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Q: Yesterday you mentioned that -- well, it kind of leads out of the question of the issues which you were just dealing with, which are for reasons for treating patients with bone marrow transplants and the fact that some reasons are fairly poor. And yesterday you mentioned that your relationships with patients had been very important in structuring the question. I wonder if you could talk a little bit about that and the sort of responsibilities to patients and how that relates to the work you do.

Beutler: Well, through my whole career I made myself the physician of some patients. In other words, I'm their doctor. Obviously I can't do that with very many patients and be sitting here and talking to you, or running the department or the laboratory. But I do it with some. And I guess I would have to say that I find that having people depend upon me and my being able to give them what they need is very gratifying. At the same time, the work that I've become involved in often is derivative, and I can give you several examples right off hand. Primaquine sensitivity is perhaps not a good example because those weren't patients of mine. In fact I might tell you that when my children were very small and they asked “Daddy what do you do?” and I would say I'm a physician, and what a physician ordinarily tells his children is that I make sick people well. I would have to say I make well people sick because I was giving malaria to people. I was giving primaquine to them and giving them hemolytic anemia. So these were not patients I was making well. These were subjects in some very important clinical investigations. But there have been groups of patients that I've been very interested in. One problem that I worked on in the fifties that I haven't even mentioned is that I became interested in women who were very fatigued and who had either no anemia or very mild anemia and who were written off as being psycho-neurotic. I discovered that when I did bone marrow examinations on them, that some of those women had no iron in their marrow. They were iron deficient. I reached the conclusion that iron deficiency could produce symptoms without producing anemia, an idea which was very radical at that time and quite generally dismissed, but which now I think is quite well accepted. For a number of years I worked on iron metabolism, particularly with this question and I worked on experiment with animals. I made them iron deficient and studied their enzymes and I looked at their performance.

Q: When you say they were "written off" as psycho-neurotic do you mean the conventional tools for distinguishing an iron deficiency of some kind did not reveal --?

Beutler: Well, the conventional tools that were used then. Serum ferritin had not been invented. Plasma iron was considered to be a very esoteric test that wasn't usually done. People looked at their blood, they applied the Wintrobe indices and standards for normal blood counts and they were normal and they said, "Well, they're normal."

Q: So it was a kind of iron deficiency that did not really reveal itself --?

Beutler: That's right. So that was one group of patients that led me into an area of research. Now, a second group would be the patients with acute leukemia.

[tape interruption]

Beutler: When I first started in hematology acute leukemia really was 100 percent inexorably fatal in adults. And this has changed a great deal of research. To be able to give a patient like this a chemo-therapeutic regimen and see that their blood returned entirely to normal was really very exciting to me. This is what led me into bone marrow transplantation as a way of extending this response and really curing some of these patients. I've mentioned to you that my interest in Gaucher's disease, again began with a patient. She was actually the first patient that we tried to treat with enzyme replacement. She died, nonetheless, and now, unfortunately, I see that the reason was that we just weren't able to make enough enzyme. Now that a firm is making it commercially, patients are responding to the enzyme but in 1977 when I gave [omitted] -- that was her name -- enzyme, it just didn't do enough for her. She died. Most recently the other clinical aspect which I was going to mention is a drug that's been developed in this department, 2-chloro-deoxy-adenosine. This drug was synthesized, really designed and synthesized by a young man in the department, Dr. Dennis Carson, who is really a very outstanding young scientist. He came to me in about 1980 with his laboratory findings and he wanted to know whether he could test this drug on people. He had already written to the FDA and they had told him that he would have to submit all kinds of information which he couldn't possibly get together. I pointed out to him that the FDA had no jurisdiction over this drug because we made it in California and we used it in California. And so I wrote to the FDA. I established that they did not have authority and we started giving it to patients here. And that I might say is quite unique, that this drug was not made by a pharmaceutical firm. It was not made by some research institute somewhere else and sent out for testing. It was made in this department right across the corridor and we tested it on our patients.

