Q: What others?

Beutler: Well, sickle cell. I have a theory of diminishing returns of research. In fact, I call it, to borrow a term from biochemistry. "substrate inhibition". If you have a field like sickle cell disease and there are good people who are working in it as have been right from the fifties, then you make good progress in that field. Now if you put a huge amount of money into that field, what you do is you draw all the unsuccessful people from other areas into the field and what they do is they create noise, you know, in the communications sense. They create data that aren't correct and they actually then retard the field. So you see, if you put a large amount of money into an area, whether it's AIDS, or sickling, or aging, or whatever it is, the scientists that you're going to draw in the field, aren't generally those who are highly successful in what they're doing. You're not even going to draw on those who are really motivated to do something about that field. You're going to draw on scientist who say, "Gee, I didn't get funded on my thyroid project, so I think I'll work on AIDS". But the reason they didn't get funded on their thyroid project might be that it wasn't a very good project. So, I think that it's fine to target areas of importance, and I think AIDS is an important area and I think sickle cell disease is an important area. And I think these areas deserve support at a good level. But I don't think that the political process should suddenly jump the amount of support from these areas three or fourfold. And then very likely some years later, when it's not quite as popular anymore, suddenly drop it, to a low level. Cancer exemplifies the same problem, with all these cancer centers. Apart from not helping the field that the politicians are trying to help, they harm the others, because they do take away money. Right now two problem areas are the genome project and AIDS. They are eating up a lot of money that could be going for very good research which might actually help those projects. So that's where I think the NIH could perhaps try to improve a little bit.

Q: You also mentioned the way in which clinical researchers need to respond to NIH requirements for patient control groups and that sort of thing. Any reflections on that?

Beutler: Oh, I think that's just a minor irritant. That's one that came across my desk last week, you know. I mean, there's another one that came across my desk the week before and that is that apparently every institution has to have a course for their research fellows on research ethics. Well, I think research ethics are extremely important. I don't think you teach it to people by giving them a course. I think you teach it to them by being ethical and if they are trying to cut a corner you say, now wait a minute we don't do that here. That's the way people learn. Not by setting up a course where they have to attend six hours and we have to certify that these people are trained in ethics -- but that's a part of the administrative political process.

Beutler: My feeling is that the situation is getting better and that there is a tendency now for hematology and oncology divisions to come back together. I have always resisted splitting hematology and oncology divisions because I think it's easier not to break a plate or a vase, then it is to glue it back together. I think that's sort of passed through its heyday. Oncology was a new specialty, I think they so wanted to feel their oats and I get less of that feeling now.

Q: What time period is this in which oncology became a new type of field.

Beutler: I think it started happening in the late sixties, early seventies. They very aggressively took over quite a lot.

Q: That probably had something to do with increased funding -‑

Beutler: Yes, probably so. And then you see because of the increased funding and because of the patient revenues, they became political powers in university medical schools. And they very commonly were able to get deans to say -- or chairmen to say, "Well, we need a separate oncology division." And then some guy who is number two or three in the hematology-oncology division became number one in the oncology division, which eclipsed the hematology division. That's happened a lot of times. But I don't think that's as much of a problem anymore, but maybe it's just that I'm not as aware anymore. I'm not sure. I'm not very close to that situation.

Q: It sounds like one of the pictures you're painting of the liberal structure of medical research today is quite different from the one in which you were trained in. That might seem a general question.

Beutler: Well, I think in some ways that's true. And I think that that's true in medical practice, too. There are things that I hear here and that I don't like and I think probably people hear them everywhere. That is that the top administrators, who themselves are MDs, are talking about "market share”, about "product line”. I was taught that medicine was a profession, an art, and not a commercial enterprise. But the people who lead major institutions now, even academic institutions, I think believe that they are at the cutting edge if they talk like they're corporation executives. I like to think they're not.

Q: One question that I've been interested in is do you think that your particular set of interests during the course of your career, hematology, hemo-genetics, nutrition, is that unusual for a hematologist in this country?

Beutler: Well, in this time or in my time?

Q: In your time.

