This will be a brief review on the relationship of viruses to carcinogenesis. Although I am a virologist with continuing interest in virus-induced tumors, I am not trying to advance the virus theory of cancer. The question is not whether all tumors are caused by viruses but what tumors are so caused, and how.

Viruses and cells are inseparable associates. Modern study of viruses has been and continues to be responsible for vast strides in the understanding of human disease. Before 1950, only 21 human viral diseases were recognized (1). In a single decade since, more than 150 hitherto unknown viruses have been characterized, and many others under study are known to be distinct from established types (1, 2). This amazing accomplishment reflects the development of a new discipline, cell culture. Cell cultural methods, technologically improved since 1950 (S), have turned up a host of viruses in the human environment. The human respiratory tract, orointestinal tract, genitourinary tract, and even the viscera have harbored unsuspected viral nonpathogens, opportunist pathogens, and viruses newly associated with particular diseases.

I wish to consider some particular aspects of viruses, cells, and cancer as my associates and I at the University of Minnesota see the problem. We believe that understanding disease at the cellular level (4, 5) is prerequisite to understanding and treating it at the level of the intact host.

What Is A Virus?

Most people ask whether a virus is "alive." This is not an idle question, because we must have some idea what a virus is, apart from the way in which it is identified. Perhaps we should first ask: What is a cell? A cell is a natural device for carrying out certain biochemical syntheses and for building replicas of itself. To permit this accomplishment, it incorporates a built-in code of instructions, the genic-chromosomal apparatus. The virus likewise has built in it a code of instructions, in the form of nucleic acid wrapped as a package to facilitate entry into a susceptible host cell. This concept of virus involves two key points: (a) foreignness to the cell, implied by the fact that the nucleoprotein code includes instructions for specific packaging, and (6) complete dependence of the virus on the cell for physiologic activity. This dependence results from absence of a mechanism within the virus capable of independent fulfillment of the instructions incorporated in its nucleo-protein code. This concept readily differentiates transforming agents and cellular genes from the category of virus. The virus is a relatively passive partner in a peculiar host-parasite relationship. It is a packaged blueprint that causes a cell to divert its energy partly or wholly to the manufacture and packaging of more virus. Incidentally but as a result the cell is physiologically impaired or destroyed. We call this the cytopathogenic effect of a virus. We do not know whether this impairment is a direct or indirect consequence of virus production. Impairment might be attributed to: (a) deleterious toxic influence of newly replicated virus particles as they accumulate within the infected cell; (6) a simple inadequacy of the cell to bear the combined load of cell maintenance and virus manufacture; and/or (c) the diversion of essential metabolic processes from cell maintenance, the natural economy of any cell, to virus production. Despite this concept of virus as. a packaged code, for purposes of classification viruses are accepted as parasitic microorganisms. Is a virus "alive"? Present concepts of viruses indicate why the question has no real answer. The transition from "alive" to "not alive" has no discontinuity. From the foregoing consideration, it is apparent that the infected cell-virus complex in a sense represents an entity, a new microorganism. Any virus produced by this complex therefore is a reflection of the complex, a cell product. Cells cannot be regarded simply as media. Cells are intricate factories which in the body are arranged as intricately organized tissues. Cells under direction of virus function vicariously and/ or they are destroyed.

Virologists now have at their disposal primary cultures of cells taken directly from tissues, stabilized strains of cells in continuous culture, and purified continuously propagated strains derived from single cells. A major contribution to medical research has been the evolution of mass preparation procedures. For example, at Minnesota we employ weekly from 3,000 to 5,000 cell cultures prepared from 31 cell strains of human, monkey, horse, cow, pig, domestic and cottontail rabbit, and mouse origin. Development of culture technique is continuing, in search of improved means for characterizing animal cells and production of cells of desired characteristics. One member of our group (6) has developed use of an enzyme, collagenase, for better disruption of tissues as a source of cells, so as to obtain primary and continuous cultures of pulmonary and other body cell types. Another member of the group (7, 8) has devised a hemagglutination test for species specificity of cultivated cells, so that now we can at least verify the identity of cells originally derived from different animals. Studies of cellular chromosome morphology and number, and of the physiologic activities of cells, are being pursued (4). The ultimate objective is to propagate cells of known type continuously from body tissues with normal chromosome constitution and defined relation to cells in vivo for comparative studies of cancerous cells of similar origin.

Viruses And Cancer

The relationship of viruses to cancer in the past has been clouded by emotional factors. Today our attitudes are not free of emotion, but do have a more rational basis. Cancer concerns you and me as individuals and as practitioners of medicine or research. At present, 1 of 4 or 5 of us in this room can expect to have cancer, and there is every reason to believe that, as the incidence of other diseases is reduced and the lifespan prolonged, that proportion will rise. Although we do not yet know that a single human cancer is caused by a virus, we are vitally interested in viruses as the causes of human cancer. Studies of experimental cancer and the existence of a large number of known tumorigenic viruses of animals support the belief that at least some human tumors must be similarly incited.

In a discussion of the cause of cancer, it is not unusual for authorities to state that there are many kinds of cancer and that cancer therefore must have many different causes. This view is conditioned by the observation that cancer can develop from any of a wide range of cell types located at any part of the body and exposed to widely assorted environments. The pathologist recognizes a sameness in the spectrum of cancer as shown by the same general defects, by progression in autonomy and by the assumption by malignant cells of an embryonal morphology or "anaplastic" appearance. Capacity or ability of a pathologist to recognize changes becomes intuitive. A conjunction of observations has led many investigators to consider that cancer cells result by "somatic mutation," induced by one of a number of possible factors. Although cancer researchers categorize "causes" of cancer, it is more helpful to consider the factors in the disease process simply as exciting, mediating, operating, and modifying. For instance, diphtheria is excited by a bacterial virus (9-11), mediated by Corynebacterium diphtheriae, operated by a bacterial exotoxin, and modified by the reaction of the host. We have good reason to believe that cancer is a disease modified by the host. We know that it is operated by altered body cells. Since experimentally it can be shown that the altered cells exhibit heritable properties, at some stage in the evolution of a tumor the disease is mediated by cellular genetic constitution. This view directs emphasis away from the categories of "causes"; what we want to know is how the various factors interact.