Q: Now when you say the FDA had no jurisdiction is it because the California laws -‑

Beutler: Because the FDA is a federal agency and it only has powers in interstate commerce and at that time there was no California law. There is a California law now, and actually we proceeded to get approval from the FDA about five years ago, but that was much easier for us to do because we'd already given it to one hundred patients and we had the needed data. And this drug has been tested now in a number of lymphoid malignancies and it's rather effective in some of them, but it's spectacularly effective in hairy cell leukemia, where it produces complete remissions in about 80 percent of the patients. The first patient we treated is four and a half years out and he's not relapsed. No patient has relapsed. And so I played a major role in the development of this drug and again, it is really based on my clinical interest. In the first three or four years when I gave it to patients, basically I could only really give it my own patients because I couldn't get the other staff interested in enough to give it to their patients. So if I hadn't have been seeing patients myself, there wouldn't have been anybody who'd gotten it. Then one of our fellows, a young man by the name of Larry Piro, became interested in the drug. And he's a very outgoing guy, and he got other people sort of interested and he's been doing a lot of the testing with the drug now. But basically this is an area in which I've been very active in over the last six years or so since this drug has proven to be as good as it is. In fact, we're having an international meeting here next week, where collaborators from other countries to whom we've sent the drug are going to report their results and the following week I'm going to the FDA with representatives from Johnson and Johnson, which is the pharmaceutical company which is now going to make the drug for us. And I think that within a year or so the drug will be licensed.

Q: How do you go about getting jurisdiction over a patient? Is that a point of tension at all, or--

Beutler: Well, not for me. Why don't you rephrase the question, so that I understand what you really mean?

Q: I guess what I mean is I'm not quite sure how a person who devotes a significant amount of time to research -- what is the relationship on one hand with the clinical staff?

Beutler: Well, for eight years I was in charge of the clinical staff. That's what my relationship was. But I feel that being in charge of a clinical staff, just like being in charge of a research staff, is really an obligation which one discharges, not by telling people how to take care of their patients, but by facilitating the overall process. So if, for example, Dr. [Joan] Kroener, who is one of the hematologist oncologist, who trained with me as a matter of fact, has a patient and she wants to give that patient drug z, I'm not going to tell her that that patient should have drug x. In many departments it would be different, you know, where I would simply say, well, if you want to stay here, you give this experimental drug to all of your patients with chronic lymphocytic leukemia, or -- you know," My way or the highway", I guess. But I just don't feel comfortable about dealing with professionals in that way. As long as she's doing a good job taking care of patients, I don't feel that I can press her to participate in my research program. So she doesn't. But if a patient is referred to me, and I see that patient, with a fellow let's say --and I always have a fellow see the patient -- when I'm the staff physician, then there's really nobody between me and the patient. But if it's Dr. Kroener, or Dr. [Bill] Miller, or Dr. [Robert] MacMillan, who are staff physicians, then it's their patient. Now, if I had wanted to when I was head of the division I could have forced them to do it, but I just didn't want to do it.

Q: What are some of the special responsibilities that go along with as you said making, in the research context, well people sick?

Beutler: Well, I think the overriding moral, consideration is that you are not subjecting people to unreasonable risks for what can be gained by society on the one hand and the patient on the other hand. There are two very different kinds of situation. When I gave malaria to inmates at State Penitentiary I wasn't giving them malaria to make them healthier, but I was giving them malaria so that we could learn how better to treat malaria and then we would do a lot of good for society. And of course they were volunteers and they went into this fully understanding what the risks were, and they were quite willing to do it for various reasons. They had some personal gain in that they were paid a very small amount of money. They were able to stay in the hospital, which was nicer than staying in their cell. There were some who felt they were repaying society, and some felt that perhaps when they went up for parole that the parole board might take this into account in deciding whether or not release them. So those were their motivations. So that's one kind of situation. Another kind of situation is when you do a bone marrow transplant on a patient early in the course of developing transplantation as a treatment. And there I think that you have to decide, is this patient likely to benefit, and is that benefit enough to justify the risk of going through it? Now, what's grown up in the last two decades is a complex web of consent forms, committee approvals and so forth that we have to go through, which I think hampers clinical research. But it all comes down to the same thing. I must say that I don't have trouble getting consent for the kinds of things I want to do because I think that I want to, generally, are things that are pretty darn reasonable. Some of the studies we're doing now are treating patients with Gaucher's disease with enzymes. There is no other treatment they can be given. The treatment seems to be very safe and the tests we're doing are very reasonable to check to see whether they're getting better. When it comes to giving 2CDA in a patient, the first few patients we treated were patients who had end stage leukemia. They've all died, but they had very little to lose and it was a chance for them to get well, although a very small one. And nobody lied to them and told them, "You take this and you'll get well." I'm sure that what I said to them is "You take this and we hope that it'll make you better." But it's up to you.

Q: How do you think that this, whole web of consent forms hampers the function of clinical research?

