Molecular Evolution Activities

Interview with Emile Zuckerkandl

The Molecular Clock

In 1964, Emile Zuckerkandl and Linus Pauling christened the approximate rate constancy in the rate of amino acid substitutions in proteins the molecular clock.

The following is a transcript of an intervew between Gregory Morgan, Emile Zuckerkandl and his wife Jane Zuckerkandl. The interview was conducted on July 11, 1996 in Palo Alto, California.

Interview Table of Contents:



The Molecular Clock

Personal Background  Return to top of page
Gregory J. Morgan: You were born in Vienna, is that correct?
Dr Emile Zuckerkandl: Yes, I grew up there until I was about 15. After Hitler came into power my family and I moved to Paris. We were more fortunate than others, as it was not an up rooting to the same extent as it was for others, since part of my family was French by marriage. I was familiar with France as a small kid. In 1938, the Nazi's took over Austria and my mother, grandmother and I moved to Paris. My father was already there. Then during the war, after the collapse of France, my parents, one grandmother and I found refuge in Algiers and lived there from 1940 to 1945.

Gregory J. Morgan: By this stage, were you studying?
Dr Emile Zuckerkandl: I had begun to study biology but soon was prevented from attending lectures at the University by the anti-semitic laws promulgated by the Vichy government of France. On the other hand, I had a piano teacher who was very enthusiastic about making a pianist out of me. I was never satisfied with the idea of becoming a professional pianist. I thought that I would become a M.D., but when I began to study biology in Algiers I came to understand that it was biology that I was interested in, more than Medicine per se. So I never made it to Medical School, I only took science classes.

Gregory J. Morgan: At which university were you studying?
Dr Emile Zuckerkandl: Right after the war, I began at the Sorbonne and then I took advantage of the scholarship that I had won to study in the United States. While my family and I were in Algeria there was a definite possibility that the Nazi army could invade the then French North Africa. Through a close friend of the family who was perhaps the closest collaborator of Einstein, the mathematician Walther Mayer, who was then like Einstein Professor at the Institute for Advanced Study in Princeton, I got a scholarship upon the urging of Einstein. When I was about to take advantage of it and come to this country, the Allied troops, British and American, landed in Algeria, Morocco. And this completely transformed the situation -- there was no question that I would then leave North Africa. Actually my grandmother had been in particular danger, she was known for her anti-Nazi activities. But we all stayed in Algiers and after the end of the war in Europe we moved back to Paris and I spent one year at the Sorbonne and during that year found out that my scholarship which at that time was three years old was still valid. I went to the University of Illinois for a year and then undertook a research project toward master’s thesis at the Marine Laboratory in Woods Hole, MA. I then returned to France.

Gregory J. Morgan: Oh, I thought that you got your masters from the University of Illinois.
Dr Emile Zuckerkandl: Yes I did, and my principal advisor at the University of Illinois was C. Ladd Prosser and he suggested that I do my thesis work at Woods Hole at the end of my period at the University of Illinois.

Gregory J. Morgan: What did you do when you returned to France?
Dr Emile Zuckerkandl: Then I studied biochemistry and after completing my course work I went to the largest Marine Laboratory in France. I spent many years there as a permanent member. There were only a few such members at the laboratory, which like Woods Hole was alive principally in the summer with many researchers, both French and International. In the winter it was very solitary, there was just a small group of permanent people. My wife and I loved it.

Gregory J. Morgan: Would you have called yourself a Marine Biologist?
Dr Emile Zuckerkandl: Well, not really. My mind was never made for identifying species and so on, although I admired the people that did that. I was interested in biochemical problems, although, at that time, we did not speak of molecular biology yet. I got interested in copper proteins in crabs. The professor under whom I did my thesis was a specialist of crabs and he proposed a certain subject matter that related to the molting cycle of spider crabs and I carried the project through. But what I was really interested in were the copper proteins during the molting cycle and in general. I began getting some results that were pretty interesting in what they seemed to imply -- regarding structural changes in the position of the copper atom in the molecule. The change in position being measured by accessibility of strong chelating agents. I thought that was an important direction to pursue -- copper enzymes. Although, I studied primarily hemocyanine which is not an enzyme. I was interested in whether a change in the conformation in the vicinity of the copper atoms was a prerequisite for enzymatic activity to appear. I proposed a hypothesis to that affect, but then did not pursue it. Later that type of approach became the induced fit theory.

Gregory J. Morgan: of Koshland?
Dr Emile Zuckerkandl: Yes, of Koshland. I always regretted not having pursued work along those lines. After having been, for many years, in Roscoff and, as I have said, part of the year in pretty great isolation, visiting American friends suggested that I go, after my thesis, to a first rate university in the US. A couple of people mentioned [working with] Linus Pauling, but that idea did not seem very plausible to me at first. I was not a physical chemist and I did not see why Linus Pauling would be interested in me. However, I took their advice and when I was told that Dr. Pauling would be in Paris on some professional trip I wrote to him and he gave me an appointment in a Hotel in Paris. At that time the trip between Brittany where I was and Paris was quite a trip.

Gregory J. Morgan: When did you make that trip?
Dr Emile Zuckerkandl: I could not pinpoint the year, but it was probably 1956 or 1957.

Gregory J. Morgan: Do you remember the name of the hotel?
Dr Emile Zuckerkandl: No.

Collaboration with Linus Pauling  Return to top of page

Dr Emile Zuckerkandl: Pauling was, as he always is, very friendly and welcoming and heard me out. He thought that my proposal, which was in the field of hemocyanine and copper oxidases, was all right and he probably could provide me with a post-doctoral scholarship. It was not 100 percent certain, but it looked good. My joining him at Caltech was postponed because my principal thesis authority, biochemist, Claude Fromageot died suddenly and that caused a years delay. My wife and I eventually came to Caltech in September 1959. I always remembered my first conversation with Dr Pauling at CIT. He said, "You know this subject of yours on hemocyanine and copper oxidases, I think the results are going to be very difficult to interpret and I think you would do better to work on a protein about which more is already known." Very little was known about hemocyanine and copper oxidases. "Why don't you work on hemoglobin? You could look into how hemoglobins have evolved in apes" or perhaps he said "apes and monkeys." At any rate, I extended that investigation which was, from the point of view of structural data, up to date at the time, but rather superficial with regard to the information that one got out of the technique. That was the technique of fingerprinting invented by Vernon Ingram. This technique gave indications of structural changes, but you could not say what they were. You could not count them especially when they multiplied. Yet, you could say this looks identical, this looks very similar, this looks somewhat different and this looks so different that you cannot even say how many differences there are. I thought that evolution should be approached on a wider scale and include primitive vertebrates, invertebrates. Let me tell you a anecdote. When Dr Pauling made this suggestion to me, I was not too happy. I was very interested in my copper oxidase project. Also, then I did not understand why one should work on something that is already well known rather than something that is unknown. Later I understood how right Dr Pauling was. In the field of hemocyanine there would never have been the flourishing that there was in molecular evolution. It happened to be a decisive time for the field of molecular evolution. So, it was very lucky for me that Dr Pauling was interested in that idea. At first I did not know how lucky I was!

