Dr. FARBER. Yes, indeed. They are working in a number of veterans' hospitals, both on a research level and on a clinical level. Some of these chemical compounds we are talking about are being used in veterans' hospitals throughout the country.

Mr. DOLLIVER. I somewhere have the impression that the Hines Hospital in Chicago was the center of the Veterans' Administration activities with respect to cancer.

Dr. FARBER. For that area, yes.

Mr. DOLLIVER. Thank you, Mr. Chairman.

The CHAIRMAN. Any other questions, gentlemen? If not, we will proceed.

Dr. HELLER. Mr. Chairman, in extension of the consideration of research we would like to call on Dr. Keith Cannan to discuss that portion of research to which you referred, which is the basic research, the advances which have been made, which, of course, make possible some of the advanced clinical research. Dr. Cannan.

STATEMENT OF DR. R. KEITH CANNAN, CHAIRMAN, DIVISION OF MEDICAL SCIENCES, NATIONAL RESEARCH COUNCIL

Dr. CANNAN. Mr. Chairman, members of the committee, and colleagues, I think much of my argument has already been anticipated in the discussion, but perhaps it might be helpful if I attempted to restate in a brief way what the cancer research problem looks like at the experimental and laboratory level; and I will speak very much as one watching the scene from the sidelines and not as an active participant in cancer research. Nor will I speak of any specific program of a particular agency, for the simple reason, I think, that when a scientist is engaged in research he does not think of his contribution to the program of a particular agency but thinks of it simply as a contribution to knowledge on a worldwide basis.

We might begin with the old dilemma of medicine: prevention or cure? Or perhaps, as it might be rephrased at the laboratory level: the search for causes or the search for cures ?

Now, I would like to say at the outset that I hope in some degree I can persuade you today that although these two questions are posed as alternatives-they are phrased differently-it transpires that our approach to both of them seems to be down the same avenues of investigation, and it is rather arbitrary to draw the distinction between the search for causes and the search for cures.

To my mind it is as probable that the seeker for causes will stumble on the next good cure as it is that the seeker after cures may actually find a cause for cancer.

If we begin, then, with causes and restate our concept of cancer, we have considered it as a disorder of growth of cells. We can be more specific than that and say that it is a disorder that resides within the individual cell. This is not a disorder that is imposed from without; it is a disorder intrinsic to the malignant cell. Moreover, it is a disorder that is passed on, as we have heard. It is inherited by the daughter cells of the malignant cell. So it becomes self-multiplying as a disorder and therein, of course, lies its malignancy.

Now, what causes this disorder? We have heard today, and one may just repeat, that there are certain extrinsic causes of disorder, inciters to cancer, which impinge on the organism from without:

radiation, X-ray, radioactive materials, and even excessive exposure to sunlight. Then there are a group of heterogeneous chemicals, including a few metals, a number of hydrocarbons of curious chemical structure, a few tars and intermediates of the dye industry.

Now, this is a very mixed bunch from the point of view of the chemist, and there is no common thread of property in all these extrinsic inciters or carcinogenic agents, as we call them, which gives any clue as to why they should have this one unique biological activity of inciting the cell to malignant growth.

These agents have been immensely valuable in the laboratory, because they have allowed us to take the living cell in the laboratory and under control conditions to submit it to carcinogenic stimulus and then to study in detail not only the cancerous state developing, but to probe back into the region of the hypothetical precancerous state, the first disturbances that are a result of carcinogenic stimulants; but I will not dwell on the extrinsic causes of cancer because they are not a material contribution to the human cancer problem except, perhaps, as it may transpire in the field of lung cancer or in particular industrial hazards.

The majority, therefore, of causes, if there is more than one cause of human cancer, must be intrinsic to the organism itself. They must arise within the body, and they may arise possibly within the malignant cell or they may be inciters produced in one part of the body which actually create malignancy in other areas.

Here, if I may presume just for a minute to emphasize one thing which is perhaps more than obvious, though it can be forgotten, may I say that when we speak of cells, cells are not things. Cells are processes. They are not structures. We speak of living beings. They are not living beings. They are living becomings, and the whole process of growth must be conceived of as a constant flux, a constant process of change.

