BEUTLER, ERNEST

INTERVIEW
MARCH 8 - 15 2007

Ernest Beutler was born in 1928 in Berlin, Germany. He received his medical degree in 1950 from the University of Chicago when he was twenty one. He began his research career in medical school studying influenza in mice. He went on to serve in the army as a Medical Officer and worked on malaria and primaquine research on prisoners. He returned to the University of Chicago as an instructor and he researched Glucose-6-Phosphate Dehydrogenase Deficiency while there formulating the glutathione stability test. In 1959 he moved to the City of Hope National Medical Center, a clinical research hospital, as Chairman of the Department of Medicine. He went on to study X chromosome inactivation and established a marrow transplant program at City of Hope. He moved to Scripps Clinic and Research Foundation (now the Scripps Research Institute) in 1979 as chair of the Department of Clinical Research and studied many hematological diseases such as Gaucher’s disease, hairy cell leukemia. He was also president of the American Society of Hematology in 1979. He was Chair of the Department of Molecular and Experimental Medicine until a month before his death in 2008.

This interview is organized chronologically beginning with Beutler’s move from Germany to the US; education and family life; student research in influenza; time in the Army’s service: working with malaria and primaquine on prisoners, move to Fort Detrick and then returning to the University of Chicago as an instructor studying G6PD Deficiency; move to City of Hope as Chairman of the Dept of Medicine; studying X chromosome inactivation and establishing a marrow transplant program; move to Scripps as Department Chair of Clinical Research and studying Gaucher Disease and helping to create 2-CdA; and founding Research Information Systems, a computer software company, with his son. Major topics of interest include the criteria for a healthy laboratory environment; the ethics of using prisoners as research volunteers; a discussion on collaboration with other scientists; assigning intellectual credit and recognition in science; the relationship of hematology and genetics; using genetics to understand disease; Gaucher disease; 2-CdA; gene therapy; galactosemia; hairy cell leukemia; and reminiscences of Leon Jacobson, Amo G. Motulsky, Susumo Ohno, Joseph Sorge, Jack C. Sipe, and Dennis A. Carson.

I. From Germany to the US: Family Life and Education

AM:     It is March 8th, 2007, and I'm with Dr. Ernest Beutler at his office at the Scripps Research Institute.  I'm Andrea Maestrejuan and we're here to conduct his oral history interview for the UCLA Oral History of Human Genetics Project. We'll start off at the very beginning and I'll ask you when and where you were born.

EB:      Okay.  I was born on September 30th, 1928, in Berlin, Germany.

AM:     Well, tell me a little bit about Berlin, or when you left Germany.  What's the chronology here?

EB:      Well, I left Berlin in 1935. My parents were both physicians.  My father was an internist, my mother was a pediatrician.  Their families had lived in Germany for several generations.  My father had been a medical office, or sub-officer, because he was still a medical student in World War I.  I think that, like most Jewish Germans, they considered themselves to be Germans, but when Hitler's virulent anti-Semitism became apparent, I think they were a little bit more prescient than many other people. 

My father first thought that we would immigrate to Palestine, so he took a trip to Palestine, I think probably early in 1935.  He found that there were a lot of doctors there.  Almost everybody was a doctor. Doctors were working as streetcar conductors, as laborers, and so forth. 

He had a fairly distant cousin, by the name of Max Carter, who lived in Milwaukee, so instead of coming back from Palestine, he traveled to the United States.  This cousin was willing to give him an affidavit, which was necessary for us to be able to immigrate to the United States.

My mother told me a story just a year or two before she died, which was really only two years ago, that I'd never known, and that is that he called her from the United  States and asked her whether he thought that we should go to Palestine or to America.  She said she would think about it and talk to some people about it and get back to him.  So she called him back the next day.  And then she told me, she said, "I told him that I thought we should go to Palestine, so of course we went to America." 

So at the end of 1935, my mother took my brother and my sister -- my brother at that time was nine, I was seven, my sister was four, or three perhaps -- on a train.  We took a train to Paris and another train to Cherbourg.  Then we took a Cunard liner, the Aquitania, to New York.  And then a day or two in New York, and then to Milwaukee.  I think we arrived early in 1936.

I still have a fair number of memories of what things were like in Germany.  It was fortunate for me that they had engaged what I guess we would now call an au pair, from England, to take care of us, so I had the advantage of being able to speak some English.  As a matter of fact, I was thrust into public school I think three or four days after we arrived in Milwaukee.  I also remember that it was difficult at first because I didn't understand everything that was being said.  It was not only the language but also the accent because this was a British woman who had taught us English, and now we were talking Midwestern American.

As a matter of fact, I remember one of my most embarrassing episodes in school was that I was sitting in one of these little double desks with a little girl, and I couldn't understand the instructions, so I did what she was doing, which was writing. The teacher came by, and I suddenly realized that the instruction had been write your name, and I was writing her name because I was tracing what she had written.  (chuckles) But, as children do, I learned the language fairly fast.  I feel fairly comfortable with English now.  So I went to public school in Milwaukee.

AM:     You had started school in Germany, in Berlin?

EB:      Yes, I had.  I had about two years of school.  Actually, my parents were afraid to send me to public school because of the level of anti-Semitism was such that they felt that it might be difficult or not safe for me.  So I actually went to a Zionist school (1).

AM:     What part of Berlin did you live in?

EB:      Well, it was the district called Charlottenburg.  We lived on a circle that was called Reichskanzler-Platz.  It was later renamed Alolf-Hitler-Platz.  After the war it was renamed again.  Actually, I've been back there a couple times trying to sort of revive childhood memories, which I was able to do to a limited extent.

            We actually lived in a large apartment, and part of that apartment was my father's office, and then there were some French glass doors, as I recall, and the other was our living quarters.  I still remember quite well our sitting at dinner, or sitting at breakfast, and my father going to his office.

            My mother practiced pediatrics but to a more limited extent.  She didn't see as many patients because she already had three children.  And, although we had help, I think that she probably felt that she wanted to take care of her own children. 

            When we came to America, to Milwaukee, she did get a license to practice medicine. My father practiced medicine.  That was his livelihood.  At the time I didn't realize it, but it must have been very difficult for him because, basically, they came without any money, three children, lived in a rented house that I still remember.  It was not too bad, but obviously not living on the scale that they had in Germany, where they were reasonably prosperous, and from reasonably prosperous families. 

The first year, my father was unable to afford a car, so he made his house calls on a streetcar.  But he built up a very successful practice in Milwaukee and was able to send three children through school.  He did all right.  She got a license to practice in Wisconsin as well, but she would only occasionally see patients in his office. She really was not a very active practitioner.

AM:     Can you tell me a little bit about your parents' background?  Did they come from families with tradition in education, university education, or in medicine, medical training?  Had they been in Berlin, or in Prussia, or --

EB:      Both my mother and father's family were in business.  I don't know that there were any other scientists or physicians in the family prior to their generation.  My father's father was a factory owner, textile factory.  My mother's father was in some kind of business.  Actually, I think my mother's mother came from a family of bankers and diplomats, people who had done quite well, but they were not in the medical profession. 

And my parents met because they were both physicians.  My mother, I think, was an intern, and my father was a resident, or something of that sort.  He was several years older than my mother was.  They worked at the Charite Hospital, which still exists in Germany.  At that time it was the Kaiser Wilheim Institute [for Brain Research], and then it became the Humboldt University. 

As a matter of fact, I used to visit that institution, which it happened was on the east side, it was in East Berlin.  But I had a, let's say, valued colleague, Samuel [M.] Rapoport (2), who was a professor at the Humboldt University and who gave symposiums in the field of red cell metabolism, and I used to go there every few years.  I've also been back since Berlin's been reunited and seen the places where my parents worked many years ago, in the twenties, really.

AM:     What kind of memories do you have of growing up in Berlin, good or bad?

EB:      I think just generally fairly good.  As I think for most children that age, the political environment, things of that sort, were not very important.  I think I was very close to my mother.  I was a little less close to my father because he was there less of the time, and my mother took care of us mostly.  I knew that there were problems with Hitler.  I'd heard that at home. 

As a matter of fact, many years later, my mother told me that we had gone on a vacation to Czechoslovakia, to the Sudetenland, and that we were in a public dining room, and knowing that we were no longer in Germany that I could say anything I wanted to, I said loudly, "I think Hitler should be shot."  Of course, there were many Germans in the area, and my mother was terrified of what might happen.  But nothing did happen.  So I remember some of those things.

I remember, too, that -- you know, I went to the Zionist school, I didn't go to public school.  And I went to my grandmother's house sometimes.  She lived quite far away.  She lived in a small town called Reichenbach, where the factory was. 

I remember playing with my brother, who was only two years older than I and whom I -- during all of my childhood, I think in Germany and also later -- held in considerable awe because he knew so much more about everything than I did.  He could read when I couldn't read, he could figure when I couldn't figure, he knew more music than I knew.  So I think I was very close to him in those years, as I think children often are when they're that young and they're all at home together.

AM:     If your grandmother was within traveling distance, did you have extended family that you knew as a child?

EB:      Somewhat, yes.

AM:     And were they able to leave Germany as well, or do you know --

EB:      Most of them were not.  Actually, my grandmother did.  She came to Milwaukee and died there.  My grandfather stayed in Berlin, and actually he died in an old people's home before sent to concentration camps.  My paternal grandfather had died long before I was born, and my maternal grandmother died before I was born.  There were relatively few cousins, though whoever there was, a few of them got out of the country.  One branch of the family went to Chile, some came to the United States, some went to England. 

So when I was growing up, I really didn't have the abundance of cousins and aunts and uncles that other kids did.  I sort of was a little bit aware of that, that everybody else seemed to have cousins and I didn't.  But it wasn't really because my cousins were lost in the war.  I only had one first cousin, and he lived in Switzerland.  So I just didn't have cousins.  I did have an uncle who lived in New York.  He was a businessman.  But there was a much larger extended family of second cousins, and so on, most of whom I never got to know.

AM:     Okay.  And, particularly going to a Zionist school, where you're clearly set apart from other kids on the block, I would imagine, how did you experience -- or do you have any memories of experiencing anti-Semitism that was pretty rampant?

EB:      I didn't really, because I don't think my parents allowed me to go out without them.  I think they sheltered me a great deal.  I don't remember playing with other children particularly, except the ones I went to school, and my brother and my sister. 

I went to a children's camp once, I remember.  Actually, that was rather traumatic for me.  People did things with children in those days, in that society, that we would not do now.  When I was only five years old, I was sent away to camp for two or three months, by myself. I remember being terribly homesick.  One year I went to a place called Norderney, which I think is on the Baltic coast. I think it was in Germany, it may have been in Denmark, but I think it was Germany. I think that time my brother may have been with me, but of course he was two years older and that's a very big gap when you're five years old, so he had his own friends.

Then another year I went to Switzerland, a place called Mürren, and there I was by myself for a month.  Then my brother came and was at the same children's camp.  And then later my parents came.  So I do remember those things.  I remember being very homesick, and I know that in later years, when I told my wife about this -- my wife was born in the U.S. -- and she was real shocked that parents would send children that age away for that length of time.  Of course, at the time that's what people did.

AM:     So I take it you probably didn't send your children away at five years old.

EB:      No.  No, we didn't.

AM:     Well, what kind of Jewish religious traditions did your family practice?

EB:      Well, I think before the Nazis came, none.  After the Nazis came, then we had Friday night Sabbath, and we had Hanukah celebrations.  In the school, I think we had a Purim celebration.  But my parents were certainly very secular.  The number of times that I went to synagogue in Germany, or in the United States, would have been maybe once a year, perhaps for Yom Kippur.  So there was no strong religious tradition.

AM:     And did that change when you got to the United States?

EB:      Well, if anything, there was less.  Now, actually, when we first got to the United States, they sent me to a reform temple where I went to Sunday school.  Actually, I was not bar mitzvahed, but I was confirmed, which I guess would be sort of the reformed equivalent of a bar mitzvah.  As a matter of fact, I think I was the only kid in the whole group who could read Hebrew, because I'd learned it earlier in the Zionist school.  Actually, one of my regrets is that, even though I did speak Hebrew at one time, that I lost it all.  So when I go to Israel and people speak a language, it just sounds vaguely familiar, but I don't understand anything at all.  It's just totally gone.

            On the other hand, I'm still fairly fluent in German.  There's sort of an interesting story about that.  The first time I went back to Germany was when I was about thirty-one or thirty-two years old. I went to a scientific meeting in the Black Forest.  When I returned and I was talking to my mother, I said to her that it's really kind of surprising, I haven't spoken German for twenty-five years, and it all really came back to me without any problem.  She looked at me and said, "What do you mean you haven't spoken German for twenty-five years?  Don't you know that your father and I always spoke German with you?"  But I was not aware of it, because I think that, certainly in those days, and to a certain extent now, I’m really quite bilingual.  For example, when I'm engaged in a German conversation, or I'm listening to something in German, I don't do any translating, I just work in a different part of my brain.  So that's still there, but the Hebrew's completely gone.

AM:     When you were in Milwaukee, did your parents speak German at home?

EB:      Apparently so.

AM:     You just never noticed it.

EB:      Yes, I never noticed.

AM:     Okay.  And this is just to zoom forward a little bit, but I want to ask what religious practices did you have at home when you were raising children?

EB:      None.  We did send, I think, one or two of our children to Sunday school for a brief time, as we say, to teach them to know what it is to be Jewish and to suffer.  (chuckles)  I'm not only not religious, but I think I would have to say that, to a considerable extent, I'm anti-religious.  I think that one doesn't have to be very perceptive these days to know that most of the troubles in the world come from religion.  Shiite against Sunni.  Muslim against everybody else.  Christian against Jew.  I don't think that religion has lived up, let's say, to what it is supposed to do, which is to make the world a peaceful and pleasant place to live.

AM:     Okay.  Well, what expectations, in terms of educational achievement or career achievement or life achievement did your parents have for you and your brother and sister?

EB:      It's a little hard to say, because I don't think they ever expressed them.  On the other hand, perhaps the fact that all of us wound up having doctoral degrees may suggest that there was this expectation.  Although I don't think it was ever verbalized.  I don't think they ever said we want you to get a graduate degree.  They never said to me I want you to become a doctor, like me.  It was never said.  As a matter of fact, with three children, I'm the only one who went into medicine. 

My brother went into mathematics and engineering, and he's still alive and lives in Ann Arbor, Michigan, where he's retired.  He's been retired quite some time from the University of Michigan, where he spent most of his career as a professor in mathematics and for a long time, chairman of the department.

My sister passed away quite a few years ago after a very long bout with multiple sclerosis.  She had a doctoral degree in psychology and she worked as a school psychologist much of the time.

AM:     In the Milwaukee area?

EB:      No, she lived in the San Francisco area.  Berkeley, actually.

AM:     So, clearly, they probably didn't voice it but expected you to go to college, or wanted you to go to college.

EB:      Yes.  I don't think that the idea that we wouldn't go to college was ever entertained by anybody in the family.

AM:     As you were growing up, getting older, how unusual did you think to have both parents as physicians, but also to have your mom be a physician?

EB:      Of course, I didn't consider it unusual because that's what my parents did.  But I could tell that other people considered it unusual.  As a matter of fact, one of the things that used to really annoy my mother is if I said to somebody -- well, I remember telling her that I had told somebody that she was a doctor and they said to me, "You mean nurse."  I thought maybe the word was different in English.  (chuckles)  I brought this home to her and she said no, she was not a nurse, she was a doctor.

            It's interesting, too, that modern women have a very distorted idea about history.  The feminist movement has made them believe that women never had an opportunity until 1970 or something of that sort.  That's certainly not true.  As a matter of fact, in Berlin, where my mother practiced as a pediatrician, I think well over half of the pediatricians were women.  And in American medicine, too, there have been distinguished women physicians going back to the beginning of last century.  When I was in medical school, which was in the late forties, we had women who were professors, full professors, in the medical school.

            Even now, when I tell people that my mother was a physician, they sometimes say, Wow! In those days?  A woman, a doctor?"  I think the idea that women never had an opportunity is a politically convenient myth.

AM:     Certainly, Germany, where medical training wasn't -- there was more equal access to programs.  I don't think it would have been unusual for a woman in that time period to be a --

EB:      Well, I don't think it was that unusual in the U.S., either.  I mean, there were less women in medicine than there are now, but I started medical school in 1946, and we had a class of sixty-five, and I think about eight of those were women.  Now, that's now half, but it's not as if a woman in medicine was a rarity then.  It was not.

AM:     How much do you attribute that -- I know that the few women I have interviewed, they all went to medical school during, basically, the early forties when many men were off fighting, or were soldiers or in the military, and they said that there were more opportunities to go to medical school for women because there were less men going to medical school.

EB:      Probably not true.  I started medical school after the war.  Most of the people coming back had been at the war.  You'd think there would have been a dip, but I don't think that was a dip. 

In those days, in American medicine, there was some discrimination against women, and it was rationalized.  As a matter of fact, it's not a totally off-the-wall rationalization, that the resources for training physicians were rare -- or scarce -- and that many women who went into medicine ended up not practicing medicine.  That was true.  Because in those days, it was much more difficult for a woman with children to actually have a profession.  That doesn't make it right, but I think that was the thinking.

But there was certainly no barrier, total barrier.  As a matter of fact, there was more of a barrier for Jewish students to get into medical school than women because there were Jewish quotas, and they were usually less than five percent.  There were usually more women in medical school than Jewish students.

I think the idea that women never had an opportunity until the current generation made it possible is in error, and it's the kind of error that every generation makes about the previous generation with respect to a lot of different things.  For example, in, let's say, your generation, when girls went to college they probably often wore blue jeans and a tee shirt or sweater or something of that sort.  Right?  That's the way it was when my kids, probably your age or older, went to college.  But one of them once said to Bonnie, my wife, that when she went to school that they all wore skirts and blouses.  Of course, Bonnie always wore blue jeans and a shirt.  It was the same.

So the innovation of new generations is rarely as innovative as they think it is.  I think that goes for the opportunities that women have had.  They have more opportunities now, but it isn't as if there was no chance.  As I say, we had several very distinguished professors in medical school when I was student who were women.  There were people, like Helen Taussig (3), for example, or Marie Curie (4), for example, who did very well in science, long before the current generation.

AM:     What do you think accounts for the generational difference in explaining differences or how unique things are in this particular generation?  What do you think accounts for this -- I'm just thinking about it in terms of memory formation.  Why does the younger generation want to --

EB:      Be different?

AM:     Be different, yeah.

