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Fostering Communication and Collaboration
The nihCatalyst A Publication fob NIH Intramural Scientists
of of Director Volume 13 Issue 1 a January-February National Institutes Health i Office the e , 2005
Nanomedicine Initiative: Roadmap Recap: A New Pathway to Discovery A Year’s Worth With Evolving Turns and Destinations Of Milestones by Karen Ross by Fran Pollner he aim of nano- raised for her “flawless execu- medicine, one of tion of a very complex process” T nine major NIH by NIH Director Elias Zerhouni, P Roadmap initiatives, is to NIH Roadmap coordinator Dushanka treat disease by intervening Kleinman delivered a first-year at a molecular level. It is a progress report at the De- Roadmap close cousin of nanotech- cember 2004 meeting of the Advi- nology, which is con- sory Committee to the [NIH] Director. cerned with building de- In general, she said, 2004 could vices that are 0.1 (i or less be characterized as a year of seed- in size. (For reference, the ing new tools and technologies for head of a pin is 2,000 jli, a the team science and clinical research typical human cell is ap- of the future. Among the year’s proximately 5 p, and a Intrigued by the Invisible: NEI Director Paul Sieving achievements: large protein complex is (left) and NHGRI tech development guru Jeffery Schloss Establishing four National Centers (right), co-cha irs of the NIH Roadmap Na nomedicine approximately 0.005 p.) for Biomedical Computing (with more Implementation Group flank Richard Fisher, director of Nanomedicines, for ex- , to be funded in 2005) the NEI Corneal Diseases Program and Nanomedicine Launching the Patient-Reported ample, could beof tiny ma- Project team leader Outcomes Measurement Information chines that compensate for System, with seven grants, six to primary the function of defective proteins or very bust systems that operate at the “nano” research centers precisely targeted pharmaceuticals that scale. Funding 20 nanomedicine concept- have no side effects. But he does sound a cautionary note. planning grants, which will form the so- However exciting and promising the licitation base for Nanomedicine Devel- Deeper Levels of Quantitation field of nanomedicine may be, it is also opment Centers in 2005 and 2006 (see Before these treatments can become a field in its infancy. story, page 1) a reality, scientists first need a detailed, It is extremely hard to predict what Funding 21 interdisciplinary re- quantitative understanding of cellular direction nanomedicine research will search exploratory centers and identify- ing institutional barriers to interdiscipli- processes. Many of today’s approaches take in the near future, Schloss says, and nary research to biochemistry and molecular biology this uncertainty has presented special Conducting an inventory of clinical are much more descriptive than quanti- challenges to the nanomedicine imple- research networks (500 already identi- tative, says Jeffery Schloss, director of continued on page 4 fied) to identify best practices Technology Development Coordination, H Launching 12 pilot studies to assess NHGRI, and one of the chairs of the the feasibility of integrating and increas- CONTENTS implementation group that directs the Nano-sampler ing the interoperability of clinical re- Roadmap nanomedicine initiative. 1 search networks and to pave the way Nanomedicine: 6-7 The nanomedicine initiative, Schloss for NECTAR (National Electronics Clini- A New Pathway Translational says, scientists to take cal Trials and Research network) encourages an To Discovery Research: Careers Designing the scope for engineer’s view of the cell—to think of planning Roadmap Recap ...And RAID as circuits to grants to be funded in 2005 and 2006 for molecular pathways and For Core Services regional translational research centers, as make careful measurements of physical well as for core services similar to the and chemical processes that take place. From the DDIR: 8-11 Intramural NCI RAID program (see stoiy, page 7) IRP Round-up 2004 Nanotechnology will contribute both Accomplishments Completing the first of the round the tools to make these measurements 11-15 NIH Director’s Pioneer Award (see and, ultimately, the devices that can re- Recently Tenured
. . i - From the Deputy^Director for Intramural^ Research
Intramural Research Accomplishments
his issue of The NIH Catalyst includes There is our annual enumeration of selected probably T intramural scientific achievements. no better At a time place in when budgets the world are tightening than NIH and scrutiny for both and restric- laboratory tions are in- and ap-
creasing, it is a plied re- heartening re- search in minder of the immunology. The research highlights in- quality and clude several examples of contributions impact of our work. The special intramu- to basic immunology, such as cytokine ral environment that facilitates this science research, as well as specific contributions is what attracted most of us to the NIH to HIV pathogenesis and vaccine devel- and what keeps us here through thick and opment, including progress in both HIV thin. and SARS. In addition to the extraordi- In my talk at the NIH research festival nary concentration of talent at NIH in these
this year, I focused on three components areas, we have several energetic trans-NIH of the intramural program that have been grassroots scientific interest groups under especially critical in the umbrella of the its success. Richard Immunology Inter- Florida, in his book est Group, as well The Rise of the Cre- as the Vaccine Re- ative Class, referred search Center, that to these as the three facilitate communi-
T’s : Technology, cation and collabo-
Michael Gottesman Talent, and Toler- ration in these re- ance (for out-of-the- search areas. box and creative en- Creativity in the deavors as well as a intramural program diverse work-force). is frequently mani-
The abbreviated list fested as novel in- of accomplishments beginning on page 8 terdisciplinary studies, amply illustrated in
highlights all three of these aspects of the the list of annual achievements, that break intramural program. down barriers between Institute-specific NIH continues to be pre-eminent in the research programs. Because we tolerate discovery and characterization of genes in- and encourage structural biologists in volved in disease, especially in cancer, NIDDK to work on HIV-AIDS and mental illness, Alzheimer’s disease, or cardiac physiolo- and neuro- gists in NHLBI to develop imaging tools logical prob- relevant to neurobiology, we are able to lems such as make novel and innovative contributions Parkinson’s to biomedicine. disease. Ow- Obviously this brief synopsis of achieve- ing to the es- ments cannot do justice to the extraordi- tablishment of nary breadth of intra-
an NHGRI in- mural science. I hope
tramural pro- it will serve to remind gram and ge- our scientific staff of netics core fa- why NIH is a very cilities several special place. years ago, we had a big —Michael Gottesman headstart on disease-gene discovery, and Deputy Directorfor Intramural Research this technology has spread to most of the intramural program, facilitating bench-to- bedside applications of basic genomic re- search. The new Clinical Research Center will undoubtedly facilitate these advances.
2 , January — February 2005
11 * 11,11 (IT "I 1 Ethics Forum
Accountable Authorship: Comments from NIH Scientists byJoan Schwartz Assistant Director, OIR Who Took the Research Ethics Computer Course
n July we launched the Research Eth- guarantor of the paper. The journals ducing lots of ics Computer Course (
I notified all of you about it through a conducive environment, being the Units).” column in The NIH Catalyst (July-Au- spokesperson, or providing published Kovac has
gust 2004 issue). Since then, I have re- reagents or procedures are not activi- written a com- ceived approximately 300 comments, ties that warrant authorship without a mentary, pub- via the built-in e-mail address for re- significant contribution to the scientific lished in Chem- sponses, and am pleased to report that content of the paper” (PNAS 101:10495, istry & Biodiv- Joan Schwartz
1 : 99 percent of them have been highly 2004). They believe that these criteria ersity ( 6 0 6 complimentary. will protect against ghost or gratuitous 2004), in which he notes that the quality Some of the comments have raised authorship. of chemistry papers has been declining stimulating questions about specific top- These new guidelines represent ex- despite increasing sophistication of meth- ics and/or quiz questions or cases, and tensions of the rules for authorship pro- ods, reagents, and instrumentation. the NIH Committee on Scientific Con- vided in the course. It would be worth- One reason is that the “number of pa- duct and Ethics has decided to address while to discuss these in one of your pers whose experimental results cannot those. Future issues of the Catalyst will future lab meetings. be reproduced because of lack of data contain responses to issues raised about Paul Kovac, NIDDK, raised a differ- presented, as well as the number of com- the cases involving human subjects. We ent kind of publication issue of con- pounds described for the first time that will also write about specific authorship cern to him. In the course module on have not been properly characterized, is questions regarding one of the cases. publication and authorship, page 3 increasing at an alarming rate.”
In this column, I would like to ad- states: “Even though each paper should Kovac, like many of us, is convinced dress more generic authorship issues contain sufficient information for the in- that “the progress of science is not di- raised by three of our intramural scien- formed reader to assess its validity, the rectly proportional to the number of tists. Rose Mage, NIAID, provided a PDF principal method of scientific verifica- pages available in journals.” file with the new PNAS authorship cri- tion is not review of submitted or pub- As stated so elegantly by Rene Dubos teria, and Germaine Buck Louis, lished papers, but the ability of others (and inscribed on the sculpture bridge NICHD, noted that the International to replicate the results. Therefore, each in the Science Court of the Hatfield Clini- Committee of Medical Journal Editors paper should contain all the informa- cal Research Center): “In science as in
cific contributions to the publication, progress of science. But . . . tions, and to publish only complete stud- either by checking off appropriate re- “Each publication should make a ies with all the necessary details avail- sponses from the journal’s list or put- substantial contribution to its field. able to enable replication. ting the information into a footnote. “Fragmentary publication of the re- Perhaps the most important result of Authors are asked to agree on au- sults of a scientific investigation or mul- heeding all this advice would be that thorship order based on these contri- tiple publications of the same or simi- there might be fewer—but better—jour- butions. The PNAS guidelines state that lar data are not appropriate; e.g., using nals and articles for busy scientists to the corresponding author should be the a tactic termed salami slicing or pro- read!