Gregory J. Morgan:
I saw Richard T. Jones and he told me a similar story.
Dr Emile Zuckerkandl: He taught me everything in the laboratory.

Gregory J. Morgan: This was in Dr Schroeder's laboratory?
Dr Emile Zuckerkandl: Yes, you see Dr Pauling no longer at the time had his own lab in the department, the Division of Chemistry and Chemical Engineering, but he had students. Richard T. Jones was doing his PhD work under him. Dr Pauling had asked Dr Schroeder, whom he had brought to CIT I believe and who was a very good protein chemist, whether he would accept a couple of Dr Pauling's students. So I was a guest in Walter Schroeder's laboratory and closely associated with his collaborators, but I really depended on Dr Pauling. The contacts with Dr Pauling were just going to his office, or, from time to time, him coming down one floor in Church Laboratory and looking me up in Schroeder's laboratory. After a very few months I understood that I had to take initiatives to go and see Dr Pauling. I didn't at first as I did not want to bother him. I just pursued that work in collaboration with Dick Jones. Then a few months later, Dr Pauling asked me to give a little presentation, and I presented the work that I had done. Dr Pauling was quite surprised that there so many results that were obtained and he had not known about. I realized that I really should make frequent visits to his office. His office was always open to talk with people. I must say that this remained true through the many years that I knew him, except for the very last period.

Gregory J. Morgan: Pauling was very busy, was he not?
Dr Emile Zuckerkandl: He was very busy, he would usually set aside what he was doing and listen to you and discuss. It was always interesting and I hardly ever left his office without a sense of ...

Gregory J. Morgan: Elation?
Dr Emile Zuckerkandl: Elation, yes.

Gregory J. Morgan: Did Pauling suggest that Dick Jones teach you techniques?
Dr Emile Zuckerkandl: Yes, he said that, and there was no question about it. Dick Jones was so nice and helpful, and he was much more clever than I was. I shall never forget what I did to Dick Jones. This was not at Cal. Tech., but at Oregon. In 1963 I went up to Oregon and visited and worked in his laboratory. I poorly connected a glass tube in a water circulation device. During the night the thing burst and water ran through the ceiling onto computers on the floor below. That was the worst thing that I ever did in the laboratory and it was pretty bad. He was a generous person and always positive. I owe him a lot.

Gregory J. Morgan: What species did you begin with?
Dr Emile Zuckerkandl: Chimpanzee, Gorilla and Orangutan. And then I added Macacus mulatus ... [Looking at the 1960 paper] here were the apes and monkey, then cow and pig, bony fish, lung fish, shark, hag fish and an echiurid.

Gregory J. Morgan: This was your first publication at Cal. Tech?
Dr Emile Zuckerkandl: Yes.

Gregory J. Morgan: Did Dr Pauling ever tell you why he wanted you to work on the evolution of hemoglobin? Did he have comparative studies rather than evolution in mind?
Dr Emile Zuckerkandl: I do not have a precise recollection of this, but I can say why by inference. Surely the time dimension, which is evolution, was present in his mind because comparative studies, even among apes meant that one was looking at evolution. I believe that he had an interest in evolution. It was not a dominant preoccupation for him, but as we progressed in the work he appeared to be more tickled by it, so to speak.

Gregory J. Morgan: I was wondering whether it was Pauling's work on radiation damage due to fallout that lead him to think about mutation and rates of mutation. Hence the work on hemoglobin.
Dr Emile Zuckerkandl He had mechanisms regarding mutation very much in his mind. I remember him proposing a notion that did not turn out to be right. That there is a state of stability in a gene, mutationally speaking, and if the state is disturbed by mutation then it would tend to re-establish itself. There does not seem to be such a mechanism.

Gregory J. Morgan: This mechanism is independent of natural selection.
Dr Emile Zuckerkandl: Yes I think that is sort of the idea that he had for a time.
Is there a mention of this in the paper? Let me see.

Gregory J. Morgan: There is some discussion at the end of the paper.
Dr Emile Zuckerkandl: I thought that I could have done better in the discussion than I did.

Gregory J. Morgan: Did you principally write this paper?
Dr Emile Zuckerkandl: I possibly wrote this paper, but I don't have a clear enough recollection to be sure. I would have to find the original manuscript and unfortunately my documents are in Southern France. I wrote it largely, but in other papers I can pinpoint the pieces that Dr Pauling did. Here I am not so sure.
Here it is "in addition to natural selection the thermodynamic stability of the genes themselves may be an important factor in determining the distribution of alleles in the population."

Gregory J. Morgan: I have here a summary of all the things that I found in the archive. In June 1957 Pauling came to Paris.
Dr Emile Zuckerkandl: Here you mention Nishiwaki, the anecdote that I have not yet told you involves Nishiwaki. Nishiwaki, a professor of physics, came to California to see Dr Pauling in relation to a suit that was waged around a ship having insisted on going into a zone of atomic testing as a protest against atmospheric testing. Nishiwaki had come to testify at the trial. He was a Caltech and I was introduced to him. Dr Pauling asked him whether he would like to stay and work with me on hemoglobin. Nishiwaki said "yes". So Nishiwaki and I began a collaboration and after a couple of months or so we became good friends. One day I took him out to a coffee shop and we opened up to one another. I expressed to him my regret that I could not work on hemocyanine. Dr Pauling never said you have to work on this rather than that -- that was not his way. But I felt I owed him so much for having taken me at all that, of course, I would do what he preferred, for a while -- that was my idea. I would go back to hemocyanine later, and I, of course, never did because hemoglobin became so interesting. Nishiwaki was one of those Japanese who could not say no. He too was unhappy because he was not at all interested in working on hemoglobin.