Beutler: In my time. Well, I think there have been a few other people who have had similar kinds of interests. I think Arno Motulsky, whom I mentioned earlier, started out as a hematologist, then became one the most prominent geneticists. The person who just took over after his retirement, George Stamatoyannopoulos is also in the same vein. No, I think it's not that unusual. Another one is David Weatherall. He is now Knight of the Realm and the Nuffield professor of physic at Oxford University. And he's a hematologist who works in the basic aspects of Thalassemia. Y.W. Kan started out as a hematologist. You'll probably interview him. He's the current President. No, I think there is a small group of people like that. What is changing almost inexorably, I would say, is the extent to which these people are clinically involved. That as I see the younger people, they tend to have less and less clinical involvement. There is much more polarization and the rationale for it is that science is just becoming too complicated to allow you to do clinical work as well. I don't think that's true. Like all older people I think the younger generation just does not work hard. That's all. That's what I tell my kids. I think that there is a distinct reward, both personal reward but also professionally in terms of research and to continue to see patients. I have three children who are physicians and one who is in the computer business with me, and one of my children is a --the oldest boy is a clinician who specializes in infectious disease, and does it very well. My younger boy is a MD also, but he is really a full time researcher and I continually try to encourage him to see patients; but he really doesn't want any part of it. I think he's wrong.

Q: I have one final question and that's about -- you mentioned the reference manager. I wonder if you could reflect a little bit on the origins of –

Beutler: Yes. In the middle 60s I was being asked to write many reviews about G6PD glutathione iron deficiency and so forth and I've always liked to document what I write very well and it became quite a chore to always try to find the references that I needed, particularly with the medical literature growing as fast as it did. And so two years after I arrived at the City of Hope I decided to use marginal punchcards to hold all my references, and then I could sort the cards and make a bibliography. I thought it was a great idea. The secretaries always hated it, and it worked reasonably well, but once I got up to about 10,000 cards, trying to sort those with a needle and I don't know -- you're probably too young probably to know what these marginal punchcards are like. Do you know what I'm talking about?

Q: No.

Beutler: They're like file cards but they have holes all around outside. And you can code them by punching out the outside, and then if you use a needle and put it through a hole in a stack of them, the ones that have been punched out, they drop out, you see? So it's sort of a primitive mechanical computer. In 1972 or so, '73, our clinical laboratory at City of Hope purchased a PDP 11/40 computer, which was a mini-computer, state of the art at the time. And one day I was having lunch with Art Schneider who was the person in charge of the department of pathology, and he and I were talking about bibliographic retrieval and he had a programmer, had a computer, and he had space on the computer and we decided to write a program that would take care of my work. And so the programmer worked for me for a period of six months or a year and he wrote an assembly language program for the PDP 11/40, which I used then for the next 10 years or so. By the time I came to Scripps, the program had grown and I had accumulated about 8,000 references. It really didn't fit on the discs, the machine -- no more than that fit on the disc -- the machine had three disk drives, and worst of all, I had to bring the computer with me because the program wasn't transportable. So I bought the computer from City of Hope and brought it here. In the meantime my son, Earl, had graduated with a Master's degree in computer science from UCSF, and was working for a publishing firm, and he and I decided to form a company and rewrite this program so that it'll run on a micro-computer. In this way it could be used by others.

I really needed a new program because this computer was costing me $8,000 just to maintain my bibliographical retrieval material. And so the plan was that we'd incorporate a company in California called Research Information Systems with $65,000 in capital, $40,000 which came from me and $25,000 in the form of a note. Came from him [laughter]. He's not dumb. And then he was to write the program. And months went by and he didn't write it. And then about Christmas eve in 1982 I said, "Earl, I need that program. When are you going to start writing it?" "Well," he said "Dad, I'm really all burned out with programming. Why don't you write it?" Well, actually this was not a preposterous suggestion because I'd been programming since the 60s and I'm actually quite a good programmer. In fact I like programming so well that once I get into programming I do very little else. Eight hours goes by just like that and I'm just sitting at the computer. But against my better judgment I started writing the program and I wrote the whole program. It took me about a year and a half to get the program to a point where we could market it. We showed it first at a clinical meeting in Washington. My wife and I, and also one employee from here whom we hired for this purpose, went out together with Earl also. The program was very well received. It started selling very well and a year or two went by and I spent a lot of my time improving the program, modifying it, changing it for the more advanced computers that became available and so forth. Sales were very good. But it really was eating into my time and of course once you sell software you have to provide service to your customers, you have to answer phone calls, you have to ship, you have to bill, all that sort of thing. So we talked to my son about the possibility of his giving up his job, with the publishing firm and taking over the program. We hadn't wanted him to do that initially because he had good job, a very good job, and we didn't know whether our endeavor would be a success or a flop, but now it was clearly a success. So in about -- I think it was probably February '86 I would guess, he took over the program and he rented a small office and the agreement was that he would do everything himself. That he wouldn't hire a bunch of people, but that as things went on he could hire some people. To make a long story short, we now have 35 employees and an 8,000 square foot office facility in Carlsbad which is about 15 miles north of here. And we have several additional products, one of which is called Reference Update, which is very strong competition for "Current Contents”, an old service. We now have 5 programmers and we've just come out with new versions of several programs one for the Macintosh. It's a business venture that has given me a lot of satisfaction. It's entirely different from what I do normally, but I use the programs in my work, of course, and I really enjoy working with my son, and I enjoy seeing the business being profitable. As a matter of fact one of the things that we've been doing for the last few years involves ASH. This year we make a meeting edition which we send anybody in the Society a disc, which has all the papers from the meeting on it. And they put the disc in their computer and they run the program. They type in whatever their areas of interest are and it creates an itinerary for them with all the papers that touch on those topics. We're doing that for ASH this December. So those are the company products, Reference Manager and Reference Update.