EB:      Would the term human nature _____?  (chuckles)  I don't know.  There are certainly recurring themes throughout history.  One of the interesting things that one sometimes reads is an account of how bad the youth are.  It sounds like a current account, and you find out this was Greece 450 B.C.  So I think every generation thinks that the previous generation doesn't work as hard, doesn't learn as well, doesn't suffer as much, and gets more than they deserve.  Then every younger generation thinks that the older ones don't understand life, that they were really stick-in-the-muds.  And I think that if we go back ten generations, twenty, forty, you'll probably see the same thing.

AM:     Okay.  Well, let's get back to your history. So how did you make the adjustments to living in the United States and living in Milwaukee?  We certainly had a large German population and northern European population.  I know they had a relatively thriving Jewish community there.  Where did you fit in, and how well did you adjust?

EB:      Well, I think I adjusted reasonably well, but I think there were problems in a sense that I think affect almost every youngster who immigrates to another country, and that is that my parents were different.  And our home was a little different.  So I never really felt that I was sort of in the in-group.  You may not believe this, but they had cliques even then.  I got along reasonably well, but I always felt a little bit like an outsider.  And it seemed like a long time, at the time. 

However, I think that pretty much disappeared when I went away to college, and I went away to college very young because of the Hutchins [College of the University of Chicago] four-year college program.  I left Milwaukee, although my parents still lived there and that was still my home, in 1944 to go to the University of Chicago.  This was at the end of my second year of high school.  I might say that when I came to the United States I was demoted to first grade.

AM:     You were eight years old when you came here?

EB:      I was seven.

AM:     So you should have been in second?

EB:      Yeah. It was a little painful to be demoted, but, on the other hand, I didn't take it too personally, I guess, at the time.  Then I did make that up and was back in my -- I was with my regular age group. 

            During my second year of high school, a recruiter from the University of Chicago came by to talk to people.  Robert Maynard Hutchins had become chancellor of the university, and he put into effect a unique program in which students went into what he called the four-year college.  Basically, that included, or subsumed, the last two years of high school and the first two years of college. 

One of the many things that was unique about that program is that people could progress at their own speed.  For a really good student, even a very good school with good students has to peg the work pretty much to the lowest denominator.  So there's an awful lot of boredom, I think, for a good student. I remember watching the clock while they were going over stuff that I really kind of knew.  I was a good student in high school.

AM:     And this was the public school system in Milwaukee?

EB:      Yes.  It was a good school system.  The way that the four-year college plan worked is that you went there and you took a series of placement exams.  When you took those placement exams, they put you in the courses that you thought you should be in.  If, for example, you were very good in biology tests, instead of taking Biology I and II, which were two years of biology, they would put you in Biology III, which actually just included everything in one year and was more advanced.  People who had already graduated from high school would normally go into Biology III, but students who did well on their placement test could go into Biology III also, you see. 

            But there was more than that.  You didn't have to take the course, you didn't have to go to class.  All you had to do was to take a six-hour comprehensive exam at the end of the year.  Your grade on that comprehensive exam was your grade in the course.  It didn't matter how much you apple-polished in class, or what good term papers you turned in, or what you did on your quarterly exam, or anything else.  It was all that one exam.

            So I saw this as an opportunity to kind of learn at my own rate.  I was, I guess, a fifteen-year-old adolescent at that time, and I think my mother was kind of glad to get me out of the house.  It wasn't very far.  It was ninety miles away from Milwaukee.  I lived in a dormitory.

AM:     This is the experimental high school of the University of Chicago?

EB:      No, it isn't.

AM:     It's a different program.

EB:      It's a different program.  And I don't think they have the program anymore.

AM:     I don't think so.  I can remember looking into it when I was interviewing Janet Rowley (5) because she went to this -- I thought she called it the experimental high school, and it was like two years of high school and the first year or two of college, so that when you went into the University of Chicago you were already advanced.  But it may be a different --

EB:      She might have been trying to simplify the program.  What complicates it is there was a high school, but that's separate.  I know Janet very well.  We're contemporaries.  We were there at the same time.  I don't know when she -- I think she was a year or two older than I and was in college before I was, but then in medical school, I knew both Janet and her husband very well and have seen them frequently over the years.

            So that was a real boost for me.  Nineteen forty-four, when I started four-year college, we were still at war with Germany and Japan, and young men were going into the draft.  Nobody knew how long the war was going to last, but one knew that if one were in medical school, for example, then one would be allowed to finish medical school.  That seemed like a fairly good idea.

            So I went, and I took the placement exams, and I placed out of a lot of the courses.  Then a lot of the courses I didn't take, I just took the exam.  So I was able to finish the whole four-year curriculum in a little less than two years.  Then I was admitted to the medical school.

AM:     Is that what the PhB on your -- baccalaureate in philosophy, is that what it --

EB:      That's right.  They gave two degrees.  They gave a B.A. and a PhB.  They were very similar.  The difference was that the B.A. was really lock-stepped into thirteen, I think, courses that you had to take, while with a PhB you had a little more flexibility.  I think you had to take ten of them, but you could be elective about three of them, or something of that sort.  But that was a special degree, a bachelor of philosophy.

            I received that degree in 1946 and I started medical school.  Then I got a four-year -- no, I got a master's degree, I guess, in anatomy along the way.  That's an M.S.  I think they sort of wanted to legitimize -- or lets say launder or cleanse my academic record.

AM:     You also have a B.S. with honors in 1948.

EB:      Oh, that must be the one.

AM:     Okay.  Do you have a high school diploma, or did it just not --

EB:      No.  I'm a high school dropout.

AM:     Well, at the University of Chicago.  We can't say too much about that.  Well, before you got to this new kind of learning for, obviously, very motivated high school students, teenagers, had you given much thought to what you were going to do when you grew up?  If some adult asked you, what did you --

EB:      I was sort of attracted, both by research and by medicine, and I had trouble making up my mind which I wanted to do.  I think what probably stimulated me more than any other single thing was Paul De Kruif's book, Microbe Hunters (6).  I really thought that was terrific, discovering these microorganisms, causes of disease, and the drama of vaccinated and seeing the people, or dogs, or whatever was vaccinated, or cattle, I guess, didn't get the disease if they'd been vaccinated.  I was really very much stimulated by that.

            Of the various courses that I took in high school -- and I say, I think it was quite a good school system -- it's really the sciences and mathematics that I liked the best.  I always really thought I wanted to be a scientist or a physician, and I recognized early on that the two could be combined, and that one of the reasons for going to medical school rather than graduate school was that it allowed me a lot of flexibility.

            My father had a mink farm as sort of a side kind of business/avocation kind of thing, and he used to love to go out and do work with the minks on weekends.  I think it was probably very good for him.

AM:     This was in the city?

EB:      It was outside the city, but it was within driving distance.  It was probably about twenty miles from where we lived, twenty-five miles, out in the country.  He bought a farm.  So he had a mink farm, had a house on the farm, had a lot of mink, and he had a man there who fed the mink and took care of the mink.

            The reason I bring this up is that, since we're talking about early days and we're talking about genetics, I knew about genetics from school, I knew about Mendelian genetics.

AM:     From high school or college?

EB:      From high school, but maybe even grade school.

AM:     Really!

EB:      Yeah, I think probably grade school.  In the mink business, at that time, there were several different kinds of mutations that one bred to get more valuable pelts.  So there was the plain black mink, which were, I guess, fairly valuable, but there was one mink called a Kohinoor, which was a white mink, as I recall, with a black stripe.  And that was, I think, autosomal dominant. Then there was another one called Aleutian mink, which, as a matter of fact, turns out to be, I think, Lyososomal disorder, but that wasn't known at the time.  It actually just had a fur that had a lighter color.  And then there was another mink called a Sapphire, I think. 

            So I got sort of interested in the breeding of those animals and how one would go about maximizing the number of kind of mink that you wanted.

AM:     And was your father kind of developing a breeding program to --

EB:      Well, I think he was doing it because that's what all mink breeders would do.  I mean, if he hadn't been a physician or scientist, he probably would have been doing pretty much the same thing.  I don't know that I had any impact on this, but I had these early thought processes.

            The other early thought process that I remember about genetics, which might have been -- I would place probably junior high school, probably about seventh or eighth grade, maybe even earlier, is that either one of our textbooks, or one of our teachers, said that if you removed homozygotes for an autosomal recessive disorder from a population that you wouldn't influence the number of homozygotes that were born.  That seemed preposterous to me, just preposterous.

            What I remember doing is taking a piece of paper and setting up a breeding diagram, and breeding all possible combinations in the frequency that they occurred, and trying to see how the outcome would be if you removed the homozygotes and if you didn't.  I found it a rather daunting task, partly because the piece of paper I chose was a little too small and the pedigrees began to run off of it.  But I remember giving it a lot of thought at the time and actually trying to simulate what would happen.

            So I had some interest in genetics early on, although I can't say that I said wow, I want to be a geneticist.  Actually, I think if I'd said anything, I'd have said I want to be a microbiologist, I want to be like these people in Paul De Kruif's book.  I even got some -- or my parents got me some Petri dishes and I made some agar plates (7), and I tried to do some cultures, and things of that sort.  That was really my interest, although there was an interest in genetics early on, too.

AM:     Well, to get to this Microbe Hunters.  Now, your parents are both physicians involved generally in this kind of endeavor of improving health.  Did you see your parents' lifestyles and professions as exciting as De Kruif's microbe hunters?  I mean, this book is important for generations of scientists and physicians that I've interviewed.  You're an exceptional case in which you have a sense of what it's like to practice medicine, and here's this dramatic version, and then your parents are living the lives of practicing physicians.  Did it capture you in the same way?

EB:      I don't think that I saw a strong connection between what they were doing and what Robert Koch (8) was doing, but I think they both seemed interesting to me. 

To digress for a moment in that respect.  Three of my four children received an M.D. degree, and one is in business.  He's actually in the computer business.  I have many friends who have no children who pursued medicine, and they sometimes wish they had.  So why did my children do it?  What I think the best explanation is, is that I've always enormously enjoyed everything I've done.  I enjoy practicing medicine, or I did when I did it, and I enjoy doing science.  That's why I'm still doing it.  I never told them that, but I think they could probably tell.

I think my father, who was really the one who practiced medicine, would sometimes complain about patients or one thing or another.  But I must have senses that he found it a rather fine profession or I wouldn't have found it attractive.  So I think it's probably the non-verbal signals, maybe body language, and so forth, that makes a most important difference.

There's one other thing about my childhood that I thought of when you -- you sent me a list of questions, I think, so -- I have to confess I didn't give it a great deal of thought.

AM:     That's all right.  We don't expect you to.

EB:      In fact, to tell you the truth, I didn't look at them, but then I showed my wife the folder last night and she said, "Did you see these questions?"  I don't know if I did or not.  So anyway, I looked at them.

            One of the things that I think is of paramount importance in science is integrity, which sometimes seems to be in shorter supply than it should be.  I think that that's something that was very much part of my upbringing, that you don't lie, you don't cheat, you don't do the wrong thing.  You always try to do the right thing.  Which, by the way, I think, goes to show you that you can embrace those values even if you don't have a formal religion.  In other words, you don't have to do it because of fear that a god is going to strike you down, but you learn that's the right thing to do.  Again, here, I think that it's, obviously, of very little use to tell children that they should be honest and never lie, and then they hear their parents lie. 

I think that one of the reasons that these values have stuck with me is that I think my parents adhered to them, too.  But there was one exception, and because it was an exception, I remember it and I remembered it at the time.  I mentioned to you the dining room that we sat in in Germany, in the other half of the office.  Also, I have similar memories from the United States.  In those days, doctors often made house calls.  That was part of what my father did.  So the phone would ring, and my mother would answer then phone.  Then I would hear her say, "He's on the way."  And then she would hang up.  But he was sitting there having his breakfast.  (chuckles)  It dawned on me that she really wasn't telling the truth, and that made an impression on me.  She sort of tried to explain that away, and I forgave her for it.  (chuckles)

But apart from that, I think that those were really important values.

AM:     Well, I'm impressed that you had an understanding of Mendelian genetics from school because that's generally -- for your generation there weren't --

EB:      That's just what your generation thinks.

AM:     Well, I've interviewed a few geneticists, and they --

EB:      (laughs)  They forgot.

AM:     They said there was no genetics, even in medical school.  But we haven't gotten that far.

EB:      What I suggest you do as a good historian is, if you go and look up some of the books that they worked with and find out what they really said.  I can tell you, for example, that when I took biochemistry in medical school, which was in 1946, there were -- and I still probably have the book somewhere.  DNA was in it and the idea that it was a genetic material. 

            Now, obviously, the code wasn't known, the double helix wasn't known, but the idea that there was genetic information and that genetic information had to be encoded in the molecule, that that molecule was probably DNA.  That was 1947.

            The textbooks that we used didn't have things about genetics in them.

AM:     And I want to just clarify this.  It was an introduction to Mendelian genetics.  You learned about Mendel's work.  Did they talk about Darwin in this context, or was it just Mendelian patterns of inheritance?

EB:      I can't remember.  I can't remember.  But we certainly learned about Darwin in college, yeah.  But whether we had that in junior high school or not, I don't remember.  The textbook we used was by Ella Thea Smith.

AM:     Wow!  You have a great memory.

EB:      So look it up and see what she said about it.

AM:     Okay.

EB:      I once wrote her a letter, when I was a student, about something in one of her books, which I either questioned or wanted to know more about.  And I got a long answer from her.  And then I wrote her again, and she realized I was a student and she was obviously pretty pissed off about it because she thought I'd been a teacher that had been writing to her, who was part of her support mechanism.  So I got a very short answer the second time.  (chuckles)

AM:     Well, I can tell you were quite a precocious student, and motivated student.  Did your siblings have the same opportunity to go to this program, the university program?

EB:      No.  My sister did, yes, but my brother, who was two years older, actually ended up in the army.  But he was fortunate in that he was sent to what was then called the ASTRP program.  There was an ASTP program, which was the Army Specialized Training Program, and then this was the Army Specialized Training Reserve Program.  They sent him to a very good school called St. Norbert College in Wisconsin, which actually was sort of a feeder school for MIT [Massachusetts Institute of Technology].  Then he went to radio repair school, I think, in Kentucky, and then the war was over, and then he was discharged.  And then he got into MIT, then he went to Cal Tech [California Institute of Technology and developed a career in mathematics and engineering.

AM:     Okay.  So his college education was interrupted by the war, and you were part of the program.

EB:      That's right.  Because I was only -- when I started at the University of Chicago, I was just short of sixteen, so I wasn't really ready for that yet.  When I started medical school, I was just sort of eighteen, so I got into medical school before I had to register for the draft.

AM:     And was there any question that you would not go to the University of Chicago, either to finish your second bachelor's or to go to medical school?

EB:      I applied to medical school at Harvard, and my application had not been acted on at the time I was offered a place at t he University of Chicago.  Now, in those days, people applying for medical school were expected to honor their commitment if they accepted a position.  It's not that way now, as you may know.  But in those days, it was.  Or at least I thought it was.  So when I was offered a position at the University of Chicago, which was a very good school, I grabbed it and I wrote to Harvard and withdrew my application.  I was happy to stay at the University of Chicago.

AM:     I'm going to pause here for a minute because I need to put in a new video tape.

EB:      Okay.

AM:     Okay.  In this high school/college program that you were in, was there any particular subjects that were emphasized over the others?  Was there a choice that students could make to focus on one?

EB:      Very few.  That was part of the Hutchins plan.  His idea was that everybody should have a general education, and that one might as well start after two years of high school because the last two years were usually a waste.  And then two more years after that.  Then, if people wanted to specialize, they could.  That was probably very good.  Even though it's been many years, I still feel that much of what I know are things I learned in that program, even in science, even in fields like chemistry that I use all the time, or physics, which I use often.  Still are things I learned in college.

AM:     And what about music training or history or other more liberal arts --

EB:      Yeah, there was a lot of that.  Well, the music training I didn't really need because music was omnipresent in our home.  I played the violin.  As a matter of fact, I played quite well, and I even continued taking lessons after I went to the University of Chicago.  I would come home on weekends and have my violins.  My mother played the piano and also the viola, my father played the cello, my brother played the cello, my sister played the clarinet.  And we would play chamber music together.  Still, I would say today, music is probably my main avocation, although I don't play violin anymore.  I haven't for many years.

            On the other hand, art has sort of always been kind of a blind spot.  We had that, too, and the little I know about art I think is partially what I learned there.  History, same thing, a lot of history, language, and so forth.

AM:     Well, how seamless was this transition between being an undergraduate at the University of Chicago in a special program and getting accepted in medical school at a reasonably young age?

EB:      Pretty seamless, yeah, no problem.

AM:     And when you started medical school, what did you foresee your medical training doing for you?  You have this example of your parents being physicians.  Was that what you expected?

EB:      I didn't really know.  I was interested in medicine, I was interested in science.  I don't think I knew at that time how it would fall out, although I think I was aware at the time that people don't always succeed in science and that people always succeed in medicine, if they have a license, in terms of making a livelihood.  So in a sense -- and after all, those were days when people were expected to make their own living, not like the younger generation that we talked about before.  I think I was realistic enough to know that if a research career didn't work out for me, that I could make a good living being a doctor because that's what people could do. 

I certainly didn't go into medicine because I thought it would make me rich, but I went into medicine because I thought it gave me two alternative paths and that I could decide which one I wanted to go on.  As it turned out, I ended up going on both.

AM:     And the two paths were either kind of an academic bench science career or a more purely clinical career.

EB:      Well, yes, that's right.  I mean, in those days, there was no biotechnology industry, so basically, you wouldn't have to say academic bench type career, but either a laboratory-based scientific career or a clinical career, or both.  And I ended up doing both.

AM:     And in terms of your medical school classmates, or cohorts, how did this differ from what most of your other classmates were preparing for, what kinds of medical careers they were preparing for?

EB:      I'm sorry, I didn't understand the question.

AM:     How typical was this idea of combining both, at the University of Chicago?

EB:      We had a very small class. I think I mentioned, about sixty-five people in the class, sixty or sixty-five.  I read a statistic some twenty years ago that the classes graduating at that time -- mine was the class of 1950 -- from the University of Chicago, about thirty percent of them went into academic medicine, which was more than any other school in the country.  So there were a lot of people there who had academic aspirations.  How many wound up being outstanding scientists?  I'd have to think about it.  Not a great many, but it wouldn't be in any class, I guess.

            But the University of Chicago was really very much geared toward academic medicine.  For example, in our Department of Medicine at the University of Chicago, there were probably between sixty-five and seventy-five faculty members.  They were all full time.  At the University of Southern California, which is where I went when I came out to California five or ten years later, there were four full-time faculty, and probably a hundred part-time faculty. 

