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Dr Jim Boothe

Conversations about Dr Yellapragada SubbaRow

by S.P.K. Gupta

with Dr Jim Boothe

Dr. SubbaRow was instrumental in setting up a number of graduate fellowships in pharmacy schools and different schools throughout the country, and one of these was established at the University of Minnesota through Professor Charles 0. Wilson who was my professor. I was the first graduate student at Minnesota to have this Lederle fellowship, and from that developed the contacts with Dr. SubbaRow, which resulted in my coming here for an interview for a job.

I worked on the fellowship for 1 year - this was for a Ph.D. The only other one from Minnesota is Dr. Martel who is in my group quite new. My wife was hired by Dr. SubbaRow too about the same time I was - she's a Ph.D. bacteriologist. She's from Yale. Her maiden name is Jane Hill. I was acquainted with SubbaRow's work only because I was working on a Lederle fellowship. I never did any work that was connected with the work that he had done. The impression I got from my interview with him was sort of an odd one.

He asked me very few questions and made up his mind in a few minutes, and made me an offer of a job right away. I think I embarrassed him a little bit. He asked me how much money I expected and I named a figure, and I think it was less than he expected to offer me. He explained that it wasn't going to cost me more to live here than I think and he said we're going to offer you such and such, which was more than the figure I'd mentioned. His office was exactly where

I am now - the blackboard was his. I have a little shelf where the telephone is, which I think was his also. His secretary was Barbara Merriam. The men working with me then were Dr. Bohonos, Hutchings, Stokstad - those 3 were the main ones I was actually working with. Stokstad was working on folic acid. Jukes was here, but he hadn't been here very long. He was in Sales Education. I worked for actually 2 months on a separate problem called the sprue factor which was related to folic acid and later became part of it.

There was a material that Dr. Bohonos had isolated from liver which was known as the sprue factor and it was thought at the time to have something to do with sprue - perhaps the lack of it causes sprue. The compound was identified in a mater of a few months - it was identified as a known compound and then we no longer worked on that. It was identified as one of the B vitamins which had nothing to do with sprue and nothing to do with folic acid either. After that I started working on folic acid problem. The first few months I was helping in isolation - the isolation had already been worked out by other people - Hutchings, Bohonos and Stokstad but there was a problem of continual supply and I was doing this. Yes, it was made from fermentation. I was doing the last few steps in the isolation. I was also doing chemical work on the pteridines at the time we thought pteridines were somehow related to folic acid - there were some known pteridines in the literature at the time and I was spending some time making these - they are related as there is a pteridine ring in folic acid.

The work I was doing in the first year was mainly these two things - doing the last steps in the isolation fermentation of folic acid, and making a few known pteridines for practise and seeing what they were like in preparation for determining the structure of folic acid. After 6 or 8 months we started to study the degradation and try to determine the structure of folic acid. Most of the degradation work was done by Hutchings and Stokstad. It was at about this time Dr. Mowat came on the problem. He and I began to work sort of together in synthesizing things that we thought were closely related to degradation products. In other words, Hutchings and Stokstad were doing the actual degradation work on folic acid and Mowat and Boothe were doing the synthesis of the degradation product that they were getting out. Waller came after about 1 year and Mowat and I had already done some work on synthesizing these pteridines. Waller also began to work in this area and Angier came about that time also. I think Waller made the first successful synthesis.

Of course, SubbaRow was overseeing all of this. He wasn't doing any laboratory work himself. He was constantly in the laboratories and my laboratory was right next to his and SubbaRow was in and out all the time. He knew day to day what we were doing. This was a natural product problem that he could see a solution coming up and he was very interested in finishing this problem. This was a new vitamin and new growth factor and he wanted us to be first in this. He would walk in and pace around and talk and he would ask us how are things.

