American Society of Hematology

ASH Oral History: R. Wayne Rundles (1/3)

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ASH provides the following oral history for historical purposes. The opinions expressed by the interviewees are not necessarily those of ASH, nor does ASH endorse or make claim as to the accuracy of any of the information included here. This oral history also is not intended as medical advice; you should always seek advice from a qualified health provider for your individual medical needs.

The following oral history memoir is the result of two tape-recorded interviews with Dr. R. Wayne Rundles, conducted by Madeline Marget on July 11, 1989, in Durham, North Carolina. Dr. Rundles reviewed the transcript of his interviews and made corrections and emendations. In 2007, Dr. Rundles's daughters, Drs. Charlottee Cunningham-Rundles and Susanna Cunningham-Rundles, reviewed the transcript and made additional minor corrections. The reader should bear in mind that the following oral history is a verbatim transcript of spoken, rather than written, prose.

July 11, 1989

Q: This is the first session of the American Society of Hematology oral history project interview with Dr. R. Wayne Rundles. It is July 11, 1989. I am Madeline Marget. We are in Durham, North Carolina.

--your early life, then, Dr. Rundles, what you can tell us about early influences on you?

Rundles: Well, I'm looking over the C.V. that you have. It reminds me that my escape from the farm in Indiana came from being a Rector fellowship at DePauw University [Greencastle, IN] in 1928. This was the beginning of the Depression and any fellowship support was welcome. I was lucky in getting a good assignment at DePauw University where the people that I fell in with were predominantly premedical students. At that time I didn't know what I wanted to do other than some field of science. As time went on, Dr. [Caswell] Grave, who was professor of zoology, suggested that I might like to take a summer vacation and course at the Woods Hole Marine Biological Laboratory, which I did and enjoyed very much. This led to an appointment in the department of anatomy at Cornell University in 1933. At that juncture I was interested in the first year or two, or the first two years, of medicine which were being offered at Cornell at Ithaca. I spent four years then in doing research with Dr. James Papez, who was interested in comparative neurology. After finishing a doctorate in this area, I decided one couldn't really succeed in medical schools without having an MD degree in clinical training. It happened that the individual in charge in neuropsychiatry at Duke was visiting one summer at commencement time and told me they were developing or trying to develop a new medical school at Durham, North Carolina, and that possibly I would like to look it over. On his invitation, the next day I drove with him 600 miles from Ithaca to Durham.

Q: What was his name, Dr. Rundles?

Rundles: Dr. Raymond Crispell. To make a long story short, I liked what I saw and two weeks later I was enrolled as a second year medical student at Duke. Duke in those days was a young school. The reputation in the Ivy League area was probably that of more or less of a country club: they didn't know what was going to happen. But at any rate, the faculty, which had been recruited from Johns Hopkins for the most part, was young, energetic, and turned out to be a competent group of people. Dr. [Wilbert C.] Davison, the dean, had finished his medicine and training at Oxford and was somewhat of an Anglophile, so he took a broad view of medicine in this world and wanted the students here to intern elsewhere, to spend some time abroad and to invariably have a more extensive postgraduate experience than was customary. Having had graduate work before, I found Duke a congenial place for exposure to patients, doing laboratory work as one desired, and having a very flexible curriculum.

Nevertheless I thought it would be best for me to intern somewhere else and I took an internship at University Hospital, Ann Arbor, Michigan, whose chairman at that time was Dr. Cyrus Sturgis. Michigan turned out to be a good place for me. It was a different kind of medicine than I'd been used to and I had the privilege there of following up some interests that had developed actually at Duke as an undergraduate. While working the clinic here I was interested more or less in neurology to start with, having done my Ph.D. in neuroanatomy. In the clinic in those days I saw some interesting sequeli of encephalitis that developed during the World War One: a particular group of patients with diabetes seemed to have some strange physiologic and neurologic problems. As it turned out, they had some neurologic complications that were new at that time, particular to the involvement of the autonomic nervous system was not clinically recognized at that time in classic neurology, and wasn't understood by medical people dealing with diabetes. At Ann Arbor there was a very well-organized diabetic clinic, so I spent my elective time there and for a period of two years studied some of the neurologic anomalies that we were seeing. It turned out that diabetic neuropathy was of interest to many people and I was able to get together a small monograph which was published in the Quarterly Journal of Medicine. Dr. Sturgis noted that I was interested in the neurologic problems of medicine and suggested that in the blood institute, the Simpson Memorial Institute, one of the major problems was neurologic problems associated with pernicious anemia. So, after finishing that residency in medicine, I transferred as instructor of medicine over to the Simpson Memorial Institute to work with Dr. Sturgis and Dr. Frank Bethell on hematologic matters.

Q: This was also at Duke?