If one does that, then one must take the next step and acknowledge that the cancer cell is a chemical machine, a chemical engine, and that, therefore, this constant flux which is a characteristic of growth is a chemical flux, a constant turmoil of chemical change. Therefore, if cancer is a disordered cell there must be something different somewhere in the chemistry of the malignant cell as compared with the normal cell.

Now, I would like to lay down as the first direct inference, I think, in contemporary thinking in cancer, that the intrinsic cancer disorder must be a disorder somewhere in the change of events of chemistry within the malignant cell. Ten years ago or perhaps 15 years ago that might have had to be accepted as an axiom, without definitive proof; an act of faith. But it has been possible in the last 10 or 15 years to initiate intensive study of intimate chemistry of the living cell as distinct from overall balance sheets of the chemistry of the whole animal, and that has been made possible simply because the time had arrived in the history of the basic sciences at which methodology, instruments, isotopes, and a whole lot of methods adaptable at the micro level could be called into service to study the chain of events within the living cell.

So that the timing of the chemical approach to cancer has been determined by events outside of the cancer problem, by the progress

of basic science as a whole. And science became ready to make this attack.

The attack is only 10 or 15 years old at most, and we have far from explored the complete chemistry of the cell, but it becomes increasingly possible to believe that by persistent effort we can ultimately link up the whole chain of events in any particular sequence of processes in the life history of a cell.

Even so we have discovered already that there are significant differences in the chemistry of the malignant cell as compared with that of the normal cell from which it may have derived. None of these differences as yet seems to give any very definite hint as to what therefore was the chemical cause of the cancer, but they do establish and reaffirm the point that Dr. Rhoads and Dr. Farber have both made, that there is something chemically different about the cancer cell. With that faith one can move steadily ahead.

So we find from surveying, perhaps, and trying to summarize in 4 or 5 words the current thought about the cause or causes of cancer, the intrinsic ones, we assume that they must be chemical in their basic nature. They are chemical stimuli and they are chemical agents produced probably within the body, and there may be a multiplicity of them, or there may be 1 or 2 uniquely carcinogeic molecules which ultimately emerge in the life history of the organism, and the probability of whose activity seems to increase with the age of the animal. In the second place, we are clear that this cause acts in some way, direct or indirect, on the hereditary mechanism of the genetic makeup, as we call it, of the living cell, so that it stamps a permanent and irreversible change ultimately on the cell, and the cell goes on to multiply its own criminal kind.

Again, we know that the susceptibility of different cells to a single inciter-and I go back to the extrinsic agents and by inference, of course, to a normal spontaneous cancer-can be modified by influences of the organism as a whole. Here the most clean-cut example is the influence of some of the hormones, notably the sex hormones, on the progress of an induced or spontaneous cancer.

So that one has then, to put it in the broadest terms, perhaps to conceive of some inciter material which triggers off the event by operating with or against that-maybe what we call the homeostatic mechanism of the body, the various defense mechanisms, stimulating and growth-restraining substances, these acting on the cell that has been the inciter of the target. They will determine in a large degree how rapid the progress of that cancer may be.

So you have two influences to consider: the inciter influence and the residuum of control that the body is still able to exert over the random and rampant growth of the disordered cell.

I believe, again from outside, that those of us who watch the cancer program in progress believe that in this one generation or less of intense study of the living cell considerable progress has been made, and one need only emphasize that there have been these unified contributions of biologists, microbiologists, chemists, physicists, pathologists, and the whole corps of investigators in the physical sciences.

But I believe that the most significant thing in basic science as it concerns cancer research at the present time is not that everybody is in it but that everybody who is in it is beginning to talk the same 89087-53-pt. 1-20

language. One of the dilemmas of the physical science is always that each discipline talks its own language and we cannot understand what they observe because they cannot explain it in our terms. But progressively in physiology and in the whole problem of growth we are beginning to talk about the problem in terms of biochemical language and chemical language and the geneticist and the physiologist and the virologist and the rest of us can now talk to each other because we have a common language. That is the best assurance or guaranty, I believe, of rapid advance in the future.

I will not turn to cures in any detail, because Dr. Rhoads and Dr. Farber have displayed that side of the picture in detail.