He would often suggest, why don't we try this, or how did this go - he vas intimately interested in the results each day. He was a good supervisor - sometimes it did seem he came too often - I don't think anyone resented this at the time. There was a feeling that this was a very important problem and there was a feeling that you were being pushed some. There was a feeling that Dr. SubbaRow was anxious and that the people above him were anxious too - there was a feeling of urgency, of getting the thing done. If we weren't first in this there was something wrong because we had a good head start - we had a lot of people working on it and we felt we should be first. It gave us all very good experience on working on many things - natural products, the difficulties involved, good experience in how to attack other natural product problems.

The name of the degradation product was 2-amino-4-hydroxypteridine-6-carboxilic acid. This was always known in our laboratory as fraction l B. That was the first degradation product that gave a clue to the structure of the whole thing. And there was also 2-amino-4-hydoxy-6 methylpteridine. Xanthopterin does show some activity and I think it must be that the species - fish or animals - converted it somehow biologically. Maybe they can use it as a precursor to make folic acid.

Dr. Waller was the first one to synthesize folic acid. Later, I synthesized it also by a couple of other methods and later synthesized the fermentation folic acid. I was the first one to synthesize that - that has 3 glutamic acids in place of 1 and the main problem there was that it added on the 2 extra glutamics. Lederle did sell for a number of years the fermentation folic acid that was known as Teropterin. We thought we were hot on the trail for a cure for cancer at the time and that was why were trying so hard to synthesize the fermentation folic acid so that we would have enough of it to really try. We didnt have enough from fermentation sources and the synthesis did provide rather large quantities. We made quite a number of kilos in the very early years. That was clinically tried in cancer. Liver folic acid has been synthesized by a large number of methods. Each of us in the group - there were 5 of us - each of us synthesized it by a different method.

I don't remember the day Dr. Waller synthesized folic acid - he was not in my lab at the time and I'm a little hazy about that. No one knew it until it was assayed because the material that he got out was not pure. You couldn't even tell that it had folic acid in it until it was biologically assayed - this took a few days and then no one believed it so it had to be repeated a few times. The discoveries never come all in one day - it's sort of a gradual thing.

It was made on a large scale by that process for quite a long time. Several years later I think there was a different one substituted rather than the first original shotgun method but that was used for quite a number of years and was as cheap as any. The way this interest in cancer developed there was a group in a hospital in New York City that had a cancer testing program in which they transplanted cancer into mice and then tested compounds to see which ones prevented the growth. This group tested fermentation folic acid and they claimed it was active in cancer - they claimed it prevented the growth of these transplanted tumours in the mice and this vas the first connection we had between folic acid and cancer. This then stimulated the work toward synthesizing the fermentation folic so that we could have enough to test it.

I can vaguely recall Dr. SubbaRow coming and talking to Mowat and myself. Mowat was the first one who started to work on this and then I joined him a few months later. There are several ways you can put 3 glutamic acids together and it was by chance that Mowat selected certain ones that were the wrong ones and I selected the ones that were the right ones. This took a year or year-and-a-half. Jukes was sort of on the sidelines - an advisor to Stokstad but he was not directly connected with the synthesis of folic acid at all. Stokstad also worked on the mode of action and the citrovarum factor - but this came later. I was not involved with citrovarum at all - the synthesis of the pteridin-6-carboxilic acid was a key to the good bit of the structure. We worked on the synthesis of that for quite some time and this was first synthesized by Mowat.

The problem involved with pteridine was there was no good method for purification. When we synthesized the product - it was very difficult to purify. I think this WAS the main stumbling block in the folic acid work and pteridine was difficulty in purification. We had meetings but I never remember any minutes or records kept of meetings. We had many verbal meetings during which we discussed these things and used blackboards, but I don't know of any records of meetings. I think SubbaRow often wrote on the blackboard, but I don't remember that he ever wrote on a sheet of paper. The biggest problem of solving the problem before I came was the discovery of the way to ferment.

Liver folic acid was extremely hard to isolate - this was Dr. Hutchings discovery - the method of micro organism that would make a folic acid that we could isolate. The fermentation method was a practical way whereby we could get a half a gram a week whereas from liver it was much less than that but I can't quote any amounts. Before the folic acid was synthesized someone did a cost estimate by making by fermentation and it was possible that you could make and sell this by the fermentation procedure. Of course once it was synthesized it was much cheaper to make it that way.