New Fogarty Scholar, Immunology Giant, To Be at NIH One Year
iorgio Trinchieri, the France, Trinchieri will pur- tive response G discoverer of IL-12 sue research focusing on: Means to harness innate resistance and murine plasmacytoid The interface between for antitumor therapeutic effect based dendritic cells (DC), has natural resistance and on tumor antigen-specific and nonspe- been named an NILI adaptive immunity, espe- cific mechanisms. Fogarty Scholar for one cially mechanisms regulat- Trinchieri will work closely with year starting November 15, ing DC subsets, natural NIAID and NCI investigators involved 2004. killer cells, and T cells in related research and will be based Currently the director of The role of cytokines primarily in the Laboratory of Parasitic the Schering-Plough Labo- and DC in regulating early Disease, NIAID, according to Robert ratory for Immunological innate response to infection Seder, chairman of the Cytokine Inter- Giorgio Trinchieri Research in D arc! illy, and deviation of the adap- est Group, who nominated him. 3 The NIH Catalyst
Nanomedicine Initiative continued from page 1 mentation group. Nanomedicine is one of the five ini- tiatives under the major NIH Roadmap theme “New Pathways to Discovery.” The initiative is directed by an imple- mentation group whose members are drawn from all over NIH. Along with Schloss, the 16-member nanomedicine implementation group is chaired by NEI Director Paul Sieving, whose institute is responsible for ad- ministrative oversight of the initiative. The group’s primary mission is to de- velop a program that will fund the es- tablishment of Nanomedicine Develop- ment Centers. This initiative, Schloss and Sieving ob- serve, has relevance to disciplines throughout the entire NIH. The tools and concepts that will emerge will en- hance basic biological understanding and should eventually result in medi- cal interventions that touch the mission of every institute. Overseeing the initiative to quantify the unseeable: (left to right) Paul Sieving, Richard Fisher, andJeffery Schloss Approaching a Visionary Center
No one is sure yet just what a funding. Says Sieving, “We want . . . the vision of a nanomedicine development Nanomedicine Development Center will groups that are funded by this [initia- center. look like. The investigators that make tive] to have free intellectual space to The implementation group received up a center could all be from the same develop the concept of nanomedical 81 such white papers, from which the institution, or there could be a core technology in a way that we hope will members, in consultation with a group group at one institution that has collabo- speed its emergence.” of extramural scientists, chose 20 to re- rators in other places. ceive planning grants. “They can also be virtual centers; A Unique Process Criteria for judging the white papers there’s really no requirement for bricks This degree of freedom is possible included the characteristics of the sug- and mortar,” says Richard Fisher, direc- because of the unique process the gested model systems; the attention paid tor of the Corneal Diseases Program, implementation group devised for fund- to quantitative measurements and engi- NEI, and Nanomedicine Project team ing the centers. neering design principles; and the leader. Typically, when NIH program staff multidisciplinary nature of the team’s ap- The idea, he says, is to bring in top identify an area in biomedical science proach. Overall, the group sought to en- investigators from many disciplines to that needs investigation, NIH issues a sure the inclusion of a broad range of work on a common problem. “They can request for applications (RFA), and in- biomedical areas (see sidebar, page 5). work together across oceans; what’s im- terested scientists submit an application. In another departure from the tradi- portant is their chemistry.” Then, two levels of peer review, the tional grant-application process, in The requirements for a center have study section and the advisory council which investigators carefully guard the intentionally been sketched out only in of the funding NIH institute, are invoked confidentiality of their proposals, rep- rough outline: to assess the scientific merit of the pro- resentatives from each of the 20 groups A center should bring together sci- posed work. will present more detailed 15-page pro- entists from a wide range of disciplines For the Nanomedicine initiative, how- posals to each other and to members of including biology, engineering, chemis- ever, the implementation team designed the implementation group at a meeting try, physics, and mathematics. a multistep process whereby extramu- to be held in March 2005.
E The group of centers that is funded ral investigators work collaboratively This meeting, Fisher observes, will should form a collaborative network that with NIH staff to craft the content of “really stimulate the interactive nature shares both intellectual and physical re- the Centers RFA that will be issued in of the process.” The cross-talk and ideas sources. April 2005. generated during the meeting, together The research should focus on de- The initiative was launched at a pub- with the applicants’ written proposals, veloping quantitative approaches that lic meeting May 4, 2004, at NIH; ap- will inform the implementation group’s are applicable to a wide range of bio- proximately 300 scientists from all over final RFA for the Nanomedicine Devel- logical problems. the country attended. After this meet- opment Centers. The details have all been left to the ing, investigators were invited to sub- In 2005, only the 20 groups that par- creativity of the scientists who apply for mit a five-page “white paper” of their ticipated in the planning stages will be 4 .
January — February 2005
Nanomedicine Sampler: Plumbing the Depths of Cellular Processes
by Karen Ross
he 20 groups awarded nanomedi- want to gain a detailed understanding of ply this knowledge to the design of cine development cen-ter planning the signaling pathways triggered when the nanoconducting devices. T grants reflect diverse scientific in- immune system encounters an invading Gary Johnson and his team at the terests and approaches: microorganism. Ultimately they hope to University of North Carolina, Chapel Hill, A group at Brown University, Provi- be able to manipulate the immune re- focus on the stressome, a multiprotein dence, R.I., led by Clyde Briant plans to sponse in individual cells or in the body complex that responds to cellular stress. study the interactions between human of an organism. They have developed probes that can tissues and foreign materials on a mo- Douglas Eaton of Emory University, detect the conformation of individual lecular level, with the goal of develop- Atlanta, and his group plan to use scan- components of the complex. ing more biocompatible medical implants ning probe microscopy techniques, which A group at the University of Con- and devices. can zero in on structures as small as a necticut School of Medicine and Den- Wah Chiu’s group at Baylor College, molecule interacting with the surface of tistry, Farmington, Ct., led by Leslie Loew Houston, wants to examine how molecu- a cell, to study how cells communicate will address cellular processes on “su- lar chaperones help proteins to fold into with each other. pramolecular scale.” These experiments their con-ect three-dimensional structures. A team at the University of Pittsburgh will take a broader view than studies of This research could lead to the design of led by Susan Gilbert will investigate the individual molecules but provide more protein-folding machines that could be motor proteins involved in mitosis at the detail than studies done on a cellular used to fight diseases, such as nanometer level with the goal of devel- level Alzheimer’s, that are thought to be caused oping better strategies for controlling cell Edward Pugh and his colleagues at by the accumulation of misfolded pro- proliferation. the University of Pennsylvania, Philadel- teins. Kevin Gillis’ group at the University phia, will study supramolecular cellular On a similar theme, Yuri of Missouri, Columbia, plans to study the compartments (SMCCs) such as photo- Lyubchenko’s team at the University of protein and lipid machines that move receptors and nerve growth cones. They Nebraska Medical Center, Omaha, will material into and out of cells. These ma- want to understand how these compart- explore what causes proteins to misfold chines are implicated in many diseases, ments assemble and eventually hope to and aggregate. They will develop tools including cystic fibrosis and diabetes, and develop artificial substitutes that can be to observe individual proteins as they ag- are prominent drug targets. used to treat diseases, including retinal gregate and techniques to manipulate Chih-Ming Ho at the University of degeneration, that are caused by defec- these proteins in the test tube. California, Los Angeles, and his colleagues tive SMCCs. James Baker’s group at the Univer- will use tools to visualize and manipulate A group led by David Needham at sity of Michigan, Ann Arbor, proposes to the cytoskeleton, whose dynamic rear- Duke University, Durham, N.C., plans to study the structure and function of mem- rangements are critical for many cellular apply engineering principles to the study branes using nanoscience tools. This processes. of four biological problems: drug deliv- work could lead to better strategies for Samuel Stupp and his team at North- ery, measurement of forces inside cells, delivering drugs to cells as well as a western University, Evanston, 111., also inflammation, and orthopedic bioengi- deeper understanding of agents that dis- plan to tackle the cytoskeleton on the neering. The knowledge they glean will rupt membranes. nanoscale. The group will study the as- be used to design nanoscale machines. Gang Bao of the Georgia Institute sembly of cytoskeletal structures and the A Columbia University (New York, of Technology, Atlanta, leads a group that involvement of the cytoskeleton in cell Morningside campus) team led by studies the biological nanomachines re- division and movement. Michael Sheetz will explore the connec- sponsible for RNA synthesis and DNA Ehud Isacoff s team at the University tions between cellular processes and repair. They will develop imaging tools of California, Berkeley, will study the physical factors such as spatial organiza- that can reveal the behavior of single membrane receptors that detect condi- tion and mechanical force. This work molecules inside cells. tions in the extracellular environment and could lead to improved production of Richard Wood and his group at the the signaling pathways that relay this in- artificial tissues and therapies to enhance University of Pittsburgh will focus on the formation to the nucleus. tissue repair. large protein complex responsible for A group led by Eric Jakobsson at the Wendell Lim’s group at the Univer- nucleotide excision repair. University of Illinois, Urbana-Champaign, sity of California, San Francisco, plans to James Crowe and his team at will embark on detailed studies of bio- build machines that can direct cell move- Vanderbilt University, Nashville, Tenn., logical ion-conduction systems and ap- ment.
allowed to respond to the RFA and of formed by everything we’ve done and As for their financial future, it is pos- those, three or four groups will receive learned this first round,” Fisher says. sible that they will continue to be sup- five-year grants to establish their cen- The team hopes that at the end of ported by the Roadmap, or they might ters; the grants will total $6 million. five years the first-round centers will be adopted by individual institutes at have become productive, self-sustain- NIH. Alternatively, they could seek out Beyond 2005 ing entities. funds from regular NIH grant programs The implementation group anticipates The centers are expected to have a or from private agencies. another $6 million for a second round cohesive set of investigators, to have a "Were hoping to build something so of Nanomedicine Development Center well-defined, workable topic of study, exciting,” says Schloss, “that NIH and grants. Competition for this second and to have made substantial progress other agencies . . . can’t resist putting round will be more traditional but "in- in their research, says Sieving. more money into it." H
5 ) — ..