The way that medicine was taught in those days, in most medical schools, even very good medical schools, was with practicing physicians who had the title of Clinical Professor of Medicine or Clinical Professor of Obstetrics and Gynecology, who would come in one day a week and teach the students.  At the University of Chicago, it was all full-time faculty.  They were all doing research.  It was a very different environment than most clinical schools.

Endnotes:

1.    Zionism: A political movement that supports a Jewish state in Israel. 

2.    Samuel M. Rapoport: (1912 – 2004); a prominent physicist and biochemist who fled to East Germany during the era of communist persecution for his political tendencies.

3.    Helen Taussig: (1898 – 1986); A noted American cardiologist who worked on a procedure to elongate the lives of blue-baby children.

4.    Marie Curie; A famous Polish physician and chemist who was awarded two Nobel Peace Prizes for physics and chemistry. She discovered two elements and worked extensively on radioactivity and isotopes. See http://nobelprize.org/nobel_prizes/chemistry/laureates/1911/marie-curie-bio.html for her life story.

5.    Janet Rowley; (b. 1925), An American geneticist who studied chromosomal translocations while taking care of her children. See Janet Rowley’s interview in this collection. 

6.    Microbe Hunters by Paul De Kruif: A book by an American microbiologist that is said to have inspired many people to enter science. It details several scientists and their contributions.

7.    Agar plates: A plastic dish with a growth medium on it to help cultivate cells. Typically the growth medium includes agar (a sugar derived from  red algae) and other nutrients.  

8.    Heinrich Hermann Robert Koch:  (1843 – 1910); A German physician who worked on tuberculosis, anthrax, cholera, and developed Koch’s postulates for identifying whether or not an organism is the cause of a disease. Koch is a Nobel Prize Recipient, for more information see http://nobelprize.org/nobel_prizes/medicine/laureates/1905/koch-bio.html.

II. Research and Genetics in Medical School; Creating a Positive Laboratory

AM:     And how did they incorporate both the clinical training and the research training in the curriculum at Chicago's medical school?

EB:      Well, they didn't really in the sense that it was a part of the curriculum.  There was no requirement for doing research.  But when I was probably a junior medical student, I started working in the laboratory of Horace [M.] Gezon, who was an infectious disease pediatrician, and who had a laboratory.  I worked on influenza virus, and I guess that was my first professional, let's say, research experience.  Of course, I'd had laboratory experience in chemistry class and biochemistry.  We always had laboratories, and I liked working in laboratories.  But this time, I was doing research.

            I received a degree with honors, which meant that I had done a research thesis.  I would guess, but it would just be a guess, that maybe a third of our class did that, but it was not a requirement.  And there were certainly people there who wanted to go into practice, but it was not nearly as large a proportion as, let's say, at the University of Illinois or University of Wisconsin, or other schools.

AM:     Well, this work on the influenza virus leads to your first publication, as well.

EB:      Right.

AM:     So, was your thesis in immunology or microbiology?

EB:      Yeah.

AM:     And how were you honing your medical interests?  Was the interest in the influenza virus, could we trace this back to the power of the Microbe Hunters?  Or were you developing other research interests as well, or clinical specialties?

EB:      Well, I can tell you what my thinking was.  First of all, it was my project, it was not -- and when I think back on it, that's a little unusual.  Usually when I have people, certainly people that junior, they come into the laboratory and they say, "What do you want me to do?  Have you got a project for me?"  But I had a problem. I used to get colds very frequently, and I thought that somebody should isolate the cold virus.  So I think maybe that takes me back to the Microbe Hunters story.  I knew people had tried to isolate the cold virus by injecting animals with secretions from people's colds, and it didn't work.  I thought what one might want to do is to try to use an immuno-compromised host. I figured I needed to work with a model system to see whether I could increase the susceptibility of an immuno-compromised host to a viral infection, so I chose an irradiated mouse and influenza virus, because that was the system that existed. 

Horace Gezon, who was a very nice man and I think quite a capable scientist -- he was quite young at the time.  I'm sure he was an assistant professor, maybe an associate professor.  He gave me space in the laboratory.  He even gave me a technician, although she was a pretty substandard technician.  But she was able to help me pick the dead mice from the live mice in the cages.  Especially if I was away, she could take care of a few things. I remember that. 

I learned how to inject embryonated eggs and to make viral preparations.  I had a classmate by the name of Larry [Lawrence S.] Sonkin, who actually had a Ph.D. degree before he went to medical school.  He had been working on a related problem, and he had a chamber that one could use to aerosolize a virus to infect animals.  So I would aerosolize the virus and infect the animals. I had access to an X ray machine somewhere on the campus.  I learned how to measure a radiation dose.  I measured the LD50 [median lethal dose] (1) to radiation.  I picked the dose for the radiation and treated the mice.  And I learned to -- I autopsied them when they died, and I fixed their lungs with Zenker's formalin, and I embedded the lungs. So that's the kind of things I did. I enjoyed it.

AM:     Well, give me a sense of the context in which you were working.  You've mentioned model systems.  How did one think about model systems, and what was available for a researcher in training to use as an animal model?

EB:      Well, there were certainly the mice, and there were certainly embryonated eggs.  If I'd wanted chimpanzees, could I have gotten them?  Probably not.

AM:     Drosophila (2)?

EB:      Drosophila, sure.  But Drosophila don't get colds, you see, so I didn't really use Drosophila.  I'd worked with Drosophila, it may have been in high school.  I remember models, culture medium, larvae, eyes, yeah.  I used to work with Drosophila.  But for this, I used mice.  I had something very specific in mind, and of course I didn't isolate the cold virus, but I learned a lot of laboratory techniques and I learned to do them myself.  It worked out fine.

AM:     Tell me a little bit about the environment at Chicago.  How integrated was the medical campus with the basic science campus?  I'm assuming you get a Ph.D. in biology or some sort of life sciences.  Was there any cross-training between sections?

EB:      They were unusually integrated, they were completely integrated.  The University of Chicago was organized into divisions, a division in physical sciences in that there was a Department of Chemistry, there was a Department of Physics, Department of Mathematics, and so forth, Department of Social Sciences.  Statistics was there.  Economics.  Department of Humanities.  And there was a Division of Biological Sciences.  The medical school was within the Division of Biological Sciences, so it was under the same management.  The Ph.D. students actually attended many of the same classes we did.  It was very integrated. 

And it was the same campus.  You see, many medical schools are separate from the university by virtue of the patient load.  So, for example, the University of Illinois main campus is Urbana[-Champaign], but you probably don't find enough patients in Urbana to train doctors, so you have to have the medical school in Chicago.  Now, sometimes what they do is they have their first two years on the science campus, and then they go to the hospital later.  But we had everything all together, integrated during the whole period.

AM:     Okay.  This is a little bit of a tangent.  Did biochemistry have its own program or department at that point?

EB:      Yeah.

AM:     It was separate from the chemistry or --

EB:      Yes.

AM:     And how much genetics was being taught to medical students at that time?

EB:      I don't remember.  I don't really remember.  I mean, basically, all I can say is that I had academic contact with genetics all the way through high school, probably junior high school, college, medical school.  I assume.  I don't really remember.  I will say there was not a department of genetics, there was not a division of genetics, it was not a clinical specialty. 

But we certainly thought about genetics.  We saw patients with genetic diseases.  One of the genetic diseases that I've been very interested in over the years is Gaucher disease (3), and I had patients with Gaucher disease when I was in training at the university.  So we must have thought about it.

AM:     How did these diseases present themselves?  Was this an interest that you had, or was it an interest that was presented to you in the clinic?  Basically was it through patient observation or patient --

EB:      Now you're doing a fast forward?

AM:     Okay.

EB:      Okay.  I think almost always it was a patient I saw.  But not invariably.  Sometimes it was corollary.  Now, in the case of Gaucher disease, it was a very specific patient, and I first saw her when she was about eighteen, nineteen years old, must have been about 1967 when I was at City of Hope.  So I did a little reading about the disease.  Enzyme defect had just been discovered.  I thought one should be able to do something with this disease in terms of treatment and diagnosis.  That's how I started.

            Then I became interested in Tay-Sachs disease (4). I'd never seen a patient, never have seen a patient, with Tay-Sachs disease.  And Fabry's [disease] (5), I did have a patient with Fabry's.  These diseases are all related, and then you become interested in all of them.  I would have to say that my medical training has probably been very important pointing me in various directions, so that even if it wasn't a patient I saw, it's a disease I knew about. 

Another disease I worked in quite a lot many years ago is  galactosemia (6).  Well, I never saw a patient with galactosemia, but I knew about the disease because I was a doctor.  I thought it might be useful to screen for the disease because early diagnosis made a difference.  I had a call from one of the vice presidents at Calbiotech [Incorporated], that he had made some galacotose-1-phosphate, I think.  Is there anything that could be done with that?  I realized then -- and I was working with red blood cells.  Kurt [J.] Isselbacher (7) had shown that the defect was in udp [uridine diphosphate]galactose transferase.  So it kind of fell together. If I hadn't known about the disease, it never would have happened.  When I see a patient with a disease, of course, it makes it more likely to happen. 

I think I should tell you at some point that I'm much less of a geneticist than most of the people that you're interviewing.  Maybe you already know that because you looked at my CV.  I'm very interested in genetics.  A lot of the work I've done has been in genetics.  But I don't consider myself to be bounded by genetics. It's just that a lot of things I do tend to come into that area.  But there are things that I do that have nothing to do with genetics.   I've had major programs just not genetically related at all.  Like blood preservation, for example.

Right now, most of the work we're doing has to do with iron homeostatis, and the starting point is hemochromatosis (8), which is a series of genetic diseases.  We're trying to understand the fundamental biology.  But you can't really separate those things out.  I was talking to a young man in my department yesterday. The issue had to do with the fact that his mentor was leaving and he wondered whether he would continue to be welcome in this department.  Now, he's working mostly in neurosciences.  This is not a neuroscience department.  But I don't care, because the things that's he's doing impinge upon various other things that people are doing. 

It's very difficult to compartmentalize science.  Because I have a longer perspective than most people because I have the privilege of being older than most people, I have to say it's always been true, that it's never really been possible to completely separate genetics from biochemistry from physiology from pharmacology.  They're all related to each other.

AM:     Well, I think we're going to pick that up maybe in the next session, as we move through your career, because that's, I think, a really important topic, about how these boundaries that we think are boundaries now may or may not have been more fluid before the highly professionalized and socialized idea of human genetics and medical genetics and the creation of these medical specialties and the formalization of the field. 

But to move you a little bit through your medical school and how you go about choosing your medical specialty.  Because you do work in the field of immunology, and then you certainly get into, very quickly -- well, and we haven't talked about this, how you get involved with [Alf S.] Alving's (9) group in hematology (10) and biochemistry.  So why don't you talk a little bit about what solidified your idea of what kind of medical specialties you would train in.

EB:      That's a very interesting question.  The medical specialty that I chose was hematology.  My primary identity, at least for people on the outside, is hematology, not genetics.  So why did I choose hematology?  The answer is pretty simple, I think.  That is that the person that was the head of hematology at the University of Chicago when I was an intern or senior student was somebody that I admired.  So I decided that would be kind of a nice place to work, with that group of people.  They're a nice group of people, they're doing interesting things, and they're somebody, they're thoughtful.  That man was Leon [O.] Jacobson (11).  So I went to see Leon Jacobson and asked him whether I could work in his department.

            I might go back a little bit and explain that, after the first year of residency, people had to choose a subspecialty to concentrate on.  That didn't mean they would be a subspecialist because they were still internal medicine residents, but they were concentrated a little bit more, so that instead of just rotating one month in every clinic, they might take, let's say, three months in the one they chose and still go _____ the other clinic.

            He asked me only two questions.  He said, "Do you get along with everybody in the department?"  And I said, "Yes, as far as I know."  Then he asked me if I was in trouble with anybody in the institution.  I said, "No, not as far as I know."  He said, "Fine, you can work with me."  What impressed me was that it was so important to him that people get along with each other.  I never forgot that, and it's been one of my guiding principles.

            When I come to work, I want to enjoy myself, I want to feel comfortable with everybody, I want to feel friendly with everybody, and I want them to feel that way with each other.  I wouldn't want the most brilliant coworker or technician, or whatever, if they were abrasive and made other people feel unhappy.  That's one of a number of things I learned from Leon Jacobson. 

            In one sense, I've never had a mentor.  That may seem strange, and it's a little bit contrary to what I told you about early on, that things never really change, that people only think they do. But things were a little different then.  There were no fellowships, you see.

            When I worked in the laboratory of Horace Gezon, in a sense he was a mentor in that he showed me how to inject eggs and that sort of thing, but basically it was my project.  I did my own work and that was it.  It was the same as Jacobson's.  I learned a lot from him, but it wasn't about science.  It was about how to manage people, how to behave in science.  Things like sharing information with other people.  This is something that people do -- I think there are a lot of things that are very fixed in people's behavior by the time they're twenty or twenty-two years old.  You can't make somebody who's fundamentally dishonest honest because they have an honest mentor.  You can't make somebody who has no people skills suddenly become very skillful in interacting with people when they're twenty.  I mean, those things happen much earlier.

            But there are some things in terms of scientific behavior which I think people do learn from their mentors.  One of those things is to what extent to share ideas.  How open to be.  Jacobson was always very open.  At least I thought he was, I think he was.  And I've always been that way.  On the other hand, I've seen people who have grown up in a laboratory of people who are distrustful and who don't share information, or even try to deceive other people.  They tend to behave in that way, too.

            I was really rather dismayed when I read Jim [James D.] Watson's (12) book, The Double Helix.  I might say he was a classmate of mine in college, although I don't remember him from them. Somebody else mentioned to me, "Don't you remember Jimmy Watson?  He was in our gym class," he said.  There was another colleague that I had gotten in touch with.  "Jimmy wrote a book."

AM:     At the University of Chicago.

EB:      University of Chicago.  He was an undergraduate at the same time I was.  But the idea that you skulk around and you try and look in somebody's notebook, or talk to somebody's son to find out what they're doing, or, you know, spy.  That's not the way science should be.  I think that when you -- if you want to train people to be scientists, then they're going to behave the way you do, and if you think scientists shouldn't behave in that way, then you shouldn't behave in that way.

            Another thing I learned from Jacobson that has always stuck with me is the structure of the laboratory.  My laboratory has always been very different from most research laboratories.  Most research laboratories, certainly at this institute, and most others, successful scientists, consist of a group of postdoctoral fellows, five, ten, sometimes fifteen, and maybe two or three technicians to help with the work.  And they have a lab.  Our laboratory, my laboratory, has always consisted of five technicians, who report directly to me, and two or three postdoctoral fellows.  There have been some changes, especially with time, but that's the way Jacobson's laboratory was.  He had three technicians.  They had been with him at what at the time seemed to me forever, twenty, twenty-five years.  They were good.  They were loyal.  They were honest, and nice people.  That's the way he built a highly successful research career. 

Actually, Jacobson had the distinction of doing more than one important thing in science, which I always sort of thought was a mark of a great scientist.  Anybody can get lucky once, but it's pretty hard to get lucky twice.  Now, he basically made some of the fundamental observations in radiobiology that ultimately led to bone marrow transplantation.  But he also discovered that erythropoietin is made in the kidneys.  Totally different kind of things.  And he did it with these technicians.

Now, as I've gotten older, unfortunately some of the technicians that have been with me for a very long time retired.  There's not much I can do about that.  One of them retired about a year ago, and she'd been with me for thirty-eight years.  One of them is still with me, and she's been with me for twenty-eight years.  Some of the others retired after they'd only been here for twenty-five, twenty-seven years.  I brought them with me from the City of Hope.  That's kind of been my research group.

Now, what about fellows?  I think fellows are very important, because you have to train the next generation.  When you're training technicians, you're not training the next generation.  They're not going to carry on the science, or the art of the science.  But they do the work.  While the fellows get trained and then, presumably, they become scientists, some of them do.  Some of them don't make it, of course.

What people do nowadays is they use the fellows to do the work, and they do it because the fellows are cheap and sometimes work hard.  But I don't think that's right.  There's a strong downside to it.  First of all, they're not as good as a good technician, not nearly as good.  But there are other problems, too.  If you have an idea that is original, the probability is that it's wrong, okay?  And if you give that kind of idea to a fellow and it turns out to be wrong, as it almost always does, then you've ruined that fellow's career.  If somebody works in your lab for three or four years, they don't the qualifications, where are they going to go from there?  But if you do that with a technician, no problem.  So they're better, and you can give them innovative bad ideas.  So that's the way I like to work. 

One of my best technicians was a wonderful woman by the name of Wanda Kuhl [Crater?], or Wanda Crater was her married name.  She worked with me for almost thirty years before she retired. I had an idea about twenty years ago that we might be able to identify leukemia (13) viruses by hybridizing out DNA from normal cells against cells that had leukemia, and then we would wind up with just the leukemia virus.  Well, you know, this was pretty much early in molecular biology and very early for me in molecular biology, and in retrospect was not a very good idea, but we worked on it for three or four years.  Never got anything out of it.  You would see nothing _____.  Well, it didn't really hurt his career.  We went on to something else.  We learned a lot.  We learned a lot about how to handle DNA.

I think that when you do an experiment that doesn't work the way you want it to, it's usually not a total loss.  You learn something.  And then the next time you do an experiment, you use that knowledge, which may not be related to the dumb project that you were working on, to make something else work.

But with fellows, you really have an obligation to give them a project which will lead to a publication so they can build a career.  And there are projects like that.  So at a steady state, I have had usually an average of three, sometimes four fellows.  I don't like to have more.  I don't have that many good ideas, and I don't want to give them bad ideas.  I sometimes do, but clearly, ideas must have a hierarchy, really good ones, not so good.  You've got twenty fellows, a colleague of mine has forty fellows.  So what does number forty get?  It's not going to be a great project.  Or worse.  One thing that happened to one of my sons when he was a postdoctoral fellow is that he gets put on the same project as another fellow, and this gives rise to problems.

So right now I have actually only one fellow in the lab.  But that's partly because I feel a little reluctant at my age to take on fellows.  Not because I don't think that I'll last, although we never know, but it would be nice to help them along their path in science ten years from now, fifteen years from now, twenty years from now, and they're much more likely to get that kind of help from a younger mentor.  I don't know whether I'll take more fellows or not, but I have one very good one now and it seems to be working out okay.

AM:     Okay.  Well, to take you -- you really fast-forwarded, but we will get to that.

EB:      You told me I could be discursive if I wanted to.

