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EXECUTIVE SUMMARY Since its initiation in 1976, the Medical Research Program has expended over ~45 million to basic biomedical research. The focus of this support has been on the processes of various chronic degenerative diseases. In addition, work has been supported in frontier areas of basic biomedical research, and recently an increasing emphasis has been placed on fellowship support of young scientists, immunology, and research into the interaction of selected lifestyles and chronic degenerative disease. The overview of the Medical Research Program is by the Medical Research Committee, chaired by Mr. Charles A. Tucker. Committee members include: Mr. John L. Bacon, Dr. G. Robert Di Marco, Mr. Donald Haver, Dr. A. Wallace Hayes, and Mr. Wayne W. Juchatz. Current scientific advisors to the Committee include: Dr. Dolph O. Adams (Duke University), Dr. Alvan Feinstein (Yale University), Dr. Frederick Seitz (Rockefeller University), Dr. Charles D. Spielberger (University of South Florida), and others as needed. In 1987, the Medical Research Committee focused its support of biomedical research on the following four areas. Focus One - Basic research on the part played by the 'N interaction of individual attributes and selected « lifestyle modes in the genesis and progression of chronic degenerative disease. Within this general area, programs of a multidisciplinary nature were funded in areas such as stress, hypertension, personality traits, behavioral patterns and genetic background. Focus Two - The biological basis of chronic degenerative diseases. This program includes studies that may be multidisciplinary and deal with such chronic degenerative diseases as cancer, coronary heart disease, and chronic lung disease. Most of these studies emphasize the immunology of chronic degenerative diseases. Future gifts in this area will focus on the immune system at the cellular-molecular level.

j~*r :F,W-a.aeKAaX eA. F ocus Three - New fr ntiers of basi.c biomedi.cal research. This program supports scientists working in frontier areas of research that appear basic, unusually innovative, and pioneering. In 1987, the Medical Research Committee supported such research in the areas of immunology, cancer, infectious diseases, and electron microscopy. Focus Four - Fellowship support for bright, young scientists working in frontier areas of basic biomedical sciences of interest to RJRN. RJR Nabisco, Inc. initiated its Research Scholars Award program in 1985. It is designed to foster the research careers of academic postdoctoral scientists in their formative stages. The award is designed to promote research that will yield new insights into pathophysio- logical responses of the lung and the airways. Each year, three Awards are made to academic institutions on behalf of individuals selected on the basis of scientific merit. Candidates are chosen by a Selection Committee composed of distinguished medical educators. A second Research Scholars Award program will be initiated in 1988 which emphasizes research on basic immunology.

SUMMARY OF THE RJR NABISCO, INC. BIOMEDICAL RESEARCH GRANTS PROGRAM FOR 1987 INTRODUCTION 1 v,•{ The Medical Research Program which was initiated in 1976 had an authorized budget of $5,500,000 in 1987. However, only $4,454,740 of this budget was committed during the calendar year. The totalr..~ommitment up to December 31, 1987 since the inception of the program in 1976 has been $45,611,636. During 1987, 26 research programs were funded and 6 young investigators received RJRN research scholarships. A total of 43 research investigators (excluding Scholars) have been supported up to the end of 1987 - 17 of the grants having been completed. Eighteen of those funded in 1987 will continue to be funded in 1988. While in the past, including 1987, considerable emphasis was placed on new frontiers of basic biomedical research on a very broad front, a decision was made to concentrate the program in the future into three areas as follows: Focus One - Basic research on the part played by the interaction of individual attributes and selected lifestyle modes in the genesis and progression of chronic degenerative disease. Within this general area programs of a multidisci- plinary nature will be considered in areas such as stress, hypertension, personality traits, behavioral patterns and genetic background_ Focus Two - Basic immunology research. This program is by invitation only. Within this area large multifaceted programs will be established at major medical centers with emphasis on molecular immunology. Immunology is broadly defined as host-resistance to foreign materials and to replicating cells or organisms.