Q: And it's generally used by researchers to maintain their own bibliography?

Beutler: Oh yes. Our sales of Reference Manager I would estimate, are running about 350 copies a month and we probably have over 20,000 programs out there and our Reference Update Service has many thousands of subscribers. In spite of the fact that we're supporting 35 employees and my son and his family we're very profitable.

Q: What's the name of the company?

Beutler: Research Information Systems. We're just going to test a new version of a grant accounting program. Our target audience or market so to speak is biomedical scientists. And I think the reason that we've been very successful is that I'm a biomedical scientist. I wrote the original program the way a biomedical scientist would want it, not the way a programmer thinks he wants it or the way a librarian thinks he should want it. And so our products hit a very responsive chord with our audience because they're people like me. One of the good traits that my son has is that he's quite willing to listen to others and to create products that they want. If he sends me something that he's done and I don't like it and I say "Look, Earl it needs to have this and that done." He doesn't always and do exactly what I' tell him, you know he is my kid. But on the hand he's not stubborn about it. He listens and if what I tell him makes sense or if he asks some others and they agree he'll change it. So our products have really been very much tailored to the community to which I belong.

Q: And what role did programming play in your work as early as the 1960s?

Beutler: Until very recently I wrote almost all my own programs, and the earliest programs I wrote were on a desktop computer, the Olivetti 101, which was the first desktop computer ever made. I wrote programs that allowed my laboratory staff to compute the results of routine laboratory studies that we'd do, enzyme studies for example. They would enter the raw data and it would automatically calculate for them. Then I wrote some standard statistical routines, regression equations and standard deviations. And later I did that with other computers. Then when I did some population genetic analyses I wrote programs to analyze that. For example, when I was trying to calculate gene frequencies for galactosemia I wrote programs that would handle the thousands of assays that we have done and analyze those. I wrote those programs in Fortran for an IBM computer. One of my other avocations is the financial markets, particularly the stock market. So I wrote programs to keep my personal stock records and transactions. And I've written programs, for example, that examine all the G6PD variants, to show you one example right now. Nobody would write -- well, I could hire a programmer to do it. [Computer turned on.] OK suppose, for example, I wanted to see what the characteristics are of G6PD for Marion. Here are the characteristics, this is the electrophoretic mobility. This is the activity as a percent of normal. This is the Km of G6PD. So it has all of these data. Now, suppose I want to see what other variant a G6PD variant is most closely related. These are weighting values I can change if I want to. I don't particularly want to. There are 291 variants. Now it's comparing about 12 characteristics for each of these variants other variants, picking the one which is closest, according to an algorithm designed. It finds that the most closely related is GASTONIA, which by the way is very interesting. I didn't know it would come out this way because now we've got DNA analysis that shows that these are, in fact, identical.

Q: So, in other words, your computer program is in fact very closely -- it's actually predicting the effect you found.

Beutler: That's right. To some extent. Sometimes the predictions are not as one would think and then that gives one something to think about.

Q: So has this been a way for stimulating questions --?

Beutler: Yes. Actually, one can -- what I've done with this, for example, is to compare every variant with every other variant and calculate distances and there are 43,000 such comparisons, which this computer program does in about 15 minutes. And then I've written a little routine that dumps the results into another file and which then I put into another program which plots out the distribution of the data. And then I can see where different comparisons fit on this distribution. So there are a lot of things that I do that call for a computer.

Q: How would you say that other people in your field are as computer literate or use computers as frequently?

Beutler: Yes. I think that I'm into computers much more than they are.

Q: OK. I think that's about all the time we have.

END OF INTERVIEW

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