AM:     You could, and I'm totally encouraging you, but I am going to take you back right now, but on the same topic, and that is, How unique was it with Jacobson's lab that he had these technicians that had lasted for a long time?  Did you have a sense that he was unique in this regard?

EB:      I think he was unusual, yeah.  He was a very nice man.  He had worked as a schoolteacher, a one-room schoolhouse in North Dakota or South Dakota before he went to medical school.  He had really very good people skills.  But, obviously, a very, very good mind.  He ended up -- he was elected to the National Academy of Sciences (14).  He became chairman and then dean of the medical school.  So professionally he was very successful. 

I think that he taught me a lot.  He taught me a lot about administration.  I've done a lot of administration.  I've probably been a department chairman longer than anybody else has ever been.  I became a department chairman in 1959 and I've been department chairman ever since.  And I found that the way that I deal with problems sometimes, maybe even often, reflects the way that Jake [Leon Jacobson] used to deal with problems.  That's basically not to try to meet every problem head-on, because a lot of things resolve themselves, but not to let things fester.  The other thing is that if you're going to make an unpleasant decision, make it and tell the person right up front. But we're way ahead of the game now.

AM:     Okay.  Well, one question I want to ask about -- because your tenure at the University of Chicago stands as an important period, although towards the end of it -- is, How aware were you, either as an undergraduate or a medical student at the University of Chicago of the Manhattan Project (15) --

EB:      I not only knew about it, I knew what they were doing.  I knew what they were doing because we had a loose-lipped physics instructor who -- this was in about 1942 or '44.  He said to us in the class that the amount of power, energy, that you release by splitting an atom is enormous, and that's why the work under the west stands [of Stagg Field] is so secret.  (laughs)

AM:     And was there any sense at that time within the fields of life sciences what the impact of all this radiation would have, and radiation science would have, on biology?

EB:      I think so.  I'll tell ya, that's another interesting point.  When you hear about, for example, radiation examination of the Utah tests, and from early atomic tests, that people say, well, in those days they didn't realize what radiation could do.  Of course we realized what radiation could do.  That's not new knowledge.  As a matter of fact, Leon Jacobson started his career by being the kind of physician-consultant to that group.  But the idea that total body radiation kills, we knew that.  Radiation was used in the treatment of cancer.  We knew radiation caused cancer.  Marie Curie developed cancer from radiation.  We wore lead aprons when we did radiologic examinations.  That was all known.

AM:     And how about in terms of genetics?  Because [Hermann J.] Muller (16) had shown years ago that this could be --

EB:      Muller had shown it years ago.  I learned that in high school.  I learned about Muller in high school.

AM:     Oh, did you?

EB:      Yeah.  Maybe junior high school.  Remember, there was a picture.  Later, he came to the City of Hope and for a short time he was a friend.  He was a very, very nice man, very nice man.  And always thinking.  At the time he seemed very old.  Now he's probably fairly young.  But this was some forty-five years ago or so.  I remember standing in the cafeteria line with him, and his speculating about the mutational load of Sequoia trees because they lived for such a long time and they had all this radiation, so they must have accumulated a lot of _____. 

No, all those things were known.  I'm often a little bit taken aback at what I read about, well, in those days they didn't realize that the radiation was harmful, so they -- of course they knew.

AM:     So basically, your subspecialty of hematology, you moved in this direction because of Jacobson and his -- can I use the term role as a mentor?  Or role as a --

EB:      Role model, more than mentor.  He put me on one project, which was a very interesting project.  But after that, I always just did my own thing, and he encouraged me to, and he supported me.  He gave me technicians, he gave me supplies.  Until I went to the City of Hope I never had to get a grant.  He always just took care of me, although I was an assistant professor.  He was the director of the Argon Cancer Research Institute. 

He had a very interesting idea, which I think -- well, the story's worth telling perhaps.  Jacobson's interest at that time was trying to protect against radiation, which would have been foolish if no one thought it was harmful.  He made an interesting observation, and that is that if you radiate a mouse, let's say with six hundred rads, it dies.  Now, if you take that mouse, or take another mouse because that one is dead, if you take another mouse, you put a lead shield around its spleen.  You exteriorize the spleen and put a lead shield around it.  You take the control mouse, exteriorize the spleen and you put a paraffin shield around it.  Now you radiate those mice.  Then you put the spleen back in and sew up the mouse.  The one that had its spleen shielded during radiation survives, and this one dies. 

So Jacobson realized that the spleen played some role in protecting against the radiation, and he thought there was a humoral factor produced by the spleen that protected against radiation, and he wanted to try to isolate that humoral factor. 

It turned out that he was mistaken.  And that's an interesting story, too.  Because he took marrow from a rat and injected it into a mouse, and it saved it from radiation.  No, he took a -- I'm sorry.  He radiated a rat, I think, and then he took the spleen from that rat and put it into the radiated mouse, and it rescued the mouse.  At that time, nobody dreamed that rat cells could grow in a mouse, so it must be humoral because you can't transfer cells from one species to another.  But, of course, it turned out that because that mouse was so immuno-compromised that the rat cell did grow.  And there's a difference in the alkaline phosphatase activity of rat _____ cells and mouse cells, and someone else -- I think it was [Egon] Lorenz (17) -- showed them that actually the rat cells colonized the mouse. 

The spinoff of that was, as I said earlier, that this was really the beginning of marrow transplantation.  But this led Jacobson down the wrong path, and he thought there was a humoral factor (18).  So he had a really imaginative idea.  He said, If you irradiate bacteria and you put them into a mouse, the mouse will -- let's see.  If you put radiated bacteria into a normal mouse, that it might kill the normal mouse because the humoral factor would repair the bacteria and they would then kill the mouse.  While if you put it into an irradiated mouse, the mouse would live.  It's just exactly the opposite that you would expect.  And I like people who have that kind of really counter-intuitive idea.  So he said, "Why don't you do that experiment?"  So I did.  It didn't work.

But then I got interested in the effect of radiation on bacteria, and I think my second paper showed that the _____ phase of E. coli was prolonged by radiation.  So if you took E. coli and you irradiated them and you put them in a culture medium, then you sampled the culture medium at intervals, that it would take a long time and then the culture would go up while normal cells would just go up straight like that. 

That was a wonderful idea that he had, that you could -- and, see, basically what he was aiming at was an in vivo microbiological assay (19).  Of course, microbiological assays were really very much in their infancy.  You've probably heard someone talk about one.  You may know that it was, for example -- I'll give you another piece of medical history since you're a medical historian. 

The effect of liver extract in saving people with pernicious anemia (20) was discovered in about 1926 or 1928.  But for more than twenty years after that nobody was able to isolate the factor of liver that protected the pernicious anemia or cured pernicious anemia.  The way that it was done was by a microbial assay in which there was a microorganism that would grow in the presence of liver and that seemed -- the activity of the liver on this microbial organism seemed to parallel its effect on patients with pernicious anemia.  So now, suddenly, instead of trying to purify the principle by fractionating it, giving each of the fractions to a patient and seeing the patient respond, and then doing another and finding other patients, they could do it all microbially.  So a woman by the name of Dorothy [C.] Hodgkin (21)  -- also a woman -- isolated vitamin B12 using microbial assay.  That was 1950. 

So microbial assays were just beginning then, and Jacobson had this idea that perhaps the humoral factor could be used in in vivo microbial assay.  It was kind of interesting.

AM:     And in this period of time, how important was it that every project that you get put on ends up in a publication, at least one publication?

EB:      Nobody ever said anything.  Nobody ever said that.

Endnotes:

1. LD50: the dose of radiation or of a substance required to kill 50% of a given population. It is often used to compare levels of toxicity.

2. Drosophila; A genus of fruit fly, most commonly Drosophila melanogaster is used in labs. A model organism used in many scientific experiments since it is relatively inexpensive, has a high fecundity and a short life span, and has a discernable phenotype and genotype.

3. Gaucher Disease: A genetic disease affecting the enzyme glucocerebrosidase whose defection causes fat to build up and accumulate in various parts of the body leading to severe complications. With enzyme replacement therapy, an individual with this disease can expect a normal life.

4. Tay-Sachs Disease; An autosomal recessive disease which causes large quantities of fatty cells to build up in the nerves of the brain. There is currently no treatment. For more information see http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm.

5. Fabry’s Disease: Also a lysosomal storage disease like Tay-Sachs Disease, Fabry’s Disease is an X-linked genetic disease affecting the enzyme ceramide trihexosidase. This deficiency results in an improper breakdown of lipids and allows them to accumulate in the body.

6. Galactosemia: A genetic disorder where one of three enzymes needed to break down the sugar galactose are not present. This can lead to many dire consequences. The three enzymes are: Galactose-1-phosphate uridyl transferase, galactokinase, and UDP galactose epimerase. Most newborns are screened for the disease shortly after birth.

7. Kurt J. Isselbacher: A Gastroenterologist and director of the Massachusetts Cancer Center and of Harvard’s gastroenterology unit. For more information see: http://www.mgh.harvard.edu/cancer/research/isselbacher.aspx#.

8. Hemochromatosis: A genetic disorder characterized by excessive iron absorption by the body.

9. Alf S. Alving; A scientist noted for his study in malaria research. For an example of his work see http://history.amedd.army.mil/booksdocs/korea/recad2/ch5-2.htm.

10.Hematology;  The branch of science dealing with the study of blood, the blood producing regions, and blood diseases.

11.Leon O. Jacobson (1911 – 1992); A notable hematologist who also worked in chemo and radiotherapy; he is also remembered for being one of the physicians charged with monitoring the health of the scientists working on the Manhattan Project.

12.James D. Watson; Watson and together with Francis Crick (English) were the first to propose DNA as a double helix structure and are renowned for having done so. The duo, along with Maurice Wilkins, received a Nobel Prize for their work on nucleic acid research. See http://www.time.com/time/time100/scientist/profile/watsoncrick.html

13.Leukemia: Blood or bone marrow cancer where blood cells accumulate, generally white blood cells.

14.National Academy of Sciences; A society that holds meetings to bring all types of scientists together to address national issues and provide scientific advice for the government and the citizenry. Crow is a member of the National Academy of the Sciences.

15.Manhattan Project; Created in 1942, this was a secret project created by the US Government to create atomic bombs. It ended in 1946.

16.Hermann J. Muller; (1890 – 1967), A highly noted American geneticist who was awarded the Nobel Prize in Physiology or Medicine for displaying artificial mutations that can occur as a result of X-ray manipulation. See http://nobelprize.org/nobel_prizes/medicine/laureates/1946/muller-bio.html.

17.Egon Lorenz: (1891 – 1954); a German scientist who worked on the Manhattan Project and is most noted for his work on the effect of radiation on living things. He also helped develop bone marrow transplantation.

18.Humoral Factor: A substance that is transported via the circulatory system including hormones and antibodies.

19.Assay: A method to test the virility of a biochemical compound or a drug on an organic sample of some kind. There are many different forms of assays.

20.Pernicious Anemia: A decrease in red blood cell count that occurs when the body is impaired or incapable of absorbing vitamin B12 from the body’s gastrointestinal tract. This is due to either a protein not being produced well or in sufficient quantities (it has genetic causes). Vitamin B12 is necessary for the development of healthy red blood cells.

21.Dorothy C. Hodgkin; A British biochemist and crystallographer who used x-ray crystallography to determine the structure of many different molecules including insulin, B12, and penicillin. She was awarded a Nobel prize, see  http://nobelprize.org/nobel_prizes/chemistry/laureates/1964/hodgkin-bio.html for more information.

III. Working as a Military Medical Officer; Malaria and Primaquine Research in State Penitentiary

AM:     Okay.  Why don't you bring us at least to the period  -- you're finishing up your training, but then you owe the U.S. government some time?  Or were you always attached to the military because of -- I know there's a two-year gap in which you're part of the -- in '53 to '55 that you're --

EB:      I didn't owe anything, except as an American citizen.

AM:     Right. I can recall that if -- you missed the draft.

EB:      Yeah, I missed the draft.

AM:     Okay, completely.

EB:      Yeah, I missed the draft, and I didn't go into one of these programs where there's a payback.  I had to pay back without getting.  But my military experience was very good.  I certainly don't want to give the impression I didn't --

AM:     Yeah.  I was just trying to figure -- because you're in the period of time of the Korean War, and I was wondering if you had enlist or you were drafted as a medical student, but that's not the case.

EB:      No, no.

AM:     Tell me about your military service.  It seems to me you're finishing up your medical training and --

EB:      I'd finished.  I'd finished, I'd had my internship, had a year of residency, and my second year of residency in internal medicine, attached to hematology.  There's a war in Korea and they're drafting people.  I can't remember the exact circumstances, but I remember that my option was either being drafted as an enlisted man or applying for a commission as a medical officer.  Well, which would you do?  So I applied for a commission for a medical officer. 

But there was a twist to it.  The University of Chicago was operating a malaria research program at the Stateville Penitentiary.  People going to that program were generally house officers from the University of Chicago who had to do their military service.  They had the same thing in the Vietnamese War, and there, what they called the "yellow berets" went to NIH (1).  So in a sense, I might have been the yellow beret in the Korean War.  There wasn't the NIH program, but there was this program at Stateville Penitentiary.

I didn't go to basic training, never went to Fort Sam Houston, I just went to the army store and bought a uniform and my wife and I drove out to Joliet, Illinois.  We found a place to live, rented an apartment, and I reported to the prison.  We'll take a break now and I'll tell you a little bit more.

AM:     Okay, great.

AM:     Well, we had kind of paused for lunch.  You were just talking about your military career, that you had a choice of being drafted or enlisting as a medical officer, and you ended up at state prison in Illinois.

EB:      Right.

AM:     You did mention that your wife -- you were married by this point.  Before we move on there, tell me a little bit about when you got married and how you met, and did you have children at this point, and how keen was she on moving next to the state prison?

EB:      I wasn't that close to the state prison.  When the new school year begins at the University of Chicago, which I think is several times a year because it's on the quarter system, the chancellor has a reception for the new students.  At one of those receptions, 1959, I decided to go look over the new crop of girls, I guess, and Bonnie [Brondelle Fleisher Beutler] decided to go and look over the new crop of boys.  (chuckles)  Because neither of us were new students.  She was a student in the college, and I was a student in the college.

AM:     And you had worked yourselves through the older students.

EB:      Well, it's always good to see what opportunities may exist in life.  So we were introduced by a mutual friend, somebody who knew her and knew me.  We started dating.  And then we were married about a year after we met.  We got engaged, I think, in January of 1950, but we got married June 15th, 1950.  I graduated from medical school June 16th, 1950.  So we were married the day before I graduated from medical school.

            I like to tell people that we were so young that we went on our honeymoon together, first with my brother and then with my parents. 

AM:     Wow!  How romantic.

EB:      Yeah.  The story behind that is that my brother was getting married in Boston three or four days later, so he took us to Niagara Falls, and my parents, who were driving to Boston, picked us up in Niagara Falls.  We all met in Boston for my brother's wedding.

            We had our first child in 1952.  That's Steven [Beutler].  He is now, I guess, about fifty-five years old and is a physician.  He specializes in infectious disease, and he lives in Redlands, which is about a hundred miles north of here.

AM:     Is he at Loma Linda?

EB:      No, he's in private practice.  He has an appointment, I think, at UCLA, but basically he covers -- nowadays, it's rather unusual for a subspecialist to be able to really practice only a subspecialty.  Mostly, physicians who specialize, let's say, in cardiology really do internal medicine and they get to do a bit of cardiology, too.  But he does only infectious disease.  He doesn't really follow patients too long, he just sees consultations.

AM:     Did you give him a copy of Microbe Hunters when he was a child?

EB:      I don't remember.  I think he's probably read it.  I don't know. 

            Our second son was born right after I finished at Stateville, just before I went to Fort Detrick, and that's another part of the story.  So we had one child at that time.  We moved to Joliet.  We didn't live on the prison grounds.  Actually, it was probably four or five miles away from the prison, in a sort of a nice housing development.  Actually, having lived in Chicago before, it was really quite nice because we had a little bit of a backyard behind the row house in which we lived, and it was quite pleasant.

            I was assigned to the Meat and Dairy Hygiene School.

AM:     Okay.  I wanted to ask about that.  What is the Meat and Dairy Hygiene Branch of the army?

EB:      I don't know.  But, you know, they had to put me somewhere.  That was the point.  I suppose they had to do with meat quality or something.  But the point is that I was an army reserve officer on active duty, so I had to have something I was assigned to, and there was no military installation there, so they assigned me to that.  I went down there once to sign some papers or something, but that was my formal assignment.

            Basically, I left my residency at the University of Chicago, moved my family to Joliet.  We moved into this nice house, row house, I guess.  And I went to work.  It really was a prison.  Every day when I went in I had to be searched with a metal detector and go into a locked prison ward.  We were actually up there with twenty or thirty prisoners, no guard.  There was a civilian female nurse and there was one other army officer, Ray [Raymond J.] Dern, and myself.  We were both from the University of Chicago.  Ray was quite a few years older than I and very nice and very able man.  He had actually, I think, served in World War II, been doing research in Rochester. I think he was a Ph.D. scientist at that time.  He was there for some time before I was, maybe a year or part of a year.  And we worked together very well.

            Basically, it was the two of us working on a prison ward with the prisoners.  Our technicians were prisoners, our secretary was a prisoner.  The only person who was not a prisoner up there was the nurse we got.  Our main job there was to test the effect of anti-malarials.  We infected prisoners with malaria, either by a mosquito bite or by an intravenous injection.  And then put them on various drug protocols to see how effective it was in curing them.

            Nowadays, when I talk about prisoner volunteers, people sort of wink and sneer as if these people weren't really volunteers.  But again, people didn't force prisoners to undergo medical experiments.  And they really were volunteers.  They actually signed informed consents that were witnessed.  Things don't change as much as -- there was no IRB [Institutional review board] (2).  There were less constraints, but certainly nobody was ever forced to do this.  They were paid twenty-five dollars a year if they took malaria, as we said, ten dollars a year for drug testing.  That wasn't a lot of money, not even in those days.  But on the other hand, their alternatives weren't all that great.

AM:     What was the incentive for them?

EB:      Well, the incentive was that, first of all, it was really probably more pleasant for them to be in this hospital unit, where they could play cards with their friends, than being on the rock pile or the laundry or whatever else their work assignment would be. 

And the other was that most of them had indeterminate sentences, so they would periodically go to the Parole Board.  Now, obviously, we had no authority, or any wish, to offer anybody time off for doing this.  That was not part of the deal.  But, of course, they knew they would go to the Parole Board and they could say, And to help to atone for my bad deeds, I allowed the doctors to give me malaria and took the drugs.  Whether it helped them or not, I don't know, but they had the opportunity to do that.