Focus Three - Fellowship support for bright young scientists working in areas of basic biomedical sciences of interest to RJRN. This program is by invitation only. RJRN has established two research scholars award programs for young scientists who have limited or no federal support. One program focuses on basic immunology and the other deals with pulmonary diseases. One of the program's key objectives is to encourage the development of physician scientists. As in 1986, the overview of the Research Grants Program is carried out by a committee consisting of full-time employees of RJR Nabisco and outside advisors. The committee is chaired by Mr. Charles A. Tucker. The other inside members are: Mr. John L. Bacon (Staff Vice President and Assistant Secretary) Dr. G. Robert Di Marco (Senior Vice President, Research and Development, RJR Tobacco Company) Mr. Donald Haver (Vice President, Contributions, RJR Tobacco Company) Dr. A. Wallace Hayes (Vice President, Biochemical/Biobehavioral Research and Development, RJR Tobacco Company) Mr. Wayne W. Juchatz (Senior Vice President, General Counsel, and Secretary, RJR Tobacco Company) The outside members are: Dolph O. Adams, M.D., Ph.D. (Duke University) Alvan Feinstein, M.D. (Yale University) Frederick Seitz, Ph.D. (Rockefeller University) Charles D. Spielberger, Ph.D. (University of South Florida) Dr. Maclyn McCarty of Rockefeller University serves as a permanent consultant and participates in a number of on-site research reviews. Other professional advisors are called on as needed. The Committee suffered a very great loss in 1987 with the death of Dr. Leon Golberg of Duke University - an internationally distinguished toxicologist and a rare human being.

The Committee has had six meetings in 1987 and will continue to meet as required to serve the needs of the program. Each full meeting is accompanied by a separate meeting of the inside members who determine policy. Each group being supported by more than ab_oarz-C't150, 000 per year is expected to have its own outside advisory panel consisting of three or four experts in a related field of research. In general the review panel is expected to provide a report on the program both to the principal investigator and to the corporation. The participation of members of the Medical Research Committee is optional but usually provides an excellent opportunity to obtain a discussion of the goals and accomplishments at the professional level. Appendix A contains the budgets through 1987 of completed grants. Appendix B contains a list of current grants with anticipated expenditures through 1990. Appendix C contains the current Biomedical Research Focus Statement and Procedures for Submitting Proposals. Appendix D contains a chart of ongoing and completed biomedical research contributions since 1976. Appendix E contains a chart of ongoing and completed biomedical research contributions from 1985-87. c~ ~~'Appendix F contains a list of institutions to which RJR.,has contributed over *l million for biomedical research since 1976. Summaries of research in each of the areas supported in 1987 are given in the following four sections. As stated previously, the areas of support will be reduced to three as existing programs are phased out.

I. DEGENERATIVE DISEASES ASSOCIATED WITH SELECTED LIFESTYLE MODES It has long been suggested in medical circles that the psychological attitude of a patient can play a significant role in determining the course of a disease or, more generally, factors derived from temperament and lifestyle can influence the health of an individual. Quantifying such relationships is, however, not an easy matter because of variations of a statistical nature that arise from several sources. First, individuals selected from a random population, particularly at the human level, differ from one another. Second, even in a given individual, there may be fluctuations from one time to another. Finally, uncertainties may creep into measurements of both the psychological and physiological parameters depending upon the skill of the investigator, the time at which measurements are made, and the characteristics of the measuring equipment being used in an experiment. For these reasons, research in this area inevitably requires expert interdisciplinary talents at the psychological, statistical and physiological levels. Support of this field of research under the auspices of the Medical Research Committee was initiated in 1984 and is now a major focus to the extent that promising groups of investigators can be found. In 1987 six major programs were supported. 1. Dr. Robert Ader at the University of Rochester Medical School, who has been supported since 1985, continues to study the effects that stress arising from various sources, such as disease, the therapeutic use of drugs and overloading of %the sensory system, can have on- the immune system, particularly on the killer and suppressor cells. The latter play very important roles in the defenses provided by the immune system. In some of the experiments, for example, special strains of mice are subject to feed or drink in which a distasteful chemical is inserted to see if this induces changes in the number of natural killer cells. Particular.emphasis is given to the use of an additive agent (Poly I:C) which stimulates the production of interferon - one of the molecules which plays a role in the activity of the immune system - to see if differences in its action can be observed when this is incorporated in the feed or is injected directly into the subject. The group working with Dr. Ader has obtained particularly interesting results working with a strain of mice which have an overactive immune system and are subject to what are termed autoimmune diseases. The course of this