On the Road to Clinical and Translational Research Careers
by Dianne Needham
s part of their so-called “year off” from school to en- During the CIST gage in concentrated research, more than 250 medical Forum, established A and dental students converged on the NIH campus for investigators repre- the second annual Clinical Investigator Student Trainee (CIST) senting both NIH Forum. and other academic For three days in November 2004, the students were im- medical centers pre- mersed in lectures, panels, and workshops to fortify their sented their ideas nascent interest in becoming clinician investigators. They were and experiences in invited to attend because they are currently participating in the realm of how to clinical and translational research fellowships—often referred succeed as a physi- to as “year-off” programs and sponsored by NIFI and other cian-scientist; they academic medical centers around the country. (For info on also explored con- the NIH program, see
January — February 2005
Re-engineering the Clinical Research Enterprise A Look at the Roadmap’s RAID For Translational Research Core Services
by Annie Nguyen
ebruary 2005 marks the beginning Stephen Straus and in- diseases, would be of an NIH Roadmap pilot pro- cluding representa- among NHLBI target F gram to expedite the transition of tives from 13 different projects. novel therapeutic discoveries to early- institutes, the imple- NIEHS RAID pri- phase clinical trials. mentation group will orities, according to A component of the Roadmap’s clini- appoint a review Dennis Lang, deputy cal research re-engineering initiative, board to select those director of extramu- the NIH-RAID (rapid access to projects to be awarded ral research and interventional development) pilot will grants. Once the training, include en- make available, on a competitive ba- projects are actually vironmental compo- sis, the means to address regulatory approved, however, nents of childhood and/or technical barriers to moving a the oversight will asthma, allergies, promising idea from the bench to bed- largely go back to the and cardiovascular side testing. co-sponsoring insti- Annie Nguyen diseases, as well as Josephine Briggs tute(s). research related to Process Funding to support individual projects countering potential terrorist activities According to Josephine Briggs, di- will come from both the Roadmap and or, as described at the NIH-RAID rector of the Division of Kidney, Uro- individual institutes, with the institutes website: “development of new thera- logic and Hematologic Diseases, assuming the bulk (three-fourths) of peutic approaches for treating or pre- NIDDK, and co-chair of the implemen- support in the specific disease areas akin venting injury and disease caused by tation group for Translational Research to their mission. Briggs points out that the intentional release of chemical Core Services, this pilot program will institute co-sponsorship is critical to agents by terrorists.” provide services for academic investi- ensure disease-specific expertise in the For an overview of each institute’s gators, as well as for some intramural oversight of the projects. RAID research priorities, visit researchers, “of the sort that are more Applications for NIH-RAID awards
public health challenges. that frequently do not attract private whether it can get the projects into Co-chaired by NCCAM Director sector investment, such as hematologic early clinical testing.”
Getting to the Core Preliminary Request Submission Date Preliminary Evaluation Notification Full Proposal and Request Submission Date
Cycle 1 February 1, 2005 March 8, 2005 May 2, 2005 Cycle 2 June 1, 2005 July 6, 2005 September 1, 2005 Cycle 3 January 2, 2006 February 6, 2006 April 3, 2006 Cycle 4 June 1, 2006 July 6, 2006 September 1, 2006
7 "
Selected* NIH Intramural Research Accomplishments 2004
Add to the body of knowledge about new target for therapeutic interventions to tributing to immune evasion, and providing normal and abnormal biological func- improve learning and memory (NIA) a selective advantage for CCR5-tropic vims tions and behavior Development of a natural-challenge mouse that may explain its preferential transmission Identification of disease genes model for plague infection and testing of an in nature (VRC) Variants in a single gene on chromosome experimental plague vaccine that proved to Enhanced oligodendrocyte progenitor dif- 20 (hepatocyte nuclear factor 4a, or HNF4a, be 100 percent effective; the model will be ferentiation found to promote remyelination, a transcription factor that influences insulin used to test other plague vaccines in devel- suggesting that drugs designed to target the response to glucose) found to confer a 35 opment and to track the spread of plague sigma-1 receptor may be useful in treating percent increased risk of type 2 diabetes in bacteria through a host to study possible demyelinating diseases or other myelination- Finnish populations (NHGRI) therapeutic interventions (NIAID) related pathopsychiatric disorders (NIDA) Identification of two genes through Development of a mouse model of SARS Identification of the basolateral complex microarray screening— ezrin and SIX]—that replication that demonstrated that mice pro- of the amygdala as a key factor in environ- regulate the metastatic phenotype of rhab- duce neutralizing antibodies to the SARS vi- mental triggers of drug-induced brain reward domyosarcoma cells in mouse models, sug- rus that protect them from re-infection and and therefore a key target for antirelapse gesting the possibility of clinical interven- that immune sera from infected mice pro- therapies for alcoholism and drug addic- tions to prevent metastasis (NHGRI, NCI) tected other mice from SARS infection; thus tion—hitherto poorly understood and poorly Identification of five chromosomal regions far, the mouse model has been used to dem- treatable (NIDA) that harbor attention-deficit hyperactivity dis- onstrate the efficacy of a DNA vaccine, an Elucidation of the underlying mechanism order susceptibility genes (4ql3-2, 5q33-3, inactivated vaccine, a vectored vaccine, and of mental retardation in Down's syndrome 8qll.23, Uq22, and 17pll) (NHGRI, NIMH) three candidate immunotherapies (NIAID, through the finding in Drosophila that A polymorphism in the serotonin trans- CC) overexpression mutants in the homologous porter gene found to be associated with anxi- A small dose of cholera toxin protected a relevant human region results in severe learn- ety and a risk for depression in the face of rodent model of uveitis from developing the ing defects induced by biochemical alter- adversity in female, but not male, rhesus disease (by countering the Thl immune re- ations, not by maldevelopment of the brain monkeys, possibly helping to explain the sponse), offering proof of concept for an (NINDS) increased incidence of certain stress-related immunomodulatory approach to this autoim- Use of the hunger hormone ghrelin found disorders in women (NIAAA) mune disease that may prove a safer alter- to inhibit proinflammatory cytokine expres-
The cloning of dardarin (LRRK2), a new native to chronic administration of immu- sion upon immune activation in vitro and gene for Parkinson's disease, mutations in nosuppressive agents (NEI) within in vivo sepsis models; strategies to which cause autosomal dominant Lewy body Improved heart function after ischemia- treat human inflammatory and autoimmune disease and account for approximately 5 per- reperfusion injury in transgenic mice with disorders might be entertained (NIA) cent of cases (NIA) cardiac-specific overexpression of the heart The finding that autophagy is a key im- A new Fanconi anemia gene for FANCB, enzyme CYP2J2—pointing for the first time mune cell death mechanism and is, para- the only one transmitted in a sex-linked man- to an endogenous role for this enzyme in doxically, induced by inhibiting one of the ner, identified through biochemical tech- the heart, with implications for the treatment very enzymes that initiates apoptosis, niques that recovered components of the of ischemic heart disease (NIEHS) caspase-8—along with the identification of purified complex of interacting Fanconi pro- Injection of a glutamate receptor agonist heclinl and ATG7 as key genes involved in teins (NIA) into the ventral tegmental area of the brain autophagy—suggests the protein products Identification of a polymorphism in the diminished contextual cue-induced relapse of these genes as targets for drug discovery promoter of the C\T2J2 gene that increases to heroin seeking in a rat-relapse model, sug- in the effort to inhibit this form of cell death; the risk of coronary artery disease, the first gesting that group II metabotropic glutamate awareness of this previously unrecognized evidence of disease relevance for this P450 receptors be targeted in the treatment of re- pathway may also aid in the design of treat- gene (NIEHS) lapse to heroin and other drugs of abuse ments for autoimmunity (NIAID) Identification of a variant in a gene that (NIDA) Identification of critical basic molecular governs the activity of the brain chemical Discovery and evaluation of a novel mechanisms whereby small GTP-binding messenger glutamate that increases the risk dopamine D3 receptor antagonist—the first proteins of the Rho family coordinate rapid for schizophrenia; the gene codes for the water-soluble compound in its class—in ani- changes in cell shape, motility, and overall glutamate receptor GRM3, which is respon- mal models of cocaine abuse to elucidate cytoskeletal function with the nuclear ex- sible for regulating glutamate in synapses the role of D3 receptors in drug reinforce- pression of growth-related genes involved (NIMH) ment (NIDA) in both normal and cancerous cell growth (NIDCR) Important new animal models Basic discoveries in cell, molecular, and Demonstration that estrogen promotes an- A transgenic mouse model with reduced structural biology’ with implicationsfor giogenesis and tumor growth by downregu- levels of Notch protein exhibited impaired the treatment of human disease lating a naturally occurring soluble “decoy” communication at neuronal synapses in the Advances in understanding the develop- protein, suggesting that inhibition of sVEGFR- hippocampus critical for learning and mental pathways involved in bone and joint 1 expression represents a novel mechanism memory but responded to Notch activation formation, namely, the balanced interplay of an estrogen-driven "angiogenic switch" by another protein, suggesting Notch as a in Wnt signaling that results in osteoblast that is responsible for breast carcinoma pro- tissue that eventually becomes segments of gression (NIDCR) * For this year’s IRP research roundup, IC sci- bone separated by regions of cartilage that Demonstration that SLPI, a protease in- entific directors were asked to limit their selec- become joints (NHGRI) hibitor in mucosal secretions, inhibits HIV tions tofour to six "discoveries/new models/new Identification of two novel mechanisms from infecting macrophages by binding to