Gregory J. Morgan: So he spent a few months working on hemoglobin?
Dr Emile Zuckerkandl: At Caltech, yes. I thought it was a very funny situation where both of us were working together, each believing that the other was very interested in hemoglobin when neither of us was.
I see Itano's name, have you spoken with him?

Gregory J. Morgan: No I have not. I do not know where he is.
Dr Emile Zuckerkandl: I do not remember where he is. He is a retiring person; he does not put himself forward in any way. I have never really established with him anything more than an acquaintanceship. He contributed some very important things. Actually I discovered some concepts that I thought were original with me, he had, two years earlier formulated. He was very much the first in some important aspects of molecular evolution.

Gregory J. Morgan: Where was he working at the time?
Dr Emile Zuckerkandl: He worked with Pauling in the late 1940s. When I came to Caltech he was no longer there. He was at the NIH, I believe.

Gregory J. Morgan: Did you talk to him very much?
Dr Emile Zuckerkandl No. I met him from time to time. We had nice conversations, but nothing substantive.

Gregory J. Morgan I was wondering who Prof Stern was. He apparently introduced you to Dr Pauling.
Dr Emile Zuckerkandl Absolutely. His first name was Alfred. He was a professor of philosophy at Caltech. He was Viennese by origin and he was a friend of my family. I knew him as a youngster, although not very well. He was kind enough to say a word to Dr Pauling about me at the time when I tried to elicit the interest of Dr Pauling in me. It was probably through him that I learned of Dr Pauling's trip to Paris. Later when Jane and I came to Caltech we saw a lot of the Sterns. Eventually when he retired, they moved to somewhere in the Caribbean.

Gregory J. Morgan: Was Anfinsen's Book, The Molecular Basis of Evolution, (1959) important?
Dr Emile Zuckerkandl: Yes.

Gregory J. Morgan: Did you read it?
Dr Emile Zuckerkandl: Yes, I read it. I do not remember when, but early on. I think Anfinsen was the first to say that it would be very interesting to compare proteins from different species. The question was, what was the central question of molecular evolution. There were early contributors to the field of molecular evolution, but molecular in a very general sense. Since informational macromolecules could not be analyzed properly, they were not among the interests of those pioneers. At least two of them wrote books. Both Baldwin and Florkin, in their books, focused on molecules in various physiological processes. It occurred to me that what they had done was interesting and important, but that it was, in a sense, peripheral to the center of the field. The center of the field had to be informational macromolecules, everything else was ...

Gregory J. Morgan: secondary?
Dr Emile Zuckerkandl: Yes secondary. So Anfinsen was, I would say, a precursor of that general concept because he realized the importance of proteins, and I cannot remember if he spoke of nucleic acids.

Gregory J. Morgan: I could not find any substantive correspondence with Anfinsen. Was there contact with him?
Dr Emile Zuckerkandl: I never had contact with Anfinsen at that time. I met him later. I had diner with him years ago in Washington D.C. at the occasion of one of the Linus Pauling Medal for Humanitarianism dinners. They usually took place in San Francisco but on this occasion it was in Washington. I remember Anfinsen insisting on eating only kosher food.

Gregory J. Morgan: Was this in the 1980s?
Dr Emile Zuckerkandl: Yes.

Gregory J. Morgan: So Anfinsen was not an important collaborator in the early days.

Dr Emile Zuckerkandl: No. He died two years ago?

Gregory J. Morgan: I did not know.
Your one year fellowship was renewed?
Dr Emile Zuckerkandl: Yes, I stayed on and on at Caltech and became a very old post doctoral fellow there. Actually, I outlived Dr Pauling's presence there!

Gregory J. Morgan: You stayed on because your work was going well and Dr Pauling wanted to keep you on?
Dr Emile Zuckerkandl: Yes, yes.

Gregory J. Morgan: After your first paper, people started sequencing proteins?
Dr Emile Zuckerkandl: Yes, that is right. That happened in the very laboratory where I was a guest -- Schroeder's lab. There was a competing lab in Germany, Braunitzer's laboratory.

Gregory J. Morgan: Were they involved in some sort of race?
Dr Emile Zuckerkandl: They were rivals, but they worked on different adult hemoglobin amino acid chains. Braunitzer would not tell Schroeder where he stood. He was very possessive. But Max Delbrück, on a trip to Germany, was able to get from Braunitzer a N-terminal sequence of the chain that Braunitzer analyzed. Braunitzer himself jotted down the sequence of about 30 amino acids for Delbrück. Max Delbruck gave the sequence to me and I made a copy of it.

Gregory J. Morgan: Later on did you talk with Braunitzer.
Dr Emile Zuckerkandl: Yes I met Braunitzer at meetings. I also visited him at the Max Planck Institute. Actually I visited him at two sites: Once in the old set up in Munich and then they built a big complex of buildings and Braunitzer had a much larger lab. We had some correspondence. He was, as I knew him, he was nice, positive and friendly. I perceived him as somewhat limited in his interests, very much the biochemist -- very eager to win out in the race of having this sequence and that sequence, but not seeing much beyond this achievement, not knowing what to do with the sequences.

Gregory J. Morgan: What techniques were being used to sequence the hemoglobin chains?
Dr Emile Zuckerkandl: The famous method of the Swede [Edman Degredation].

Gregory J. Morgan: In July 1960, Pauling notes in his date book "To Montpellier".
Dr Emile Zuckerkandl: Was this occasion --I thought it was 1961 -- that he went to get an honorary doctorate from the University of Montpellier? Perhaps it was.

Gregory J. Morgan: Did you have some association with the University of Montpellier?
Dr Emile Zuckerkandl: Not yet. Dr Pauling was instrumental in establishing it. Dr Pauling asked me whether I wanted to stay on permanently at Caltech. I replied that I was very happy at Caltech, but in the long run I really wanted to go to Montpellier. That [wish] had nothing to do with science, but there was, besides science, something very important and that was a certain quality of daily life and beauty around one.

