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History |
Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Address correspondence to : 1417 East 52nd St., Brooklyn, NY 11234.
At the start of the 20th century, clinical chemistry emerged into its own space on the mosaic of medical practice. The pattern of its future growth and development took shape during the first two decades of the new century. Before that time, the United States had played no role in the growth or development of clinical chemistry, but at the turn of the century important work began in the US.
One of the names that dominated this period was that of Donald Dexter Van Slyke. His systematic explorations on blood and urine led to practical and clinically applicable methods of analysis based on a new approach to methodology: analysis of small volumes of biological fluids. Using colorimetric and gasometric techniques, his work influenced the practice of medicine and played a major role in guiding the direction of clinical chemistry for the remainder of the century.
I met Donald Van Slyke in August 1960 at the Fourth International Congress on Clinical Chemistry in Edinburgh, Scotland. I had presented a paper at an afternoon session after an earlier paper by Dr. Van Slyke. During a break for afternoon tea, a friend and I spotted Dr. Van Slyke sitting alone at a table and asked if we could join him. He welcomed us and started to tell us about his visits to various laboratories on the Continent before the Congress, especially about his reception at a laboratory in Germany. When introduced to the supervisor, he was greeted by shock and surprise: "Ach, du lebst noch!" (What! You're still alive?), she exclaimed. Van Slyke could barely suppress his laughter. He thought this was a very funny story!
This history, dealing mainly with Donald Van Slyke's career at the Rockefeller Institute for Medical Research in New York, is derived from the transcript of a 5-h audiotaped interview held with Peter D. Olch, MD, of the History of Medicine Division, National Library of Medicine, Bethesda, Maryland, in Van Slyke's office at Brookhaven National Laboratory, Upton, Long Island on May 27 and 28, 1969. Van Slyke went to the Brookhaven National Laboratory of the Atomic Energy Commission in 1949, a year after he became an Emeritus of the Rockefeller Institute. At Brookhaven, he became assistant director of the departments of biology and medicine while also serving as chief of the chemical division of the medical department. The interviewer, Dr. Olch, is an "ex-surgeon, ex-pathologist".
Dr. O.: I do know that you were born in Pike, New York.
Dr. V.: That's right. At the time of my birth, my father, Lucius L. Van Slyke, was an instructor in chemistry at the University of Michigan. It happened that my mother was staying with his parents in the town of Pike when I arrived on the scene. I don't know why it was particularly convenient for her to be there, but that was the way it happened. So my birthplace was Pike, New York. The old name was Pike Hollow because it was in the valley between two rather high hills. It was a village of a few hundred people on one of the main wagon roads between Buffalo and New York and was rather active in early days. It had saloons where drivers would get comfortably drunk. It had a small river which was used for water power to run a woolen mill and a gristmill, and provided a millpond which was good for swimming. I went with my parents to Ann Arbor and was there until I was 2 years old, then my mother died of puerperal fever when a younger brother was born. There were no antibiotics to prevent that sort of thing then. My father went to the Hawaiian Islands as Professor of Chemistry in the Punaha School in Honolulu and left me with an older sister of his, who lived on a farm only 3 miles from the town of Pike where I was born.
Dr. O.: Your father did later move to New York State, did he not?
Dr. V.: Yes, he came back after 3 years in Hawaii. At the end of that time, he married again and came back and took a position again on the faculty at Ann Arbor. So I had a year in Ann Arbor when I was about 6 years old. I still remember that. Well, we were 1 year in Ann Arbor, and then my father went to the Johns Hopkins to do some postgraduate work with Ira Remsen, and during that year I went back to live with my uncle and aunt on a farm which was 3 miles from Pike, so I got in contact with Pike again. Then Father became chemist at the New York State Experiment Station at Geneva. So I joined him again and grew up in Geneva, which was a delightful town. It had a very good high school with excellent teachers. There were no junior disturbances in those days!
Dr. O.: Were there any particular teachers in high school you think that had any major role in your education?
Dr. V.: Yes. There was a Miss Florence Parker. She had an administrative position in charge of the girls' side of the high school—but she taught English and she was better than any English teacher I had in college. She taught the rules of grammar and how the English sentence was formed and how you should express yourself in a way that would be clear to the particular people who would read what you were writing. I think the fact that I have been considered a fairly lucid writer in scientific work has been to a very large extent due to what Miss Parker taught me. She eventually retired, and I went back to see her every year when I'd be back in Geneva—I'd go back to visit my stepmother. When Miss Parker was 90, there was a great celebration in Geneva and she had greetings from a great many important people, I think including the President. She lived to be 103! I saw her every year until the year she died. She was a very fine teacher. She had both the technique and the feeling.
Dr. O.: Did your teachers influence you in your decision to go further in your education into college, or specifically toward the sciences?
Dr. V.: No. I always took it for granted that I would go to college. I didn't know when I went to college whether I would go into architecture or chemistry. I was always interested in architecture, but after my first year in college I decided on chemistry.
Dr. O.: Had you had any chemistry in high school? Was there any sort of a physical science course in high school?
Dr. V.: No. I had physics in high school, but not chemistry. My first year at college, I went to Hobart College, which is in Geneva—an excellent small college. I enjoyed it very much. I made the varsity football team there, which I wouldn't have done in a big university! And I knew every man in college practically. I loved the small college, but it only had 1 year of chemistry, so I couldn't stay longer than that. Then I went to Ann Arbor. Although it was my father's college, the chief reason I went there was that Moses Gomberg was there. If there was any outstanding American organic chemist, it was he. I went on my father's advice and had his help in planning my course of study at Ann Arbor. As a matter of fact, he went out with me when I went there; he knew the faculty. We went around and saw the professors of chemistry and laid out a definite plan of organic and physical and analytical chemistry, which was a great advantage.
