependents to attend affiliated univer- view of intramural investigators, which ral reviewers. Moreover, the use of IRP sities on a tuition-free basis—a privilege is then sent to the full BSC for further scientists from different institutes would also available to employees at other review and recommendations. The cri- help standardize the review process national labs such as Los Alamos, where teria for scientific review of intramural across the NIH intramural program. they may enroll dependents tuition-free investigators are significance, approach, I know of an instance in which an at any of the University of California innovation, environment, support, inves- intramural investigator participated in campuses. tigator training, productivity and the review team for another institute and As most of the current tenured NIH mentoring; see guidelines for intramu- was well received by both the site-visit faculty will attest, this is a very signifi- ral scientific reviews team members and the institute under cant financial reward for a family, and it
18 — . November— December 2003
Clinical Research Training Programs NIH Duke The NIH-Duke Training Program in Clinical Research, implemented in
tuition benefit is also mention that this privilege is ex- — Though a for employees 1998, designed primarily for phy- desirable is sounds , NIH a government sicians dentists desire for- tended to all permanent employees at and who agency with no legal authority to provide some universities. mal training in the quantitative and such a benefit— nor could it solicit such a methodological principles of clinical There are several mechanisms used “gift” from a university. Unsolicited tuition research. The program is offered via by different universities to support this waivers would be considered a gift and sub- videoconference at the Clinical Cen- privilege that could also be used by ject to analysis under standards conduct of ter and includes formal courses in re- NIH so the cost of its implementation rules. The situation at Los Alamos is not com- — search design, research management, need not be an issue. parable because the laboratory is run by the and statistical analysis. — Jordan Grafman, NINDS Un i versify of California —Ed. Academic credit earned in this pro- gram may be applied toward a Mas- ter of Health Sciences in Clinical Re- Relay Revelry search degree from Duke University his year’s NIH Relay demonstrated that School of Medicine, Durham, N.C. TNIH scientists are just as competitive out- Applications for 2004-2005 are side the lab as they are in it. More than 70 available in the NIH Clinical Center, teams competed in a five-leg, 2.5-mile re- Office of Clinical Research Training lay race around Building 1. The prize: a and Medical Education, Building 10, place for the team on the coveted Allen Room B1L403- The deadline for ap- Lewis NIH Memorial Trophy. plying is March 1, 2004. Applicants Inscribed this year on the trophy, which who have been accepted into the pro-
is located in the fitness center in Building gram will be notified by July 1, 2004. 31, will be “Parasites on the Run,” the team For additional information on that also bested competitors (and host de- course work and tuition costs, visit fenses?) to win last year. In 14 minutes, 20
“.Parasites on the Run ” and “Wurtz
19 . — The NIH Catalyst
Digit Designs: An Experiment with Fingerprints
Catalytic e’re all born with them, we know they’re used to catch criminals, but how much do we Wreally know about fingerprints? With this experiment, you will learn more about finger- Reactions? prints, including their differences and frequency, and amaze your classmates, all while doing a science project!
f you have a photo or Fingerprinting your entire class isn’t time-consuming or messy at all. I other graphic that reflects All that you need are: an aspect of life at NIH H A roll of large, clear packing tape (including laboratory life) Baby powder or a quotation that scien- Dark construction paper, cut into 3x5 sections, tists might appreciate that enough for two cards per person would be fit to print in the Ask your classmates to rub their hands in a little space to the right, why not bit of baby powder. (Your teacher will thank you send it to us via e-mail: the science room will smell great!) Then carefully [email protected]>; remove a 6" section of the clear tape from the roll, fax:402-4303; or mail: making sure not to put any smudges anywhere. Building 2, Room 2W23. Put the tape sticky-side up on a flat surface, and have your classmates roll each powdered finger on Also, we welcome the tape. You will see beautiful fingerprints! “letters to the editor” for Then put the fingerprinted tape on the dark card. Leftfourfingerprints of an anonymous NIHer publication and your The fingerprints show up even better! Have your reactions to anything on the Catalyst pages. classmates repeat the process with the other hand, and write their names on each of the cards. All of the prints will be different (even if you have twins in the class?), but will fall into three major categories (check out the pictures): loop, whorl, and arch. Whorls look like a tornado, arches look like a hill, and loops look like a mountain. In Future Issues... Now, to the analysis. Write the name of each classmate down the left side of a piece of paper. Across the top write loop, whorl, and arch. Now count the number of loops each person has and Leto’s Plowshares write it down in the appropriate box. Is one pattern more frequent than another? Now, within each person’s set of fingerprints, are almost all of them one pattern, but one is different? If you To the Beat figure it out, please write! ® Of the Tabors For more information on fingerprint analysis and forensic science, visit
The NIH Catalyst is pub- Publisher Scientific Editor Editorial Advisory Board lished bi-monthly for and by Michael Gottesman Celia Hooper Jorge Carrasquillo, CC the intramural scientists at Deputy Director David Davies, NIDDK NIH. Address correspon- for Intramural Research, OD Managing Editor Dale Graham, CIT dence to Building 2, Room Fran Pollner Hynda Kleinman, NIDCR 2W23, NIH, Bethesda, MD Editors Elise Kohn, NCI
20892. Ph: (301) 402-1449; John I. Gallin Copy Editor Susan Leitman, CC fax: (301) 402-4303; Director, Warren Grant Magnuson Shauna Roberts Bernard Moss, NIAID e-mail:
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