We cooperated with the group from Bound Brook and I'm not too sure when it started - in 1944 or sometime. There were 8 people from Bound Brook and 8 from Pearl River that were cooperating and we did have meetings quite regularly. We had meetings quite often in New York City - we'd meet in the New York office of Cyanamid. I remember one time we were scheduled to meet there for a meeting. Dr. SubbaRow always drove us and we got there and no one came from Bound Brook. Dr. SubbaRow called up and they said they didn't know there was a meeting so we had dinner and drove back home. He'd always take us to dinner when we had one of these meetings.

Dr. Northey was the supervisor of these people from Bound Brook. I would say that Dr. SubbaRow contributed more than Dr. Northey. Dr. Northey was at his best in planning the manufacture of something. He was very practical minded - he knew how big a plant it would take to manufacture so many kilos of folic acid per month. In the ideas for research purposes Dr. SubbaRow had a better grasp of that.

I don't know of any real disagreement among the group. I think for the number of people involved and the number of individualists involved it was remarkable that we didn't have more disagreements than we had. In addition to these meetings we also telephoned quite regularly and we had meetings about once a month. I consider that Dr. SubbaRow was a direct contributor to the research. He contributed as much perhaps more than others. I don't think anyone of us considered him a supervisor but an actual contributor as much as anyone to the problem. Folic acid is certainly one of the required vitamins and I think it's probably as important as most of the others. It has this one difficulty of disguising the symptoms without curing pernicious anaemia but this doesn't make it any less important on the basis of nutrition. Nutritionally it's still a very important vitamin.

SubbaRow wasn't a very good driver and we were always a little worried when there was 6 of us in his car. The trip we made to Bound Brook and brought back the first bottle of folic acid they made - a large quantity and this was not too long after the first synthesis. This was very impressive to see perhaps a kilo of folic acid. They had scaled it whereby they could make a kilo. SubbaRow was more of a biochemist than an organic chemist although he had a good understanding of organic chemistry. I think this cooperation with Bound Brook began because SubbaRow was short of chemists and they wanted to put a lot of effort in it and this was the best way to do it quickly.

But I don't think he intended to amalgamate the two labs together. In the period just after the war until 1948 he had continually added chemists and the number increased but I don�t know how they compared with Bound Brook and Stamford. I think he felt that the person with background and training was not really the important thing - they could learn any of these. If an organic chemist had an interest in biochemistry he could learn any of this material. I don't think he felt if an organic chemist came he didn't have to stay at that. I don't think he felt you had to stay at the thing you majored in college.

I think there was a change in SubbaRow's personality even before I came - he was much more demanding. Everyone felt they must work long hours. Even before I came here in 1943 most people worked, some at night, and in the years later they told me everyone felt they must do this. But this was sort of sloughing off when I came, and after I came people no longer felt they were compelled to work at night. He felt that this wasn't the only thing you had to do.

At the time I came he was investigating many hobbies. He was looking for things for his spare time, and this was an indication that he no longer felt his work was the only thing. He had taken up horseback riding and golf and airplane. There were many hobbies he took up - some he discarded very quickly, some he continued with. I felt that he no longer had this urge to work continually so people felt that they didn't have to work as hard. He was interested in many things in regard to medical research - almost any subject he was interested in and would have liked to work on. I can remember discussing with him the problem of polio before it was ever worked on here at all and he was interested in cancer research. He was the one who really got it started here - our connection between folic acid and cancer and his interest in it. I think his interest stemmed from . . . from New York. I think his interest stemmed from that. I don't think there was any fundamental concept. I think it was just a chance observation by another group and his taking advantage of this.

I think he had a broad interest in any medical, biological problem but I don't think - I wouldn't give him credit for having fundamental idea of testing anti-metabolites in cancer. I think this was sort of a gradual thing that came along. I don't think his interest in sprue was an obsession but he had an abiding interest in it. He did have more of a personal interest in that than the rest of us. I only knew it by name - I didn't even know the disease existed until I came here. I think his interest was as a medical man who had seen examples of this - seen the effects of it on people - maybe his family, I don't know.