Gregory J. Morgan: Is it a scenic place?
Dr Emile Zuckerkandl: A scenic place and what was man made was also very appealing. Jane and I discovered Montpellier and this region more or less by coincidence in 1953 and since that time we had always thought that if professionally there could be any justification for doing it, we should like to move there. I said this to Dr Pauling. You know that Dr Pauling had an extraordinarily open mind. Other people would have said this is a joke. He said, "as it happens I am going to Montpellier in a short time and when there I shall look around for you." He came back with some information, some business cards of scientists there and another name and you could contact so and so and they may be able to help you.

Gregory J. Morgan: On 15 February 1961 Pauling had written "Cocktails, Zuckerkandl" in his date book. Do you know what this is?
Dr Emile Zuckerkandl: We lived in two locations while at Caltech. The first one was a very mediocre apartment, not far from Caltech. And then we found a lovely house, which was originally part of the stables of a bigger compound. It was not a very big house, but it was an oldish, a little peculiar, but attractive and it had a very nice garden. Maybe that was a little party that we gave and Dr Pauling came. This seems not unlikely to me.

Gregory J. Morgan: You had little parties now and again.
Dr Emile Zuckerkandl: Yes, yes.

Molecular Disease  Return to top of page

Gregory J. Morgan: There was this important paper that came out in 1962, "Molecular Disease, Evolution and Genetic Heterogeneity." Could you tell me about the genesis of this paper?
Dr Emile Zuckerkandl: Dr Pauling once came down to the lab where I had a desk and said that he had been invited to write a paper to honor Szent Gyorgyi for his birthday. He wondered whether I would write the paper with him. I said that I would with pleasure. He said "You know it is for Szent Gyorgyi, so we should say something outrageous!" So I went about writing the paper.

Gregory J. Morgan: Do you think it was an outrageous paper?
Dr Emile Zuckerkandl: Well some people thought that it was. Dr Pauling said about the manuscript I had presented to him: “The more I read it, the more I like it.” But the clock idea that was first applied there was by no means successful with the biologists at the time. They thought that it was more or less crazy to think that there could be such a thing at the molecular level when morphological observations of evolution showed that there was absolutely the greatest possible variation in rate.

Gregory J. Morgan: It is an interesting paper. Did you write it and then give it to Dr Pauling to look at.
Dr Emile Zuckerkandl: I essentially wrote it. The last section, "Fighting Molecular Disease" was entirely Dr Pauling's idea. Perhaps I wrote the sentences. He told me that he thought we should say that sort of thing at the end of the paper. This reminds me -- the first sentence, "Life is a relation between molecules, not a property of any one molecule" reminds me of something. I was somewhat annoyed that in the 1970s when I was in Woods Hole I saw a book whose author happened to be at Woods Hole also -- the cytologist Ebert. He wrote a nice little book on cells. Under the title of a chapter he quotes the sentence and he attributes it to Linus Pauling, not Zuckerkandl and Pauling. It so happens that I wrote that sentence. I had an occasion to ask him about that. He told me that he got the quotation out of another article in Naturwissenschaften just by Pauling in which he used this sentence.

Gregory J. Morgan: This is an interesting passage: "The appearance of the concept of good and evil was interpreted by man as the expulsion from Paradise ..."
Dr Emile Zuckerkandl: That is not Dr Pauling.

Gregory J. Morgan: That is you?
Dr Emile Zuckerkandl: Yes.

Gregory J. Morgan: This is unusual material for a scientific article. Don't you think?
Dr Emile Zuckerkandl: I did such things repeatedly. Not feeling absolutely obliged to being stuffy!

Gregory J. Morgan: Do you see this close relationship between disease and evolution? Was it something you were thinking about?
Dr Emile Zuckerkandl: Yes. Actually that sort of thinking came down to me from my father. He was a philosopher and who always considered that the so-called "fall" was really progress a jump into our humanity.

Gregory J. Morgan: And you linked progress with Evolution.
Dr Emile Zuckerkandl: Right. Subjectively what we would have called progress must often has amounted to having a molecular disease. I don't think that you would find that sort of preoccupation with that type of subject in Dr Pauling's other writings.

Gregory J. Morgan: Although, Dr Pauling did give a number of speeches with the title "molecular disease and evolution". His interest in molecular diseases goes back to his work on Sickle Cell Anemia in the late 1940s. I was wondering why one would link the molecular disease and evolution.
Dr Emile Zuckerkandl: I was, of course, introduced to the concept of a molecular disease by Dr Pauling and his writings. And I think the link between molecular diseases and evolution could be postulated. I am quite convinced that without Dr Pauling's interest in molecular diseases I would not personally have been preoccupied with looking at the link between molecular diseases and evolution. The idea of molecular diseases was totally Dr Pauling's. I then took the idea and developed it further in one direction -- namely a particular type of molecular disease, diseases of the gene regulatory system. I called them controller gene diseases. I proposed that they were important in evolution.

Gregory J. Morgan: Was this later on?
Dr Emile Zuckerkandl: It was later on. I have a paper called "Controller-Gene Diseases" in 1964.

Gregory J. Morgan: Other than the last section of the paper "Fighting Molecular Diseases" you wrote most of it. Is that correct?
Dr Emile Zuckerkandl: Dr Pauling corrected the style and had me take out something I had written in connection with cancer, I do not remember what. The whole thing on gene duplication and the rest I presented to Dr Pauling, then the final section was written, something was removed and various things were corrected. That manuscript, I believe, I have it in my apartment in Montpellier.

Gregory J. Morgan: Do you consider this one of the more important papers of this period?
Dr Emile Zuckerkandl: Actually, beside the molecular clock idea, there was another idea in the paper. This other idea attracted somebody’s attention who thereupon invited me to a meeting in 1962. That was what I called dormant genes. For a long time I regretted the choice of that name. The name was based on the assumption that in many cases genes that had been inactivated would be reawakened so to speak and become functional again. Later my thinking on this changed. I thought that yes that could happen provided not too much time had elapsed between the gene becoming dormant and being reawakened. It was very unlikely to be a general process and very unlikely to be a source, as I thought in this paper, of innovation. And so I should have called them dead genes rather than dormant genes. No matter what they were called, the concept was that of pseudo-genes. So the concept of pseudo-genes was around for years before pseudo-genes were discovered.