tools reported in 2004 that . . . most advance that allow human antibodies to overcome annexin 2, a newly recognized HIV cofactor the knowledge base in the field or have a sig- HIV-l's defenses and enhance recognition (NIDCR) nificant impact on diagnosis, prevention, or of the virus, thus providing new targets for The discovery that human cells can splice treatment of heretofore poorly understood con- therapeutics (VRC) proteins, strongly enhancing the understand- ditions or conditions that are importantfrom a HIV-1 vaccines and Demonstration that CCR5-tropic HIV pref- ing of protein antigens and T-cell immunol- public health standpoint . . . . [also] clinical tri- als ofnew therapies/strategies launched in 2004 erentially infects certain dendritic cell popu- ogy (NCI, NIAID) that address the types ofconditions noted above. lations, possibly enhancing infection, con- Demonstration that growth factors
8 ) January — February 2005
interleukin-2 and interleukin- 15 have con- Interleukin-22, a T cell-derived cytokine, ide particles) and that single-particle detec- trasting roles in the life and death of lym- demonstrated to be a novel hepatoprotective tion should prove useful for cellular imag- phocytes, which allows understanding of the cytokine that may have therapeutic poten- ing (NINDS, NHLBI) maintenance and survival of T cells that con- tial in treating acute liver failure (NIAAA) Development of a dynamic micro-mag- fer long-term specific memory immune re- Establishing that a major role of WRN, the netic resonance mammolymphangiography sponse (NCI) protein found to be deficient in Werner syn- method to visualize lymphatic flow from Infusions of nitrite ions into several mam- drome (WS), is at the telomere end, where breast tumor tissue to draining lymph nodes malian species shown to induce production it functionally interacts with other telomere to identify a sentinal lymph node and deter- of nitric oxide and resultant blood flow proteins and where it participates in main- mine the presence or absence of nodal in- changes, suggesting that pharmacological use tenance and repair, the lack of which leads volvement; this approach may provide sur- of nitrite solutions for various diseases may to genomic instability, a key feature of WS geons with a precise map of involved and be possible (NIDDK, CC, NHLBI) cells (NIA) uninvolved lymph nodes (NCI, NIDDK) Demonstration that the mouse X chromo- Determination of a series of high-resolu- Development of the technique of pico- some is enriched for all genes preferentially tion structures of sequence-specific as well second time-resolved X-ray crystallography, expressed in sexually dimorphic tissues (such as nonspecific endonucleases, thereby re- achieving stunning agreement with molecu- as the uterus, ovaries, prostate), thereby rec- solving the dilemma of substrate specificity lar dynamics simulations (NIDDK) onciling all previously published data on this and metal ion requirement and gaining in- The use of atomic force microscopy to subject from flies, worms, mice, and humans sights into DNA repair, phage restriction, visualize individual rhodopsin molecules (a (NIDDK) retroviral replication, and integration key vision signal transduction protein) in Shuffling the prion domain of Ure2p (ran- (NIDDK, NICHD) native disk and reconstituted membranes, domizing the amino acid sequence without Evidence from a decade-long MRI study providing a foundation to study medically changing the amino acid content) found to of normal brain development from ages 4 important proteins in biological membranes, produce sequences that can still form prions to 21 that the prefrontal cortex, the center with possible applications in nanotechnology (NIDDK, NIAMS) of reasoning and problem solving, is among (DBEPS, NIAAA) Demonstration through mutation studies the last areas of the brain to mature and Novel fluorescence and photoactivatable and quantum chemical calculations that does not fully develop until young adult- imaging tools to document that the behav- Seri 13 of heat shock protein 90 (I ISP90) is hood (NIMH) ior of chromosomes, cytoskeleton, and Golgi critical for the binding of the anticancer com- Findings suggesting that the basal ganglia during mitosis is coordinated through the pound geldanamycin to HSP90 (NCI, CIT) are involved in both initiation and suppres- activity of the small GTPase Arfl, elucidat- Overexpression of the enzyme Cdk5 found sion of saccadic eye movements in complex ing the activity of organelles and raft-associ- to decrease the activity of the Src enzyme behavioral contexts (NEI) ated plasma membrane proteins (NICHD) and inhibit cell migration and wound clo- Elucidation of the role of brain-derived Identification of a new series of com- sure in corneal epithelium, suggesting a new neurotrophic factor in synapse formation and pounds with extremely high affinity for a4 approach for treating persistent corneal ul- in achieving long-term hippocampal plas- (32 nicotinic acetylcholine receptors (nAChRs) cers and other conditions with impaired ticity (NICHD) that show promise as imaging agents for wound healing (NEI) Findings in an ex vivo human lymphoid extrathalamic nAChRs (NIDA) Discovery that adiponectin, an adipokine tissue system that suggest that triggering in Development of a new PET radioligand secreted by adipose cells, directly activates vivo HIV viral production in latently infected for 5-HT1A receptor to use in the study of endothelial nitric oxide synthase and stimu- cells in combination with therapies may be- the molecular basis of mood disorders (CC, late production of nitric oxide in vascular come a meaningful strategy to purge latent NIMH) endothelial cells, providing a molecular ba- viral reservoirs (NICHD) sis for the ability of adiponectin to improve Enhanced understanding of the kainate Advances in bioinformatics insulin sensitivity and oppose accelerated ath- receptor gene family: solving the structures Implementation of a web-based protocol- erosclerosis in diseases associated with in- of the GluR5 and GluR6 ligand-binding cores, tracking system that enables Pis to manage sulin resistance (diabetes, obesity, hyperten- demonstrating that kainate receptor efficacy clinical studies as well as monitor review sion, dyslipidemias, and coronary heart dis- is controlled by domain closure, and eluci- processes, view status changes, and respond ease) (NCCAM) dating their slow recovery from desensiti- to requests for additional information and
First report to demonstrate that it is the zation (NICHD) allows protocol coordinators to manage the human pregnane X receptor that mediates Further elucidation of the role of mam- entire Institutional Review Board approval induction of the daig-metabolizing enzyme malian mitochodrial fission and fusion me- process (NINDS, CIT) CYP2C9 by rifampicin, phenobarbital, and diators in apoptosis (NINDS) hyperforin (found in St. John's wort), explain- Demonstration that multivesicular release Advances in biotechnology ing how concomitant exposure with certain at mammalian ribbon synapses is coordi- Identification of stem cells in human post- prescribed drugs (such as anticoagulatory, nated among release sites (NINDS) natal periodontal ligament that regenerate antidiabetic, and antihypertensive agents) cementum-like and periodontal ligament- leads to increasing the rate of disappearance Develop new or improved instruments like structures when transplanted into im- of drugs and compromised efficacy (NIEHS) and technologies for use in research and munocompromised mice; these findings sug- Endocannabinoids demonstrated to toni- medicine gest that these easily accessible cells may be cally suppress cardiac contractility in hyper- Advances in imaging useful in repair of periodontal tissue (NIDCR) tension and to normalize blood pressure in Development of an automated, fault-tol- Development of a simple plasmid trans- three different models of experimental hy- erant system to enhance high-throughput fection method for efficient intracellular pro- pertension, suggesting the endocannabinoid NMR protein structure determination (CIT, duction of papillomavirus-based gene trans- system as a novel therapeutic target in hy- NIDDK, NCI, NHLBI) fer vectors utilizing the viral LI and L2 pro- pertension (NIAAA) Development of a novel functional MRI teins; the availability of high-titer papilloma- Interleukin-6 found to ameliorate alcohol- technique for measuring cerebral blood vol- virus vector stocks should facilitate future and obesity-associated fatty liver disease and ume, blood flow, and blood oxygenation studies of papillomavirus replication and tro- to prevent ischemia-reperfusion injury of fatty signals in a single scan (NIDA) pism, and the vectors may have future util- livers, suggesting therapeutic potential for IL- Demonstration that MRI can detect single ity as vaccine or gene therapy vehicles (NCI 6 in human fatty liver disease (NIAAA) particles (single, micrometer-sized iron ox- Demonstration that highly proliferative 9 Selected* NIH Intramural Research Accomplishments 2004
cells for islets of precursor Langerhans can risk of rare but aggressive malignant mixed chemical precursor of serotonin, suggests that be generated from cadaver pancreases and mullerian tumors, as well as a 2.3-fold risk tryptophan depletion unmasks an inborn trait redifferentiated in cell culture then (NIDDK) for endometrial adenocarcinoma (NCI) associated with depression and that a ge- Development of new pepitomimetic netic predisposition to inadequate serotonin ligands for integrin targeting that will pro- Vaccine development activity may be at the root of the mood dis- vide a new approach for targeted delivery Development of a recombinant DNA vac- order (NIMH, CC) of nanoparticles into human vasculature (CC) cine against SARS coronavirus that induced The finding that couples diagnosed as clini-
