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i - - ~ - 1230YORKAVENUE NEWYORK,N.Y.10021 June 7, 1979 Ms Sarah Shuping Executive Assistant to Mr. Roemer R. J. Reynolds Industries, Inc. Winston-Salem, N.C. 27102 Dear Ms Shuping: Enclosed, as you requested, are the 31 copies of Dr. Seitz' presentation to the International Advisory Committee. These have been mailed in four r .'.:: separate packages of which this is # 1. C. ~ Sincerely, Ann Elskus Dr. Seitz's Office ~ 0 a ~ ao 0 ~ -4 a

< Presentation to International Advisory Committee - R. J. Reynolds Industries by Frederick Seitz May 29, 1979 About a year ago, when my period as President of The Rockefeller University was nearing its end, Mr. Sticht asked if I would be willing to serve as advisor to the Board of Directors of R. J. Reynolds Industries, Inc. as it developed its program on the support of biomedical research related to degenerative diseases in man - a program which would enlarge upon the work supported through the consortium of tobacco companies. Since this program lay very close to my own interests and R. J. Reynolds Industries had provided very generous support for the biomedical work at The Rockefeller University, I was more than glad to accept. As you know, since then we have evolved a plan whereby Mr. Sticht, Mr. Stokes and Mr. Roemer represent the board in a group advisory to the board on which I also serve. Mr. John L. Bacon provides the functions of an executive secretary. Dr. James A. Shannon, a former director of the National Institutes of Health, and

RJR - page 2 , Dr. Maclyn McCarty, the former Vice President for Medicine and Director of the Hospital of The Rockefeller University, have worked closely with me in establishing guidelines and evaluating the merits of both ongoing and proposed research programs. Most outstanding research investigators receive some support from the federal agencies such as the National ' Institutes of Health and the National Science Foundation as well as from their own institutions although there are, from time to time, exceptional cases where the ever-growing rigidity of the support provided through federal funds excludes the support of an important program in the hands of a distinguished and imaginative investigator. In view of this situation, our advisory group has concluded that the funds provided by Reynolds i*ndustries would serve the purposes of medical research best if they are used to supplement other sources in such a way as to' make it possible to do work, particularly of an interdisciplinary kind, that would otherwise be delayed or neglected. We hope that

RJR - Page 3 this policy will optimize the effectiveness of the use of the Reynolds funds. As a matter of policy we have also agreed that the groups being supported should appoint an appropriate group of outside advisors who are experts in the fields of investigation and that they should provide annual reports of their progress. Interestingly enough, our experience thus far seems to demonstrate that the most promising groups that fit within the guidelines I have stated are closely associated with a clinical environment where human disease is of immediate interest. I should add that in addition to providing an overview of the research programs funded by Reynolds, Drs. Shannon, McCarty and I have agreed to maintain close contact with the programs funded through the consortium of tobacco companies, to which Reynolds contributes about forty percent of the budget. Let me turn to scientific issues and to individual programs that are now being funded or are under serious con- sideration. As you undoubtedly know, life has existed on earth for about three quarters of the age of our planet which NI O ~ a m 0 a c

RJR - page 4 is estimated to be about 4.5 billion years old. The earliest forms of life which have been detected so far were single- celled organisms, many of which still exist. They have some- thing in the nature of immortality since they both renew and reproduce themselves by a process of cell division - a mechanism which in one way or another lies at the heart of the continuity of all life. Multi-celled organisms appeared about seven hundred and fifty million years ago and account for most of the life we see with our naked eye. Such organisms, which include our species, have the great advantage that different groups of cells in the organism can serve different functions and thereby permit very great flexibility and adaptability. The manner in which the initially undifferentiated cells of the embryo which develops from a fertilized egg specialize and retain their specificity is still an unsolved problem. Our species stands at the top of the evolutionary ladder, having the most complex of all inter- cellular relationships although we have a great many properties ,..

