— Fostering Communication and Collaboration The nihCatalyst A Publication for NIH Intramural Scientists National Institutes of Health Office of the Director Volume 15 Issue 6 November-Dece.mber i , 2007 Research Festival Research Festival of Age: Getting to the Bottom Coming Tissue Engineering and Regenerative Medicine Of the Beta Cell by Fran Pollner by Julie Wallace or some, the quest is to increase the progenitor pool of pancre- anel chair Rocky F atic beta cells, to derive stem Tuan noted that cells that can be controlled in cul- P this was the NIH ture and serve as replacements for Research Festival’s damaged or lost beta cells; for oth- first dedicated sympo- ers, the quest is for new treatments. sium on tissue engi- neering and regenera- Stem Cell Studies tive medicine, a re- Typically, cul- flection that the field tured human beta is steadily approach- cells do not prolif- ing the threshold of erate well or retain clinical application. the mature pheno- Indeed, applying type, noted Marvin biological and engi- neering principles to Gershengorn, chief Fran Pollner The Re-Generation: (left to right): Pamela Robey, N1DCR; of the Clinical En- Marvin repairing and replac- Cynthia Dunbar, NHLB1; Catherine Kuo, NIAMS; and panel docrinology Branch Gershengorn ing damaged and de- chair Rocky Tuan, NIAMS and scientific director, NIDDK, who stroyed tissues has at- has been exploring the optimization tracted researchers across NIH; scientists adipocytes, and chondrocytes derived of hIPCs (human islet cell-derived from three institutes described their on- from MSCs could indeed be made to precursor cells) for about five years. going research involving adult stem cell- switch identities. This capacity to de-dif- Gershengorn’s lab has established based approaches to tissue regeneration. ferentiate generated the hypothesis that that hIPCs are a special type of mes- there might be “sternness” genes that enchymal stromal cells that can be Tuan: Creating the Matrix regulate MSC self-renewal and multi- induced to differentiate into Adult stem cells and nanomaterials are potency. adipocytes, chondrocytes, and osteo- Tuan’s basic building blocks in his quest Using microarray analysis, Tuan and cytes, as well as cells of the endo- to regenerate skeletal tissues. Encourag- his colleagues determined that differen- crine pancreas. “We can change the ing results thus far in repairing joint de- tiation genes were upregulated in dif- culture conditions that result in epi- generation in rabbits foretell the appli- ferentiation and downregulated during thelial or endocrine-like cell clusters; cation of his team’s techniques to the continued on page 4 we can upregulate the insulin tran- treatment of patients with musculoskel- CONTENTS script level, generating clusters of C etal diseases such as osteoarthritis. 1 peptide-expressing cells,” he said, With the right scaffold and physical RESEARCH FESTIVAL The Eyes Have It noting that his team has transplanted and chemical environments, a cartilage Regeneration Sweat Secrets these cells into mice and demon- micromass could be developed from The Beta Cell Job Fair strated in vivo human mesenchymal stem cells (MSCs) hIPC functionality. 12-13 The lab of Sushil Rane, of the Re- to replace the degraded tissue, said Tuan, From the DDIR: Chem Informationists generative Biology Section in the chief of the Cartilage Biology and Or- Trans-NIH Initiatives: Why? How? When? 14-15 NIDDK Diabetes Branch, has been thopaedics Branch, NIAMS. The chal- GraduateStudent examining the role of the cell-cycle lenge is to generate a cartilage construct ResearchFestival/ regulator CDK4 in beta cell regen- of sufficient size to transplant into a hu- Solicitations: On Tenure Track eration. man joint, he said. Biomarkers/Speakers 16-19 Tuan’s lab evaluated whether differ- Hyperglycemic and hypoinsulin- 6-11 Recently Tenured/ emic, CDK4-knockout mice have entiated MSCs could transdifferentiate RESEARCH FESTIVAL Demystifying Agenda Chemistry Lessons clearly lost beta cell mass, Rane said; change from one differentiated state to Chromosomes, 20 continued on page 5 another. The team found that osteoblasts, SNPs, and Disease CFC Kickoff Kicks It The NIH Catalyst From the Deputy Director for Intramural Research Trans-NIH Intramural Scientific Initiatives: Why? How? When? ast year, with the encouragement of NIH Direc- ratories and core facilities to facilitate complete tor Elias Zerhouni, the NIH intramural research phenotyping of the human immune system and ab- L program (IRP) set out to identify important sci- normalities in autoimmune diseases and in inflamma- entific initiatives that would be difficult for any one tory processes that underlie or affect common dis- institute to support, that would exploit the special eases like cancer, asthma, and heart disease. Most of characteristics of the IRP, and would scientifically draw the studies will involve the NIH clinical center and from and benefit multiple NIH institutes and centers. human subjects. After a series of meetings involving many of our Richard Leapman, scientific director of the new principal investigators