neutralizing antibodies in mice; a Phase I cally infertile due merely to not having Develop or improved approaches new clinical trial is underway (VRC) achieved pregnancy after a year of trying for preventing or delaying the onset or Phase I clinical trials at various stages to (without additional clinical indicators of re- progression of disease disability and evaluate the safety and immunogenicity of a productive dysfunction) should continue at- Genetic counseling shown to improve ad- DNA vaccine against Ebola virus in adult tempting for up to two years before consid- herence to recommendations for colon can- volunteers, a recombinant adenoviral vac- ering potentially risky assisted reproductive cer screening and prevention in both muta- cine against multiple clades and genes of technologies (NIEHS) tion-positive and mutation-negative individu- HIV-1 in uninfected adult volunteers, and a als in families with hereditary nonpolyposis six-plasmid DNA vaccine against multiple Gene expression patterns colorectal cancer, supporting the clinical clades of HIV-1 in uninfected adult volun- Development of an expression microdis- practice of genetic susceptibility testing teers (VRC) section instrument that facilitates more rapid (NHGRI, NCI, NNMC) Ongoing clinical trials, in Baltimore and and precise genomic and proteomic analy- Dietary fiber intake, especially from grains, Costa Rica, of an HPV 16 (human papilloma- sis (NCI, NICHD, CIT) cereals, and fruit, found to lower the risk of virus type 16) LI virus-like particle vaccine Development of a novel model for quan- colorectal adenoma among individuals en- to prevent cervical cancer (NCI) titatively analyzing cell cycle gene expres- rolled in the Prostate, Lung, Colorectal, and sion that promises enhanced understanding Ovarian Cancer Screening Trial (NCI) Develop new or improved methods for of tumor cell growth and the effects of Determination that breastfed babies in the diagnosing disease and disability genotoxic agents on specific cell cycle check- United States have a 20 percent lower chance Development of a "lab-on-a-chip" rapid point genes (NIEHS) of dying between one month and one year immunoassay for the measurement of hor- Identification of transcription factor nuclear of age across all causes of death, including mones in real time, enabling rapid patient factor-kappa B (NF-kB) as an important mod- the most common at that age—SIDS, infec- assessment with minimal intervention dur- ulator of the altered gene expression profile tions, and trauma; about 720 deaths could ing other clinical or surgical procedures and malignant phenotype in squamous car- be prevented if all children under one were (DBEPS, NICHD, NIDDK) cinoma; inactivation of NF-kB inhibited ma- breastfed (NIEHS) Development of a minimally invasive lignant phenotypic features, including pro- Finding that asthmatic children with a ge- sample procurement needle, based on a 32- liferation, cell survival, migration, angiogen- netic deficiency of glutathione S-transferase gauge acupuncture needle, enabling in vivo esis, and tumorigenesis (NIDCD, NCI) M1GSTM1 may be more susceptible to the sampling of skin, muscle, or other organs Patterns of genes active in tumor cells deleterious effects of ozone on the small air- while causing no discomfort beyond that shown to predict whether patients with dif- ways and might derive greater benefit from associated with acupuncture (DBEPS, NCI, fuse large B cell lymphoma are likely to be antioxidant (vitamins C and E) supplemen- NIAMS) cured by chemotherapy, suggesting that gene tation (NIEHS) Development of a new microanalytic tech- expression profiling may facilitate clinical The finding that intake of fiber, specifi- nique to distinguish patients with and with- treatment options for standard or other thera- cally from fruits and soy products, is related out painful myofascial trigger points through pies (NCI) to a decreased risk of developing persistent continuous myofascial fluid sampling (CC) Identification of a target RNA motif for cough with phlegm production (NIEHS) Temporarily disabling dopamine receptors RNA-binding protein HuR by immunopre- Decreasing levels of free testosterone in monkeys’ brains found to result in the cipitation of HuR-RNA ribonucleoprotein enrolled in the Baltimore Lon- among men performance of all tasks as if a reward were complexes, cDNA array analysis of target gitudinal Study on Aging found to predict anticipated for each one, suggesting that RNAs, and elucidation of the primary and increased risk of developing Alzheimer’s dis- highly specific manipulations of brain recep- secondaiy structures of the bound transcripts ease (NIA, NCCAM) tors could be a useful approach in discern- (NIA) The first direct experimental demonstra- ing the molecular mechanisms that control Continuing development of a microfluidic, tion in humans that calorie restriction in- other cognitive functions (NIMH) flow-through immunoassay for simultaneous creases psychoactive drug self-administra- Brain imaging to pinpoint the site of a quantification of multiple proteins in sub- tion, using cigarette smoking (nicotine) as defect in a brain circuit associated with a microliter samples; advantages over existing the drug (NIDA) specific thinking deficit in Williams syn- array technology include protein detection Establishment that exposure to benzene drome, a rare genetic disorder, offers clues by single-point capture and reusable cap- at levels even lower than the U.S. occupa- on how genetic flaws may translate into cog- ture antibodies (DBEPS, CIT) tional standard of 1 part per million results nitive symptoms in more common and com- in lowered white blood cell and platelet plex major mental disorders (NIMH) Develop new or improved approaches counts, with especially marked effects on Identification of an area near the left for treating disease and disability progenitor cell colony formation; individu- temple of the monkey brain as the site of Clinical trial evidence that retroviral gene als with genetic variants in two metaboliz- processing species-specific vocalizations sug- therapy yields gene-corrected lymphocytes ing enzymes—myeloperoxidase and gests that this is not only a higher-order au- and clinical improvement in patients with NAD(P)H quinone oxidoreductase identi- : — ditory processing area but also one that is a X-linked severe combined immunodeficiency fied as especially susceptibility to benzene precursor for acoustic language circuits in disorder who have failed standard bone hematotoxicity (NCI) humans (NIMH, CC) marrow transplant and have no other thera- Establishment of the magnitude of risk for The finding that an emotion-regulating peutic options (NHGRI, NIAID) subsequent uterine cancer among breast brain circuit is overactive in people prone A clinical trial of humanized anti-CD25 cancer patients treated with tamoxifen who to depression and that depression relapse is (daclizumab, developed in the NCI intramu- survived 5 years or more: an 8-fold relative induced by a depletion of tryptophan, the ral program) shown to inhibit disease activ-
10 January — February 2005 People
Recently Tenured
Nilanjan Chatterjee was trained in math- typically require a large sample size, effi- librium of the genotyped SNPs with ematical statistics at the Indian Statistical cient designs and analytic principles for untyped causal variant(s) in the same re- Institute, Calcutta, and received a Ph D. gene-environment interaction studies are gion. I have collaborated with Jinbo Chen in statistics from the University of Wash- an important area of epidemiological and in developing methods for haplotype- ington, Seattle, in 1999 In his thesis, he statistical research. based genetic association studies in the developed efficient methodsfor analyzing I have shown how the power of case- context of cohort and nested case-control data from two-phase studies in which in- control studies to detect gene-environment studies. Previous methods for haplotype expensive exposure information is col- (G-E) interactions can be increased under analysis relied on binary logistic regres- lected on a relatively large number ofphase the assumption that genetic and environ- sion models. We have developed meth- 1 subjects and more expensive exposure mental risk factors are independently dis- odologies for testing and estimation in the data are collected on a smaller subset of tributed in the underlying source popula- Cox proportional hazard model that is efficiently selected subjects. Chatterjee tion. In one manuscript, I presented a more appropriate for analysis of prospec- joined NIH as a research fellow in the Di- general likelihood framework for exploit- tive cohort-based studies. vision ofCancer Epidemiology and Genet- ing the G-E independence for population- It is becoming increasingly clear that ics (DCEG), NCI. Since 2001, he has been based case-control studies of unrelated many cancers (and other complex dis- a principal investigator in the Biostatistics subjects. eases) show phenotypic variation, yet the
Branch. In a second manuscript, I standard approaches for etiologic analy- Advances in molecular and presented a conditional like- sis do not readily allow for the evaluation cellular technologies have lihood framework for analy- of risk factors in relation to disease het- given epidemiologic research- sis of family-based or other erogeneity. Besides traditional pathologic ers new opportunities to study type of matched case-control data, such as stage, histology, and grade, the pathogenesis of complex studies. My framework relies various molecular technologies are now diseases through population- on a relatively weak within- increasingly available for disease classifi- based studies. The advent of family (or within matched-set) cation. these data in epidemiologic G-E independence assump- Analogous to multivariate statistical studies also has given rise to tion, rather than indepen- methods for the study of multiple interre- challenging theoretical and Fran Pollner dence in the entire popula- lated risk factors, I have developed a methodological problems in Nilanjan Chatterjee tion. method for risk factor evaluation in rela- statistics. In recent years, I One of my long-term re- tion to multiple interrelated disease char- have initiated methodologic projects in search goals is to study efficient design acteristics. The method has proven use- three major areas of molecular epidemio- and analytic methods for using single ful in a series of studies to identify hetero- logic studies, including gene-environment nucleotide polymorphisms (SNPs) to de- geneity in the effect of various genetic and interactions, genetic association, and etio- tect disease susceptibility genes. Once the environmental risk factors on the size, his- logic heterogeneity of diseases using mo- SNPs to be studied have been selected and tologic characteristics, and multiplicity of lecular and pathologic markers. genotyping has been completed, an im- adenomatous colorectal polyps.
