Dr. Bose: No, the question is really that, by the time you see the malignant cell and the virus particles in it, it may then be that the malignant cell has become infected with some nonspecific virus. This has nothing to do really with the question of whether the virus under study actually induced the carcinogenic process in that particular cell.

This is not the problem of carcinogenesis at the moment. It is a problem of micro-heterogeneity and response, in that it occurs only in a few cells and nothing is to be gained by examination of the whole tissue. In fact, the carcinogenic process could be developing in one series of cells which are not actually infected with the virus and you would not know about it.

Dr. Beard: Your remarks are not particularly relevant to the matter of this meeting. You certainly have no basis for questioning the knowledge of the malignant state of the cells under study. The myeloblasts about which we have spoken are certainly neoplastic, and without virus malignancy does not occur. Within the limits of the evidence thus far obtained, these cells-every one of them-contain virus. There is no reason to suppose that virus is absent from any Rous sarcoma cell, and the same thing may be said for mouse mammary carcinoma.

Dr. Bose: The process of carcinogenesis may not have occurred, however, in the cell that contained the virus. It may have occurred in some other cell. When you see the process at the end and you see a whole malignancy, then the cells are infected with the virus. That, however, does not mean to say that the specific and rather rare sort of process in which one or two cells become malignant can be examined by examining the whole tissue. That should be fairly clear. If a process is occurring in one cell in a million, how do you detect that process by examining the whole million cells together?

Dr. Friend: May I suggest one thing? Dr. Rose has raised a provocative point and, in so doing has devised for himself a wonderful problem to carry home with him. He can take a thousand cells, isolate them one by one, study what they produce, do exactly the same thing with another thousand normal cells, putting one little virus into each little cell, and come back in 10 years to tell us what he finds.

Dr. Dmochowski (M. D. Anderson Hospital): I think this was a most unfair question. The symposium was meant to be concerned with phenomena of tumor viruses and not with the means by which viruses induce cancer. This is quite a different subject about which so little is known. But I would ask Dr. Rose how much he knows about the process of carcinogenesis. Induced by anything? By benzan-thracene? Any dye stuffs? He knows as much (I hope-perhaps I am wrong, perhaps he does) as we do about the way viruses induce cancer.

Dr. Sabin (Childrens Hospital Research Foundation, Cincinnati): I suppose I have as little or as much right as anyone else to comment on this broad question, and I would like to say what I am carrying away with me after these 2 days.

We came here, it seems to me, to analyze the processes in a number of tumors, with which viruses have been associated, in a way that one can reproduce those tumors with the respective viruses. The association of the two is at least established, and now we have been trying to solve, in effect, the very question that Dr. Rose raised. How are these viruses involved with the formation of the tumors?

I am interested in that problem, particularly to find some rational approach to what may be done in the study of human tumors, when it is not possible to utilize 1-day-old humans for inoculation with an extract and then wait several years to see if they will develop tumors like those produced by the polyoma virus. We are searching for guides in all these processes to see how so-called tumor viruses may be associated with the end product. I gather that, for one thing, not all tumor viruses are working with their tumors in the same way. IjDt us take these avian leukemias that Dr. Beard and his associates have been working with so long. He gets so much virus there that I should think he ought to be able to get it in large quantities from the blood. It seems that the whole gist of the discussion was whether a malignant cell that continues to multiply is producing the virus, or is it perhaps that the virus comes from the dead cell? I have been trying to decide from the work his associates have been presenting whether it is the 5 percent of the cells which die that produce all this virus or the 95 percent that remain alive.

It is not impossible for me to believe that the cell can continue to divide and produce some virus, so it may well be that some malignant cells are multiplying and yielding virus, but others not. I think the most important matter now coming into focus is the polyoma model. In this system, Dr. Rose, the virus is multiplying in millions and billions of cells, from one or a few of which, after many months, there develops a tumor. It is most striking and important that the tumors, after several transplantations in virus-free hamsters, do not yield any virus or any evidence of viral antigen or viral reproductive material. And now, the question arises: Is this the polyoma virus-induced tumor cell in which we cannot demonstrate any trace of the original virus, such as its nucleic acid or its provirus? Or, does the tumor now consist of cells that bear the same relationship to the polyoma virus as the cells of a malignancy induced by methylcholanthrene bear to the chemical? This cannot yet be answered. There are being studied different modes of action of viruses which, with regularity, result in the induction of tumors. Many mechanisms may be involved, and that all the questions have not been answered is not disturbing at all, since, with the reports at every new meeting, a little more light and a little more progress are introduced.

Dr. Beard: The time has come to close this symposium. I should like, personally, to thank all of you for coming, and I know that the members of the Virology and Rickettsiology Study Section are gratified to know your interest in the conference.

It was the aim of this program to bring together people of widely different disciplines in the attempt to arrive at some general understanding of the total problems. It is unlikely, of course, that a close correlation can be effected of the findings in this presently complex and confused field. It. might be possible, however, to bring the numerous people now working with virus tumors somewhat closer together.