NHLBI Special Emphasis Panel on Integrative Research April 19, 1996 Minutes and Consensus SUMMARY: This document highlights the discussions of a meeting hosted by National Heart, Lung, and Blood Institute (NHLBI) on April 19, 1996 in Bethesda, Maryland to explore promising areas of research and training that might benefit from greater emphasis on the integration of molecular biological processes with physiological function. The meeting also provided a forum to assess the potential for cooperation among the NHLBI, professional organizations, and industry. A list of invited attendees and participants is attached. Integrative research was defined as investigations into the role of molecular biological processes on the physiologic function or regulation of a cell, tissue, organ, or intact organism. In addition to providing a summary of discussions about research areas, opportunities for research and training support, this report presents the major points on which there appeared a consensus of opinion. A follow-up plan of action is also presented. STATEMENT OF NEED: There is a growing concern among some in the biomedical research community that integrative physiology is on the decline at a time when advances in molecular and genetic research would warrant studies of how the molecular/genetic changes influence the intact organism. It is generally believed that there is a divergence between molecular and physiological types of research. Many investigators believe that the NIH peer review system favors reductive research over integrative research. Young scientists are opting for training in molecular biology, with a reduced emphasis on physiology. The needs are: 1) to improve the integration of molecular approaches into physiological processes that address major health concerns, and 2) enhance the training opportunities for scientists to be knowledgeable in both fields. PROMISING AREAS OF RESEARCH: It was agreed by all participants that an enhanced integrative approach would benefit every area in heart, vascular, lung, and blood research. Rather than focusing on each area individually, participants moved toward discussing more general concepts that cover all these areas. Expression of a molecular change in a small animal (e.g., mouse) is relevant if it has some direct implication or expression in humans. While there are some knock-out models in larger animals (e.g., rat, rabbit, pig) the mouse model remains the standard for molecular/genetic research, even though it has species limitations. Development of a national resource for larger animal models would require more basic research on smaller animals. Remodeling is an example where integrative research can be applied to heart, vascular, and lung investigations. A perturbation causes an acute change in the organ system which results, in turn, in a change in molecular/genetic expression. This expression leads to a more chronic change. The issue becomes a question of how to best use molecular tools to determine the physiological mechanisms or to assess the efficacy of therapy. Tools include the appropriate animal model, manipulation of gene expression, analysis of short term changes, and appropriately trained individuals to use particular resources. OPPORTUNITIES TO PROMOTE INTEGRATIVE RESEARCH: There was unanimous opinion that National Institutes of Health (NIH) Study Sections need to have a better focus on, and sensitivity toward, integrative research. It was acknowledged that reductive molecular studies are often perceived as more tightly focused than integrative studies; thus, the integrative applications do not fare as well as the molecular applications. At present there is no DRG Study Section devoted to integrative applications. A single Study Section in this area may be impractical because of the broad focus of integrative research. Several integrative research groups might be needed, each covering a specific area. For instance, there might be one Study Section that reviewed all integrative applications in heart, lung, and blood research areas. A paradigm shift in thinking about research is needed. Industry focuses on a specific issue with a project team made up of members with particular expertise. Academic researchers tend to focus on projects of direct interest, and infrequently use their skills in projects peripheral to their own interests. Paradigm shifts need to involve better collaboration among investigators, and greater interactions between academia, professional organizations, and industry. The idea of a coupled grant was discussed at some length. In essence, a coupled grant would be like an R01 grant that had two (or more) co-principal investigators. One investigator would have expertise in physiology, the other in molecular biology. Both would have an equal share of responsibility. This type of grant would bring together the two disciplines to address a specific integrative research objective. The synergy between the investigators would be like that of a Program Project Grant (i.e., the whole is greater than the sum of the individual efforts). Review of coupled grant applications would likely require a special Study Section that realized the unique nature of this type of integrative approach. Part of the review would evaluate evidence of active collaboration between the co-principal investigators. The cost of a coupled grant would probably be greater than the average R01 grant, but would likely be less than double the average R01 grant. Training slots could be included in the requirements for a coupled grant? possibly supported, in part, by cooperative partnerships. The need for preliminary data might be a major stumbling block to the development of coupled grants. Pilot or feasibility studies might need to be conducted before submission of a coupled grant application. A model for such an approach exists with the NHLBI and Cystic Fibrosis Foundation cooperative effort. In this model, the CF Foundation supports pilot studies at $50,000/year for two years. The pilot studies are competitively reviewed apart from the subsequent submission of the main application (a Program Project Grant application, in this example). For the coupled grants, it might be possible for outside organizations to provide support for the pilot studies. This approach was appealing to some industry representatives. Partnerships for joint support of clinical studies were also discussed. Using asthma research as an example, it was suggested that the