and scientific leadership, we National Institute for Bioimaging and Bioengineering, settled on three major initiatives with cross-cutting will lead an effort to develop new imaging technolo- impact: (1) Immunology, Autoimmunity, and Inflam- gies for studying molecules and cells, beginning with mation, (2) Molecular Imaging from Molecules to Cells, a center in which senior fellows from physics, com- and (3) Systems Biology. putational biology, and engineering can interact with For nearly a year, groups have met to define the NIH biologists to address the need for higher resolu- nature of each of these initiatives and how to bring tion, real-time molecular-imaging technologies. them to fruition. The resulting consensus proposals The Systems Biology proposal is the least advanced on how to proceed were then presented to me and to of the three. The proposal involves recruitment into Dr. Zerhouni—and, on October 22, 2007, to a larger leadership positions as well as the creation of an in- group of NIH scientists and scientific leadership at a cubator space for interaction of current and newly retreat held for this purpose. recruited NIH scientists. Most of us appreciate that systems approaches will begin to replace the more Why? reductionist approaches we have taken in our labora- Discussion at this retreat focused not only on the tory and clinical studies, but how this necessary evo- substance of the proposals, but also on the rationale lution will occur is still unclear. for this new approach to science at NIH. In the past, virtually all of our scientific initiatives have been in- When? vestigator-initiated or have sprung from programmatic Both the scientific community and the NIH director imperatives of the institutes (for example, the Vaccine expressed frustration at the October 22 retreat about Research Center). This worked well for the IRP dur- why it has taken so long to get these initiatives off the ing the time of continuously rising budgets (real in- ground—although we all realize that achieving true creases adjusted for inflation of approximately 2 per- consensus among the working groups takes time. cent per year from 1980 to 2000) when new funding With nearly every square foot of space on the NIH was available to each institute or center to create a campus currently occupied with active laboratory and venture capital fund for high-risk, high-impact novel clinical science, finding appropriate space to initiate science, or even through the development of new these programs has not been a trivial undertaking. intramural programs (such as the NHGRI IRP). But we have recently figured out how to reorganize Even so, the IRP failed to be at the cutting edge of existing space to some advantage. With budgets tight some new technologies and/or model systems—such everywhere, funding was hard to find, especially be- as yeast genetics to study cell biology, and RNAi— fore goals and programmatic needs were clearly de- until they were well established in academia or in fined. To jumpstart these three projects, the NIH di- industry. Now with real budgets dropping in the IRP rector has provided $4 million from his Discretionary for the past four years, it has become increasingly Fund for equipment needed in the instrument cores. difficult to initiate large-scale new scientific initiatives, Individual institutes and centers are expected to sup- and the need for trans-NIH cooperation and planning port the modest needs of these programs, at least dur- has become obvious. ing a period of evaluation, but most support will be in Some of the larger institutes have had the flexibility kind as the centers that are established reach out to to provide core support for expensive new technolo- the affiliate members in various institutes and centers. gies (such as transgenic mice, microarray facilities, The NIH director will meet with the scientific direc- biostatistical support, and clinical research infrastruc- tors to discuss fostering implementation of these cen- ture), but the smaller institutes have definitely been ters. We fully expect the Center for Human Immunol- disadvantaged. ogy and the Molecular Imaging Center to be function- All of these factors, plus the obvious observation ing in calendar year 2008, and the Systems Biology that working collaboratively across NIH will increase initiative will soon begin to identify leadership. creative input and reduce inefficiency and duplica- Getting NIH scientists and scientific leadership to- tion, led to the trans-NIH initiatives concept. gether to discuss these ideas has been a new and rewarding experience in itself. We anticipate a con- How? tinuing dialog between scientific leadership and sci- The original three proposals listed above were spe- entists on how to ensure that the NIH IRP remains a cifically chosen because they could provide infrastruc- vital, creative contributor to biomedical research. Com- ture for the work of many different scientists through- mitted to this objective, the NIH director has proposed out NIH and had the potential to revolutionize how a Grand Challenge program that provides one-time we do science.