Dr. O.: I'm sure this was.
Dr. V.: I expected to go into agricultural chemistry, which was my father's line. He was sort of the Dean of Agricultural Chemists in his day. He was 39 years in the Geneva Agricultural Experimental Station.
Dr. O.: He also had received his training in chemistry at Ann Arbor, is this right?
Dr. V.: Yes. So besides chemistry I took bacteriology and plant physiology as minors for my Doctor's degree. I stayed on in Ann Arbor after I took my Bachelor's degree and took my Doctor's degree also there. Then I took a competitive examination for a position in Washington in the Bureau of Chemistry and won it and was enrolled among the government employees and expected to go there right after commencement in 1907.
It happened at the spring meeting of the American Chemical Society that year, my father sat next to Phoebus A. Levene, who was chemist at the newly started Rockefeller Institute. They got to talking about how there was so much more demand for well-trained chemists than there were available for research work, and my father mentioned the fact that I was taking my degree at Michigan that time and there were various positions I could have had, and Levene asked if I'd be interested in coming to the Rockefeller. As a result, I got a letter from Dr. Simon Flexner, who was the head of the Institute, inviting me to come to New York for an interview. Well, the Rockefeller Institute had just gotten started; it didn't amount to anything, and the government was a big thing. I didn't have the slightest idea of taking a job with the Rockefeller and giving up the government one, but here was a chance for a trip to New York with expenses paid! (Laughter).
Dr. O.: Little did you know!
Dr. V.: And so I went down and it happened Levene was away at the time, but I had a long talk with Flexner, and he told me what was the probable future of the Institute. On the way back to Ann Arbor, I stopped at Geneva and talked it over with my father, and the result of it was that I resigned the job with the government before I ever went there and took the position with Levene. So that shifted my general field insofar as it was applied chemistry from agricultural chemistry to medical chemistry. I worked with Levene for 7 years—worked in his department, worked on proteins and amino acids, and it was a marvelous time working with Levene. He arranged for me to go over, in 1911, to Berlin to work for a semester with Emil Fischer, who was the great "sun and god" of organic chemistry as long as he lived. There was no doubt that Emil Fischer was the number one man of that world. I had a chance to see how he worked. He got interested at one time in the problem he gave me and had me go into his private laboratory and work right beside him for 3 or 4 days.
Dr. O.: For heaven's sakes. This was quite an honor in those days, I'm sure, because a professor's private laboratory was generally off-bounds for the fellows.
Dr. V.: Oh, very much. Everything he did was in a quantitative way. That is, if he were going to do the solubility on a new compound, instead of just putting some of it into a test tube with ether or chloroform or whatever it was to see whether it dissolved or not, he'd take so many milligrams of it and mix it with so many ccs, and he'd have an approximately quantitative idea of how soluble it was.
Dr. O.: How could one really compare perhaps Gomberg, Levene, and Fischer as chemists? Did they have any similarities?
Dr. V.: Well, their personalities were very different. Fischer was a man of terrific power. If he had gone into politics he would have been another Bismarck! He was a big man; he was about 60 when I worked with him. His handshake was like an electric shock then! He looked like a typical German professor; he had a beard. But he was a man of terrific force. I was told that in his earlier days he'd had a terrific temper when things went wrong.
Dr. O.: Was he an egotist?
Dr. V.: Well, I wouldn't say he was an egotist. He was a great man; he knew it, but he was informal.
Dr. O.: How about Dr. Gomberg, was he that forceful an individual?
Dr. V.: No, Gomberg was very gentle. Very gentle. Very lovely personality. He lived with his sister. They came over from Russia when they were both, I think something like 12 years old or so. Gomberg never got over his Russian accent. He was an exquisite worker. He did all his work himself: he didn't have a technician, and he didn't have many PhD candidates to share his work. At that time, there was only one other PhD candidate working with him. Gomberg had a laboratory about 6 feet wide and 20 feet long, with a window at one end of it. And out on one side there was a big laboratory where the elementary organic chemistry was being done. On the other side of his laboratory was a room about 20 feet square where two or three research men could work. I did my doctor arbeit in this special room. One of his teaching assistants was there, and we worked together.
I was engaged, the last year before I took my Doctor's degree, to a girl who was a senior, also taking chemistry; a very charming girl. She was due to do her organic chemistry laboratory work out in the big laboratory. Gomberg and his assistant knew I was engaged to her. They debated whether they'd put her out with the crowd or put her in where I was working. If they put her out in the crowd, I would be likely to lose time going out to visit her, and if they put her in the room where I was working, that might be distracting! So, the assistant told me about it afterwards. Gomberg said, "We'll flip a coin and if it's heads, she goes out with the crowd!" Well, it turned out heads, and Gomberg said, "We flip again". (Laughter). So she worked in the same room with me that year, and that was very pleasant. I worked right next to Gomberg. Anytime I had anything to talk about he was right there. Those were days when your professor was not at a distance.
Dr. O.: Yes, that's so true. I imagine there are some instances where it's still this way, but certainly not at some levels.
Dr. V.: There are so many graduate students now that they can't have that intimacy. Fischer had a certain number of places. He would only take so many people; about a dozen. The only reason I got to work with him was Levene who had worked with him before and knew Fischer personally; Levene arranged it. I worked with Fischer for a semester. Berlin was a lovely town in those days.
Dr. O.: This would be 1911?
Dr. V.: Yes. That was before World War I. Germany was the scientific center of the world. It was a tragedy that the military people of Germany got her into that war. They were the only ones that wanted it.
Dr. O.: That would be the period that was the tail end of the great migration of physicians to Germany and Austria.