disease can be mitigated with the use of immuno-suppressing agents. It was found that if the initial treatments with the suppressive agents are accompanied by immunologically neutral agents such as saccharin or saline solution, some degree of immuno-suppression continues to be exhibited if the neutral agents are continued after the immuno- suppressive agent is stopped. This indicates that the neutral agents can have suppressive effects on appropri- ately conditioned animals. With the cooperation of the university, Dr. Ader has greatly improved his laboratory resources during the past year. While this process has slowed the experimental research to a degree, the ultimate effect should benefit the range and quality of experiments that can be carried out by the group. 2. Dr. Paul H. Black of Boston University, who has been supported since 1984, is studying the interrelation between the emotional framework and the state of both the immune system and neural hormones in a family of depressed patients in a psychiatric clinic. A portion of the earlier part of the research program was spent developing standards of measurements for the experiments. However, 1987 has been a productive year. The work shows that patients with major psychological depression have a suppressed immune system in the sense that the reactivity of the protective cells is lower than normal. Moreover, the number of killer cells is substan- tially diminished. These effects are greatly accentuated in individuals who have become so depressed that they have attempted suicide. In parallel with these changes are various shifts in some of the hormones. In particular, some of the hormones which can act as suppressors of the immune system are elevated in keeping with the observations on the immune system itself. Research on these findings is being extended in both breadth and depth. Along with the foregoing work, Dr. Black and his colleagues are carrying out similar measures on individuals who are responsive to hypnosis and in whom various emotional states can be induced during hypnosis. Special emphasis is given to anger, sadness, happiness and what might be called a state of "neutral" emotion. The study is repeated on each of the subjects during four independent sessions to determine the extent to which the results obtained in one session are repetitive. Thus far the work shows that in some of the subjects the states of anger and happiness are associated with increases in natural killer cell activity and in the

responsiveness of the entire immune system. It should be emphasized that this phase of the research program is still in its early stages. However the results obtained thus far seem to be consistent with the well confirmed observations on animals that those which display anger under stress are more highly immuno-responsive. 3. Dr. Jan Breslow of The Rockefeller University has initiated a program to study genetic abnormalities that, along with lifestyle, can lead to premature atherosclerosis. Prominent among the materials which transport fatty agents through the blood stream are the lipoproteins - a family of molecules in which the fatty agent is bound to a protein. The concentration of these in the blood is, in turn, controlled in part by enzymes which participate in the way in which the balance of such molecules is maintained. The portion of Dr. Breslow's work supported by RJR Nabisco deals with the study of the genes which serve as the template for generating the effective enzymes. The analysis of the structure of the relevant genes is being carried out both in selected strains of mice and in human subjects. In the case of humans the research involves normal as well as abnormal subjects in which the controlling enzymes are deficient. The research with mice has been developed in sufficient detail and precision to provide highly specific information regarding the gene structure and the effect of various agents such as insulin upon the effect of the enzyme. Fortunately much of the research can be done with the use of cell cultures. The work with human subjects must proceed much less directly. However, Dr. Breslow and his group have, through extensive surveys, found about a hundred individuals who exhibit abnormal control of the crucial lipoproteins because of abnormally low levels of the enzyme. As is common in a genetically mixed human population, the subjects exhibit a statistical range of physiological behavior. The aspect of the work dealing with human subjects is still in its early stages. 4. Professor Leo Herbette of the University of Connecticut Science Health Center is studying the way in which chemicals interact with protein receptors on the outer surface of artificial and cellular membranes in solution. His ultimate goal is to determine the relative speed with which such agents can reach and affect the properties of the cell. Comparisons will be made when the membrane is in various states of hydration or is influenced