Gregory J. Morgan: When were pseudo-genes discovered? Was it the 1970s?
Dr Emile Zuckerkandl: Yes I think so, but I forget who was first.

Molecular Clocks  Return to top of page

Gregory J. Morgan: I read the article that you wrote in the Journal of Molecular Evolution (1987) and there you mention that the idea of the molecular clock came to you in, I think you said, late 1960 or early 1961. Was there time between coming up with the idea of the clock and writing the paper?
Dr Emile Zuckerkandl: The paper was published in 1962 and written in 1961, no doubt. I think that I evolved the idea of the clock while writing this paper. Yes, probably.

Gregory J. Morgan: There was no earlier period where you had some revelation?
Dr Emile Zuckerkandl: No. But I have a clear recollection of a revelation. I speak of it in the 1987 paper. That was a time when I really had the feeling of being at the forefront and being first with a very important idea. That was the idea of sequence homology which is, of course, now taken so much for granted that no-one quotes the person who was first in the literature with the idea, Vernon Ingram.

Sequence Homology  Return to top of page

Gregory J. Morgan: I wanted to ask you a question about that. You mentioned that you also had that idea but for some circumstances Ingram published first.
Dr Emile Zuckerkandl: Let me tell you first about my discovery about homology. It all happened due to the little sequence that Max Delbrück brought back to Caltech from a visit to Braunitzer -- 30 amino acids of a hemoglobin chain. In the lab in which I was a guest, in Schroeder's absence -- he was on a sabbatical in Scandinavia -- I had access to his associates’ results. They had sequenced a number of triptic peptides. They had not been able yet to put them together in the proper order, but they had a number of triptic peptides sequenced. Even though if you looked at fingerprints of the alpha chain and the beta chain there was nothing there that would suggest a similarity. It occurred to me that it was likely that these chains be homologous in the sense of having a common ancestor and having then diverged from the common ancestor. I asked my friends in the laboratory whether I could have their sequenced peptides. And I examined these to see if I could fit some of them on the 30 amino acid sequence from Delbrück. I found the fit with the exception of one amino acid insertion or deletion that had to be postulated. Now I knew that this was really of general importance. I always thought that it was more important than the clock. The clock today is more important because it is still controversial. Since these were Schroeder's results and at that time I had not yet discovered that it was not necessarily dishonorable to write theoretical papers I felt obligated to wait for Schroeder's return to propose to him that we publish this idea together. Meanwhile Ingram invited me to a meeting to the east.

Gregory J. Morgan: When was this?
Dr Emile Zuckerkandl: When did Ingram publish his paper? If Ingram published his paper in 1961, then the meeting was in 1960.

Gregory J. Morgan: You said June 1960 in your 1987 paper. When this idea appeared to you.
Dr Emile Zuckerkandl: I wondered what I would present at that meeting. Because I could not talk with Schroeder about it, I had to put the thing on ice. I thought it was imprudent to present that hot stuff. I spoke about something much less interesting there. And Ingram spoke about something. I had no idea that at that very time Ingram was evolving the same concept. Had I presented it, it would have been the right thing to do, then the two of us would have had to get together over it. What happened was, when Schroeder came back from Scandinavia and I told him about sequence homology his response was an ironic smile. "Ha, ha, evolution the sacred cow of the century." He turned out to be a creationist. I told Dr Pauling. Dr Pauling was very astonished. He had no idea. People don't ask their neighbor about their religious convictions. So Schroeder refused to publish. And before I got out with the concept in a form that would not use Schroeder's results, -- after all Ingram did not have Schroeder's results either -- I found there it was, the very story in Nature. It happened to me several times in my scientific life: The other party being very quick. As soon as I saw the picture of introns and exons the same thing happened to me. I saw the possibility that exons often are the remains of originally functional smaller proteins, that exons could combine during evolution in various ways, and that introns permitted this type of combinatorial evolution. It was Wally Gilbert who beat me to that inference.

Gregory J. Morgan: Did you know Ingram very well?
Dr Emile Zuckerkandl: Yes, but he was never a close friend. He was a good acquaintance. He was one of those who was very much opposed to a molecular clock.

Gregory J. Morgan: Do you know what the meeting was called, the one you attended with Ingram?
Dr Emile Zuckerkandl: It was at Endicott House which was owned by Harvard or was it MIT. I have forgotten what it [the meeting] was called. Dr Pauling was there too. It was at that meeting that Dr Pauling told me about an idea in he had had in molecular evolution. Namely that from comparisons among contemporary polypeptide chains one could derive the probable identity of ancestral amino acid residues and thus reconstitute the ancestral polypeptide. He gave me that as a personal communication. I don't think that he spoke about it there. And I remember being quite skeptical about it because I thought there was probably too much convergence, coincidentally going on, for deriving the ancestral sequence with a good enough likelihood. But I changed my mind. Then Dr Pauling asked me to write a paper about this subject. That was the 1963 Acta Scandinavia paper Pauling and Zuckerkandl.

Gregory J. Morgan: This was where you introduced the new nomenclature [for describing ancestral chains]
Dr Emile Zuckerkandl: Yes. I have written something that may be I should give you a copy of about the origin of the molecular clock. I wrote it last fall after a scientific friend of mine had told me that he was at a meeting where somebody by the name of Easteal [Author of The Mammalian Molecular Clock] had presented a case to show that the molecular clock concept was not really Zuckerkandl and Pauling's, but--

Gregory J. Morgan: Margoliash's.
Dr Emile Zuckerkandl: Yes Margoliash's.

Gregory J. Morgan: I read this.
Dr Emile Zuckerkandl: In reaction to that I wrote something that I sent to my friend and just recently, a little bit in anticipation of your coming, I completed it a bit. I added a few things. Margoliash must be a very elderly person by now. I have not been in touch with him for ages.

Gregory J. Morgan: You do not want to enter into a--
Dr Emile Zuckerkandl: Dispute. Maybe I will make a copy of this for you.