Rundles: No, this was all the University of Michigan. The work there was evolving rapidly with the development of anti-folic compounds and the early studies that had related to the biochemistry of the blood diseases, so my interests for a year or better there were finishing up the neurologic complications of diabetes and studying the neurologic complications of pernicious anemia. Leukemia and hemolytic anemias appear to be more challenging problems though, and from then on I stayed in the field of hematology.

Dr. Fred Hanes the first long-term professor of medicine at Duke invited me to return to Duke in 1945, the fall of that year, as an associate in medicine. This turned out to be a good move for me also, because there were many problems to deal with and there wasn't a whole lot of research being carried on at Duke at that time, partly because of the war and partly because of the youth of the institution. As time went on I was able to start a number of projects in hematology here at Duke which attracted some attention. We were studying some of the manifestations of metastatic tumors and found that what had been called metastatic disease in the past was often actually due plasma cell myeloma. We were soon having an epidemic of myeloma in our wards and this led to studies in reference to the control of plasma cell myeloma. During the first years here we were interested in a primitive chemotherapeutic agent, ethyl carbamate or urethane which produced some remissions.

Q: When was this?

Rundles: This would be in 1950. Early 1950's. This agent was very difficult to use and of course is obsolete now, but any regression in the disease activity of myeloma was welcome and some of these were quite spectacular.

Q: Can you say how you came upon the substance and what it actually did do?

Rundles: The first report of Ethyl carbamate was published in Lancet by the individuals at the Chester-Beatty Hospital in London. Dr. Alex Haddow, Dr. David Galton, Dr. George Sexton, and others were involved in the studies at that moment in London. They had looked at the field of leukemia as an abnormal type of growth and decided to investigate to all the all of the chemicals that had some antimitotic effect. Of the group that was studied were two that seemed to be outstanding: one was the carbamate compounds which are still around but not used in medicine and the sulfonic acid analogues which developed into myloran busulfan. This was my first knowledge of the work going on in London at the Chester-Beatty Institute. We extended the work and set up ways to evaluate quantitatively what happened in plasma cell myeloma, which led to studies that dealt with the plasma and urinary proteins. We were lucky here in having two individuals who were interested in that area: Dr. Joseph Beard who's in experimental surgery and Dr. Hans Neurath who later became professor of biochemistry at the University of Washington. With their facilities and collaboration we were able to study some of the proteins in myeloma and everybody was excited to see these striking anomalies reversed for the first time in the patients who responded. This actually led into the field of antitumor chemotherapy, as far as I was concerned. Along with this particular study I might mention that other problems that we had dealt with hemolytic anemia and refractory anemias which in later years became known as myelodysplastic syndrome. One of our early patients, one of the prominent textile executives here in the South developed a type of refractory anemia that was not treatable effectively at home and responded only modestly to what we did here. In looking at this type of problem it seemed to me that there might be some relationship between this type of entity and an abnormality in the synthesis of DNA and RNA which were then coming on the horizon. I thought it would be useful to meet some of the people in this field and made a trip to Tuckahoe, New York to visit with Dr. George Hitchings and Dr. Gertrude Elion at that time and was warmly received and we struck up a friendship that turned out to be useful in the long run. We weren't able to solve the problem that we started out on, but we were able to show that there were some abnormalities in nucleic acid synthesis in patients with gout. We were able to give hypoxantine, for instance, to a former mayor of Durham and produce a fulminating episode of gout which didn't do him any good perhaps, but it didn't hurt his anemia either. As time went on we began to work with more of the better established agents, particularly 6-mercaptopurine and thioguanine and derivatives with Drs. Elion and Hitchings. This project occupied about ten years of time, from the early fifties through the 1962, and we were able to show that among the great number of antipurine compounds that a few that looked very good in animals were not really effective in people. We decided that we needed to know more about the metabolism of these compounds, how they were degraded, how they were absorbed, and so forth, and undertook these studies in collaboration with the Wellcome group in Tuckahoe. To make a long story short, there were several dozen or more patients studied and specimens --urine, blood, blood cells -- transported to Tuckahoe and back. It appeared that while the mercaptopurine was presumably incorporated into DNA, that one of the ways the compound was destroyed was oxidative degradation somewhat similar to the process with which purines are degraded into uric acid. With this knowledge in hand Dr. Hitchings suggested that a compound which we knew at that time as a hydroxypyrazolopyrimidine but later allopurinol might be a useful therapeutic agent in this connection, used with the aim of reducing the destruction of the compound that we were giving. This compound was interesting in as much as Dr. Hitchings early on had studied a large number of compounds as to their effect in inhibiting an enzyme xanthine oxidase. The pyrazodolpyrimidines were suggested as chemotherapeutic agents and investigated at Columbia and NIH, it was found that the most active of these compounds produced a hemorrhagic disease and no antitumor effect. There was one that was an effective enzyme inhibitor that did not have these effects, however, and that was the hypoxanthine derivative, allopurinol. So, it was his inspiration to take an inactive compound as far as leukemia was concerned but was active in inhibiting the enzyme to see if it would improve the efficacy of mercaptopurine. This turned to out to be true and our first patient was a lady with chronic granulocytic leukemia that we studied here in May 1962. In the first study, which has been published in different areas, we were able to find out a number of things: One, it changed the metabolism of 6-mercaptopurine in a desirable way -- it protected it against being destroyed; it reduced the level of uric acid in the urine -- uric acid in the serum; and increased the amount of the precursors of uric acid that was excreted, the oxypurines. Well, in one patient we identified the changes that would take us about five years or better to nail down. As a spin off we were not able to show that the allopurinol improved the efficacy of 6-mercaptopurine anyway. It was a dose reduction economy rather than an increase in qualitative effect. The effect in monitoring uric acid seemed to be more promising. In those days we had on the ward usually one or two or more patients who had either the renal insufficiency of gout or had had acute flare-ups of gout associated with the use of moonshine or plain, ordinary, hereditary overproduction of uric acid that we were accustomed to seeing at the end stages of gouty arthritis. We explored the effect of this compound and recruited a number of patients with gout and were able to show that it was a very useful compound. Within two or three years, with many others who were recruited to study this, it was established more or less as a standard therapeutic agent in perhaps a half a million patients in the U.S. We were able to find out that there were some limitations in its use: one patient in 50 developed a sensitivity reaction. There were some other minor effects produced in nucleic acid synthesis and elimination that were potentially important but turned out not to be. On the whole this turned out to be a happy experience for this purpose.