As a matter of fact, it's my feeling that it's really wrong not to allow prisoner volunteers to participate in research projects. I think this is just part of the politically correct over-reaction now to biomedical ethics. I think it's perfectly all right to use these people. Obviously, they shouldn't be forced to do it, but there are people who want to do it, and they're an ideal population for studying certain kinds of problems.  I daresay that that project has probably saved many lives over the years because of the discoveries that were made doing this, which couldn't have been done anywhere else.

AM:     And why couldn't it have been done -- I do want to go deeply into the history of this particular research program, and why couldn't it have been done anywhere else?

EB:      Well, how would you get people to come back every day for two or three months, hospitalized for two or three weeks at a time?  You couldn't do that with people who were working.  You could do it with army troops.  They're much less volunteers than the prisoners.

AM:     Was there the possibility of using soldiers to --

EB:      I suppose it was possible, but I'm not sure that would have been ethically any different.  The next stage, which I can tell you about, when I went to Fort Detrick we did use soldiers.  But that was for a different disease.

            The prisoners were easy to work with.  In those days, I suppose most of them had been in the military at some time.  They respected the army, the uniformed army officer.  I never felt the least bit vulnerable.  There were really never any problems.  The technicians worked hard.  Of course, we had to train them from scratch.  They didn't have college degrees.  The didn't really have much training, but that was fine. 

            The primary aim was to work on cures for malaria, but it was already well known that one group of drugs that was very effective in malaria, the 6-methoxy-8-aminoquinolines, produced severe hemolytic anemia (3) in some individuals and produced no hemolysis (4) in others. 

            So the challenge -- and one of the challenges I went there to try to resolve -- was what was different about those people.  We were able to do this by doing a series of experiments, some of which could not be done today, in which we took red cells from somebody who was not sensitive to primaquine (5), labeled them with Chromium-51, radioactive chromium, put them into a person who was sensitive, or was not sensitive, and the other way around.  Then we would give these people primaquine, follow the Chromium-51 activity, and this made it possible for us to show that what was different about primaquine-sensitive people was not the way they metabolized primaquine but rather there was something different about their red blood cells.

            Then, in the course of those studies, we began to notice that if we continued primaquine administration that after the initial destruction of red blood cells, the hemoglobin (6) leveled off and went back up, even as they were getting primaquine.  We were able to show that the cells which were in the circulation at that time were still sensitive to primaquine if they were put in another person and allowed to age. 

            From this, and some other findings, I reasoned that perhaps only the older members of the red cell population were destroyed when primaquine was given.  So I labeled the red cells of a primaquine-sensitive subject with iron-59/[Fe59], and iron-59 was incorporated into newly formed red blood cells.  Then it stays with those red cells, it doesn't exchange with other body iron pools.  I was able to show that the young red cells were resistant to primaquine, but when those same red cells aged that they were sensitive to primaquine.     The fact that all cells were sensitive to primaquine suggested that this might be some kind of metabolic defect.

            Now, at the same time, I tried to see how the primaquine-sensitive cells were different in vitro, whether we could detect who was primaquine-sensitive or not just by examining the red blood cells.  So I had the opportunity to learn a lot of different techniques by which red cells were examined in those days -- osmotic fragility (7), mechanical fragility (8), antigens (9) on the cell, and so forth -- and they seemed to be perfectly normal. 

I'd observed that when we gave primaquine to a primaquine-sensitive subject, before the hemolytic anemia developed, particles of denatured protein could be seen in the red cells.  These are called Heinz bodies (10), and Heinz bodies can be formed in vitro, I mean be formed in a test tube.  So I examined the formation of Heinz bodies in red cells from primaquine-sensitive and non-sensitive individuals treated with another drug, which I used for certain reasons.  That was acetylphenylhydrazine.  Acetylphenylhydrazine is a very good Heinz body forming drug.  I found that the pattern of Heinz body formation was very different in the primaquine-sensitive and non-sensitive individuals.  That was the first time that we could tell, in vitro, the difference between a primaquine-sensitive and non-sensitive individual.  Before that, we'd have to give them a drug and see if they developed anemia.

Even more important was the fact that now I could sort of probe these cells with inhibitors to see whether I could make the normal cells behave as if they were deficient by inhibiting some metabolic process. And I found that there were two inhibitors that had that effect.  One was sodium arsenite, and the other iodoacetate.  These are both sulfydryl reagents. 

So that kind of got me to thinking about sulfydryl compounds in the red cells, and I remember I went to a meeting in  Atlantic City and talked to Irving [M.] London (11), who at that time was already a very well-known hematologist, internist, academician.  He mentioned the possibility of looking at glutathione (12).  As a matter of fact, that was sort of on my list of things to look at.  So I went back and I developed a method for measuring red cell glutathione.  Sure enough, the normal red cells had slightly higher glutathione levels than the deficient red cells.

Then I measured the glutathione content of red cells of people getting primaquine and I found that if they were primaquine-sensitive, the glutathione all but disappeared from the red cells after I gave the primaquine.  So I went back to the in vitro system and I measured the distruction of glutathione by acetylphenylhydrazine. 

I'm sorry.  I've gotten ahead of the story.  I've got it a little bit out of sequence.  I did to that, but I did it a year later.  Because my work then was interrupted because the army decided that they were running short of medical officers and they were no longer going to assign medical officers to civilian research projects.

AM:     Okay.  So this was the tradition before that?

EB:      That's right.  And at that point, they said, okay, no more of this.  We need all our medical officers in army facilities.

            I'd been doing some other studies as well, which is quite important in this regard.  When we'd been doing these cross-transfusion studies, studies we would no longer be able to do, we noticed that there were some people who developed a mild short febrile (13) illness about two or three weeks after they received infusion of red cells from another individual.  Then I found that if I took red cells from that individual and put it in another individual, then two or three weeks later they developed febrile illness.  So we clearly had some kind of transmissible agent.  As a matter of fact, we published that in the JAMA [Journal of the American Medical Association]. 

And trying to identify that agent was far beyond our capabilities, so I made a trip to the Walter Reed Hospital and I met with Joe [Joseph E.] Smadel (14), who then was the Director of Infectious Disease there.  They were very interested in pursuing this, and they started to do so. 

They never identified the agent, but there was an unintended consequence.  When I realized that I was going to have to leave Stateville and go somewhere else, I discovered that one could actually shop around for jobs in the army, that it wasn't just a matter of my waiting and their saying you're going to Korea, you're going to Tennessee, whatever.  I had two job offers.  One was from a very well-known hematologist whom I greatly respected and who, as a matter of fact, was -- I was instrumental in his coming here in 1970, and then he was instrumental in my coming here in 1979.  That was Bill [William H.] Crosby [Jr.] Bill Crosby (15) was head of Hematology at Walter Reed and he wanted me to come to work for him.  So I agreed to work for Crosby.

Then I got my orders, which I expected to be for Puerto Rico, where he had his unit.  My wife and I were ready to move to Puerto Rico.  But when I got the orders, they were for Fort Detrick.  It turned out that they had started a new secret project there, which now has been declassified, and it was to study Q fever [Coxiella burnetii infection] (16) in human volunteers.  So they wanted medical officers for that project, and Joe Smadel, whom I had met, decided I would be a good person to do that.  So my papers were moved from one place to another, and when I got my orders it was for Detrick, and that's how I happened to go to Detrick.

My work with primaquine sensitivity, which as you know, turned out to be G6PD [glucose-6-phosphate dehydrogenase] deficiency (17), was interrupted for a year while I went to Frederick, Maryland, to Camp Detrick.  There, I set up a laboratory to study Q fever.  I remember bleeding hundreds of guinea pigs and setting up laboratory procedures.  It was again a very stimulating project.  I really had a very good army experience.  Many people have been much less lucky and have gone to some very out-of-the-way place where they see a few patients, or something.

A few years ago when there were anthrax cases around, I was making rounds with the clinical group, and I said to them, "How many of you have ever seen a case of anthrax?"  Nobody had ever seen one.  I saw them, saw them at Detrick.  Not actually at Detrick, but they had a case of an abattoir worker in Philadelphia and they took us to Philadelphia so we could see what a case of anthrax looks like, cutaneous anthrax (18).  So I learned a lot.  And I learned how to set up another laboratory to do infectious disease work, and so on.  It was only one year.  Actually, it was less than that.

I actually had told you about my first son, who had been born while we were still in Chicago and came with us to Joliet.  While we were in Joliet, my wife became pregnant with what turned out to be our second son, and she was scheduled to deliver about a week or two before we left, but she didn't.  So I took her to my family's home in Milwaukee, which was only about a hundred and twenty miles away, and the next day she went into labor.  As a matter of fact, I had to assist in the delivery because it was done in a very small hospital, and the physician who delivered her was a friend of my father's.  I mean, this was all arranged at the last minute.  Then a nurse came in and finished the delivery with him.  That was Earl [Beutler].  He's now in business, and we may talk about him later.

So I left my newborn and my wife in Milwaukee. I drove to Detrick.  I had this idea that while my orders were for September 10th, that's when I had to be there.  I'm sure in that respect if I'd said I'd just had a child, can I have a two-week leave of absence, they would have given it to me.  But I never thought of it. I got there, and they couldn't tell me what I was going to do because my secret clearance hadn't come through yet.  So I cooled my heels there for a couple weeks.  Then my wife joined me there with the two children.

I had a very good two years there.  While I was there, Leon Jacobson came to visit. I think he may have been consultant to one of the groups.  And he asked me if I would come back to the University of Chicago.  As a matter of fact, I'd always sort of thought I would, but nobody had ever asked me.  That was nice.  So he asked me and I came back as an instructor.  Then I started to work on the G6PD problem again.  That was in 1955.

You had mentioned [Alf] Alving's group.  Alving was a nephrologist and was a professor at the University of Chicago.  He had become involved with the army malaria program as a consultant, I think because malaria patients develop proteinuria (19) and they wanted to have a nephrology consultant.  Somehow or other, this led to his having set up the program at Stateville.

AM:     Was he also attached to the military the same way you were?

EB:      No, he was a professor at the university.  He would come out every Friday and we would explain to him what we had done.  He had virtually no intellectual input into any of the work, but he was the head of the project.  This created some real friction with Ray Dern.  Ray Dern was many years senior to me.  He was ten, twelve years older and he felt that people were talking about Alving's work and it was his work.  Alving hadn't really done anything. 

I remember one of the first papers I wrote, I asked Leon Jacobson whether he would like to be a co-author on it and he said, "No, I didn't do anything."  And that's the way it should be.  But Alf didn't feel that way.  It was his project, he put his name on it, and his name was well known.  It didn't bother me very much because in a way I sort of expected it. I was quite young, and I figured I'd have my turn.  And I did.

So Ray Dern and I did all this work, but then, when I came back to the University of Chicago, I started to work on this problem again.  Alving's nose was out of joint about that.

AM:     Because?

EB:      Because he felt that was his project.  They were continuing to work at Stateville, but now I was back at the university.  Somehow or other, he thought that I wasn't entitled to work on that.  So I talked to Leon Jacobson about it.  He said, "Sure, you should be able to work on it."  Then the Chairman of Medicine, who was a man by the name of Wright Adams, thought, well, he didn't want problems in the department, why didn't we all get together and talk.  And Alving refused to talk.  So I just went ahead with the work.

            That led to what I think was a very important breakthrough in the field, and that is because I had noticed just before I left that the glutathione in the red cells of these patients vanished when they were given primaquine, I now went back to acetylphenylthydrazine, which I'd used for Heinz bodies, and I set up a test in which I added whole blood to this.  Instead of looking for Heinz bodies, I measured the glutathione. I found that now, instead of there being just a slight difference between the glutathione level of normal and deficient cells, the glutathione level dropped very steeply in the deficient cells, in the sensitive cells, and was maintained in normal cells.  I called this a glutathione stability test. 

This was really the first robust way to identify this defect, and it led to the work that [Barton] Childs published, but it was actually done by a medical student by the name of [Elizabeth A.] Brown, and there was another student by the name of Exall [L.l] Kimbro [Jr.].  They actually did the work.  And there were some people upset at Hopkins that Barton Childs put his name on that work. 

Actually Exall Kimbro came to my lab.  See, he wasn't one of Barton Childs' students, he was a student of [C.] Lockard Conley.  Lockard Conley was the professor of hematology at Johns Hopkins.  I presented a paper at the Big Atlantic City meeting, the plenary session, on the glutathioine stability test in 1955, I think.  Soon after that, I had either a call or a letter from Lockard Conley saying that he had a student that he would like to have set up this test and would I allow him to come to my laboratory to learn it.  I was flattered and delighted and said of course. 

So he came and we showed him how to do the test, which was really quite simple.  Then he went back, and he and the other students started look at African American families.  They showed that there was a pattern of x-linkage.  Then they went to talk to Barton Childs (20) about it, and then Barton Childs published it with them.  Conley (21) was upset about it because they were his students.

But the group was still working at Stateville, and there was a man there by the name of Paul [E.] Carson, who then investigated the -- he tried to understand why glutathione was unstable in primaquine-sensitive cells.  It was known that the enzyme that kept glutathione in the reduced form was glutathione reductase and that it used NADPH as a hydrogen donor. 

In those days, NADPH was very costly, so he set up an experiment in which he tried to make his own NADPH from NADP+ [nicotinamide adenine dinucleotide phosphate] (22), which was cheaper by adding glucose-6-phospahe [G6PD] to hemolysate (23).  But it didn't work, except with a normal hemolysate.  That then led to the understanding that the defect was in the enzyme G6PD. 

That and the glutathione stability test opened up the field to a lot of other people, who did a lot of interesting work in areas like favism (24) and neonatal icterus (25).  Arno [G.] Motulsky (26) developed a very ingenious screening test which used the decolorization of brilliant cresyl blue, which made possible big population studies.

Should I go further with that?

AM:     Well, let me go back a little bit and ask some more specific questions as we're going through here, and then we can move on.  When you arrived in Joliet, how long had this program been going on, this research been going on?

EB:      Probably four or five years.  But not with respect to the primaquine sensitivity.  That was just the malaria project.  The primaquine sensitve work had been going on for about six or eight months before I came.

AM:     Okay.  And why was the army supporting this research, or encouraging this research in malarial studies?

EB:      Well, there was actually a lot of malaria -- well, first of all, the project was started, although maybe not at Joliet, in World War II when the supply of quinine (27) was cut off, and when our troops were fighting in malarious areas in the jungles of Asia.  But there was also a temperate form of malaria in Korea, and they had a lot of problems with soldiers coming back and having vivax malaria (28), so they were very keen to treat those.  This malaria was very sensitive to chloroquine (29), but chloroquine only killed the blood states, and the tissue stages, which are responsible for relapse, were not affected by chloroquine.  But primaquine could, you see.  But the problem with primaquine was that some people got very sick when they took it, so this was something that the army was interested in knowing.

AM:     And do you have a sense of what the relationship was between the army and the University of Chicago?  Why they chose the University of Chicago, and what did it mean specifically?  How much money was the army providing for the research program?  Obviously, they were providing medical personnel, but in terms of materials and lab space and --

EB:      I wasn't in that loop.  I was just working there.  But I will say that Alf Alving had a very good relationship with the warden, whose name was [Joseph] Ragen, as I remember, Warden Ragen.  I think that this setup was arranged by Alving, that he was consultant to the army and he either knew or got to know the warden, and he arranged this, and it was a contract between the university and the army.  But how much money, resources involved, I have no idea.

AM:     So did you get the equipment and the supplies that you needed from the University of Chicago?

EB:      I think the army bought them, but I'm really not sure.  I don't remember.

AM:     Okay.  So Dern was similar -- because he was a captain at this point, so he was also assigned to this project as well, or did he -- I don't know if you can volunteer to be assigned to a project.

EB:      No.  I think it was pretty much the same thing. I think he still had to do some army service.  He was actually in Alving's division, he was as nephrologist.  Although later, he became a hematologist as a result of this work.  So he was an army officer and he was captain, I was a first lieutenant, but we were friends and colleagues working together there in the lab.

AM:     Did he stay affiliated with the project after his commission?

EB:      No.  He went back to the University of Chicago, and then after the University of Chicago, he became a faculty member of Loyola University [Stritch School of Medicine], which is also in Chicago.  Then much later, he moved out to Southern California, where he died perhaps a decade ago, or more.  I think when he was out here he just came out and practiced.  He was very intelligent, and when he was at Loyola he did some very good studies on red cell preservation and various other things.  But his academic career never really took off, and I think he ended up in private practice.

AM:     Okay.  Well, the papers that came out of this group, these dynamics -- maybe you can talk a little bit more about how the University of Chicago group was working with you and Dern in Joliet, but they're published almost as a serialization of papers, consecutively in the same issue and then in consecutive volumes, which seems to me fairly unique that there was basically a multi-part story.

EB:      Yeah, mm-hmm.

AM:     Which you don't see in journals too often anymore. I wanted to ask, What was unique about the research that you were doing and the group that you were working with that you were able to tell the story in a very coherent and, I think, organized way that you don't see too often anymore?

EB:      I guess we were just coherent guys.

AM:     I guess so.

EB:      That's it.  I mean, you know, Ray and I wrote all the papers, except the first one I didn't -- I wasn't involved in the very first one. But all the other ones.  We worked together very well.  There was never any question about who would be the first author on which paper.  Alving was the last author on each paper, and Dern, as I mentioned, tried to bump him off but he wouldn't get off.  Then whoever, I guess, had done the main part of the work wrote the paper and then gave it to the other guy, and he would edit it, and back and forth.  Then we'd show it to Alving and he'd say that'd be fine, might change one or two words.  He'd ask us questions about what all this meant because he didn't really understand a lot of it and then it would go off to the journal.

            The journal, at that time, was published at the University of Chicago, or at least the editor-in-chief was -- I can't remember who it was.  It may have been Richard Landau.  It was one of the faculty of the University of Chicago.  Or maybe it was Clayton [G.] Loosli.  But it was somebody at the university, so there was some, let me say, incentive to publish in the Journal of Laboratory and Clinical Medicine, which was a fairly good journal at that time, and still is an okay journal.  The idea of publishing serial papers, I guess, is less involved now than it was then.

But I started working on another project, totally different project, when I got back to the university, along with some of this.  This was about iron enzymes and iron deficiency.  There too, I wrote a series of papers which got numbered up to six or seven.  But I published those in different places.  One of the reasons I did that is that I thought that if I published one, let's say, in Journal of Laboratory and Clinical Medicine and then I went over to the Journal of Clinical Investigation, that somebody who hadn't seen the first one might see it in the second place and go -- you know, that I'd get a little broader readership by jumping around, so that's what I did.