Gregory J. Morgan: [Reading the document] I think that I agree with you. I was wondering, when anyone mentions the molecular clock they normally attribute it to you and Pauling. However, sometime it is the 1962 paper that it quoted, other times it is the 1965 paper that is quoted. There seems to be no agreement over when it was first postulated.
Dr Emile Zuckerkandl: The reason is that in 1962 the clock concept was applied, but not named. In 1965 the clock was applied again and received its name.

Gregory J. Morgan: Have you seen Easteal's book?
Dr Emile Zuckerkandl: No.

Gregory J. Morgan: I might return to my chronology. Going back to October 1961. Pauling writes to you in an interoffice memo wondering if you would like to go up to Seattle and Berkeley to check some points about the paper that you are writing. Do you remember that?
Dr Emile Zuckerkandl: No. ... Ahh, well this is very interesting. I did go to Seattle and visit Arno Motulsky, but I had forgotten that Dr Pauling sent me. I saw Motulsky later too. Motulsky spent a year in Palo Alto later writing a book. And I saw Fraenkel-Conrat in Berkeley.

Gregory J. Morgan: Do you remember the content of what you were checking up upon?
Dr Emile Zuckerkandl: No. I do not remember the content.

Gregory J. Morgan: Was Fraenkel-Conrat a geneticist?
Dr Emile Zuckerkandl: A biochemical geneticist. Unfortunately my memory is not good enough. You know my memory had always been poor and I was struck when I worked with Dr Pauling that Dr Pauling after about a year or two would remember my results better than I did. He had a wonderful memory that served him well.

Gregory J. Morgan: The end of 1961 you have sent the 1962 article in to be published.
This is a bit of a mystery to me. The following note, which Pauling had scribbled in his date book regarding some paintings by your Mother?
Dr Emile Zuckerkandl: He may have made a mistake. But it is an "e" in Stekel. At 8 pm exhibition of Emile Zuckerkandl's paintings. There was an art gallery for contemporary art held by a young Mexican, Ramon Lopez I think with one "m". My mother was a very talented painter and after the war she went abstract. And Lopez thought that he might make an exhibition of her paintings and that was done. And that was when Dr Pauling went to see it.

Gregory J. Morgan: Was this in New York?
Dr Emile Zuckerkandl: No. It was where we lived, where we had the nice old house and the garden. That was close to Pasadena, but outside of it in a small town called Sierra Madre.

Gregory J. Morgan: You have some artists in your family, and philosophers?
Dr Emile Zuckerkandl: And musicians.

Gregory J. Morgan: Why did you go into science?
Dr Emile Zuckerkandl: It interested me. My father before he became a philosopher was a biochemist and his father was an anatomist. A brother of the anatomist was a surgeon, a neurologist and my mother's father was a psychoanalyst, but a doctor.

Gregory J. Morgan: You have a very distinguished heritage.
Dr Emile Zuckerkandl: Well, I don't know.

Gregory J. Morgan: Someone told me a story, perhaps it was Dick Jones, that there was another E. Zuckerkandl and references to his work--
Dr Emile Zuckerkandl: Oh yes, it was my grandfather. In citation index there is someone with an incredible career: Two E. Zuckerkandls fused into one

Gregory J. Morgan: In June 1962 you returned to France.
Dr Emile Zuckerkandl: On vacation.

Gregory J. Morgan: Pauling wrote to UCSD recommending you for a position in anthropology.
Dr Emile Zuckerkandl: If I knew I have forgotten. What happened was the following: that vacation was more than just deciding to return to France and Europe for a while. It is possible that it had something to do with my visa -- I had to leave the country and come back. I think that Dr Pauling reappointed me, so there was a time where I officially left and came back.

Gregory J. Morgan: So you did go to France.
Dr Emile Zuckerkandl: Yes, I did go to France and I spent the summer there.

Gregory J. Morgan: It seemed like you had left the gorilla hemoglobin unfinished when you had left in 1962.
Dr Emile Zuckerkandl: It was sufficiently finished to have a note in Nature. Schroeder and I published in Nature. We had found that there was one amino acid substitution in one chain and one or two in the other. And we thought that two was more likely than one, but it turned out that it was only one.

Gregory J. Morgan: Why would you get that wrong? Was it due to the techniques that you were using?
Dr Emile Zuckerkandl: Yes. Maybe the work was unfinished in the sense that it was not done over again until we were sure of it. But the analysis of individual amino acids rarely came out as perfect integers and sometimes it was ambiguous.

[End of tape 1]
[Tape 2 at the Zuckerkandl residence with Emile Zuckerkandl’s wife Jane also present.]
Dr Emile Zuckerkandl: In February '62, Pauling notes an exhibition of my mother's paintings -- Do you remember the street name where the Ramon Lopez gallery was?
Jane Zuckerkandl: I do not know what the name of the street was, but I do know that there was such an exhibition.

Gregory J. Morgan: There is one thing that I wanted to ask you. Do you remember the Hotel in Paris where Emile and Dr Pauling met for the first time?
Jane Zuckerkandl: No.
Dr Emile Zuckerkandl: I went alone.
Jane Zuckerkandl: It was mid 50's. I stayed in Roscoff so I do not know any thing about that trip.

Gregory J. Morgan: Do you remember what Emile said when he got back? Was he happy?
Jane Zuckerkandl: Yes he was happy. I can tell you the kind of things I am sure he did say, but I can't say that I heard them. ... He might have said that he was surprised with the ease the whole trip went. There were no problems ...
Dr Emile Zuckerkandl: Dr Pauling did not say at the time that it was absolutely sure [that I would go to Caltech] but he gave me indications that it was likely, but he did not made a definitive commitment.
Jane Zuckerkandl: All I am recounting is the impression I have of your attitude when you returned. You were surprised that this sort of thing could come about so easily ... there were no extensive formalities ... People that applied, Pauling took them in very readily ... you just had to ask and it happened.
Dr Emile Zuckerkandl: I did see Fraenkel-Conrat [on the trip to Berkeley].
Gregory J. Morgan: Tell me about the trip to Portland.
Jane Zuckerkandl: When he went up to see Dick [Richard T] Jones for a month or two.
Dr Emile Zuckerkandl: That we can say exactly when it was because, as we left to return to California the news of the Kennedy assassination broke.
Jane Zuckerkandl: Just as we were checking out of our hotel. ... It is labeled forever.
Jane Zuckerkandl: As for the science I don't know. I remember helping in the lab. ...