It is now thought that the risks of many portant issue is how to analyze data effi- All of my work has been directly or in- complex diseases are determined by the ciently on multiple SNPs within a genomic directly motivated by collaboration with joint effect of genetic susceptibility and region. my epidemiologist colleagues at the environmental exposures, and study of the It has often been argued that haplotype- DCEG. My training in mathematical statis- interplay of these two factors can greatly based association analysis can be power- tics and the scientific environment of enhance our understanding of the etiol- ful for this purpose, because haplotypes DCEG have yielded a rich statistical re- ogy of these diseases. Because studies of can capture interactions between SNPs as search program for modern epidemiologi- interactions, especially for rare exposures, well as association due to linkage disequi- cal studies.
ity (both on imaging and in daily activities) in an early-phase clinical trial, paving the ment of diabetes, obesity, hypertension, and in multiple sclerosis patients not respond- way for a phase III trial in a large patient atherosclerosis (NCCAM) ing to interferon-|3, the standard therapy cohort; the trial also provided solid proof Expansion of a clinical study of electro- (NINDS, NCI) that a Thl process is the final common T- acupuncture for the treatment of delayed A novel magnetic resonance imaging cell pathway of inflammation in Crohn’s dis- nausea and vomiting due to chemotherapy biomarker identifies blood-brain barrier dis- ease (NIAID) in patients with pediatric solid tumors; the ruption early enough in the course of stroke- Allogeneic T lymphocytes from a geneti- study is now a multicenter study in collabo,- induced ischemia and reperfusion to inform cally matched donor found to induce tumor ration with the Children’s Oncology Group decisions regarding adjunctive therapy to regression in patients with metastatic breast (NCCAM, NCI) reduce complications associated with acute cancer—demonstrating for the first time that The launching of the first clinical study of thrombolytic therapy (NINDS) a graft-vs-host tumor effect may have thera- a mistletoe-chemotherapy (gemcitabine) Evidence supporting the potential role of peutic value in metastatic breast cancer (NCI, combination in patients with advanced solid regulatory T cells in the diminution of HIV- CC) tumors; this phase I trial is a model for the specific immune responses in HIV-infected The launching of a double-blind, placebo- study of botanical-drug interactions in com- individuals may lead to improved therapeu- controlled, cross-over trial to determine if bination regimens for treating cancer tic and vaccination approaches designed to dark chocolate (which contains antioxidants, (NCCAM, NCI) enhance or elicit HIV-specific immune re- including polyphenol epicatechin) lowers Launching of the first "proof of principle" sponses (NIAID) blood pressure and improves insulin resis- clinical trial to test the ability of the CB1 Monoclonal anti-IL-12 proved to be an ef- tance and endothelial function in people with receptor antagonist rimonabant to reduce the fective treatment of active Crohn’s disease essential hypertension—relevant to the treat- desire to drink in heavy drinkers(NIAAA)
11 The NIH Catalyst
People Recently Tenured
2+ Ca signaling is, in essence, a discrete, methods, analytic tools, special reagents, Heping (Peace) Cheng received degrees 2+ stochastic, and digital system, rather and instruments for Ca studies. We hope in applied mathematics and mechanics, than a continuous, deterministic, ana- these “nuts and bolts” will broaden the physiology, and biomedical engineering log system, as previously thought. This frontier of technology for the field. from Peking University, China, where he 2+ concept not only sheds new light on We will continue to focus on Ca sig- served as a faculty member in the De- calcium’s complex simplicity, but also naling in subcellular compartments and partment Electrical Engineering before of allows for unprecedented precision in organelles (mitochondria, ER/SR, and earning his Ph D. degree in Physiology the detection and definition of disease- nuclei) and in vivo imaging of biosensors in from the University Maryland 2+ 1995 of related aberrant Ca signaling. at single-cell and single-molecule reso- in College Park. He joined the NIH In- In collaboration with M.T. Nelson, we lutions. But beyond this, we will con- tramural Research Program as a senior 2+ 2+ uncovered a novel Ca signaling path- sider the Ca signalome as a whole, in- fellow in 1995 and was selected as staff way in which sparks relax vascular cluding synthesizing information gleaned a tenure-track investigator in 1998. He smooth muscles. In this pathway, sub- from molecules, pathways, subcellular or- is now a senior investigator and the head surface sparks activate large-conduc- ganelles, cells and organisms. This inte- 2 the Ca * Signaling Unit in the Labora- 2+ + of tance Ca -sensitive K channels, which gration enlists the powerful addition of tory Cardiovascular Science, NIA. 2+ of shut off L-type Ca influx through bioinformatics and system theory to our In my early years at Peking membrane hyperpolariza- current research portfolio. In addition, University, recognizing the tion. This leads to reduction through collaboration, we also hope to 2+ power of multidisciplinary in- of intracellular Ca and translate our findings to pertinent disease tegration, my mentors and I muscle relaxation. This find- models, thereby advancing the under- devised a unique career path ing vividly illustrates that a standing of the etiology and enlighten- beginning with rigorous train- single simple messenger, ing the treatment of human diseases. ing in physiology, mathemat- Ca 2+ can serve different and , ics, physics, and computer even opposing roles in the Karl Csaky received his M.D. degree in science. to My dream was same cell. 1983 and his Ph.D. in pharmacology in pursue fundamental biomedi- 2+ In heart muscle cells, Ca from the University ofLouisville in 2+ 1987 cal questions by seamless in- entering through L-type Ca Kentucky. Following an internship in tegration of the philosophy, channels traverses a 12-nm Medicine at Duke University in Durham, theory, craftsmanship of these dif- and junctional cleft to activate RyRs in the N.C., he spent 15 months as a Fulbright ferent fields. 2+ SR, liberating stored Ca . This process Scholar in the University Eye Clinic in 2+ 2+ As a Ph.D. student at the University of is known as Ca -induced Ca release Essen, Germany, with Gerd Meyer- Maryland, I was fascinated with the (CICR). For years, physiologists many Schwickerath . He completed his ophthal- 2+ economy and simplicity of Ca in bio- dreamed of “seeing” nanoscale, inter- mology residency at Washington Univer- logical systems. As a divalent cation, cal- molecular CICR. Our team has now sity in St. Louis in 1990 and spent one cium undergoes neither catabolism or painstakingly accomplished the opti- year as a fellow in the Retinal Vascular anabolism, yet it plays pivotal roles in cal recording of single L-type channel Center at the Wilmer Eye Institute, Johns 2+ 2+ nearly every aspect of biology. This para- Ca currents or “Ca sparklets.” We Hopkins Hospital, Baltimore. From 1991 dox of simplicity and complexity became went on to demonstrate that a single through 1994, he completed a postdoc- even more profound as I realized that sparklet can trigger a spark in an all- toral fellowship at the NCI laboratory of the list for at second messengers work or-none fashion. These steps made it Stuart Aaronson. He joined the NEI in in any biological system is extremely possible to define the stoichiometry, 1994 and currently heads the Section on short cAMP, IP ROS, for example. — 3 , kinetics, and fidelity of intermolecular Retinal Diseases and Therapeutics. What mechanisms bestow Ca 2+ or any , signaling in real time and in live, intact Age-related macular degeneration second messenger, with such amazing cells. (AMD) is the leading cause of blindness signaling specificity versatility? and Most recently, we found that when in patients over the age of 60 years in In first English publication, co- my my a spark ignites, rapid and substantial the United States. It is estimated that 1/3 2+ 2+ workers and I reported the discoveiy of in called “Ca blinks,” decreases Ca , of all people over the age of 73 will de- 2+ “Ca sparks” as the elementary events develop within nanometer-sized velop AMD. of intracellular 2+ 2+ Ca signaling. Ca sparks stores—the junctional cisternae of the AMD has three major clinical presen- are brief openings variable of cohorts of SR. The complementary spark-blink tations: the early dry form, which is char- from one to eight ryanodine receptor signal pairs in heart may be a proto- acterized by extracellular deposits under 2+ (RyR) Ca release channels in the endo- type for similar reciprocal signals and the retina; the severe dry or atrophic form plasmic or sarcoplasmic reticulum (ER suggest space-time organization of sig- in which retinal cells undergo apoptosis; 2+ or SR). The summation of coordinated naling from Ca stores, including ca- and the wet form, where neo-vascular- 2+ 2+ activation of Ca sparks in space and pacitive Ca entry and ER/SR-depen- ization develops in the normally avascu- 2+ time generates complex global Ca sig- dent apoptotic signaling. lar sub-retinal space, so-called choroidal nals. The aims of our current and future neovascularization (CNV). 2+ Subsequent research in “sparkology” Ca signaling research are to discover My laboratory and clinical efforts are has unraveled exquisite hierarchal archi- new phenomena, functions, and focused on elucidating the pathogenesis 2+ tecture of Ca signaling. On the basis of mechanisms—leading to new concepts and developing new therapies for all these findings, we have proposed that and theories—as we develop novel three forms of AMD. As a clinician-sci- 12 January — February 2005
entist, much of the focus in my lab is on large variety of clinical presentations. We quantifying radiation-related cancer risks research that has direct disease rel- hope to determine, from patients, spe- and clarifying susceptibility factors that