As you probably know the collaboration of pharmaceutical companies with universities has been sporadic. Until probably in the 1950's it was not formalized at all. I think it appeared both to the Burroughs Wellcome people and ourselves that the closer collaboration would be useful. We were delighted then in 1969 when, after surveying the whole east coast, the Burroughs Wellcome people decided to move from Tuckahoe, New York, to the Research Triangle - New York their headquarters for research and business for North America. The American research organization and their headquarters for the business were placed here. Now this has proved to be a good collaboration. They have been good citizens here. Many of our faculty have been back and forth to their research laboratories. They have been able work with many other individuals. In recent years the Burroughs Wellcome scientific interest has verged toward the control of AIDS and virology more than the uric acid problem, which was pretty well solved for practical purposes. Their interest at the moment concerns the antiviral compounds and the molecular biology at this type of agent.

My own interests went from general chemotherapy to the uric business which more or less crosses specialty lines. I tell our rheumatologists now that we helped them with uric problems they owe us one in terms in making some advance in antileukemic areas. They haven't done so yet, but we are very much of the opinion that there's an excessive amount of specialization and restriction of scientific interests these days that in the long run is going to be a great handicap both in research and in medicine. Along the way, I might mention that in the mid-fifties it appeared that there was going to be a tremendous proliferation of chemotherapeutic agents making their debuts and that we would have to study a great deal better, more scientifically and on a larger scale, the action of chemotherapeutic agents. We were able to organize, with the support of the National Cancer Institute, the Southeastern Cancer Chemotherapy Cooperative Study Group in 1956, and I was chairman of it for ten years. We thought we made good pretty good progress in those days, when the group was small and the people who were involved were all senior investigators. In this area there's been a tremendous proliferation of work, more cooperative group, larger groups, and then more recently the founding of the community cancer centers until there are over three hundred hospitals now doing this sort of work. There are some trends in this area that are noteworthy. One is that the great flood of chemotherapeutic agents that were really good, that we anticipated 30 years ago, didn't occur. We had some good ones, but in general they are more difficult to use and have a higher range of toxicity and less potentiality of cure than some of the early ones. The organization of the cooperating groups has helped, perhaps, to establish the style or protocol type of investigation, but it has also narrowed the focus of many of our colleagues; it has led to studies that had no great rationale to start with; and at the present time is somewhat controversial in terms of how much it should be expanded and how much that which some of us think is strictly experimental should be incorporated into the standard treatment. The aggressive chemotherapy has undoubtedly saved many lives or at least it has made many people better; the cure rate is not as good as we would like and the tolerance of side effects has been increased tremendously. When we started out with, say, the simple compounds, we hoped to have few or no side reactions. Now horrendous side reactions are pretty well tolerated and accepted and one of the most obvious things about chemotherapy now in the public mind is that it deforms your body; it produces a moon face, demineralizes bone, destroys the bone marrow --temporarily at least, sometimes for longer -- and loss of hair: these side reactions are better known than the good effects. So there is an uneasy balance there between doing good and doing harm, as far as the patients are concerned. This hasn't been solved and won't be solved in the foreseeable future. In my own thinking about this area, we have of course trained a lot of so-called medical oncologists who are interested only in treating disease. I think it's fair to say that the emphasis at the National Cancer Institute, particularly since the war on cancer was declared in 1971 under Nixon's administration, has been on developing better methods of treatment. This translates with Dr. Vincent DeVita's leadership into multiagent chemotherapy, larger doses, and more aggressive types of treatment. We are now coming, some of us think, to a better defined ceiling on what can be done. For instance we now know that in carcinoma of the breast that women have what looks to be stage one disease with no evidence of actual metastases at the time of surgery actually will turn out to have disseminated disease in rates of (?) one in three perhaps. Under the most favorable circumstances a cure from surgery alone or from what have we have done in the past -- more extensive localization surgery -- is limited. In the very aggressive use of chemotherapy in, say, local extensive