Dr. V.: Physicians, chemists, physicists. I think probably Germany had more great scientists in practically all lines than all the rest of the world. Practically every outstanding scientist in this country had had part of his training in Germany. Levene spent 2 years in Germany. He graduated at Petersburg Military Medical School. He then came over with his family from Russia and went into private practice. He got tuberculosis, went up to Saranac, and was cured. He decided that he could not resume the life of a practicing physician and decided to go into biochemistry. He went abroad and worked for 2 years. Part of it was with Fischer. He came back and was eventually picked up by Flexner to start the Rockefeller Institute. When the Institute started, the senior men, with the exception of Eugene Opie, were men who for one reason or another would not be likely to be called to professorships in American universities.
Dr. O.: Why is that?
Dr. V.: Because they were foreigners! There was Levene, who was a Russian. He didn't know anybody in American medical schools; he had no political route, so to speak. And then there was Alexis Carrel, a Frenchman, and a surgeon—experimental surgery—who got the Nobel Prize for a technique he worked out for suturing blood vessels. Then there was Dr. Samuel J. Meltzer, who was a German from Riga, which had been part of Russia. But the cultural part of Riga was German. It was one of the Baltic towns. The thing he was known for was his discovery of (I think he discovered it), the fact that when a muscle contracts, its antagonist relaxes, and he worked it out in studying the process of swallowing. And in Germany, his common name was "Schluck" Meltzer. "Schlucken" means to swallow; "Schluck" Meltzer, because of that. And then there was Hidayo Noguchi, the Japanese, who nailed the syphilis spirochete as the cause of softening of the brain. Well, Flexner was keen enough to see the possibilities of these men, and they were the men that the Institute started with. Opie, who had come from Hopkins, was the one man that had background in American universities and would be likely to get a professorship, and he only stayed at the Rockefeller 2 or 3 years, then took a professorship in St. Louis.
Dr. O.: Yes, Washington University.
Dr. V.: Yes. But that's the way the Institute started; it was sort of a menagerie.
Dr. O.: I gather Dr. Flexner was really quite a good judge of men, although he may have had some help from people like William H. Welch and others.
Dr. V.: It was Flexner's keenness of judgment. The Institute was what he made it. He got his men and then he backed them up, and he personally handled the Institute. For example, I was with Levene 7 years; then the Institute built a hospital, and Levene and Flexner apparently talked it over and decided that I should be moved over into the Hospital and develop a department of chemistry in the Hospital.
Dr. O.: With the express idea being that though you would still be able to continue, to use a hackneyed phrase, in "basic chemistry", you would develop a department related to clinical chemistry.
Dr. V.: Yes. It was hoped I would take an interest in that. I was so distrustful of my ability to do that and so reluctant at leaving Levene that I made Flexner write me a letter saying that if I didn't like it in the Hospital, I could go back to Levene! But I found that the young doctors in the Hospital were all just about my age and they took me in. I began to pick up medicine pretty fast; found it fascinating. So I stayed in the Hospital the rest of the time I was at the Rockefeller.
Dr. O.: One can really then put this decision, in a sense, in the lap of Simon Flexner. He's the one basically who decided that you were the man for this particular spot.
Dr. V.: Yes. In the Hospital, it was hard work, riding two horses, because I didn't give up my basic work. At the same time, I took up the study of kidney physiology and kidney diseases, but the young doctors that were there didn't know the field. I had to learn the story of nephritis and the physiology of the kidney and what goes with that from the ground up. And, although I was a chemist, I found myself in charge of a ward of patients with Bright's disease. Well, although I was very husky, apparently it took quite a good deal out of me, and a clinician that came to work with us for a sabbatical year, that was Thomas Addis of San Francisco, he went over to Flexner and said, "Van Slyke is going to give out pretty soon unless you give him a year off".
Dr. O.: Thomas Addis of the Addis Count?
Dr. V.: Yes. Well, I didn't feel that way, but Flexner called me over. This illustrates the way Flexner handled things. He called me over to his office and he sat across the desk—he had piercing blue eyes—and he looked at me full, as though he was looking right through me, and he said, "Van Slyke, get your things in order and get out of here and go to Europe with your family for a year!"
Dr. O.: Gosh, just like that!
Dr. V.: Yes. He said, "I'm not inviting you to do this; this is an order!" If you had a thing that required a decision, you'd get it from Flexner in very quick time, and it would be as good a decision as could have been made if he had spent months on it.
Dr. O.: What year would this have been that you took this trip?
Dr. V.: That was '29. So the family and I went to Europe, and we spent the winter in Grenoble, in France. My children, who were in their teens, went to Grenoble University, or the high school and picked up French, and I, in a leisurely way, wrote one of the main chapters of Peters' and Van Slyke's Quantitative Clinical Chemistry—the chapter on the acid-base balance.
Dr. O.: So you did stay out of the laboratory for that year.
Dr. V.: Yes. There was no laboratory to work in and no assistants to be responsible for.
The publishers came to John P. Peters—Peters worked with me for a year just before the war and then he went into the Army, and when he came out he went to Yale, but we kept in contact. The publishers came to Peters and asked him to write a brief manual on clinical chemistry, and he asked me to look over his chapters when he got them done. He sent me the first chapter, and I went over it and made changes in it and then he said, "I can see that we have to do this together; it takes a chemist as well as an internist!" We thought we'd do it in one vacation, but it just grew and we didn't realize how much material there was, and it was just about 10 years before we got it finished. Some chapters took a whole year!
Dr. O.: It's still the classic and extremely difficult to come by.
Dr. V.: Oh, I think it was useful.
Dr. O.: Oh, I think there's no question that it, in a sense, revolutionized the whole field as far as the application of analytical chemistry to, again in quotes "clinical medicine". This was one of the things I'd like very much to dwell upon for a bit, if we might. I'm really not sure how to phrase the question, but when you entered the field of clinical biochemistry, I call it, perhaps unwisely, I'm not sure how you really refer to this branch, if you will, of biochemistry.