evance, drawing insights from clinical cific functions of circulating EPC’s and influence these risks. For example, I am presentations or therapeutics that can be correlate these to the various pheno- conducting studies of therapy-related taken into clinical trials. types of neovascularization. Our goal is second primary cancers in a population For example, in the atro- to develop a predictive and of more than 14,000 five-year survivors phic form of AMD, it is therapeutic blood test to of childhood cancer diagnosed between known that cell death begins identify patients most at risk 1970 and 1986. in one unique cell layer of for aggressive neovasculariz- These studies include detailed infor- the retina termed the retinal ation. mation on radiotherapy and chemo- pigment epithelium (RPE). Because only a small therapy and anatomic site-specific ra- The RPE is a nonrenewable amount of tissue needs to be diation dosimetry. Our analyses have cell that maintains retinal treated in patients with demonstrated very large relative risks for function from birth through AMD, my laboratory is also second neoplasms of the thyroid gland, death. However, the natural involved in targeted sus- brain, and breast due to radiotherapy. history of RPE cell death in Emie Branson tained drug delivery through Interestingly, risk of thyroid cancer in- patients is one of an end- Karl Csaky the use of drug implant de- creased with dose at low to moderate stage phenomenon that oc- livery systems. We have de- doses but declined at veiy high doses, curs late in the course of AMD. There- veloped a novel implant device that can probably due to cell-killing effects of fore, we hypothesized that RPE cell deliver various antiangiogenic agents for high-dose radiotherapy on the thyroid apoptosis might be different from up to three years. Clinical trials of these gland. apoptosis in cells which undergo a more devices are now being planned. Although relative risks associated with rapid time course of cell death. In another study of neovascular AMD, radiotherapy for childhood cancer are Indeed, we discovered that unlike in collaboration with Scott Cousins at very large, most patients who receive immune cells, RPE cells use primarily the University of Miami, we identified high partial-body doses of radiation do
the release of apoptosis-inducing factor the importance of innate immunity in not develop a second cancer. It is un- (AIF) and not activation of caspases to the development of CNV in animals. clear to what extent this is random or modulate cell death. In addition, the RPE This led us to develop a therapy by op- dependent on differences in host sus- cell has unique mechanisms for self-pro- timizing a steroid formulation that could ceptibility. We are evaluating whether tection from various insults. After an oxi- be injected into the eye. This novel for- polymorphisms in genes involved in dative injuiy, for example, a microarray mulation has been produced DNA protection, DNA repair, profile of RNA expression in RPE cells and successfully injected cell-cycle control, and demonstrated activation of both anti- into patients and is now in apoptosis are predictive of
oxidative defense mechanisms as well Phase I and II trials at NIH. second cancer risk. as direct downregulation of proapoptotic A multicenter Phase III trial In an earlier study of nearly pathways. We are now studying how the using this steroid formula- 13,000 women treated with loss of these survival mechanisms inter- tion is now underway in 300 radiation for benign gyneco- plays with AIF and how this process may patients with neovascular logic disorders between 1925 be involved in the development of the AMD. and 1966, I found radia- late atrophic form of AMD. If the results of these tri- tion-related excesses of acute In examining the development of the als are positive, they will be and myelocytic leukemias Peter Inskib neovascular form of AMD in various used for a new drug appli- but not chronic lymphocytic animal models, my laboratory discov- cation through the FDA. Thus, beyond leukemia, Hodgkin or non-Hodgkin ered that bone marrow-derived endo- its direct translation from lab to clinic, lymphoma, or myeloma. thelial cells (EPCs) are involved in this our work is giving us useful insights into Radiation dose-response relationships process. A key question about this and FDA regulatory issues and the econom- also were apparent for cancers of the other forms of neovascularization is ics of drug development. bladder, colon, and ovary but not for whether EPCs have some important role cancers of the uterus or rectum, which in this process. We hope to answer this Peter Inskip received his Sc.D. in epi- appear to be relatively radioresistant or- question in part by examining EPCs from demiology from the Harvard School of gans. patients with neovascular AMD. Public Health in Boston in 1989. He I also am studying cancer risks asso- Unlike neovascularization in other dis- then joined NCI as a fellow in the Divi- ciated with lower-dose protracted or eases, such as cancer or cardiac is- sion ofCancer Epidemiology’ and Genet- fractionated radiation exposures. Taking chemia, development of CNV can be ics (DCEG). In 1995, he left NCI to take advantage of unique features of the
precisely documented through multiple a position as associate professor at the Swedish health-care system, I evaluated imaging techniques showing rates of Texas A&M College of Veterinary’ Medi- the risk of thyroid cancer associated with growth, extent of growth, phenotypic cine in College Station. He returned to lifetime history of diagnostic X-rays characteristics and various aspects of NCI in 1998 and is currently Senior In- based on medical records; no associa- blood flow. In fact, when we analyze vestigator in the Radiation Epidemiol- tion was found. In one of the first sys- various characteristics of neovascu- ogy Branch ofDCEG. tematic studies of cancer among larization in AMD patients, we find a My research focuses primarily on Chernobyl clean-up workers, we found 13 The NIH Catalyst
People Recently Tenured
no excess of leukemia among 4,833 Es- tant to combine results from multiple lem with iron, as most iron in an oxy- tonian clean-up workers followed studies of brain tumors. gen-containing environment is in the
through 1993- We have expanded the Towards that end, I organized a work- oxidized form, which forms large, in- study to include an additional 12,500 shop that launched an international con- soluble polymers with oxygen and wa- workers from Latvia and Lithuania and sortium of investigators conducting etio- ter—rust. Thus, all organisms have are extending the follow-up to further logic studies of brain tumors. Our aim is evolved sophisticated mechanisms to evaluate leukemia and solid cancers. to establish a network that will enable control the uptake and use of iron. When the public became concerned investigators to collaboratively address We began our studies in the one-celled that radiofrequency radiation emitted etiologic hypotheses that otherwise could eukaryote Saccharomyces cerevisiae an , by cellular telephones might cause not be studied effectively. excellent organism in which to under-
brain cancer, I initiated a case-control stand basic processes of both eukary- Caroline Philpott received her M.D. study to explore a wide range of hy- otic cells and pathogenic fungi. We used University N.C., in potheses about the etiology of these from Duke , Durham, cDNA microarrays to ask the question 1987. Following internal medicine poorly understood and often fatal tu- an “How do cells respond to iron defi- residency the Hospital mors. Our article in the New England at Johns Hopkins ciency?” Our studies of the transcrip- in Baltimore, shejoined NICHD in 1990 Jou rnal of Medicine reported no evi- tional response allowed us to identify a clinical associate in the dence of increased risk of glioma, men- and became the set of genes involved in the primary ingioma, or vestibular schwannoma as- Genetics, Cell Biology, and Metabolism response to iron deficiency and to un- sociated with use of cellular phones. Branch. In 1998, she joined NIDDK, derstand the cell’s strategy for surviving where she is currently a senior investi- Unlike ionizing radiation, nonionizing iron deprivation. We found that the cel- gator in the Liver Diseases Branch. radiation shows little evidence of caus- lular response took three I interested in cells ing cancer. am how forms: 1) increasing the ex- Cellular telephones might not cause take up and use iron, which pression of iron uptake sys- is health brain tumors, but something does. The important for human tems, 2) mobilizing stored in a number of ways. etiology of brain tumors has become iron, and 3) adjusting cellu- Worldwide, iron deficiency my second major research focus. lar metabolism to conserve In our study of brain tumors, we ob- is the most common nutri- iron. served a significant inverse association tional disorder, and yet ge- We identified a new fun- netic of iron between the risk of glioma and history forms overload gal system for iron transport are also very common. of allergies—a finding that has been We that relied on the uptake of confirmed in subsequent studies. are only beginning to under- siderophores, which are A surprising observation was the stand the role that iron plays small molecules that chelate in the chronic lower risk of glioma among left-handed neurodegen- iron. Most bacteria and fungi compared with right-handed individu- erative diseases, such as secrete these compounds in their iron- Friedreich ataxia and Parkinsonism. als, which, if not due to chance, may free form and take them back up once over- relate to a longstanding hypothesis that Pathogenic microorganisms must they contain bound iron. Budding yeast prenatal exposure to high testosterone come the iron-withholding systems of don’t make siderophores, but they levels affects the developing brain and the human host to establish infection. readily take up those made by other thymus, resulting in an “anomalous” These systems are our first line of de- microbes. against invaders, mi- pattern of hemispheric dominance as- fense microbial and Siderophore uptake occurs through a sociated with left-handedness, devel- crobial iron uptake mechanisms that family of transporters that exhibit a opmental language disorders, and im- overcome these systems are often im- unique intracellular trafficking pattern portant virulence factors. mune dysfunction. that is controlled by the presence of the Glioma incidence was also positively Almost every organism on the planet siderophore substrate. We found that the requires iron because of its versatility in associated with age at menarche and transporter itself contained a domain that picking and releasing electrons. This inversely associated with age at first live up acted as the receptor for siderophores. birth. To follow up