carcinoma of the colon the results of chemotherapy are evident in, perhaps, five or six or perhaps seven percent of patients, but it's almost exactly negated by the frequencies of leukemia and the complications. So systemic therapy for established disease, at least in some of our opinions, is not very promising and in some areas it's completely useless and in others at best somewhat palliative. For that reason we are looking better now more aggressively to computers for what possibilities there are for actually preventing disease and then earlier diagnosis. In the field of prevention, we've prevented about all that's easy to prevent: we aren't using radiation at random; benzene, benzol, toluene, and these chemicals, as recognized, are not let loose on the population in general. The outstanding agent that will produce tumors these days are tobacco products and this has been the hardest thing for us to eliminate. In this part of the country there are many people who have a special interest, of course, in promoting the growth and sale of tobacco, and it's very difficult to get people to think in a logical fashion, think linearly about the health hazards of tobacco on one hand and the economic problems on the other. They should be separated because we have to recognize the bad effects as well as the good. And there are probably some good effects of it. One of the very interesting books recently has been that of Patrick Reynolds on The Gilded Leaf, which is a summary of the activities that affect Durham, Winston-Salem, the East Coast, and the ramification of great wealth in a very lucrative business arrangement. In this book, Dr. Fred Hanes, our first professor of medicine was mentioned and there are many other personal areas of interest. At the present moment we're thinking that while we have to continue with the development of chemotherapeutic agents, particularly those that are based on molecular biology and more selectivity, we have to continue on this but still we need to think in terms of prevention as well as early diagnosis. The greatest prevention opportunity, as I have mentioned, is tobacco. We are distressed to note that half of the tobacco raised in the U.S. is exported now and sold in other parts of the world to individuals who don't have the knowledge of its hazards that we have here. So we are storing up some very serious problems in Egypt, Africa, Korea, Taiwan, and Japan. We are exporting some major hazards there in a very predatory way. It should be recognized that there are things that add to the hazard of tobacco. We think tobacco in general is responsible for one-third of our cancer, and it pertains not only to carcinoma of the lung, but it increases the incidence of cancer of the mouth, throat, esophagus, pancreas, and bladder at least, and it has some ramifications in all of these other areas. The hazards of tobacco are magnified by heavy exposure to alcohol. Heavy drinkers, particularly in France and certain other areas have a greater incidence of, let's say, carcinoma of the esophagus. The hazard of tobacco is also magnified by exposure to asbestos and to such products as radioactive radon in houses. But if we eliminated tobacco we'll eliminate some of the secondary effects too.

Now, in the early diagnosis we don't do a very good job in teaching or in practice of recognizing, let's say, melanoma. Melanomas that come into a place of this sort [Duke], half of them are, I suppose, stage two and three in their penetration; with the prognosis as poor. We don't do a very good job in recognizing carcinoma of the breast. We teach that breast self-examination is a useful maneuver, but the facts are that we are allowing tumors to develop beyond the point of maximal control by this maneuver. The ladies who have systematic breast examinations in effect will come to medical attention earlier, but not because they have operable tumor but because they're more conscious that there is a problem. One patient in ten at this present time will develop carcinoma of the breast. The systematic use of mammography along with physical examination and recognition of risk factors and more systematic surveys that are planned ahead of time are probably the way to go in this area. One of the things that is attractive to me in this area is the rejuvenated interest of gynecologists in detecting breast carcinoma. As you probably know, some years ago there was a group of individuals in Boston who, with gynecologic training, were managing breast carcinoma. They don't do that anymore but they now have a renewed interest in early diagnosis and the use of mammography and ovular attributes.

Q: Who were the gynecologists?

Rundles: At Tufts, Robert is one, the internist there. And what is the gynecologist? I keep blocking on his name. I can find that for you. He's the chief of gynecology at Tufts. A very excellent person. But their position now is that gynecologists should not only look for gynecologic problems but also neoplastic problems in the pelvic area; but there's no reason they can't learn to be expert dermatologists recognizing melanomas and be connoisseurs of breast carcinoma. This would cover a great deal of early diagnostic problems.

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