Dr. V.: Well, that's as good a name as any, I guess.
Dr. O.: Right. It really was—if in its infancy at all—just barely in its infancy. The work of yourself and your group at the Rockefeller Institute it seems to me changed the entire method, in many ways, of practicing medicine. It was originally a qualitative science, and through the efforts of your group in this tremendously vast area, an understanding of pH and its clinical implications and acid-base balance, electrolytes, and so on was developed. One ends up in going from the qualitative to really a quantitative type of medicine. I would imagine at the onset of your career at the Rockefeller Institute, what one found as routine laboratory studies performed on patients were a totally different "kettle of fish" than what they were some 15, 20 years later. And really, your group is very much responsible for a great deal of this.
Dr. V.: We were responsible for part of it. There were others, of course, particularly Otto Folin at Harvard and Stanley R. Benedict at Cornell Medical School. I think our group at the Rockefeller were closer to the clinical application; we were working in a hospital. Benedict was working in a medical school, but not in a hospital. And it was the same with most of the other biochemists at that time. Most of the biochemists then were trained in a time when there was not a great deal of quantitative work done. You worked with proteins and peptones, and so forth. Particularly blood chemistry had just started to develop. We got into it because at the time I moved into the Hospital with my assistant, Glenn Cullen, the Hospital was starting to study diabetes. That was before the days of insulin, and the man who brought diabetes, so to speak, to the Rockefeller Hospital was F.M. Allen, who had been working on it with dogs. He made dogs diabetic by cutting out three-quarters of the pancreas. Up to that time, the theory of handling diabetics was to get them to eat as much fat as you could. They couldn't burn sugar, so you fed them cream and tried to keep their strength up by giving them the calories in fat. Allen fed some of his diabetic dogs a good abundant calorie diet mostly made up of fats, and others he put on semi-starvation. They were not completely starved, but they were thin, and kept that way. Well, the dogs that were well-fed on calories were fine for a few months, but then their diabetes got worse and they died, while the thin ones lived: their diabetes didn't progress. And Allen came to the Institute to try out what came to be called "the starvation treatment" for diabetes. His principle was to put the patient on a practically starvation diet. He fed them thrice-cooked vegetables; they were boiled three times so there was nothing left but bulk, to satisfy the desire for something in the stomach. And in a few days, they would stop excreting sugar, and the blood sugar would come down, and then he'd start building up the diet to see how much they could tolerate. That was the only way that a severe diabetic could be kept alive until insulin came along. Well, the danger was that on this almost no-calorie diet, acidosis could develop very quickly. Allen didn't think it could; the dogs don't have it. And he figured that if you didn't give them the fat which make the ketone bodies, they couldn't make oxybutyric acid and they couldn't get acidosis. Well, one of the first patients we had who was put on this treatment was a middle-aged nice lady that came in, a typical middle-age diabetic, not terribly severe. She went into a coma and died in a week!
Dr. O: On this starvation diet?
Dr. V.: Yes. Something had to be done to see acidosis coming before it got too bad, because once you go into coma you're finished. And so Cullen and I read up all the literature there was on acidosis and decided that the best clinical method would be to measure the plasma bicarbonate, and the most practical way to do that at the bedside was gasometrically, and for that reason we developed the old hand-shaken carbon dioxide machine. We measured the volume of gas at barometric pressure. After we worked out the carbon dioxide method, we didn't have any more deaths in coma because one could detect it by the analyses well before there were any clinical signs. The bicarbonate can go down to half-normal and the patient isn't uncomfortable. He may be a little dopey, a little sleepy. He's breathing more deeply than normally, but you wouldn't see it unless you were used to looking for it because he doesn't breathe faster, he just breathes a little deeper. And then when he gets much below that, then, in those days, the coma would develop explosively.
Dr. O.: You also were deeply involved in studies in renal physiology.
Dr. V.: Well, the way we switched to that was that after some years Allen left and started a diabetic research institute of his own, and the Director of the Hospital thought that it was fair to let him take the diabetic problem with him and not to compete with him. I decided to take on the renal problem because there was a chance for quantitative chemistry there—measurement of function and the metabolic things that the kidney did.
Dr. O.: How was your laboratory basically organized when you'd have people like Dr. A. Baird Hastings there or Dr. Cullen? Was there sort of a common problem that the entire laboratory staff was working on, or did each man have his own part of a common problem? Was it like Fischer's laboratory, where these people were working on a project primarily of interest to Fischer?
Dr. V.: Yes, each man there worked on a problem. They all radiated from Fischer, so to speak. If a man came to work with me, he usually wanted to work in the field that we were working with; in nephritis, for example, after we got into that. And I would start him on a problem in connection with that. If he got an idea by himself, why, that was OK, he could work on it by himself. Or if two of them would get an idea together and wanted to team up, why, that was OK. Or sometimes they would team up with people over in what was called the "laboratory part" of the Institute that was separate from the Hospital. There wasn't any rule, and you might say there was no organization! We just did work the best way that seemed desirable under the conditions. The various fields that went ahead in my laboratory started some on the original impetus from one man, some from another.
Dr. O.: All based generally on a clinical problem that he brings to the lab.
I gather from speaking with Dr. Hastings that within the Rockefeller Hospital there was really a very much open-door policy with exchange of ideas and so on amongst the various labs, but that this wasn't always the case in the Rockefeller Institute proper.
