sample="quota" bates="501007677" isource="bw" decade="19xx" class="ui" date="19000000" B11-18 TC 1230 cc for RAJ GES MLR EPcc for (there are series of initials) Ent?, RAJ, GES, MLR, EP N. Western University Phill Handler NW Academy of Science It is a high privilege to be with you this morning to participate in the Dedication of the University Cancer Center. We do so at a time that appears to be particularly felicitous for such a venture. Neoplasia -- cancer if you prefer -- is a problem of immense human concern. At this time in the history of our country, approximately one quarter of the American population may be expected to succumb to cancer in one or another form. This rate as a percentage of all deaths, has risen slowly over the years, not because of an actual increase in cancer incidence, stated on an age-corrected basis, but rather because of improved sanitation, because of our history of success in dealing with bacterial infections, because of an improved food supply and an economy that has abolished nutritional deficiency diseases, because of our success in immunizing against viral diseases and in treating endocrine disorders. Moreover, for the last few years, the death rate due to cardiovascular disease and stroke has also been declining. All of these welcome circumstances have freed us to fall prey to the ravages of cancer. To be sure, viewed statistically, cancer is not a great threat to the human life span. Because, in the main, it is a disease of our later years, were all cancer to be instantly abolished, as it were, the mean age at death of the American population would increase by only one and a half to two years. Nevertheless, we are here for a very good reason. Our purpose is not to extend the human life span indefinitely but to join in the intensely human endeavor by which this great cruelty may be relieved or, better yet, to so arrange that it not be visited upon us. When, some months ago, I accepted Dr. Berlin's invitation to speak today, I agreed to discuss the general circumstances of biomedical research in our time and the public policies necessary to facilitate the progress of such research, to review the areas of greatest progress and adumbrate what may lie ahead. But, in so doing , he set me to thinking about "the cancer problem" in its boldest outlines. In short order, I found myself puzzled. Accordingly, and with no little trepidation, I would like, instead to share some of my puzzlement with you in the hope that it may give some direction to future research. Two themes that dominate present literature concerning the etiology of cancer: (1) The primary event is a mutation, viz., a permanent alteration of the genome but of unstated nature and (2) the mutation is occasioned by a physical insult to the genome from without, i.e., by the action of a chemical carcinogen or by radiation. These are linked by the fact that, after exposure to the external agent, cell transformation occurs and the succeeding generations of cells proceed along their unheeded course in the absence of the original injurious agent. My examination will be concerned with both these considerations. Last week, on the Mall in Washington, several speakers, Jane Fonda among them, inveighing against nuclear energy, urged their huge audience to join them in attempting to shut down the nuclear energy industry so as not to exacerbate further what they referred to as "our current epidemic of cancer." There is no such epidemic. The age-corrected incidences of only two forms of cancer have altered significantly in our lifetimes. Bronchiogenic carcinoma due to cigarette smoking has risen sharply and the incidence of primary gastric carcinoma has declined dramatically for entirely unknown reasons. These two have more or less offset each other and the age-corrected incidence rate for the total of all forms of cancer has remained approximately constant for a half a century. The epidemiology of cancer has been intensively scrutinized. The principal finding has been that the incidence rates of different forms of cancer vary quite significantly among countries, and less dramatically, among regions within our country. In the U.S., there is no correlation between the incidence of any form of cancer and the ethnic origin of any subgroup of our genetically heterogeneous population. These circumstances underlie current beliefs that observed geographic differences in cancer incidence rates do not reflect differing genetic constitutions of the affected populations but, rather, arise from differences in local cultural patterns and from unstated aspects of their environments. The most dramatic evidence usually cited is the present very high rate of gastric carcinoma in Japan, the significantly lower rate in first generation Japanese in the United States, whereas second generation Japanese in this country show no more gastric carcinoma than do the rest of us. And that is even more significant in the view that, 50 years ago, the rate of gastric carcinoma in the United States was approximately what it is in Japan today. We have been doing something right and we don't even know what it is. What seems lost on some who would participate in the debate on the place of technology in our society, particularly those concerned with the possible environmental carcinogenesis by radiation or chemicals, is that the necessity for scientific rigor is even greater when scientific evidence is being offered as the basis for the formulation of public policy than when it is simply expected to find its way in the market place of accepted scientific understanding. Science itself can benefit by early publication of properly documented preliminary findings. But surely public policy should not rest on observations so preliminary that they could not find acceptance for publication in an edited scientific journal. And yet that has happened repeatedly. Political decision makers have no choice but to rely on the validity of what seems to them to be the findings of rather recondite science thereby placing a heavy onus on scientists who bring such matters to attention. Announcement in the press of each experiment, in turn, generates public alarm that can neither be justified nor assuaged. Once a compound has been publicly called into question, however meager the evidence, decision concerning its use becomes unavoidable. The sensible guide would be to accept substantial hazard only for great benefit, minor hazard for modest benefit, and no hazard if it can be avoided without penalty. But in most cases to date quantitative assessment of risk is entirely lacking; accordingly, the current guide -- as given expression in the Delaney Amendment to the Food, Drug, and Cosmetic Act -- appears to be to place a value of minus infinity on any possibility of carcinogenesis -- a position that cannot be indefinitely sustained. For most