AM:     And why is that way of publishing not in vogue anymore?  What are the advantages of publishing serially, and what are the disadvantages maybe?

EB:      Well, I think the advantages are that if you really have a topic that you're developing in a stepwise fashion, it makes a rather nice kind of group of papers.  It's a similar title, you know they belong together.  I don't know why people don't do that very much anymore.  They don't, do they?

AM:     I've come across it before in the --

EB:      I don't do it anymore.  I haven't done it for a long time.  But I never gave it any thought.

AM:     _____ certainly doesn't, and short papers are -- two or three pages are considered long anymore.  And I guess maybe it's the historian in me that would like to see this story unfold, that a full story would be -- all the different aspects of it came together in one spot.

EB:      In retrospect -- and I've looked at this retrospectively a number of times, and it may seem a little self-serving, but it's really kind of remarkable that that was all done in just a little more than one year.  It's a difficult story, and it was all developed just in a very short period of time.

AM:     And why do you think it happened so quickly?  Because it seems to me that you begin this series of description of the hemolytic activity and then in '52 is when some of these papers start to be published.  And in '56 Carson comes out with the deficiency enzyme.  And what is it about this particular topic or this particular --

EB:      That made it go so fast?

AM:     Yeah, that it moved so fast.

EB:      Well, I think there are a couple things.  One is that we didn't have nearly as many hoops to jump through.  It's no exaggeration for me to say that it would have taken it two years just to get started now, to get all the approvals necessary to do it.  So that's one thing.

            I mean, the other thing is, I guess, that we were young and eager and lucky, and we worked hard and we got it out.  But we wouldn't be able to do that now.  We wouldn't be able to use it on peers because they're prisoners.  We wouldn't have been able to do some of the transfusion studies because of disease transmission, which I think is a valid objection, which at that time didn't exist.  See, if we hadn't been able to do the cross-transfusion studies, it would have been very difficult to do this work.

            I don't want to belabor the point in terms of cross-transfusion studies, but I think that when it comes to the benefits to society of having some unlit area of science illuminated, compared to the harm that's done if you don't thoroughly anonomize every sample because somebody might steal the sample and sell it to an insurance company, which is the kind of reasoning that you get now.  We're being held back a lot by a lot of nonsense, and that was not there.  As I said earlier, it wasn't that these weren't real volunteers, it wasn't that they were abused or subjected to dangerous practices, except for the cross-transfusion, which was not understood to be dangerous at that time.

AM:     Well, you'd mentioned that they did have informed consent, and were you involved in that, being present at the prison?

EB:      Yes.

AM:     I want to ask some questions about this just because in this day and age, this would be an issue.  Even for this particular project, we had to go through an IRB because we are using live subjects.  But what did informed consent mean at that point, and particularly for these prisoners, what were you telling them about the project?

EB:      Well, I remember that either Ray or I would talk to a group of eight or ten people, and we would tell them what we're going to do.  Do you have any questions?  Then there were mimeographed forms and they would sign them.  There was a guard there and he would witness the signature.  That was it.  Then it would be filed.

            One of the things that has occurred to me in dark moments is, what if I'm hauled up in front of some congressional committee and they want proof that the consents were signed.  Where are those consents today?  (laughs)  Sixty years later, or fifty-five years later. 

But that's the way it was done.  And when we needed more volunteers, I would go on the prison radio, or Ray would, and we would tell what we wanted to do and say that any men who are interested in participating in this should come up to such-and-such at such a time and that we would talk to them further.  And then a group of people would come up and we'd talk to them.  I can't remember now whether everybody who came up participated or one said no, I'm not going to do that.  But anyway, we told them what we were going to do.

AM:     And what were the risks?  I mean, was it the standard -- I only know contemporary informed consent.

EB:      I don't think we said to them, of course, you know you might die as a result of this, or be mentally retarded for the rest of your life, but not too much chance of that.  No, we didn't do that.  As a matter of fact, there wasn't that much risk involved.  We gave people falciparum malaria (30), which is a very dangerous form of malaria.  I would watch the parasite counts, which were done by prisoner technicians every day, and I would decide when to give them chloroquine to abort the attack. And I did it and always aborted it in time. We left a margin of safety.

            No, it wasn't the kind of black crepe disclosure that IRB insists on sometimes now, but I think they had a pretty good idea of what we were going to do.

AM:     And did you have problems recruiting volunteers?

EB:      No.  So there was really no reason to try to coerce people or to mislead people because there were always more people who wanted to do this than we really had slots.

AM:     At that point, what was the population at the state prison?  Now we know that there are quite -- that the racial mix in a prison is generally skewed toward African Americans.  At that point in time, what was -- I guess the question would be how important was race?

EB:      Very important.

AM:     And how were you making this observation about the --

EB:      First of all, we knew it was only the blacks who were primaquine-sensitive, so that was very important.  In second place, the blacks didn't get malaria.  They're resistant to vivax.  So we used black prisoners for studies of hemolysis, we used white prisoners usually for malaria, because black prisoners were resistant to malaria.  We had both. 

If I understand your question correctly it was what is the ratio, and I guess it was probably about fifty-fifty or something like that.  I mean, there were a lot of black prisoners and a lot of white prisoners.

AM:     There were just a lot of prisoners.

EB:      Yeah.

AM:     Okay.  Did you design the study to get specific percentages of what percent of whites would be sensitive and what percent of blacks?  Was there a population genetics, if you could use the term, at that point, as a component to the study?

EB:      No.  We couldn't do that until the Heinz body test and the glutathione stability test, and then we did it.  Actually, it's interesting that the -- I did a hundred and ninety-nine black prisoners, and eleven percent were primaquine-sensitive.  In that terms I'd be very close to what the African American population is today.  In many of the studies that have been done since, they come out about that way.  But it wasn't until after we could do the Heinz body test and the -- I can't remember whether we did it with the Heinz body test.  Certainly we could do it with the Heinz body test.

AM:     And what were the conditions like in the prison?

EB:      I don't think I was ever in a cell block.  The prison grounds were beautiful, floral patterns.  I can show you pictures of the prison if you'd like to see them.

AM:     Okay.  Yeah, that'd be great.

EB:      They were round cell blocks, and there were three or four big ones.  We worked in a building that was not a cell block, and I never was in a cell block.

AM:     And that was the medical facility building?  Or did it incorporate --

EB:      I think it incorporated other things, too.  I can't remember the exact details, but our unit was on an upper floor, I think the third floor.  There were other offices or things of that sort on the other floors.

AM:     Well, one last area I'd like to talk about for today and then we can break, because we've been interviewing a good bit of time.  That was, I wanted to go back and ask you, so you and Dern -- you would write in Joliet, you were conducting the research but also writing?  Or were you going back to Chicago or going over to Chicago and writing?

EB:      No.  As a matter of fact, what I did is I dictated, I think, into a tape recorder and had Henry, who was our secretary, transcribe it.

AM:     And was he a prisoner?

EB:      He was a prisoner.

AM:     Do you happen to know if this particular project had an impact on what these people did afterwards?

EB:      I think it probably did not?  The prisoners were classified broadly into things like murderers, con men, and so on.  I think we got more of the con men.  I don't think they change much.

AM:     Were you ever conned?

EB:      Yeah.  As a matter of fact, the interesting thing.  We had a job which was sort of a premium job that some of the prisoners would get, and that is that they got extra pay for feeding the mosquitoes.  The way they fed the mosquitoes is to put their arms in a mosquito cage, to rub their forearms with sweat, put them in a mosquito cage and let the mosquitoes drink blood.  They got paid an extra five or ten dollars for that.  That was a much sought after job.

            Then Ray Dern noticed one day that one of the guys who was doing this had figured out a way to keep his arm just out of reach of the mosquitoes, and then he would go like this and rub it as though he had been up.  But the mosquitoes weren't getting any.  So he was conning us out of this money. 

            There was another one, too, now that you ask, that was really interesting.  I had one black prisoner who had been discharged, and now I was back at the University of Chicago and it wasn't quite that easy for me to get blood from a primaquine-sensitive individual.  This guy's, who's name was Frazier, would come in and I would give him two dollars, I think it was, and he would give me a blood sample.  Then he would come back, I'd give him two dollars, he'd give me a blood sample.  One day he told me that he'd gotten a job and he needed a suit, I think, and could I give him ten dollars in advance so that he could get his suit and start his job, and he'd be back next week for the sample.  I never saw him again, nor the ten dollars.

AM:     Well, we all have our learning curves.

EB:      Well, one thing I learned is that, although many of them protested their innocence, I think most of them were probably people who deserved to be in jail. 

AM:     Okay.  Well, again, this was kind of a little bit more of an aside than I thought, but I'll get back to this last question.  The series of papers was published not only with Alving and Dern but with [R.S.] Hockwald, [John] Arnold, and [C.B.] Clayman and [Paul] Carson.  What was your relationship with them?  Were they affiliated with the Alving lab as well?  How did this group work, and how well did you all work together?

EB:      Well, Hockwald and Clayman I think had been there before I came.  And Carson came after I was there.  And I knew them.  But there wasn't very much interaction.  As scientific work goes, sometimes you're using work that other people have participated in, so you put them on the paper.  As a matter of fact, one thing that's happened in modern science, which I'm sure hasn't escaped you, is the number of names on papers.  It always amazes me when you have a case of one patient or two patients and there are twenty authors on it.  There wasn't much of that there.  But in a way you sort of leaned over backwards to include a colleague who had participated a little bit.

AM:     Okay, great.  Well, I think we've covered a lot of ground today and we'll pick up again next week.  Thank you.

EB:      Okay.

Endnotes:

1. National Institute of Health; The United States governmental organization in  charge of regulating scientific research. It operates under the Department of Health and Human Services. See their website for more information: http://www.nih.gov/about/index.html.

2. Institutional Review Board: A governmental committee that regulates and promotes ethical scientific research involving humans. 

3. Hemolytic Anemia: A severe lack of red blood cells in the body where the destruction of premature blood cells is faster than the production of red blood cells.

4. Hemolysis: breaking of the red blood cells where the hemoglobin is released into the plasma. Can lead to anemia.

5. Primaquine; A part of a class of drugs known as antimalarials. Primaquine is used to treat malaria after one has been infected. In those with G6PD there is hemolysis (breaking of the red blood cells).

6. Hemoglobin: A protein in the red blood cells of vertebrates that transports oxygen in the body. Each hemoglobin can carry a maximum of four oxygen molecules. It releases oxygen as the body needs it.

7. Osmotic fragility: This technique demonstrates how readily blood cells will break down by exposing red blood cells to increasingly hypotonic solutions. Usually used to detect thalassemia.

8. Mechanical fragility: Determines how susceptible red blood cells are to mechanical trauma.

9. Antigens: Anything that causes the immune system to produce antibodies. There is a distinction made between self and non-self antigens.

10.Heinz Bodies: Spots that are visible in the red blood cells affected by hemolytic anemia, various enzyme deficiencies, and other abnormal hemoglobins.

11.Irving M. London: A Harvard scientist whose research involves hemoglobin and its RNA translation and transcription.

12.Glutathione: An antioxidant that helps protect against free radicals among other things. When deficient it often causes hemolytic anemia.

13.Febrile: A marked rise in body temperature, a fever.

14.Joseph E. Smadel: (1907 – 1963); A virologist who worked on many different things including typhus. For more information see: http://wrair-www.army.mil/images/Dr-Joseph-E-Smadel.pdf.

15.William H. Crosby Jr: (1914 – 2005); A noted hematologist who studied hemochromatosis and oncology primarily at Walter Reed Hospital. See http://www.americanhs.org/inthenews.htm for more information.

16.Q Fever: A bacterial infection usually caused in humans by inhalation of contaminated animal droplets.

17.Glucose-6-phosphate dehydrogenase deficiency; A deficiency caused by not having a red blood cell enzyme which would normally ensure that red blood cells are maintained properly. A deficiency of the G-6-PD enzyme results in fewer red blood cells and anemia with jaundice when certain substances are ingested such as fava beans. See http://www.g6pd.org/favism/english/index.mv?pgid=intro.

18.Cutaneous Anthrax: The most common type of bacterial anthrax. It affects the skin.

19.Proteinuria: Where there is an excess amount of protein in the urine.   

20.Barton Childs: (b. 1916): An American geneticist and pediatrician who worked on G6PD amongst other diseases.

21.C. Lockard Conley: (1915 – 2010); A physician and hematologist who worked on vitamin B12 deficiency and various other diseases. See http://www.hematology.org/Publications/Legends/Conley/3692.aspx for more information.

22.NADPH and NADP+: NADPH is an electron carrier that helps to reduce reactions resulting in various organic products such as lipids and nucleic acids. NADP+ is the form without the hydrogen.

23.Hemolysate: the product of hemolysis.

24.Favism; As a result of exposure to fava beans, people with a certain enzyme deficiency (glucose-6-phosphate dehydrogenase) can develop anemia and other complications. All people with favism have G6PD Deficiency. See http://www.g6pd.org/favism/english/index.mv?pgid=intro for much more information.

25.Neonatal Icterus (also known as neonatal jaundice): A condition where there are high levels of yellow pigment in the blood that causes the skin of the infant as well as the whites of the eyes to look yellow.

26.Arno G. Motulsky: a Professor Emeritus at the University of Washington, Seattle Motulsky is a noted geneticist and is considered the father of pharmacogenetics.

27.Quinine: A substance that can act as a painkiller, a fever reducer as well as an anti-inflammatory substance.

28.Plasmodium Vivax malaria: one of the four types of malaria; P. vivax is rarely fatal. It can result in influenza-like symptoms, diarrhea, and other symptoms.

29.Chloroquine; Similar to primaquine and used in the treatment and prevention of malaria.

30.Plasmodium Falciparum malaria: The most deadly form of malaria, P. falciparum can lead to brain malaria.

Session 2: March 15, 2007

IV. Work on Glucose-6-Phosphate Dehydrogenase Deficiency and X Chromosome Inactivation

AM:     It is March 15th, 2007, and I'm with Ernest Beutler at his office at the Scripps Research Institute.  My name's Andrea Maestrejuan and we are here to conduct the second session for his Human Genetics Oral History Project interview.  I wanted to start with a couple of questions from last time.  One just briefly, you had mentioned that you met your wife as a student.  You were both students at the University of Chicago.

EB:      That's right. I was a medical student, she was an undergraduate student.

AM:     The new students, I thought, were the medical students?  Was she involved --

EB:      No, no.  This was just for the university as a whole.  Actually, I think mostly the undergraduate school.

AM:     And what was she studying?

EB:      Mathematics.

AM:     Did she pursue a career in mathematics?

EB:      Well, when we got engaged in I think January 1950, she was a graduate student, and the next day she dropped out of graduate school, because she knew that I was going to start my internship in June and that she was going to have to support us.  So she went back to Tulsa and she took a secretarial course.  Then, while I was an intern, she worked as a secretary.  Later, when our children were all in school, she took on a second career, and that was one in technical writing, which she did for engineering firms and for JPL [Jet Propulsion Laboratory].  So, in a way, her physical science background was useful and so was her language background, because she's quite gifted in languages.

AM:     Was she a non-native English speaker?

EB:      No.

AM:     She just picked this all up in --

EB:      She's American born.  She was born in Chicago, raised in Okalahoma.  She, like Spanish, for example, was quite fluent in Spanish.  But her English language skills were very good, so she was able then to kind of meld those.  For some twenty years or so then she enjoyed a career as a technical writer.  She retired from that some years ago.

AM:     I'll be jumping a little bit around her at the beginning.  I wanted to talk one more question about the use of prisoners and your work during the army and afterwards with the University of Chicago.  In one of your articles there was a footnote saying we do not wish to imply that it is safe under usual clinical conditions to continue administration of primaquine if acute hemolysis takes place.  I was wondering if there were any fatalities or severe kind of cases among the prisoners in your experimental program.

EB:      No.

AM:     Okay.  To move us along a little bit, you had mentioned that you returned to the University of Chicago.  Leon Jacobson asked you to return after your army duty was finished up and you were returning from Fort Detrick.

EB:      Right.

AM:     I wanted to ask, What were your options?  What were you thinking about in terms of your own career ambitions, but also in terms of where you wanted to go with your research program?  Were the other opportunities besides the University of Chicago?

EB:      Well, actually, it's kind of interesting.  I thought about it a little bit at the time, but there was no Plan B.  I sort of assumed that Jake would ask me to come back, and at one point it occurred to me that I didn't really have a job there, but then one day he called or wrote me a letter and asked me to come back.  So I never really entertained any other possibilities at that time.

AM:     It wasn't going to be returning to working with Alving on his project specifically?

EB:      No.

AM:     Or collaborating with him?  It would be to start your own research program.

EB:      That's right.  Actually, to continue it, because even before I left, when I was a resident, I had my own research program.  That was Jacobson's way.  He didn't ask me or entice me or induce me to work on his projects.  He did give me one project that I think I outlined to you, but basically, mostly I worked at that time on iron deficiency, things that interested me that weren't really a part of his program.  And that was fine with him.

AM:     Okay.  And were you applying for grants at this point?

EB:      No.

AM:     Or were you part of the Jacobson grant umbrella?

EB:      I was part of the grant umbrella, and it was sort of a Jacobson grant umbrella, but my understanding is that he was the director of the Argonne Cancer Research Institute [Hospital], which was funded by the federal government, and I think that's where the money came from. And he always provided everything I needed.  It was not until I left the University of Chicago in 1959 and moved to the City of Hope that I began to apply for grants.

AM:     Okay.  Well, since we're there at that point, How long were you on the faculty of the University of Chicago when you decided to leave for the City of Hope?

EB:      I'd been on the faculty for four years.  I came back as instructor in 1955, I left in 1959 as an assistant professor.  They had indicated to me that I would be promoted to associate professor, but I didn't stay.

AM:     Were you looking to move on?

EB:      I was.  I had a very good position at the University of Chicago, but there were constraints.  For example, I had to share one secretary with three or four other assistant professors in the division, and she wasn't a particularly good secretary.  The amount of space I had was, I think, adequate, but didn't really allow much room for expansion.

            There was also, I think, an undercurrent of anti-Semitism at the University of Chicago, even at that time.  I had a number of offers at that time. Carl [V.] Moore asked me to consider coming to St. Louis to be head of Hematology, I think, at the Jewish Hospital in St. Louis, which was affiliated with Washington University.  I visited Albert Einstein [College of Medicine], where I think they wanted me to take over the Hematology Division there. I was asked to take over the Hematology Division of the [Durham] VA [Medical Center] at Duke [University School of Medicine].  But I considered all those to be pretty much lateral moves.