Dr. V.: Well, the Institute was organized, for the most part, around senior men. They were called members instead of professors, and it was a bit on the organization of European universities where each professor is pretty much dictator in his own department. The Hospital was less that way. When it started, the Director, Dr. Rufus Cole—I think he was 35—and everybody else was around 30. There were no senior older men like Dr. Meltzer was. Dr. Meltzer was a German, and naturally, things would go in his department as a German professor would organize things. Things were more, you might say, "free and easy" in the Hospital. You could work on practically anything you wanted to. If you wanted to start on a new disease, naturally you would settle that with Dr. Cole. But what you would do with it, what problems you take up with it, Cole would never attempt to dictate. When it came to appointments, if a man wanted to come to work with me, I'd see Dr. Cole about it and if possible arrange an interview with Dr. Cole. Then Dr. Flexner would approve it, and it would be approved by the Board of Scientific Directors. I never recommended a man that wasn't appointed. It was as informal as that.
Dr. O.: Could you give me your impressions of Dr. Cole? He certainly is an important figure in contemporary medicine.
Dr. V.: Yes. He was a very fine man, both personally and scientifically. I've heard it said that he was considered the brightest man that ever graduated from Hopkins at the time that he graduated. He came to the Institute with the idea that the laboratory and the clinic would work as one organism. As the Hospital started out, most of the young men there that were working on patients did their own laboratory work. Eventually, laboratory procedures got so numerous and complicated that this was no longer practical, but that was the idea—Dr. Cole's idea—that laboratory and clinic should not be separated. And they pretty much continued that way. I always had a couple of chemists working with me that were PhD chemists, but I also had usually four or five MDs working with me, but they also worked in the laboratory. All of them.
Dr. O.: You mean also in the clinic, while they were working?
Dr. V.: Yes, they had patients, they were in charge of patients, but the idea was to have so few patients per doctor that the doctor could also do laboratory work. And the idea was, furthermore, to have a few patients that should be studied as completely as possible rather than have a great many patients from whom you collected just what you might call routine data. All the patients pay nothing and can, for that reason, stay as long as it is essential to study them. They are usually happy to stay.
Dr. O.: I've seen it somewhere, I can't remember where, but somewhere the statement that the "university concept" of the Rockefeller Institute started when Detlev Bronk was the Director. This really seems to be an injustice because, obviously, taking your department as an example, you were doing one devil of a lot of teaching long before.
Dr. V.: The Rockefeller Institute, before it became a university, was really a postdoctoral university. Most of the people that worked there up to that time already had their Doctor's degrees. But not always. There were three men that started as technicians with Bachelor's degrees and used their work with me at the Rockefeller as theses for a PhD from Columbia. But for the most part, the young men that came to work there were the same as I was, they already had their MDs or their PhDs, and they would work there usually not less than 2 years—2 to 5, 7—and then go out to faculty positions in universities or to research or heads of research laboratories. It was, I think, definitely an educational institution. When Bronk became Director, he changed it to a graduate school that specialized in predoctoral students.
Dr. O.: Now, really the change in name, I don't think, has changed the concept of what they've been doing for some while. It's just that they elected to take the name University as opposed to Institute.
Dr. V.: Well, the character of the Institute has changed in that the medical side of it is much less emphasized than it was. I think that was Bronk's idea. I regretted it. I think the school's a fine thing as it is now, but I was sorry to see the medical side of it gradually de-emphasized. Senior medical men have left, and I don't think they've appointed others in medicine. And the Hospital was a definite subunit of the Institute with a very high morale under Dr. Cole and under Thomas Rivers after Cole retired, with a director as Cole and Rivers were. Now there is no hospital director, there's a Chief Physician. But the special character of the Hospital is not changed.
Dr. O.: Yes, it certainly sounds like a fair amount of reemphasis of medicine.
Dr. V.: Yes, and the Institute has a Professor of Philosophy, Professor of Mathematics.
Dr. V.: The Hospital is still running. We still have patients. But it wasn't long after Bronk came before he changed the title of the Rockefeller Institute for Medical Research, he dropped off the "Medical Research". And then after that it became the Rockefeller University. At the time, I felt that we had enough universities, but there was only one Rockefeller Institute acting as a postdoctoral university. I would have preferred to keep it that way. As a matter of fact, the National Institutes of Health was modeled on the Rockefeller. So the world no longer, you might say, needed this as an example—that is, the old Rockefeller. As a matter of fact, when they were planning the National Institutes of Health, they came up and examined the Institute in order to use the physical plan on which the Institute was working.
Dr. O.: Plus, I'm sure, the close relationship with the Hospital to the Institute—to the personnel having patient responsibilities as well as laboratory.
Dr. V.: The National Institutes of Health is a darn good institution.
Dr. O.: Certainly one of the names that to anyone who has been exposed to biochemistry, and clinical biochemistry in particular, medical students and otherwise, is Lawrence J. Henderson, who is a very, I gather, close friend of yours. I wonder if you wouldn't mind saying a few words about him. It's always nice to get some flesh onto some of the names we see from the minute you start in the field and yet you don't really have a picture of these people. I think it's very interesting and important that we have some sort of a record of what they're like.
Dr. V.: Yes. Henderson was a unique character. He was not much of a laboratory worker himself, but he was a great thinker, a generalizer. There is occasionally a scientist who comes along who is tremendously valuable in pulling things together that have been uncovered by other men and is stimulating. Usually, I think the generalizer who doesn't work himself is not likely to be the one whose generalizations are worth a great deal because he doesn't have the sense of perspective of relative values, of probable explanations against the improbable ones. But Henderson did have that sense. He did do some work himself in his early days. I first came in contact with his work when Cullen and I ran up against the problem of acidosis in diabetes. We read up the literature that might be helpful, and the paper that really got us steered on our work was a paper by Henderson on the acid-base balance of the blood, that was published in German, in which he brought out the Henderson equation and pointed out the importance of bicarbonate as the alkali reserve of the blood. Then I got personally acquainted with Henderson; I had met him before that, but now I got better acquainted with him.