RJR - page 5 in common with other living organisms. One of the great disadvantages of the individual multi- celled organism is that it ages and dies, suffering from various forms of degeneration in the process. Such organisms depend upon highly specialized cells for the reproduction of new, individual members of the species. Multi-celled organisms also suffer individually from other types of disadvantages. For example, they may be invaded by destructive foreign organisms such as parasites, bacteria, fungi, or viruses, the well-known infectious agents. Not all such invasions are bad, for example our intestinal tract harbors a wide variety of organisms which are highly beneficial. The anitbiotics and vther drugs have given us a degree of special man-designed control over the first three sources of infection but we still, in the main, depend upon natural defensive mechanisms, which I will discuss in a moment, for protection against viruses. Viruses, as you probably know, multiply within the organism by entering individual cells of

RJR - page 6 the host and taking over in some substantial way the operation of the invaded cells. Second, it occasionally happens that a member of a specialized family of cells, such as a cell in the bone, liver, intestines or skin, circumvents the control mechanisms which make it part of a well organized family and begins to divide as if it were independent of the remaining organism. If such division continues it produces a tumor which is benign or lethal depending upon whether the process of division stops before there is substantial damage or continues until the parent organism is killed. Third, cells which have very important roles to play in maintaining the health of the organism may cease to function properly and cause illness or death. For example, the cells of the pancreas may stop producing insulin and cause diabetes, or the kidney cells may fail to filter the blood properly and cause uremic poisoning or high blood pressure, or the cells in the walls of the arteries may proliferate in such a way that the artery looses elasticity or contains obstructions.

RJR - page 7 .... ~:.:. All organisms have more or less elaborate defense mechanisms to protect them against attack or malfunction. Generally speaking, the more complex the organism the more complex the total defense system. Some of the defense occurs at the level of the individual cell. For example, our skin cells produce antibiotic agents which protect us to some degree from direct invasion through the skin. Similarly, there is a family of protein compounds known as interferon produced by cells which provide resistance to virus attack. Each species produces its own type of interferon. One of the most complex but effective parts of our defensive apparatus is the ambient cellular immune system. This system involves a complex of cells which are produced in the bone marrow and circulate through the body in search of foreign agents whether foreign organisms or foreign compounds (antigens). Some of the protective cells termed phagocytes surround and ingest 'foreign cells or other objects. Others, the lymphocytes, are sensitized

RJR - page 8 by their presence in a highly selective way, multiply and produce antibodies which bind to the antigens and form compounds which are usually less toxic and are eliminated. In some cases a fraction of the antibodies may remain in the system indefinitely and provide permanent immunity to the infecting agent. There are two major types of phagocytes, namely the microphages which have a relatively short life of perhaps two days and are renewed from the bone marrow, and the macrophages which, although produced in the bone marrow, live•longer and may undergo cell division. The compounds formed by the chemical linking of antibodies and antigens - termed antibody-antigen complexes - can sometimes cause damage to the host by attacking one or more forms of tissue destructively. This effect, is responsible for rheumatic fever and other forms of disease. It is also possible for the immune system to be activated by the host's own tissue and to produce antibodies which attack

RJR - page 9 the host. This effect, designated under the general heading of autoimmune disease, is probably responsible for such ailments as rheumatoid arthritis. It is worth mentioning that there is good reason to believe that the cellular defensive mechanism I have just described goes into action if foreign tissue is placed in contact with our own, as in a skin, heart or kidney transplant of tissue from'another individual who is not an identical twin. The result normally leads to rejection of the foreign tissue or organ. There are agents called immuno-suppressors which suppress the immune systems sufficiently to permit organ transplants. Experience shows that individuals who are kept on such suppressants are highly suscep- tible to certain forms of cancer. This suggests that one of the functions of the immune system is to combat cancer cells and that cancer would be much more prevalent if we did not have this pro- tective system. It should be added that the appearance of cancer is frequently accompanied by the production of large quantitites of specific antibodies, presumably produced in an attempt of the de- fensive system to reject the cancerous tissue.