clinical research might be supported by NHLBI, industry could provide crucial drugs or reagents, and a professional organization might support a coordinating center. OPPORTUNITIES FOR TRAINING IN INTEGRATIVE RESEARCH: Academic training fellowships were considered an important means to cross train individuals, but most discussants felt that applicants were mainly from the area of molecular biology because it is perceived as a more glamorous area. Industry has a need is to find scientists with a solid physiological background and an understanding of molecular biology. Academic fellowships in integrative research represent an area of opportunity for industry to jointly provide support for trainees. Most of the academic trainees are supported through Institutional National Research Service Award Training Grant mechanisms, rather than individual fellowships. It was estimated that less than 10% of NHLBI Institutional Training Grants support integrative research. Those that do serve as a model for integrative research whereby the trainee works primarily in one field, but must become conversant and knowledgeable in the second field. Examples were cited of how this is done at some institutions through seminars, journal clubs, hands-on tutorials, and use of secondary mentors. Another simple, yet effective, way to promote training would be to provide training supplements to existing integrative research grants. The usual NHLBI mechanism for application and review could be followed. Possibilities for cooperative partnerships with professional organizations and industry to offer training supplements were mentioned. A post-graduate integrative research training course was discussed. It would be about a two week course designed to provide both a physiologist with a working knowledge of molecular biology and a molecular biologist with a hands-on appreciation of physiological processes. The NHLBI-supported Genetic Approaches to Complex Heart, Lung, and Blood Diseases course is a model for such a course. Development of an integrative course is another area where cooperation among agencies, organizations, and industry would permit outstanding faculty to be recruited, tuition costs offset, and increase the likelihood of the course becoming self-sustaining. CONSENSUS OPINIONS: The following points represent a consensus of opinion expressed at the meeting. They do not represent official policy statements of the NHLBI nor any of the professional organizations or companies represented at the meeting. They are presented here as a summary of the discussions and recommendations of the Special Emphasis Panel on Integrative Research. a. Study Sections reviewing research applications need to have a greater awareness of integrative research, and to view the uniqueness of integrative applications separately from the uniqueness of reductive applications. b. New paradigms are needed for research and training that involve collaborative partnerships among the NHLBI, professional organizations, and industry. c. Integrative research can be promoted by the development of coupled grants involving two or more co-principal investigators, one with expertise in molecular biology and one with expertise in physiology. Pilot or feasibility studies that would enhance the competitiveness of the coupled grant might be supported by professional organizations or industry. d. Individual training fellowships in integrative research should be promoted. Endorsement and potential co-sponsorship by professional societies and industry should be considered. e. Institutional training grants should be encouraged in the area of integrative research. f. Innovative partnerships could develop a training course in integrative research that provides cross-training to physiologists and molecular biologists. PLAN OF ACTION: a. These minutes will be sent to all invited attendees, including those who were unable to attend. b. Individuals are encouraged to provide suggestions for further development of integrative research opportunities for: 1) the coupled grants concept, 2) supplements to existing grants, 3) increasing the use of training grants, and 4) developing an integrative research course. c. Organizations and industry will be asked to indicate their willingness to support any of the specific opportunities listed above. d. NHLBI staff will review the issues and suggestions. Follow-up conference calls may be made to solidify ideas and issues. Organization of Special Emphasis Panels or Workshops, or the development of research/training announcements are possible outcomes of this effort. NHLBI Special Emphasis Panel on Integrative Research April 19, 1996 ATTENDEES Donald Heistad, M.D., Chair Cardiovascular Division Department of Internal Medicine University of Iowa College of Medicine Iowa City, IA Roberto Bolli, M.D. Division of Cardiology Department of Medicine University of Louisville 550 South Jackson Street Louisville, KY Barbara Campaigne, Ph.D. American College of Sports Medicine 401 W. Michigan Avenue Indianapolis, IN Brian Duling, Ph.D. Department of Physiology University of Virginia School of Medicine Charlottesville, VA Martin Frank, Ph.D. Executive Director American Physiological Society 9650 Rockville Pike Bethesda, MD Francine Gingras Biomedical Research Grants Program Bristol-Myers Squibb 10154 Park Avenue New York, NY Marilyn Hansen Executive Director American Thoracic Society 1740 Broadway New York, NY Thomas Hintze, Ph.D. Department of Physiology New York Medical College Valhalla, NY Michelle Hogan, Ph.D. Executive Director American Association of Immunology 9650 Rockville Pike Bethesda, MD Leonard Hudson, M.D. Department of Medicine Harborview Medical Center University of Washington Seattle, WA William Kramer, Ph.D. Department of Clinical Research, Boehringer Mannheim Gaithersburg, MD Michael Rosen, M.D. Department of Pharmacology Columbia University College of Physicians & Surgeons 630 West 168th Street New York, NY Walter Spinelli, Ph.D. Cardiovascular and Diabetes Division Wyeth-Ayerst Research Princeton, NJ Marc Thames, M.D. Division of Cardiology Case Western Reserve University 2074 Abington Road Cleveland, OH Richard Walsh, M.D. Division of Cardiology University of Cincinnati 231 Bethesda Avenue Cincinnati, OH Edward Zambraski, Ph.D. Professor Biological Science Nelson Labs Rutgers University Piscataway, NJ Thomas Doubt, Ph.D. Division of Heart & Vascular Diseases National Heart, Lung, and Blood Institute Bethesda, MD .