on these observa- reliance on iron comes at a cost, how- Binding of siderophores to this domain ever, because the same properties that tions, I am collaborating with other NCI affected the cellular trafficking of the make iron useful also make it very investigators to explore associations of transporter, directing it to the cell sur- brain cancer risk with genetic polymor- chemically reactive and potentially dam- face only when the appropriate cellular phisms involved in inflammation, im- aging for cells. Think of iron as siderophore substrate was available. The mune response, and hormonal path- dynamite—useful, but dangerous. regulated intracellular trafficking of Cells iron to iron ways. We also are studying brain tu- use build heme and transporters has emerged as an impor- mor risk with respect to occupational sulfur clusters, which are inserted into a tant mechanism for controlling transport exposures, including solvents, lead, and variety of enzymes that carry out essen- of many molecules in various cells. We pesticides. tial functions, such as respiration; ste- hope to uncover the processes that con- rol, acid biosynthesis; Because brain tumors are rare, and lipid, and amino trol the trafficking of transporters in no single existing epidemiologic study and DNA repair. Most of the iron inside yeast. of brain tumors has adequate statistical a cell is in the reduced form, which can One surprising finding of our studies power to evaluate gene-environment catalyze the formation of damaging free in yeast was how cells adjust to dwin- radicals. Cells face a bioavailability prob- or gene-gene interactions, it is impor- dling levels of iron. At first glance, one 14 January — February 2005
might suppose that cells simply continue sel growth and regression are still poorly Probably the most fundamental fate to use iron in their iron-containing pro- understood, but they have become a choice for endothelial cells is arterial vs. teins until they run out. But we found subject of intense clinical interest in re- venous differentiation. We were the first that far more sophisticated adjustments cent years because of the great promise to describe a molecular pathway regu- take place. shown by antiangiogenic lating acquisition of arterial- As iron is depleted, yeast turn off tran- therapies for combating can- venous identity: sonic hedge- scription of certain nonessential path- cer. hog, vascular endothelial ways that rely on iron-sulfur cluster pro- Many of the critical in- growth factor (VEGF), and teins and turn on transcription of paral- sights into regulation of Notch signaling, acting in se- lel iron-independent systems. For ex- blood vessel formation have ries. Using genetic screening ample, yeast can either synthesize bi- come from developmental and positional and candidate otin from intermediates, or take it up studies, and the zebrafish cloning methods, we identi- from the medium. Synthesis requires has emerged as an important fied a mutation in phospholi- iron, but uptake does not. Under iron new vertebrate model organ- pase C-gamma-1 leading to deficiency, biotin synthesis is switched ism for investigating early defects in angiogenesis and off and uptake is switched on. vascular development. This arterial differentiation. We Heme utilization is also adjusted in small tropical freshwater fish is geneti- showed that this gene is a major down- iron deficiency. As cells become iron cally tractable and has a physically ac- stream effector of VEGF signaling in depleted, they synthesize a heme-de- cessible, optically clear embryo. These vivo. We are currently using microarrays, grading enzyme, and this degradation features permit noninvasive high-reso- mutant screens, and other methods to of heme serves two purposes. First, iron lution visualization of every vessel in the further explore the molecular mecha- is released and reused, and second, living animal and simple, rapid screen- nisms underlying this important cell fate heme-dependent transcription is de- ing for even subtle vascular-specific decision. creased. Heme is an important regula- mutants. We are also studying the mechanisms tory molecule, and the degradation of Several experimental tools that we underlying vascular patterning and mor- heme results in the downregulation of developed allowed us to amplify the phogenesis during development, in par- many proteins that contain iron-rich basic advantages of this system. A ticular, how early vascular networks as- complexes. microangiographic method for imaging semble with defined, stereotypic ana- We don’t yet know what types of ad- patent blood vessels allowed us to com- tomical patterns. We used multiphoton justments are made in human cells in pile a comprehensive atlas of the vas- time-lapse imaging of transgenic zebra- response to iron depletion. A new fo- cular anatomy of the developing fish to obtain evidence supporting a cus of our lab is to use yeast to identify zebrafish. Our transgenic zebrafish lines novel model for genetically programmed new human proteins involved in iron expressing green fluorescent protein in vascular network formation in the em- homeostasis. Yeast and human cells have vascular endothelial cells make it pos- bryonic trunk. some clear differences in how they take sible to visualize blood vessel formation Subsequently, we showed that sema- up and use iron, and by selecting hu- in intact, living embryos. We devised phorin signaling— an important media- man genes that confer new iron-han- methods for long-term, multiphoton tor of axonal guidance in the nervous dling properties on yeast, we hope to time-lapse imaging of growing vessels system—acts in an analogous fashion as identify novel human genes of iron in these transgenic zebrafish and used a repulsive guidance factor for these metabolism. them to examine the morphogenesis of developing trunk vessels via a novel en- developing trunk and cranial vessels and dothelial-specific plexin receptor. Our Brant Weinstein received his Ph.D. adult fin blood vessels. results thus highlight similarities between from the Massachusetts Institute of Tech- We used foiward genetic mutational the establishment of anatomical pattern nology, Cambridge, Mass., in 1992. Af- screening to identify and characterize in the developing vascular and nervous ter completing his postdoctoral work at zebrafish mutations in developing vas- systems. the Massachusetts General Hospital, Bos- culature. We positionally cloned the ton, hejoined the Laboratory ofMolecu- defective genes from several vascular lar Genetics, NICHD, in 1997. He is cur- patterning mutants, including violet Poolesville Digs rently a senior investigator in that lab beauregarde (defective in Alkl/acvrll), he 500-acre NIH Animal Center and bead of the Unit on Vertebrate Or- plcgP’10 (defective in phospholipase C- T in Poolesville, Md., offers hous- ganogenesis. kurzschluss (defective gamma-1 ), and ing anci research services for a vari- laboratory is trying to My understand in a novel chaperonin). ety of animals, including primates, un- the cellular and molecular mechanisms We are currently carrying out large- gulates, poultry and waterfowl, and responsible for the specification, pattern- scale genetic screens for chemically in- rodents. Housing options include ing, and differentiation of blood vessels. duced mutants. These have yielded a conventional, sun-protected, barrier, Blood vessels are ubiquitous and vi- large number of new mutations, with and hazard-containment environ- tal components of all vertebrates, form- phenotypes including loss of all or sub- ments. For more information on ser- ing an elaborate network that supplies sets of vessels, increased sprouting or vices anci capabilities at the Pooles- all tissues and organs with oxygen, nu- branching, and vessel mispatterning. ville site, call the Division of Veteri- trients, and cellular and humoral factors. Characterization and molecular cloning nary Resources at 301-496-2527. The mechanisms controlling blood ves- of these mutants is in progress.
15 The NIH Catalyst
Kl 1. t’s cold out there! While you’re enjoying your winter, f you have a photo or 2. try this to Striped Ice. I other graphic that I 3. experiment produce some What you’ll need is: reflects an aspect of life at 4. NIH (including laboratory 5. life) a that Water or quotation 6. scientists might appreciate Minute timer that would be fit to print in Two drinking glasses (made of glass, to see the ef- the space to the right, why fect better) not send it to us via e- Patience mail: [email protected]>; Liquid food coloring; you'll need at least one color, fax:402-4303; or mail: but a great combination is red and blue. Building 2, Room 2E26. Experiment sheet with the headings "Time” and “Color” Also, we welcome Now take your glasses and fill them with water. Using the food coloring, make the water in “letters to the editor” for one glass red, and the water in the other blue—make sure the color is dark. publication and your Put both glasses in the freezer, set your timer for an hour, and go play in the snow (or do reactions to anything on some homework). You should see ice forming on the top and sides of the glass, usually in some the Catalyst pages. extraordinary patterns. Wait until enough ice has formed that there’s a solid coat of ice on the inside of the glasses. Chip away at the surface of the ice so you can pour out the water from each color into other, In Future Issues... empty glasses. This extra water can be used right away—by pouring red water into the blue-ice glass, and vice versa. Check the time, and come back in another hour. you have an Rotavirus Vaccine Now alternate stripe! ® Again a Reality Experiment with timing, different size and shape of glasses, slanted striping, and colors. (Remember, of course, to write down all of your findings.) Don’t worry if you forget to come NIH Tech Transfer back in an hour—water freezes from the outside surface in. Wonder how it melts, and what color it will turn into when it melts? People & Programs Keep warm, and no matter how much ice you have outside, you can make some really nice ® In the IRP: A Series ice inside! —Jennifer White 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 2E26, 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: U.S. Department of Health and Human Services FIRST-CLASS MAIL & PAID National Institutes of Health POSTAGE FEES DHHS/NIH Building 2, Room 2E26 Permit No. G-802 MSC 0235 Bethesda Maryland 20892 Official Business Penalty for Private Use $300 0 Printed on 50% recycled content paper and can be recycled as office white paper.