Gregory J. Morgan: Were you learning techniques,?
Dr Emile Zuckerkandl: Probably, but maybe Dick and I had some idea of common work. Nothing ever came of it. It was perhaps the time when with others I thought it would be interesting to analyze the hemoglobin of the coelacanth. ... Perhaps I wanted to learn some new techniques from Dick Jones in that connection. But then we moved to Montpelier in '64.
Jane Zuckerkandl: End of 64, late summer of '64.
Dr Emile Zuckerkandl: And that interrupted the experiment.

Gregory J. Morgan: Were you waiting for a laboratory to be built?
Dr Emile Zuckerkandl: Yes, we were housed provisionally to start with by the University of Montpelier and the National Center of Scientific Research in Montpelier. And then a building was built for our institute.

Gregory J. Morgan: So they actually formed a new institute?
Dr Emile Zuckerkandl: Yes, it was called Research Center in Macromolecular Biochemistry.

Gregory J. Morgan: Did it go well?
Dr Emile Zuckerkandl: Yes, yes, the name still exists.

Gregory J. Morgan: Did you Jane follow the scientific work in Caltech?
Jane Zuckerkandl: I helped Emile a lot in the laboratory in those years as a technician. Much of the work that Emile did, the main activities were more theoretical and conceptual and the actual experimental work was in the early part of the period. After that in the later two three years the amount of experimental work diminished somewhat in favor the theoretical and paper writing activities. And this continued in later years.

Gregory J. Morgan: How would you describe the atmosphere at Caltech?
Jane Zuckerkandl: ... In Schroeder's lab there was a mixture of people working for Schroeder and people working for Pauling. ... Dick Jones left after about a year [of us getting there]. ... Within this group of people it was nice.
Dr Emile Zuckerkandl: The atmosphere at Caltech was wonderful because what you often find in institutions is that people don't care about he guy next door, they just lead their own scientific life ... I cannot say that this did not exist at Caltech, but there was an openness and mutual interest. There were exchanges between groups, discussions. It was really great. It was more the case in the biology division than in chemistry. ... I was not a chemist, I was not a chemist's chemist.

Gregory J. Morgan: Dr Schroeder's lab was in chemistry though.
JZ & Dr Emile Zuckerkandl: Yes.
Jane Zuckerkandl: Because Dr Pauling brought Dr Schroeder to Caltech. Anyone that Dr Pauling brought to Caltech was located in chemistry. In point of fact there were a couple of labs in chemistry at that time that were going into molecular biology. Messelson was in chemistry or biology?
Dr Emile Zuckerkandl: I don't remember, perhaps biology.
Jane Zuckerkandl: There were a couple of people who were in chemistry, but really their audience was in biology. Vinograd was in biology?
Dr Emile Zuckerkandl: Yes.
Jane Zuckerkandl: But somehow his lab was located near the chemistry lab.
Dr Emile Zuckerkandl: Yes.
Jane Zuckerkandl: So his people circulated in the corridors there a little bit. And you [EZ] had some contacts with them. So in point of fact those groups who were in chemistry probably because of their connection with Dr Pauling their role was in biology. And the people that Emile interacted with were almost exclusively in biology. Emile had only a minor connection [in chemistry]

Gregory J. Morgan
: Was Beadle one of those that you interacted with?
Dr Emile Zuckerkandl: Yes, definitely. We knew the Beadles well. And it was before the genetic code was deciphered and there were discussions in seminars about what the code could be like. It was very interesting.
Jane Zuckerkandl: There were loads of people in biology then. There was all of Roger Sperry's group in the split brain work ... I had a connection with Sperry though my family's past. Ed Lewis was very close to us. And a whole group of the successors of Morgan we were friends with. Albert Tyler, we were friends with.

Origin of the Molecular Clock Idea  Return to top of page

Gregory J. Morgan: Do you remember Emile talking about the molecular evolutionary clock?
Jane Zuckerkandl: It would be hard to say.
Dr Emile Zuckerkandl: I remember that you did not think very much of the idea.
Jane Zuckerkandl: I never understood why people found the clock so newsworthy.
... We had discussions all the time ...
Dr Emile Zuckerkandl: Thinking about how the idea of the molecular clock now, I can only reconstruct the process-- it is very dangerous to do that. ... In the case of establishing the idea of homology, I am quite sure how it went. I can remember that we made an excursion to Palm Springs and I was in Palm Springs when things gelled. That I remember very clearly. The molecular clock idea I do not remember with the same clarity, but I can say that an observation that I made would lead one to this intuition. The observation was that after a few hemoglobin chains had been partially sequenced and I compared them with one another, it became immediately clear that there are places along the sequence that are more variable than others. Margoliash made the same observation with cytochrome c. That gives one the feeling -- because feeling about things plays a role in the origination of ideas -- that there are certain resistances to change that are set. And you have particular sites at which the resistance is very great and you have sites where it is least great and you observe the most changes. There is nothing extraordinary about thinking that the degree of resistance to evolutionary change at a amino acid site could be a fairly constant thing during long periods of evolution. Then if you consider the most changeable sites, they will make the clock tick if there is a clock. There could be a certain regularity in this ticking in the clock because the resistance to change at these changeable sites is more or less constant and perhaps averages out over time.

Gregory J. Morgan: Did you see the clock as being an average of a number of "little clocks" in a sense.
Dr Emile Zuckerkandl: The little clocks would not be clocks. You might have an event now and then, but not regularly enough. If you have enough sites then if you have a built-in resistance which is overcome in a stochastic way, then summing over sites you may have something that is a pretty good clock.

Gregory J. Morgan: This seems to include the idea that different parts of the molecule perhaps are more static than others probably due to selection.
Dr Emile Zuckerkandl: Yes, as a matter of fact, for a long time, I have believed that the clock is not a neutral clock. Selection is perfectly compatible with the clock. Because when we speak about that resistance to change we have two components -- mutations as they occur and natural selection acting on those mutations -- so the outcome is a mixture of the two, unless natural selection is not working -- then you have just neutral drift. But natural selection can be working and is likely responsible for most “resistance” to change.