environmental pollutants that have recently been called to attention we are concerned with potential but as of yet undemonstrated hazard. Statistically speaking, relatively few persons are known to have been seriously damaged by man-made chemicals. The absolute number is, of course, meaningful and deplorable. But as a percentage of total mortality it is very small indeed. In any case we have become conscious of environmental health problems. A host of institutions, public and private, are alert and vigilant. The result has been a stream of regulations each well intentioned, most indeed commendable. But in the absence of persuasive data concerning the magnitude of risk to humans, the sum of such regulation can engender public cynicism, ensnarl life in the work place, and slowly paralyze the economic life of the nation. I applaud the evolution of the Clean Air Act, from 1970, when it mandated the reduction of risk to zero irrespective of cost, to 1977 when it asked that decision be based on comparison of marginal cost with the marginal benefit of pollution abatement. That returns to the scientific community the burden to identify and quantify risks and relate health effects to exposure levels, as it leaves to all of us the responsibility for developing a meaningful risk/benefit calculus which is now so drastically lacking. A decade ago it may have been desirable to flag public attention to potential hazards and proceed as if each were a clear and present danger; it is time to return to the ethics and norms of science so that the political process may proceed with greater confidence. The public may wonder at why we don't already know which appears vital to decision -- but science and technology will retain their somewhat diminished place in public esteem only if we steadfastly admit the magnitude of our uncertainties and then assert the need for further research. And we shall lose that place if we dissemble or if we argue as if all necessary information and understanding were in hand -- whether the question be the health effects of air pollutants, food additives or microwaves, the economics of solar energy, the properties of a radioactive waste disposal system, the social consequences of electronic mail systems, or of linkage between large data bases. Scientists best serve public policy by living within the ethics of science, not those of politics. But, what is the possibility that much of cancer is the simple result of the normal metabolic processes that generate superoxide? Were that the case, cell lines that are defective and deficient in superoxide dismutase should be unusually sensitive to oxygen as a mutagen or carcinogen. Fridovich observed that, of several strains of yeast, those that are most sensitive to the mutagenic effects of ionizing radiation are those which contain least superoxide dismutase. Those which are most resistant contain much of this enzyme. In a similar vein, in an issue of NATURE, last fall, a group of investigators at Oregon State pointed out that oxygen gas is a powerful mutagen in the usual Ames Salmonella assay for mutagenesis. Fancy the EPA considering a ban on oxygen! More pointedly, in a recent issue of Cancer Research Oberly has reported that cancer cells, generally, seem to be deficient in at least one of the two superoxide dismutes. And there are other, teasing observations. I have not seen the paper, but I am told that there is a report from a Colombian pathologist, Otero, indicating that the incidence of lung cancer in Bogota, Colombia, is extraordinarily low despite the fact that the population smokes as heavily as do their fellow citizens. But Bogota is at 14, 000 feet elevation where the oxygen tension is diminished by more than one half from ground level. As I said earlier, the rate of superoxide ion formation by those enzymes which we tested 15 years ago is drastically reduced at this lowered oxygen tension. Finally, I am told that, if one eliminates from the total cancer rate at a variety of places at high altitude, the rate of skin cancer occurrence -- which can be occasioned by ultraviolet exposure at altitude -- the resultant overall cancer rate seems lower than at sea level. I've not seen these data and cannot say how real this effect may be. In sum, I cannot know how much truth there is in the sketchy web of an hypothesis that I have offered. But I leave with you the strong suspicion that, in significant measure, cancer mat be the price that animal life has paid for life in an oxygen environment. If so, the simplistic environmental carcinogenesis hypothesis has been seriously overestimated. I know that you expected me to discuss science policy, to discuss what we need do, politically, to get on with the tasks before us. But not today. I return to what I said at the beginning. It is a particularly felicitous moment at which you inaugurate the use of this splendid facility. The disciplines of cell biology and biochemistry are now one and investigators have acquired an extraordinarily powerful armamentarium of research methods and tools. We are just beginning to understand the normal cell cycle, just barely beginning to understand the biochemical events that are the remarkable orchestrated process by which a fertilized egg differentiates and grows into a complex intact organism., just beginning to understand the structure and functioning of the genetic mechanisms of the eukaryotic cell and how much more subtle and complex they are than the genetic apparatus of the bacteria which we had been studying as models. Somewhere in the future of such studies will lie the secret of neoplasia. And until we have that knowledge of these primary processes, of the events that govern the timing of differentiation of chemical basis, of the chemical basis for cell-cell recognition, we will be unable to understand how it can be the crude shotguns of radiation, of superoxide formation, or of chemical carcinogens can all elicit the same general sort of change in the control of the genetic apparatus, whatever it may actually be, that is the essence of the neoplastic transformation. I have not presented matters in this light today so as to discourage you with respect to the hope that, one day, cancer may be preventable -- that is a task with which we must get on with the utmost vigor. But, it may be that the most frequent event that results in cancer may be an intrinsic feature of our own biology. If so, then the alternate approach on which medicine embarked years ago, the search for selective, otherwise innocuous means of intervention once a cancer has been recognized becomes even more imperative if, indeed, one day, humanity is to be relieved of this scourge. We can all rejoice that this splendid new resource will enable the faculty, students, and fellows of Northwestern to make a truly significant contribution to that noble endeavor. Thank you.