            When I was approached by the City of Hope -- I learned later that Carl Moore, who was a very distinguished hematologist in those days, was on their advisory board.  And when I was not interested in the St. Louis offer, he suggested to them that they approach me.  At that time, I had the opportunity to become Chairman of the Department of Medicine, and that seemed like a move up.  What I liked about it particularly is that there were virtually no constraints in either funding or space, and that I really would be able to expand my program.  I didn't mind moving to Southern California from the south side of Chicago, either.  So I considered that to be a great opportunity.

            Now, it's interesting that many people, I think, thought it was very strange that I was going to the City of Hope because City of Hope, especially at that time, was very much outside the academic circuit.  At that time, you were either at a major university or you were nowhere.  Industry didn't count.  Research institutes didn't count, not unless perhaps it was the Pasteur Institute, something of that sort.

            I remember that Mila [I.] Pierce, who was professor of pediatrics at the University of Chicago -- we talked about women in medicine.  She was a professor and head of Hematology and Pediatrics.  She said to me, "It's a pity, Ernie, that you're giving up such a promising research career."  Well, I was a little surprised to hear her say that because that was not my intention, it was to develop my research career.

            So when I came to the City of Hope I didn't have to share my secretary with anybody.  As a matter of fact, I had two secretaries for myself.  I had about as much laboratory space as I would want.  And, as a matter of fact, initially, they supported my program entirely, although then I went ahead and got grant support, and was supported by grants all the rest of my career.  So I saw it as an opportunity to expand my program to do more of what I wanted to do.

            I think this is, to some extent, a very personal kind of thing because there are some people who find it very necessary to be surrounded by colleagues that stimulate them all the time with their work.  I never found that particularly necessary.  Not that I didn't interact with a lot of people, but I didn't have to do it on a daily basis. I don't collaborate very often. I'm not very keen on collaboration. I really work by myself, with my group, and I collaborate only when it's absolutely necessary.  That's very counter-culture these days, but for me, that's the best way to work.

            There were also some people at the City of Hope whom I found to be especially stimulating when I went out there for an interview.  One of them was Al [Alfred G.] Knudson [Jr.] (1), and Al Knudson, of course, has gotten to be very prominent in oncology and genetics.  Al is a very, very bright and stimulating person.  So I didn't feel like I was going out into the desert among a bunch of bumpkins.  There were really good people there.  But I couldn't get up at a meeting and say, This is Ernest Beutler, Harvard University.

            It also gave me an opportunity to build, and during the about eighteen years I was there, I derived considerable satisfaction from attracting some very good people to the City of Hope. And I think the City of Hope has really done much better since the days when I went there in 1959.

AM:     Okay.  Well, what -- so I know a little bit about the history of the City of Hope.  It starts out as basically a tuberculosis (2) hospital for workers in the Los Angeles area.  But in the fifties, it wants to have plans to expand into a more broad medical center, national medical center.  Were you part of this expansion, or was that already in place by the time --

EB:      That was already largely in place. It was largely an expansion of necessity, in a way.  In the same way that the National Foundation [for Infantile Paralysis], March of Dimes, expanded into other diseases.  Originally, their target was poliomyelitis (3).  Well, poliomyelitis became a non-issue largely, so they had the infrastructure, so they moved into something else. 

Similarly with the City of Hope.  As you correctly say, it was a TB center.  At one point I think they had three hundred and fifty or four hundred patients.  But with the introduction of streptomycin (4) and other anti-tuberculosis drugs, this got to be a much smaller problem.  They still had a tuberculosis ward there, but they obviously had an infrastructure that could support a lot more than tuberculosis.  So they decided to go into cancer and into heart disease.  That evolution, I think, took place in the early and middle fifties, so by the time I was there, they already were deeply involved in cancer.

My predecessor was a man by the name of Howard [R.] Bierman, who incidentally was the first postdoctoral fellow, I understand, of Carl Moore's, so there was sort of a relationship there.  Bierman was a very bright and very flamboyant person who did, let's say, clinical experiments that people were very concerned about in terms of their ethics, and who also tended to stimulate divisions and polarization.  There were a great many fights at the City of Hope and finally, as I understand it, the faculty all got together and told the administration that either Bierman was leaving or they would all leave.  So Bierman left.  He went into practice in Beverly Hills.  I think he may still be practicing there, I'm not certain, although he would be well into his eighties, maybe nineties, by this time.

That's the environment I came into.  In a way, it's a very good environment to come into because everybody was tired of fighting, and everybody wanted to help me.  So it was as supportive environment, and I think my work went very well.

As a matter of fact, although some people consider this to be an intellectual desert, there were some very outstanding people there, and one of them was quite young.  I didn't meet him in my original visits there, I met him, strangely enough, in Japan.  That was Susumo Ohno (5).  Ohno was quite junior then.  He was working on the x chromosome.  I attended the [VIIIth] International Congress of Hematology in 1961, I think in -- sorry, 1960, August.

AM:     In Tokyo.

EB:      In Tokyo, yeah.  In August 1960.  I heard Ohno speak, and he talked about the fact that the two x chromosomes were different.  At that time, I had been puzzling about the fact that female heterozygotes for G6PD deficiency, which was still one of my major interests, had very variable expression. 

And another thing that had happened just a month or so before, when I was in Scotland, in Edinburgh, at the [Fourth] International Congress of Clinical Chemistry.  I had spoken about G6PD deficiency and I showed a slide which showed that when one x chromosome was affected in the male that, of course, that male would have severe G6PD deficiency.  That when one x chromosome was affected in the female, then she might have normal G6PD, she might have grossly deficient G6PD, or she might have intermediate levels.

At that meeting, Harry Harris, who was one of the speakers, asked me, "Why don't women have twice as much G6PD as men?  They have two x chromosomes."  And I'd never thought of that before.  After all, I was not trained as a geneticist, although, as I told you, I was always rather interested in genetic diseases.  So I puzzled over that.

Then when Ohno spoke, it suddenly came to me.  I realized that the condensed x chromosome, which he had shown at that meeting in Tokyo, was probably genetically not active and there was only one active x.  This was buttressed by the fact that triple x females had normal G6PD activity, and they had two condenses x chromosomes.

I also realized immediately that it couldn't always be the paternally derived or the maternally derived x that was inactivated because that would not be consistent with the known mode of transmission to x-linked traits.  So it seemed to me that it must be either one or the other and that it would be a random process. Then when I realized that this condensed x didn't occur until the late _____ stage of embryonic development, it seemed to me that that could be the time that one or the other x was inactivated.

That evening, I remember this very well, I was sitting in a room with Arno Motulsky, and I told him my idea.  He thought it was a good idea.  That buttressed my thinking.  He said something that I considered a great compliment, he said, "Now, Ernie, you're beginning to think like a geneticist." 

So I went back to my laboratory, and I reasoned that if this were true, then female heterozygotes for G6PD deficiency must have a mosaic (6)of red cells, some of which are deficient and some which are normal.  So we then tried to see if we could work out a method of determining individual red cell G6PD levels.  This actually proved at that time not to be possible.  And it was about that time that Mary [F.] Lyon's (7) paper came out, in which she used a code color gene in mice, and she got the same idea that I did from Ohno's work. 

So while -- actually, there was an article five years ago or so, ten years ago, which said this was a remarkably unusual thing in science when only one person thought of a thing and it just came out of the air.  Well, it wasn't that at all.  There were actually three people who thought of it.  One was Mary Lyon, one was [Liane B.] Russell (8), and one was myself.

We couldn't do it by staining individual cells or determining individual cells, but then one day it occurred to me that if one measured the rate of methemoglobin (9) reduction, or the rate of glutathione reduction, both processes being a function of G6PD levels, that a mixture would behave differently than a single population with intermediate activity.  In other words, if you had a population with intermediate activity, then you would expect to have sort of a straight line decrease in methemoglobin level, or you would expect to have a straight line increase in glutathione level.  But if you had an artificial mixture, you'd expect a two-component curve.  And this was something we could test because we could mix cells from male hemizygotes (10) and we were able then to show that the females did have mixture of cells.

We published this in PNAS [for citation: Beutler, Ernest, Yeh, Mary, and Fairbanks, Virgil F.  The normal h uman female as a mosaic of x chromosome activity: studies using the gene for G6PD deficiency as a marker.  Proceedings of the National Academy of Sciences of the United States of America 1962 Jan. 15; 48:9-16; Lyon, Mary F., Gene action in the x chromosome of the mouse (Mus musculus L.). Nature 1961 Apr. 22; 190:372-3; Russell, Liane B.  Genetics of mammalian sex chromosomes. Science 1961 Jun. 9; 133:1795-303.] in January of 1962, and in a way, it was my misfortune that the paper didn't come out in December of 1961 and that Mary Lyon had a catchy name, so people could say Lyon hypothesis.  So I think the majority of the people in the field believe that our work was derivative of hers, but it was not at all.

If I look over my whole career, that is the achievement, let's say, for which I feel the most gratification because I thought of it myself, I did it myself, it turned out to be right, and it was important.

AM:     Okay.  There's several different areas I want to ask some questions, but I'll pursue this one with -- because Lyon's work comes out in '61 in Nature and Russell in Science a few months later, and then yours in PNAS.  How do you explain that there was this -- several groups working in relative isolation that were theorizing the same?

EB:      Well, because it all came from Ohno's work.  I mean, Ohno is really -- in a sense, I've sometimes written, that Ohno was really the father of x-activation, although he's usually not mentioned, but it was his showing that the two x chromosomes were different.  And there was evidence at that time, largely with insects, that condensed chromatin was not genetically active.  So here he shows that one x chromosome is tightly condensed and the other one is not.  So it's reasonable.

AM:     Yeah.  And just a general question about how science works.  So Russell, Lyon, and you all cite Ohno in the work, but Lyon gets the hypothesis.  How do you account for that?

EB:      Well, I think, you know, she has a catchy name.  Beutler hypothesis doesn't sound so good. 

AM:     Well, Stanley [M.] Gartler (11) has used it in the title of his -- the Lyon-Beutler hypothesis.  But doing a quick review of it through PubMed, I found a couple of Lyon-Beutler hypothesis and the majority of Lyon hypothesis.  Why do you not think that caught on, to hyphenate?  We certainly do that with syndromes.

EB:      Yeah. I don't know.  I really don't know.  Russell was a little bit off the mark, although she had the general idea, but she thought it was a position effect (12).  Do I really don't know.  I certainly didn't try to hide my light under a bushel on this matter.  On the other hand, I never pretended that Lyon hadn't published it and published it first, so I just don't know.

AM:     And why is it important to have your name attached to a hypothesis or -- I've asked this question for geneticists who've had their names attached to syndromes.

EB:      Well, I think that having your name attached to a hypothesis or to a test or a syndrome puts your name right out in the public and gives you name recognition.  Just as in politics, I think in science, name recognition is important.  As a matter of fact, tests are often now, even now, named for the people who first introduced them.  If they never did anything else but to develop that test, they're well known.  The Kleihauer-Betke test, for example.  There are a lot of them.  And some of them are very good people.  It's not the only thing they've done.  But if somebody does nothing else but a test and their name is attached to that test, they live for eternity.

            In hematology, the classical way of doing red cell survival is [Winifred] Ashby survival.  Ashby was a woman who worked at the Mayo Clinic, a scientist, who developed this test in 1919, so she's no longer alive.  Her career never went anywhere.  There's a lovely biography of her written by my former student Virgil Fairbanks.  But her name will be known a hundred years from now because it's the Ashby (13)survival.

            People have tried very hard to attach their names to syndromes.  There was a very egotistical German hematologist who described a syndrome, and he attached to it such a long Latin name that he hoped that people would call it the Hallemeier syndrome because that was his name.  But they never did.  So I think that's a part of getting name recognition in science.

AM:     Yeah, okay.  Well, to pursue one more little point on that, because it's interesting that we do name things after the scientist who discovered them, although it's come up before in the interviews I've conducted that many times, particularly for some clinical manifestation that's already been identified a hundred years ago, two hundred years ago, in the literature, but the person in the twentieth century who publishes it more recently gets attached to it.  This example of -- there were certainly different labs working on the same kind of general idea about x-inactivation or x-activation, and it seems to me that there's this one trend in science that wants to acknowledge the individual genius, or individual discovery of some ideas.  On the other hand, we have this evidence that there's certainly -- to track down the genealogy of an idea, you see that it could have come out of any number of -- do you see this as an essential tension in medical research, biomedical research or Science, with a capital S, in general?

EB:      I don't think it's a very important matter.  It's one of those things you live with, I guess.  I don't think it does a great deal of damage, and I don't think it does a great deal of good.  As a matter of fact, as far as syndromes are concerned, it's really no longer considered legitimate to name a syndrome after the discoverer.  Now it's supposed to be named after the patient.  And that's often been done.  For example, what we usually now call hemophilia B or factor IX deficiency is also called Christmas syndrome, Christmas disease.  Well, the family's name was Christmas, you see.

            I described a red cell anomaly many years ago.  I called it the Warnitz trait because it's the Warnitz family.  Of course, now with concern about privacy, you can't do that anymore, so I guess you have to call it the John Doe disease.

AM:     Okay.  Well, I wanted also to talk a little about your own work and how it was progressing from this period at the University of Chicago where you were doing some work on drug interaction anomalies and more hematological work, to in a few years moving to more -- as you mentioned, Motulsky said you're thinking like a geneticist now.  I looked at the introduction and the article that was published from this Tokyo meeting, and you had -- I'll talk about your work first, or at least the field.  At the time of this meeting, and you had written a short article on your work at the University of Chicago, and you talked about it in terms of glutathione reducing deficiency (14), and I wanted to ask, where was -- because Carson published his paper in the late fifties identifying it as G6PD deficiency.  At this point, what was know about glucose-6-phosphate dehydrogenase deficiency?

EB:      Nothing was known about the deficiency.  That was the first indication that this was a deficiency that could occur.

1. Alfred G. Knudson: A cancer geneticist who is most noted for his Knudson hypothesis which explains the effects of mutation on cancer formation.

2. Tuberculosis A highly contagious bacterial infection which can cause a number of symptoms including lung infection.

3. Poliomyelitis: a viral disease that is caused by the poliovirus and includes febrile symptoms, sore throat, as well as vomiting. The virus is capable of entering the blood stream and causing symptoms through there.

4. Streptomycin: A bactericidal antibiotic drug used to treat tuberculosis.

5. Susumo Ohno: a noted geneticist who is most known for his work on the X-chromosomes and postulating that the Barr body was actually a condensed X chromosome. He has developed many different genetic hypothesis and is still active in research.

6. Mosaicism; A mutation where there are two different genotypes in a single organism. This can affect any kind of cell.

7. Mary F. Lyon FRS; (b. 1925); An English geneticist famous for her work on radiation and its effect on mutation. She also formulated the Lyon Hypothesis stating that an X chromosome can be inactive. She is a Fellow of the Royal Society.

8. Liane B. Russell: (b. 1923); An mammalian geneticist who is known for her work on radiation biology and research on X chromosomes. For more information see Liane Russell’s interview in this collection as well as http://www.er.doe.gov/Fermi/html/Laureates/1990s/lianeb.htm/.

9. Methemoglobin: a type of hemoglobin where the iron is in a different oxidation state than normal hemoglobin. It is not capable of carrying oxygen; there is a normal level of methemoglobin in most individuals though a larger number can be a result of genetic or environmental causes.

10.Hemizygotes: A diploid cell or organism where there is only one set of alleles for a specific gene. For example, male bees are developed from unfertilized eggs.

11.Stanley M. Gartler: A molecular biologist and human geneticist who worked on HeLa cells and x-chromosome inactivation. See his profile at the University of Washington for more information: http://www.gs.washington.edu/faculty/gartler.htm.

12.Position effect; This effects looks at how a gene’s phenotype varies when its position in the chromosome is changed.

13.Ashby Technique: A method for discerning how long red blood cells will live for.

14.Glutathione Reductace Deficiency; A condition which causes hemolytic anemia due to malfunction in the enzyme glutathione reductase

V. Collaborations in Research; Properly staffing a laboratory; Assigning Intellectual Credit in Science

AM:     And in this introductory speech, you had mentioned how hematology was contributing to genetics, as well as genetics contributing to hematology.  How were you identifying yourself?  I'll just say this because I'm referring to something -- it was published in '62, but the introductory speech was given in 1960.  At this point, where did you see this dividing line?

EB:      I don't think I ever compartmentalized myself in terms of the work I did.  I don't think I saw a dividing line.  I saw them as sort of part of the whole picture.

            The work that I did after I left the army, part of it dealt with iron deficiency.  I think perhaps you asked me about the relationship between patients and the work I do. I saw a patient with a very mild anemia, or no anemia, I think she had no anemia.  I did a bone marrow on her and I can't remember why, and there was no iron in the marrow.  I gave her iron, and she felt much, much better, although there was no change in her hemoglobin level.  So I thought, well, maybe iron deficiency is more global than just producing a deficiency in red blood cell formation.  Maybe iron enzymes are affected. 

Then, as you probably saw from my bibliography since you've apparently looked at it, I published a series of papers on different enzymes, iron enzymes and iron deficiency.  This got me quite interested in iron absorption and various other aspects of iron metabolism.  So between -- I think my first work in iron was actually before I went into the army, and the I returned to that when I returned from the army.  So I was working on iron deficiency. I was also working on primaquine-sensitive G6PD. 

Now, iron deficiency had very little to do with genetics at that time.  I didn't work on iron metabolism for perhaps thirty-five or forty years between.  But about fifteen years ago, ten years ago perhaps, I started working on iron again, and this time my interest was largely in iron overload.  Here, what we tried to is to clone the gene that caused iron overload, which turned out to be the HFE gene (1), which was cloned by someone else.  My record in positional cloning is very dismal.  It's zero for two, I think.

AM:     How do you account for that?

EB:      Well, I think I'm not very good at it.  In both cases, both where I scored a zero, the actual cloning was done by a company that had about forty people working on the problem.  But I think they were also better at it than we were, because I think that with four people we should outnumber them.  But they got it.

            Now, actually, my best positional cloning is actually my son because he is a very distinguished positional cloner, and works in mice.  He's cloned a lot of genes, but I've never cloned any disease genes.