Henderson had bought this small farm up in north Vermont and built a very delightful cabin on it, or villa, whichever you would call it. It was beautifully arranged. He loaned it to me for two summers when he was in Europe, so I went there with my family. There was a barn on it, and he got the idea of fitting the barn up for a laboratory so that his men could come up there and work in the summertime. He figured it would cost $5000. I went to John D. Rockefeller, Jr. and asked him if the Rockefeller Foundation could provide the $5000, and he said, "No, Professor Henderson has got other friends that can do that!" He said if he was stuck for 5 million, "We'd begin to think about it!"
Dr. O.: Certainly another name which goes along with the textbook, Peters and Van Slyke, I understand Dr. Peters—Jack Peters, as he was known—was a rather interesting individual.
Dr. V.: He was.
Dr. O.: One who stood his ground when he thought he was in the right.
Dr. V.: He was a great fellow. His technique in the laboratory was beautiful. He had extraordinarily good hands. He was very good at drawing. When he was in medical school, McCallum was writing his textbook in pathology and Peters drew some of the figures in that.
Dr. O.: Oh, for heaven's sake, I hadn't realized that.
Dr. V.: Peters told me that. In the Peters and Van Slyke, quite a number of the drawings in the Methods volume, Peters made them. He was precise and exact, and it was the same way in the laboratory. He was red-headed and loved an argument! When we started writing the book together after he asked me to join him on it, the first chapter he sent me I made quite a lot of additions and changes in it and wrote him a letter, as I remember, explaining why I thought there should be some changes and got back a letter arguing why they shouldn't be made. Eventually, we got it straightened out, but after that I merely revised every chapter he wrote; sometimes he wrote the first draft and sometimes I would. I merely made my revisions and sent it back without comment and then it was all right! (Laughter). But if I started to justify them, that brought an argument. One time there was a meeting of a Federated Biology Society in Montreal. I didn't go to it, but Peters and Cullen did, and they stopped at my house in Bronxville, where I was living then, on their way home. They spent the night with me. Well, in the evening as we were sitting by the fireside, Peters expressed some view about a physiological point—I've forgotten what it was—and Cullen said, "Yes, I think you're right", and added some reasons for it, and Peters said, "No, you don't agree with me, and these things are different. You don't agree with what I said at all". Well, then an argument started. Peters trying to persuade Cullen that Cullen didn't agree with him, and Cullen trying to persuade Peters that he did agree, and it came 11 o'clock and my wife excused herself and went to bed. And it came 12 o'clock, and I said, "Well, we'll finish this in the morning", and I put the fire out! (Laughter).
Dr. O.: He's quite famous for that.
Dr. V.: Yes, he loved an argument. But he was a beautiful worker and tireless!
Dr. O.: While we're speaking of the book, I understand Quantitative Clinical Chemistry has been republished. Didn't Peters put out a modification or shortening or something, but was there ever any talk of a complete revision?
Dr. V.: Yes. We promised the publishers we would keep up the revision of the whole thing. I got so involved in laboratory work, that I just didn't do it, much to Peters' disgust. Eventually I told him to go ahead with the Interpretations. He agreed to that and he started. Then he said I'd have to do the last half of it with the acid-base balance and the hemoglobin and oxygen, which was practically based on work which was mostly done in the Rockefeller Institute laboratory, and I said I would, and he agreed to revise the first half. Well, he carried out his part and revised it, and I never did carry out my part. But there was so much demand for the unrevised second part, which was to a considerable extent a finished job, that the publishers have recently republished that, the last half, without revision except for correction of a few errors. I feel very much ashamed that I never did do my job on that, but the war came along and then this job at Brookhaven organizing the medical department. [A revision of Methods was never completed.]
Dr. O.: You were busy, to say the least!
Dr. V.: So I just failed. And now the applications of clinical chemistry are so numerous that nobody could write one book to cover the field.
Dr. O.: What of this vast amount of work that you and your group have done do you consider the most important, or do you think any one group of experiments, as you look back with the perspective of the succeeding years, was perhaps the contribution that's had the greatest impact?
Dr. V.: I presume the work that had the most impact, because it was taken up and applied, was the work on the acid-base balance. The series of papers that we published on the blood gasses and electrolytes. The acid-base work was needed; there was a vacuum that it filled. So that it probably had the most impact on internal medicine of anything. Of course, the work we did on renal physiology and Bright's disease have been taken up rather widely, too.
At the time, while I was still in Levene's laboratory, I worked out the nitrous acid method for determining amino acids, and with the help of Gustav Meyer, showed for the first time that free amino acids are absorbed during digestion and that there are enough absorbed to account for nitrogen metabolism. That had a marked impact on physiology at the time. I don't think it ever affected clinical medicine. There had been so much work done, and since chromatographic methods for microdeterminations of amino acids have come out—so much of that—that I think it's only an occasional historical review that would recall that work that Meyer and I did. That came out about 1912. It isn't very often that a piece of work is remembered for more than a decade.
Dr. O.: It's rather amazing. This is so true. You look at bibliographies of papers written today, and one almost gets the impression that they don't want to have a reference which goes to, say, earlier sometimes than 1964 or `63, so you know everything has to be built from the latest building blocks.
Dr. V.: I've been shocked to encounter two or three PhD chemists that didn't know who Emil Fischer was! Modern ones. He was the world's greatest chemist in his day, and he did enough to make five different men immortal. His work on the aniline dyes; he worked out the structure of the purines, the pyrimidines. He worked out the structures of the sugars on which all sugar work is based. He demonstrated the amino acid constitution of the proteins, and in his later years, he worked on the chemistry of the tannic acid series of compounds. [Fischer received the Nobel Prize for Chemistry in 1902.]