Merck announced the structure of B12 before his death. I was never exposed to the B12 work but I knew very well the man who was doing the work - Otto Wieland. He worked for years on fractionating liver and having it tested in pernicious anaemia patients. But that was hopeless because there just weren't enough patients and the test wasn't good enough. Otto used to complain about the fact that he couldn't tell what he was doing. One test would be positive and the next would be negative, but I never heard him complain that Dr. SubbaRow wasn't supporting his program.

Dr. SubbaRow wanted to be known as an inventive man in the world of medicine. I had the impression that he certainly wanted his name known. He wanted to be remembered as an important man in medicine - his contributions to be known. But I don't known of a particular incidence where he indicated this. He wasn�t considered in the same class as a Nobel prize winner - maybe someday he would have been. I think he had the normal urge to be known by his fellow scientists as much as many of us - perhaps more than many of us. I don't think it was his choice if he was not given proper recognition. Had he lived another 5 years, I think he would have gotten the publicity that Dr. Duggar did get. I think his name would have been connected with Aureomycin in place of Duggar.

I didn't work on Aureomycin until 1950. During the structure work I synthesized degradation products. I was the first one here to make tetracycline from Aureomycin - you remove the chlorine from Aureomycin and make tetracycline. I was the first one to do this here at Pearl River. We later found that the Pfizer people had done it before we did and the Pfizer people got the patent on tetracycline. Lederle was the first to market tetracycline and we were in a good competitive position. For about a year or so I worked on making analogues for folic acid and other compounds to be tested. It was sort of a cancer chemotherapy program at the time and I worked on this until 1950 when I started to work on the Aureomycin program.

I first learned of his death in San Francisco 2 days after. My home was on the West Coast in the state of Washington. I was going to a meeting of the American Pharmaceutical Association in San Francisco to talk about Teropterin. I went to my home in Washington first and then went from there to San Francisco. It was there that I learned that he had died.

I met Dr. Waller there and he was the first one to tell me. It was a shock. I probably saw him a week or two before I left. I lived in the same building he did. I lived in the apartment house where he lived and I used to see him there quite often - coming and going. I don't think I ever was in his apartment - maybe once I was in his apartment I guess. I can remember the people living under him complaining he did a lot of pacing - he used to pace up and down at night. I remember he used to buy crates of oranges and eat them. This was a large part of his diet - he ate tremendous amounts of oranges. The majority of people who lived there were Lederle people.

He was a complex person - he had a much wide range of interests. He was a nice person to work for - I enjoyed working for him. He tended to be moody and did things spontaneously - sometimes without too much thought. He sometimes spoke out without giving thought to the consequences and later sort of regretted this. I think he did have likes and dislikes - this is choosing people you expect to run your research program. I think he did decide certain people were better than other people. He did have people he liked and I think he liked them because they did a good job.

I don't think he was unfair. He chose people as his favourites but I don't think personalities had anything to do with it. He was judging their ability to do what he wanted. I often wonder how he would have run a research group as it grew much bigger. Years after he died it increased quite rapidly and he was never one who could delegate responsibility easily. He liked to keep everything in his hands - whether he would have learned to delegate responsibility to other people. If he had tried to keep too tight a hold as the thing grew he would have lost control entirely because no person could keep the control he'd like on several hundred people. He would have had to designate people to be heads of departments and this was something he had no experience with and didn't do easily. He didn't like to delegate authority to other people. He would delegate work to other people but the person was responsible to him. He wanted to know about it personally. He had a prodigious memory for details - he would have reached a point where he couldn't have done this and I don't know how he would have reacted. I think he had years of scientific usefulness yet. I think if he would have learned to delegate authority I think he would have done very well. There were people who didn't like his methods and quite a number of them left. Dr. Bohonos left a year after I came - I don't think it was any great feeling against SubbaRow though.

(Participating: Dr Edgar L Milford. Venue: Pearl River, New York, USA. Date: 7 April 1965)