Beutler: Well, it just consumes an enormous amount of time effort and paper and it -- you know, it really becomes kind of absurd. Let me give you an example. The type of research that we do here is that of a general clinical research center. The general clinical research center has an advisory board and I appoint that advisory board because I'm the principal investigator of the general research center. We also have what's called an IRB, Institutional Review Board. Every research proposal has to be reviewed by the IRB. Then it has to be reviewed by the research committee and very often it has to be reviewed by an outside agency as well. In fact, it always does as a matter of fact. So there are three separate bodies, and then they make different suggestions. And then you have to sent it back because let's say that the General Clinical Research Center committee said that you didn't mention such and such in your consent form. Fine, I'll put it in. But that consent form has to be approved by the IRB, which had already approved the previous one, you see? Now the NIH has just passed a rule where we have to indicate what is being done to involve people of different sexes, ages, and ethnic groups in any project. It's almost a Catch-22, you know? [omitted] So, I mean, everybody's always trying to achieve some kind of different balance. What it all ends up as really is just filling out more forms. So it holds up the work in just generating a tremendous amount of paperwork, which I have to generate, then my colleagues have to review. And everything takes longer. And it also means that if I want to do something very simple that really doesn't subject anybody to any particular risk, that I'm likely not to do it. Suppose, for example, that I want to measure the levels of some particular compound of somebody who smokes a cigarette. He's a smoker. I can't just say to that person, "Look, next time that you have a smoke, come on over and let me take a blood sample." "Sure Doc, I'll be glad to do it," and I take the blood. I can't do that. What I have to do is I have to write a protocol. I have to take it to the committee. I have to get the consent form. I have to have him sign a consent form. So I say, "Well, I really don't care about the blood sample of that smoker." It's just not worth the -‑

Q: There's no sharties walking around --

END SIDE 1, TAPE 3; BEGIN SIDE 2, TAPE 3

Beutler: You know, I'm quite cognizant of the fact that these practices have all arisen because of some abuse and the way that administrators and lawyers try to fix up abuses is to make rules and those rules never get rescinded, they just get piled on each other.

Q: Pretty soon it's part of a larger and larger bureaucracy.

Beutler: Yea. And then there are some very anomalous things that happen. For example, one of the things that I established here in the General Clinical Research Center when I first came, was a program for screening blood -- blood donors. This was done so that when blood is drawn from normal people to be used in a laboratory, it isn't just drawn from somebody who happens to be passing in a corridor, which is how things were being done when I came, but rather is taken from somebody who has a blood count, so you know you're not taking blood from person who is anemic. You know they don't have hepatitis. And then a few years ago we started checking it for AIDS as well. We can't check every sample every time it's given for AIDS, so what we do is we check all of our donors once a year for AIDS, and we also put them through the kind of questionnaire that is used in blood banks so that if they're homosexual they're not supposed to give blood. Well, about a month ago one of our donors screened positive for AIDS. He was called in and it turned out he was a homosexual. [Omitted] really did have AIDS, but he hadn't been tested for a year, so during that year he'd given about six donations and they'd been sent to various laboratories and we had a record of them. We could not tell them “you received a blood donation from John Jones on May 3rd and if you still have the blood you should destroy it because it could be contaminated with HIV.” The law in California does not allow us to disclose, even to the people who are at risk, what that donor's name is. And the way that we got around this is to tell them that during the week of May 1st you got a sample from somebody who has subsequently tested positive for AIDS. If you have any blood left from that week from anyone you'd better destroy it. There are strange things that happen in our society.

Q: Which brings me to one of the questions that ASH is interested in, which are questions on the increasing role of the NIH in clinical research and in your work in particular.

Beutler: Well, first, the NIH is what has made everything possible. As a result we've all grown extremely dependent on NIH. This research institute derives, I would say, probably about 88 percent of its support from NIH. When I say 88 percent I include even my salary and the salary everybody else here. I'm not talking about faculty being here and being supported by the institution and 88 percent of their research being NIH supported. I'm talking about 88 percent of everything. So when there is a cut in funding it puts us really very very much at risk. On the other hand, I don't believe that the answer to our problems with research funding are to put another billion into the pot. Putting another billion into the pot will certainly take care of the problem right now. But then there would be another problem two years from now. In other words speaking as a clinical researcher I would have to say we'll never be satisfied. What I think the best we can hope for is gradually increasing even support and support for training programs, which is geared to the availability of funding. What I consider very unfortunate is rapid growth followed by a drought. Then you get people who go to graduate school, from undergraduate school. They think they're going to have a career in the field and then suddenly it isn't there. And that's not fair. So I think that we should try to make training funds available to the extent that we're able to provide career opportunities. The other aspect of what is happening at NIH that I consider unfortunate, and this has always been somewhat of problem, is the politically inspired goals of research. Suddenly somebody gets excited about something from a political point of view and a large amount of money gets put into that. I don't think this advances the field. I think it tends to retard it, actually, and it's hard on everybody else in research. The most recent example is AIDS, but there have been others.

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