I would like to say just one word about diagnosis, because that subject was raised this morning. You have heard that largely early diagnosis depends on the intuitive recognition of symptoms fortified by X-ray diagnosis and by pathologic examination, and that these are most likely to fail with those diffuse or deep-seated tumors which are asymptomatic, which are without symptoms in the early stages. The physician undoubtedly needs a chemical test which will betray malignancy in its early stage. No such tests are available on any broad basis.

On the other hands, as it is true that not only is the chemistry of the malignant cell different from that of the normal cell, but that the malignant cell is able to modify significantly in many cases the blood and the urine of the patient carrying the tumor, then there is confidence that chemical tests will be developed. To my mind it is improbable that there will be any master test that will determine all types of malignancy. Rather we are likely to achieve a battery of tests, each specific for a particular type of cancer.

And I might add one further word, that it is more probable that those tests will be discovered as byproducts of basic studies of the chemistry of growth, than that they will be discovered by the man who goes out and says, "I will go out and find a test."

May I just in conclusion touch on the question of chemotherapy as it is seen from the laboratory level again. Tribute has been paid to the fact that the clinical student of chemotherapy depends in large measure on the basic sciences, and certainly he does. One would never think of any hit-or-miss approach to chemotherapy, in view of the fact that there are more than 1 million hypothetical, at least, organic compounds available, almost when the synthetic organic chemist presses a button.

Therefore, you must have some rational basis on which to make a narrow selection of compounds that are worth testing.

Again, if cancer cells differ chemically from normal cells, as we now have evidence they do, it is reasonable, as Dr. Rhoads pointed out, to assume that they have some chemical spots that are more sensitive than the corresponding spots in the normal cell process. Therefore, the target must surely be to find drugs whose chemical nature is such that they are likely to attack the sensitive spots in the malignant cell's metabolism. To do that you must, therefore, know all that you can possibly know about the chemistry of malignant growth.

So chemotherapy, equally with diagnosis and the causes of cancer, leans heavily on an intensive study of the intimate chemistry of the living cell.

Dr. Rhoads was confident that we should find a penicillin for cancer. I am not so confident that one miracle drug will arrive that will take care of all types of cancer, and I do not think he meant that.

Again, one may suspect we will gradually emerge with an increasing battery of chemotherapeutic agents, each of which will have particular value in the care and control of particular types of cancer.

So my broad summary from the point of view of basic science is that again it seems to me that progress in chemotherapy is likely to go step by step with the progress in the basic study of growth phenomena. Thank you.

Dr. HELLER. Thank you.

The CHAIRMAN. Any questions, gentlemen? We certainly feel indebted to you, Dr. Cannan, for the splendid statement that you have made on this phase of the matter, to which you have devoted so much time and thought, and brought such great ability to bear.

I do not know whether it would be appropriate for me to ask a question, but can you tell approximately how many chemicals have been tabulated in connection with the search?

Dr. CANNAN. How many organic chemical compounds have been tabulated? Is that the question, sir?

The CHAIRMAN. Whatever way you want to express it. I am not familiar enough with it to know.

Dr. CANNAN. There are various tabulations. I have never seen the totals. The figure is variously estimated at three-quarter million compounds. I think that is the Beilstein figure. I am not sure. It is a compendium of organic compounds.

But that is not really a significant figure, because you can point to an organic compound and tell a chemist you would like something like that, and he will go back and make 10 new ones that differ very slightly from the one you pointed out. There is almost an unlimited number statistically of organic compounds.

The CHAIRMAN. All of which points out the difficulty of making the discovery that gives encouragement to the thought that there will be some one or more compounds that quickly will take care of this whole situation.

But what you have said with respect to the study that is being made, particularly when we have in mind that men of your type are engaged in it, certainly brings encouragement to the mind of a layman, when he realizes what is actually being done day in and day out. While each of us is engaged in his different activity, and thinks he is making some contribution that is worth while, at times we overlook the fact that at this very time you and your associates who are gathered here, and those who are associated with you, are working day in and day out on this problem. It is a very inspiring thought to me to realize the vast amount of thought that is going into the question of the health of our people in this Nation. We feel deeply grateful to men of your talent, who have come here today, and who have been willing to do so, to give us the benefit of your thought, your study, and your experience. We are hopeful that as a result of the inspiration that comes to us from your contribution here today, we on our part will be able to do something which will prove worth while and of help to all. Dr. HELLER. Mr. Chairman, I would like to particularize some of