            Actually, I have to say -- and I'm really jumping way ahead now to 1996, when the HFE gene was cloned.  Actually, most people who were trying to clone it ­­-- and we weren't the only ones, there were probably about eight groups trying to do it -- I think were crushed. I was only slightly crushed because I was glad it was over because what I really wanted to do is to work on that gene and the population genetics of the gene.  And that we can get into later, but that's really been a major part of what I've done in the last ten or fifteen years.  So what I was working on in the late fifties, that was not genetic at all, has turned out to be very genetic now.  Okay?

AM:     Well, you mentioned that you were flattered when Motulsky said that, oh, you're starting to think like a geneticist.  That remark struck me as saying that there was some kind of cache value to genetics, or being known as a geneticist.  How were you seeing -- because you just mentioned that work you did in the fifties when you really considered yourself a hematologist as bearing fruit in work that we would now say is molecular genetics, and there are several decades in between, so I'm trying to figure out when did you see yourself as doing more genetics work or -- you know.  Positional cloning was more important than iron deficiencies, or something.

EB:      Yeah.  Well, never really.  Even today.  I guess I consider myself a biomedical scientist, and I have interest in genetics and hematology and whatever else comes along.  A lot of the things we're doing now are not genetics, on iron metabolism.  We're trying to work out the metabolic pathways, and genetics is one of the tools.  But it's not the only tool.  For example, we're using a _____ knock out mice. But we are measuring iron absorption in these mice, and we're measuring iron absorption in these mice using a method I published in 1959 or in 1960, which is total body counting radioiron.  The method works very well.  That's really physiology, it's not genetics. So we try to look at the overall problem.

            I think, by the way, that speaks somewhat to the comment I made a little earlier about collaboration.  There are two ways to do this kind of thing.  One is to say, well, I'm the geneticist and I don't do iron absorption, but I've got a colleague and he does iron absorption.  Then I have another colleague and he does protein purification.  And then there's somebody I know and he does transcription factors.  And we're going to work together on this.  Well, I just don't like to do that.

AM:     Okay, and why is that?

EB:      Two reasons.  One is it hardly ever works.  And the second reason is that I enjoy doing everything. It's much more satisfying.  And when I say "doing everything," I don't mean that I do it myself, but I'm talking about people that are in my group that I interact with every day, and they're not lackeys that do my bidding.  So in a sense, they're collaborators within my group.  Some of them are technicians, some of them are Ph.D. scientists, but we all work together on a problem.

AM:     Okay.  I had actually written a note down -- to get back to this issue of -- you said you were counter-culture to this era of collaboration, and a time when you will see fifty authors on a paper.  Why do you think the movement's towards collaboration, and in your case not?  You just said why not, but why is there this move towards collaboration?

EB:      I think that people tend to be daunted by new technology and are afraid to get into it and figure they'll let someone else do it.  And when they have someone else do it, they're not only missing out on the fun, but they also don't understand why things don't work. 

I don't want to say that all collaborations are bad. I do some collaborative work, but I pick it carefully.  The best collaboration I have going on right now is with my son Bruce.  He has a huge ENU [N-ethyl N-nitrosourea] (2) mutagenesis program, and he came up with a mouse that he called Mask, and this mouse has hair on its face but not on the body.  When he examined this mouse further, he found it had microcytic anemia (3).  So he asked me if I was interested, and of course I was.

We first established that this mouse was iron deficient and that it responded to a high iron diet or to iron injection.  And not only did it respond in terms of its microcytic anemia, but the hair grew back.  So everything was due to iron deficiency.  Since our laboratory is studying the regulation of iron homeostasis, and one of the key regulators is hepcidin (4), we were quickly able to measure the hepcidin message level in this mouse's liver, and we find now that it can't regulate hepcidin properly. 

Now, this is a good collaboration because I couldn't  -- and Bruce has cloned the gene, and he's not making it transgenic to prove that the gene he's cloned will correct the defect.  And he does that much better than we could, but he couldn't do these iron studies because he's not set up to do it.

But the difference is, the difference between him and me, and most of the other investigators, is that I wouldn't be afraid to start mutagenesis program if I really wanted to do that and to do it all myself.  But I don't want to do it because it's really too big an effort, and I just don't feel that strongly about doing it. 

What we are doing now, very intensively, is to study transcription factors (5).  We've never studied transcription factors before.  But the methods are all out there. I have very good people who are applying them.  It's very interesting for us to do that.  And I'd rather have our group do that than to collaborate with some transcription lab.

AM:     It struck me as you were saying this because last time you mentioned that you follow kind of the Jacobson model where he used a lot of technicians, and that you also have a core group of technicians that have been with you for many years, or were with you for many years before you retired.  What, if any, is the relationship between this kind of research where you prefer to learn yourself and limit collaborations, and the kind of laboratory personnel that you bring into your lab?

EB:      Well, I think there is a relationship in that you need really versatile people.  You can't really bring a one trick pony into your lab, somebody who knows how to do glutathione levels, because you're going to be doing them this week and maybe this month, but next month you may want her to do some HPLC (6), and she better be able to learn that, or he.  So I think you need a much higher quality technician to be able to do that.

AM:     And this wasn't as true in your training, but the postdoctoral fellow -- from the younger biomedical researchers that I've interviewed have used the postdoctoral fellowships, or multiple postdoctoral fellowships, to go into different kinds of labs to gain different kinds of experience.  How important for you is -- how essential is postdoctoral fellowships, do you think, for either bringing expertise into the lab or training the next generation into moving and thinking in different areas, and then sending them on their way?

EB:      Well, fundamentally, the way I look at it is that the technicians are there to do my research with me, and the postdoctoral fellows are there to train for science, and I try not to mix these too much.  In other words, I don't like to use the postdoctoral fellows to do work I want to get done. I try to give a postdoctoral fellow a project that he or she is going to work on and learn from, and not to plug them into my agenda of what I want to discover.

            So I would say that if I had -- with a few exceptions I'll mention, if I'd never had a postdoctoral fellow, I think my program would have been just as productive.  I don't count at all on postdoctoral fellows for productivity.  They are productive, they add to what we produce, but the core work is done by the technicians.

            Now, there are a couple of additions to that.  One is that there's at least one postdoctoral fellow who had a very profound effect on the direction our laboratory took, and that's Joe [Joseph] Sorge (7).  Joe joined my lab, I would say, about 1982 or '83.  He was an M.D., actually had been interested in surgery, but then after a year of surgery residency he decided he didn't want to do that and he went to Cold Spring Harbor [Laboratory] and he trained in molecular biology.  He was interested in gene transfer.  Because we were interested in Gaucher disease, this seemed like a good lab for him to be in.

            Now, we were at a crossroads at that point, and that was, Were we going to go into molecular biology in a serious way or not?  At that time -- this was some twenty years ago -- I was already in my late fifties, and it wasn't a no-brainer decision at that age to go into what's really an entirely different discipline.  But I decided that that's what I wanted to do, and Joe was really instrumental in training all of my technicians in the techniques of molecular biology.  That had a very profound effect on how our lab worked.

            I might say, Joe had his own program, and then he was made an assistant professor.  But he left to go into industry.  He had founded Stratagene [Corporation].  He's very bright and has been very successful in the biotech area.  He had a real impact on our laboratory, but I can't think of anybody else who had that kind of impact. 

            Now, the other kind of person that I've had in my laboratory besides the technicians and the fellows are that on and off I've had a faculty-type of person, a person who has finished their postdoctoral training but at a more junior level in the lab.  There have been several people like that I've had, and they've made very important contributions.  They bring new technologies to the laboratory, and they work independently, or semi-independently, but they also work on my projects. I generally support them.

            For a long time, that person was George [L.] Dale, who had been a postdoc with me but whom I kept on at the City of Hope, and then he came here with me to [The] Scripps Research Institute].  He's now a professor at the University of Oklahoma.

            Then in the last ten or twelve years I've been fortunate to have Pauline Lee, who is a Ph.D. molecular biologist and also a very good biochemist.  We work very well together.  She brings more basic knowledge to this than the technicians do, although the technicians are very outstanding.  But the fellows are mostly here to train.

AM:     How unusual is it for a junior faculty member to work in the laboratory of a senior member?  Currently, contemporarily speaking.  This kind of strikes me as unique, or more European?

EB:      No.  On the contrary, actually, I do this less than anyone else.  At Scripps there are a number of large fiefdoms in which the junior faculty basically works for the professor.  But Pauline is not really faculty, she's staff scientist.  She does not have grant support of her own.  Faculty, in my department, are all expected to either have or to get in a short period of time grant support and their own program.  This is the way you envision it.  This is the way I envision it.  But there are many laboratories where that's not true. 

            Basically, the people that I've had have not been people who had their own grant support or their own research programs, and who, for one reason or another, were very content to participate in this way in our work.  They've been very valuable.  And actually, there are positions like that at all research institutes.  In other words, you don't have only faculty fellows, you also have staff scientists.  They go under different titles.  Sometimes they're called staff scientists, sometimes they're called senior scientists, and so forth.  But they are generally not grant funded, and they are very valuable participants in the program.

            Another thing about training fellows, which I may have mentioned last time, is that if your laboratory consists almost entirely of fellows, then if you are concerned about their future, as you should be, you cannot do any high risk projects.  Well, if you work with staff scientists or with technicians, you can do as risky a project as you want.  And I think a good laboratory, an outstanding laboratory, should have a blend of high-risk projects and bread-and-butter projects.  High risk projects obviously don't very often work out, so you really can't give that kind to a fellow unless you're prepared to see him or his career go down the tubes.

AM:     I want to get back a little bit to the chronology.  You had mentioned that your colleagues -- the City of Hope really wasn't on anybody's register of premiere medical academic institutions.  What were your concerns about your work, being able to build a productive lab going out to Duarte [Duarte, California].  Had you heard of Duarte before?  Had you heard of the City of Hope before?

EB:      Probably not.  Well, to tell you the truth, I had no worries at all.  I had the supreme confidence of ignorant youth, I guess.

AM:     Okay.  I have several questions here, but I did want to comment.  I found it remarkable that somebody as early in your career as you would take the responsibilities of division head and be more administrative than -- considering everybody's attitudes --

EB:      Well, first of all, it wasn't division, it was department, so it was larger. It was called the Division of Medicine, but that was based on a terminology that was used at the University of Chicago, but in terms of today's terminology it was the Department of Medicine, in which I had divisions, chest medicine, cardiology, and so forth, that all reported to me.

            Well, the reason that I was able to do this was that I had learned, as I mentioned earlier, from Leon Jacobson, that one could delegate almost everything.  As I told you, I had two secretaries at that time.  One of them, number one, was a woman by the name of Grace Schall [?**], wonderful person.  Basically, she could handle almost every administrative problem for me.  Now, obviously, she couldn't recruit for me.  She couldn't make promotion decisions or salary decisions for me.  But all the little things that grind down some department chairman or some administrators she was able to do for me. 

As you know, I'm a department chairman now, I've been a department chairman continuously since 1959, which is a fairly long stretch, and it's never been much of a burden for me.  I think I must be doing the job because they keep me on.  I think it's a matter of delegating.  You delegate in two different ways.  One is that I divide the department into divisions.  I did that at the City of Hope, I've done that here.  Actually, mine's the only department at Scripps that divided into divisions.  Each division is headed by a professor, and I let them run their division, within certain constraints.  The administrative flow, all of the salary things that come through for technicians, and even for faculty because I get recommendations for them, basically are handled by Lynn [Oleski].

Well, I thought I could do it, and I did.  And it's never really interfered with the other things I wanted to do, to have this administrative responsibility.  Basically, what I learned at the University of Chicago, a decision that I made very early on, is that you either are going to be a department chair, or you're going to report to a department chair. If you're the department chair, then things get done the way you want them done.  I'd rather do it that way. 

And there are certain emoluments that come with being a department chair, not the least of which, and it was really very important to me at the time, as I mentioned before, is secretarial help. Those were the days of typewriters, you know.  I wrote quite a lot, and I didn't like having to wait for a week or two to have a typed script come back from the secretary.  At that time, when I wrote the papers, they generally went through, as they do now, eight or ten drafts before I sent them off. In those days, they would be typed.  Something I learned from Arno Motulsky, many things I learned from Arno, is start out on a pink copy, and then I would get it and I would cut it up and paste it back together and mark it up.  Then when it got to be a little better, then I would put it on a blue copy.  And then I would put it on yellow paper, and finally it went to white paper.  I still have many of those drafts, or had, I'm having them scanned as a matter of fact because I do like the idea of keeping them.

But if you have one secretary that's sharing with two or three other people, you have to wait a long time for your stuff to come through. If you're a chairman, you have a couple secretaries, much better.

AM:     And what's the advantage of moving through this color-coded scheme?

EB:      First of all, you can tell your old drafts from your new drafts because they're a different color.  And the second is, you get a sense of satisfaction as the color gets better and better.  (laughs)

AM:     Okay.  Well, I need to pop in a new tape.

EB:      Okay.

AM:     Before we move on again, I wanted to ask a question, because it was, I thought, an interesting issue that came up when I was interviewing Y.W. Kan [Yuet Wai Kan] (8).  Historians of biology or molecular biology have said that his identification of RFLPs [restriction fragment length polymorphisms] (9) in his work on inherited blood disorders is an interesting case, they thought, because [David] Botstein (10) is given credit, much of the credit, for identifying RFLPs, and his work came two years after Y. W. Kan's. 

Their argument, in this one particular article, was that molecular biology has taken a grand amount of the attention in chronicling progress made, and that clinical, the research that's been done from the side of clinical medicine doesn't get as much attention as from, say, basic science research. 

And in the issue of x-inactivation, I was wondering, Do you feel that both [Liane] Russell and [Mary] Lyon were more basic scientists, bench scientists, really weren't interested in clinical questions?  Do you feel that clinical academic medicine is not heralded as much, or the progress that's made, in contrast to what's happening at the bench?

EB:      Well, I think that's an interesting point.  There are certainly in-groups and cliques in all disciplines.  You asked me before why did Mary Lyon get the lion's share of the credit, and I think one of the reasons may have been that she was a card-carrying geneticist and I was not a card-carrying geneticist.  From the point of view of the geneticist, I was an outsider. What do I know? 

            Actually, that's a problem that I've encountered a number of times when I venture into other fields, and you kind of have to expect that.  Some fifteen years ago, or so, I started working together with one of our neurologists on the use of 2-chlorodeoxy adenosine [2-CdA] (11) in the treatment of multiple sclerosis (12).  The neurology community was very slow to pick up on this, very hostile, although our data were really better than any data for any treatment they had developed.  And you sort of expect that because who are these people coming into their turf?  Actually, Jack [C. Sipe] is a neurologist, but he's not in the academic in-group, Jack Sipe, who's my collaborator.  So this is a problem. 

And I have to say that with respect to Y.W. and the restriction length polymorphisms, I never thought of giving Botstein credit for that.  I always thought that Y.W. did it.  I didn't even know Botstein got credit for it.

AM:     Yeah.  One may make the argument that it depends on what you're reading.  So I was reading an article about -- but they were citing some of what historians would now call the canons of molecular biology history, molecular biology in the human genome project.  Their whole argument was that this fellow starts back with discovery of [James] Watson and [Francis] Crick DNA [double] helix, and for some geneticists, that just doesn't -- particularly for the group of medical and clinical geneticists that I've interviewed, that had less to do with some earlier work in genetics, that the molecular revolution was very important, but there were movements outside of molecular techniques and --

EB:      Well, of course, I think that the work that was done by [Hermann J.] Muller and [Thomas Hunt] Morgan (13) is just astonishing.  It's rather interesting that, in genetics, a lot of attention has been paid, about a decade ago, fifteen years ago, to the [repeat] expansion of certain genes, as in Huntington's [Disease] (14).  But that was all known by Morgan with the Bar Locus and the fly.  That was an expanding locus.  And he had it completely reasoned out, although he couldn't sequence anything.

            So, yeah, I think that's a good point. I think a lot of the basic things in genetics certainly came in the thirties and the forties from Drosophila genetics.  As a matter of fact, I guess base pairing is essential to the understanding of molecular genetics.  I'm not sure that the helical shape is.  And the pairing, of course, was already anticipated by the -- Chargaff's [Rule] [Erwin Chargaff] (15), I guess -- by the fact that the numbers of C's and G's, and the numbers of A's and T's matched each other.  That was already known, so I think you're quite right about that, that that was really a blip, probably an important blip, but not essential to the development of the field.

1. Human hemochromatosis protein (HFE): This HFE protein is encoded by the HFE gene and it controls iron absorption.

2. N-ethyl N-nitrosourea; Also known as ENU, this is a very strong mutagen that usually focuses on spermatogonial stem cells. The effect is genome wide

3. Microcytic anemia: Any kind of anemia that involves small red blood cells usually caused by iron deficiency.

4. Hepcidin: A peptide hormone that is made in the liver, hepcidin also controls iron levels in the body.

5. Transcription factors: A protein that specifically binds to various regions on DNA so as to copy the information to mRNA.

6. High Performance Liquid Chromatography: A method to distinguish compounds based on their interactions with the base substance.

7. Joseph Sorge and Stratagene: Stratagene is a biotech company which specializes in life science research. Sorge founded the company and is its Chairman.

8. Yuet Wai Kan; the first to diagnose a human disease via DNA, Kan is also a noted hematologist who worked on thalassemia and sickle cell. For more information see http://casn.bwh.harvard.edu/1996.htm.

9. Restriction fragment length polymorphisms (RFLP): RFLPs are used to find genes that are associated with various genetic diseases. They are DNA differences in homologous chromosomes that are made by enzyme “snipping” of chosen regions of the chromosome (restriction fragment).

10.David Botstein: An American biologist who worked on gene mapping.

11.2-chlorodeoxy adenosine: A drug, also known as Cladribine, used for multiple sclerosis and hairy cell leukemia.

12.Multiple Sclerosis: A serious medical condition where the myelin sheaths around the axons in the spinal cord and brain are eroding. This affects the efficiency with which signals are sent from the neurons and much scarring can occur as a result.

13.Thomas Hunt Morgan; (1866 – 1945) An esteemed American geneticist awarded the Nobel Prize in Physiology or Medicine for his work demonstrating how genes are the units of heredity in his work with Drosophila. See http://nobelprize.org/nobel_prizes/medicine/laureates/1933/morgan-bio.html.

14.Huntington’s Disease: An inherited genetic disease where nerve endings in the brain degenerate over time. There is no cure and the disease gets worse over time.

15.Chargaff’s Rules: The rule states that there should be a one to one ration of purines and pyrimidines. Similarly there should be an equal amount of adenine as thymine and guanine as cytosine. Thus adenine and thymine must bond together as guanine and cytosine must do so similarly.