Dr. O.: It's a rather sad commentary. It's true in medicine, too, that everybody's in such a hurry to learn new things and develop new things.
Dr. V.: There's just so much to learn. You could keep up with science 50 years ago when I started. For a number of years, I abstracted the Biochemische Zeitschrift and Zeitschrift für Physiologische Chemie. Those two journals had almost all the biochemistry there was in them, and one man could abstract them for the American Chemical Society. Now I couldn't abstract the Journal of Biological Chemistry. Some of the papers involve elaborate techniques that I have never used and couldn't understand. That is, I'm not capable of covering everything that comes out in biochemistry, which I was able to do in the early years.
Dr. O.: Did you ever feel at any time that not having an MD was a hindrance as you were working more and more in the field of clinical biochemistry?
Dr. V.: Well, I don't think it was a real hindrance because I always had good MD men to collaborate with. I would have been glad to have an MD training, but it would have taken 6 years additional, and during those 6 years I made an awful lot of progress in biochemistry. I had enough biology so that working with men that were trained in medicine, I could understand what they were doing. And, as a matter of fact, I became a pretty good clinician on Bright's disease! I made the rounds regularly.
Afterwards, in two or three papers that have come out under my name that were lectures, the MD was added without my knowing it! One of them was before the American College of Internal Medicine, in Chicago. I gave a lecture on shock kidney and was granted what you might call an honorary MD when it came out with my name on it. I did get honorary MDs from two foreign universities, Oslo and Amsterdam, which pleased me very much.
Dr. O.: Alma Hiller was the associate in your laboratory for some years, was she not?
Dr. V.: Yes. She was with me 30 years. She came—I think it was about 1916 or 1918—and she stayed with me until I reached the retiring age in `48. She had a Bachelor's degree in chemistry and she took a PhD at Columbia while she continued working with me. She really ran the clinical laboratory—after we developed what you could call a "Clinical lab".
Dr. O.: In other words, the service laboratory, as it were, for the Rockefeller Hospital, for the routine clinical lab work.
Dr. V.: Yes, and she also did research work. She was a good chemist.
Dr. O.: I was just looking through your bibliography, and I see this paper by Phillips, Van Slyke, et al. which is another standard in the blood bank.
Dr. V.: The copper sulfate method?
Dr. O.: Yes. To test someone's hemoglobin when they came to give blood.
Dr. V.: Yes. This is how it happened. The war broke out and I was called to Washington on a committee to talk over things that were needed in the army medical hospitals for field service. It occurred to me that a specific gravity method for blood concentration would be useful. Dropping methods had long been known using mixtures of organic liquids such as benzene and chloroform. Chloroform being heavy and benzene light, one can make a series of mixtures of varying specific gravity. The mixture in which a drop of blood neither rises or falls has the same specific gravity as the blood. However, such organic mixtures were not practical for field service because they have temperature coefficients about five times as great as that of water or blood. They give accurate results only if used with a constant temperature bath. We needed to have gravity standards in the form of water solutions. But a drop of blood falling into a solution of sodium chloride, for example, disintegrates. My first idea was to use sodium chloride solutions containing picric acid, which would form a sack of protein precipitate around the blood so that it would not disintegrate. It worked all right. But the next morning, Phillips with a copper sulfate solution, which was just one substance did the same thing. It also had the advantage of having a characteristic color, so that one would know what was in the bottle, and copper sulfate solutions turned out to have the same temperature coefficients exactly as the blood or plasma in which they balanced. So we developed the copper sulfate method for blood specific gravity. From the gravity of plasma one could estimate the concentration of plasma proteins, and from the gravity of whole blood one could estimate the concentration of hemoglobin. So we developed the copper sulfate method. It was adopted by the armed services of both our country and Britain, and was used especially to assay the effects of shock and hemorrhage in wounded men. The way in which it came to be applied by the Red Cross to test blood donors is interesting. I was on the Blood Bank Committee, which decided that 12 g of hemoglobin per 100 mL was the level below which blood would not be drawn from a donor. Reports came in from all over the United States concerning the percentage of volunteer donors that had the required concentration of hemoglobin. Some cities reported refusal of very few donors, and others reported so many rejections that it looked as though they had an epidemic of anemia. It was apparent that the variations were probably due to errors in the various methods for hemoglobin determination. We adopted one copper sulfate standard that would balance blood that had 12 g of hemoglobin per 100 mL.
If a drop of blood fell to the bottom of the solution, the hemoglobin was above 12 g and the donor was acceptable. The standard solutions were sent from a central laboratory all over the country. All the geographical differences in hemoglobin disappeared. The test was just a matter of drawing a drop of blood from a finger or ear and letting it fall into the copper sulfate solution. If the drop sunk, you were a donor. Phillips was a great fellow. He has been working for several years on cholera in the Orient.
Dr. O.: Yes. In the Naval Medical Research Unit in Taipei.
Dr. V.: Yes. I went out there in `61 and worked with him for a few months. He is both a beautiful laboratory worker himself and a great organizer of teamwork. The success of the method that he developed for treating cholera was extraordinary. Patients were infused with the special physiological solution of salts that Phillips had worked out to replace losses. The infusion was continued until the specific gravity of the blood, taken with the copper sulfate method, was lowered to normal, indicating that the desiccation had been corrected.
He had worked out the relative losses of potassium, sodium, magnesium, calcium, chloride, and bicarbonate that they lost in their stools. He'd worked out a routine of good replacement of solution. And he'd give enough to bring the specific gravity of the blood down where it ought to be; the specific gravity would be very high because of desiccation. His prize patient took 80 L in 4 days! But you could die in a few hours from desiccation. You go into shock and you just die. Plain desiccation.
Dr. O.: There's one question I would like to ask which more or less comes to mind any time that one sees somebody who has spent as much time as you have at a single institution. You obviously, over the course of years, had many opportunities and approaches, I'm sure, to go to various universities. I guess the reason for not doing so was being quite satisfied with the laboratory situation you had at the Rockefeller.
Dr. V.: Yes, I had everything I wanted to work with and complete freedom to do what I wanted. The most difficult thing to refuse was an invitation to go back to my alma mater, Ann Arbor, as Dean of the Medical School and Professor of Biochemistry. As I said, my father was on the faculty there when I was born, and I played in the streets of Ann Arbor when I was a child. I graduated there and my first wife graduated there, and sentimental attachments were very strong. I knew most of the men on the medical faculty at the time, and they were very cordial in their invitation. I agonized over it for a couple of months and finally decided that I'd keep on with the work I had going. I was a little afraid of administrative work because a good administrator has to know how to say "no", and I hate to do that.
Dr. O.: Didn't you, as the head of your laboratory, though, have to occasionally say no, in a sense?
Dr. V.: Oh, practically not. There were just a bunch of us working together. If one of my men got an idea that I thought wasn't any good, I let him find it out for himself, and sometimes he was right!
Dr. O.: You stayed on at the Rockefeller Institute until the compulsory age for retirement?
Dr. V.: They had a compulsory age for retirement at 65, but I could have stayed on as an emeritus with my laboratory but without patients, and I expected to do that, but the challenge to come out here and get a new Rockefeller Institute started at Brookhaven was attractive and so I rose and took the bait.
Dr. O.: Could you give your impressions of Dr. Jacques Loeb?
Dr. V.: Yes. Well, in Loeb's time, you might say there were two schools of biological thought. One school thought that living organisms were organizations based on the laws of physics and chemistry and that if you knew all about them you would understand how they work. Loeb belonged to that school. It was almost a religion with him. The other school of thought was that of John Scott Haldane, the great English physiologist who did all the work on the blood gasses and altitude and diving and so forth. Magnificent man! Haldane thought that there was some kind of vital principle that living cells had that we didn't know about, that was not explainable. It was something like the difference between Niels Bohr and Einstein. Niels Bohr felt that in the organization of atoms there were things that you could find out and express mechanically, but you could never make a mental picture of how they work. You could know what was going on and write formulas that would express it, but exactly what made it all go on, Bohr thought we probably would never know that, while Einstein was more optimistic. Einstein thought that there was an ultimate truth and that if you knew it all, you could make a picture of it. I understand that at Princeton they had very friendly arguments about it. Well, Haldane felt that there was an essence of life, or whatever you call it, that is essential for living cells, and this can't be defined on the laws of physics and chemistry, while Loeb felt that if you knew enough about it that you could so define it. And Loeb's object in life—at least one of his objects in life—was to work out the physical and chemical explanations of what goes on in cells as far as you could, and reduce the area of the unknown. The idea was that eventually you might eliminate it, if you could find out enough.
Dr. O.: The Rockefeller Institute certainly has made its mark in many ways. It's rather remarkable when you look back at this period at the people that did work there at one time in different fields. Quite a collection of scientific talent.
Dr. V.: Yes, most of the senior men there were leaders in their fields. And a very large proportion of the junior men there went out and became leaders. It was Flexner's idea, when the Institute started, and which he told me when I went down from Ann Arbor for an interview, that young men would come there and work and give their enthusiasm and energy and learn from the older men and from the experience and go out after a longer or shorter time. And that was carried on. After I'd been in the Institute about 3 years, Carl Alsberg, who was at that time head of the Bureau of Chemistry in Washington, offered me the job of Assistant Chief, which was rather an unusual thing for as young a chap as I was. I was very fond of Carl Alsberg; knew him very well. I went to Flexner and told him what the situation was, and I said, "You told me when I came here that junior positions were temporary and that when good opportunities came on it was expected the young men would go out and start other things and it seems to me that this is the time for me to move on". He said, "No, some of our young men we want to keep. I'd like to have you stay on". So, otherwise I would have gone to the Department of Agriculture, but that's a typical Flexner decision.
Dr. O.: Right, and brought on by your approaching him rather than his initiating it.
Dr. V.: Well, it only took him a minute to make up his mind! If I'd gone to Washington, I probably, to judge from other people, would have stayed there a few years and then taken a technical job in some food-producing company, and been pretty rich! But Flexner—it was a critical moment and it didn't take him a minute to make up his mind what to do. And that was quite a commitment to make because it was a commitment.
Dr. O.: Yes. And from that point on does one just progress essentially in stages?
Dr. V.: It was years before I became a full member of the Institute.
Dr. O.: There were a limited number of full members?
Dr. V.: There was never a definite number, but the number was limited because each one meant practically a department, and the Institute only had a certain amount of room. No, I was in no hurry to move up, but if I had to move out eventually, that looked like a good time and a chance to go with a man of whom I was very fond. No, I was in no hurry to leave Levene. I loved working with Levene.
For obituaries and tributes to Donald Van Slyke, see also:
The American Association of Clinical Chemists. Donald D. Van Slyke: on his 80th year. Clin Chem 1963;9:645–7 (bibliography on pp. 647–63).
Page IH. One of God's children; one of science's best. Clin Chem 1963;9:664–7.
Hastings AB. Donald Dexter Van Slyke. The 20th century iatro-chemist. Fed Proc 1964;23:586–91.
Sendroy J Jr. Donald Dexter Van Slyke 1883–1971. Clin Chem 1971;17:670–2.
Hastings AB. Donald Dexter Van Slyke 1883–1971. Managing Editor 1914–1925. J Biol Chem 1972;247:1635–40.
Hastings AB. Donald Dexter Van Slyke. March 29, 1883-May 4, 1971. Biogr Mem Natl Acad Sci 1976;48:309–60.
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