Neutral Molecular Evolution  Return to top of page

Gregory J. Morgan: It was quite surprising to me when I read your 1965 paper, because I was expecting a proto-neutralist view, but you spend a large portion of the paper considering how natural selection impacts molecular evolution.
Dr Emile Zuckerkandl: To me natural selection was never contradictory to a molecular clock. But for Kimura the clock was one of the foundations of neutral drift.

Gregory J. Morgan: And the clock became associated with the neutral theory.
Dr Emile Zuckerkandl: Right. And the funny thing is that there was a time when I had come to the conclusion that there is a lot of neutral drift in evolution. This was after the first Kimura paper --1967?--, which I did not know, and before the paper by King and Jukes. My conclusions were based on a wrong inference at the time. Namely, I had ancestral hemoglobin chains built by an associate of mine in Montpellier, Jean Derancourt. Looking at those one could observe that amino acids that were rarest in ancestral chains tended to become more numerous, amino acids that were more numerous in the deduced ancestral chains tended to become rarer. The trend as we went towards the contemporary situation was going towards what we called codon equilibrium that is different amino acids with very few exceptions tended to be represented in proportion to the number of codons that coded for them. We had a graph to that effect. A graph very much the same was then published by King and Jukes independently. I presented our work at a joint meeting of the French and Belgian Societies for Biochemistry in Brussels. The editor of a French biochemical journal asked me for the paper. He never got it, because a colleague of mine in Montpellier said that is fine but these results could also be explained by selection. Later, our friend Jack King pointed out to me that the whole approach of reconstructing ancestral sequences and then observing the trend was sort of circular. He did not believe that the conclusion that I wanted to draw was valid. At any rate, my colleague, Helmut Vogel and I wrote a paper which was much more prudent in its conclusions than I had earlier been. We submitted it to the Journal of Molecular Biology and they kept it for almost two years. By the time it came out it was not only more moderate than the first stance, but it was also old hat because King and Jukes had come out.

King and Jukes  Return to top of page

Gregory J. Morgan: So you actually knew King.
Dr Emile Zuckerkandl: Very well.

Gregory J. Morgan: When did you first met him?
Dr Emile Zuckerkandl: We were at Caltech.
Jane Zuckerkandl: You did not know Jack at Caltech.
Dr Emile Zuckerkandl: Well I see myself with Jack at Caltech.
Jane Zuckerkandl: You do. That is a surprise.
Dr Emile Zuckerkandl: I can't tell you what year. Maybe I came back to Caltech on a visit.
Jane Zuckerkandl: Maybe after you had gone to Montpellier. ... I do not see Jack in any connection with Caltech. ... all I know is that he became a very good friend and I don't now where it originated. Was he ever at Caltech as a worker?
Dr Emile Zuckerkandl: He was in Santa Barbara.
Jane Zuckerkandl: Was he always in Santa Barbara. Did you met him after the King and Jukes paper came out? ...

Gregory J. Morgan: Jukes was an interesting fellow. Was he an experimentalist?
Dr Emile Zuckerkandl: Jukes was actually in the nutritional biochemistry field. ...

Gregory J. Morgan: I read about an interesting incident. Pauling wrote to Jukes chiding him about not making references properly. Jukes responded to Pauling explaining himself and also enclosing a paper that he had just written. Pauling then sends you the paper, which is similar in content to one you were in the process of writing. He suggests that you continue the paper nonetheless. Do you remember this incident?
Dr Emile Zuckerkandl: I remember that I was in competition with Tom Jukes and he won out. I was in the process of trying to express protein sequences in terms of DNA sequences, of course it was only partially possible. I think that I would not have done as good a job as Jukes and Cantor did. The Jukes and Cantor paper realized something that I wanted to do. That was translating proteins into DNA.

Gregory J. Morgan: Tell me more about the Jukes and Cantor paper.
Dr Emile Zuckerkandl: A very well known and much quoted paper of the early '60s.

Gregory J. Morgan: I should ask you more about Tom Jukes.
Jane Zuckerkandl: Tom Jukes is a character.
Dr Emile Zuckerkandl: He is not an easy person. He is very outspoken. There are a number of people whom he does not like.
Jane Zuckerkandl: And who don't like him.
Dr Emile Zuckerkandl: There was a great antagonism between him and Dr Pauling.

Gregory J. Morgan: That is interesting because I came across a letter in which Pauling writes that he would not be happy if Tom Jukes was made an editor of a new journal in molecular evolution.
Jane Zuckerkandl: I would not be surprised because Tom was very upset when Dr Pauling was put on the board of the Journal of Molecular Evolution. Jukes semi-resigned ...

Gregory J. Morgan
: Where did this antagonism stem from?
Dr Emile Zuckerkandl: Vitamin C had something to do with it. Tom Jukes "poo-hoo-ed" it. And DDT was another point of contention. ... There must have been a personality clash--
Jane Zuckerkandl: And also a political one.
Dr Emile Zuckerkandl: Yes.
Jane Zuckerkandl: Tom is very much a conservative.
Dr Emile Zuckerkandl: Tom was very much on the side of Teller. I met Teller at the Jukes’s. Teller and Pauling were enemies.
Gregory J. Morgan: Shall we start in 1959? ...
Dr Emile Zuckerkandl: [C. Ladd Prosser] wrote a book on physiology that was a classic for years. ...

Gregory J. Morgan: What was your master’s thesis on?
Dr Emile Zuckerkandl: It was on blood pressures in invertebrates. ... I introduced capillaries into their blood system and measured the pressure.

Gregory J. Morgan
: It is a long way from chemistry.
Dr Emile Zuckerkandl: Yes, a long way.

Gregory J. Morgan: Let's look at 1960.
Dr Emile Zuckerkandl: Nishiwaki left for Tokyo in January 1960. That means that the Nishiwaki episode lasted just a few months. We arrived at the end of September I think ... about three months. ...

Early Reactions to the Clock and Moelcular Evolution  Return to top of page

Gregory J. Morgan: About this time Dr Pauling ordered a number of books on Evolution, including G. G. Simpson, Dobzhansky, and even Darwin.
Dr Emile Zuckerkandl: G. G. Simpson was one who did not want to hear about the molecular clock. Neither did Ernst Mayr.

Gregory J. Morgan: Did you talk with them?
Jane Zuckerkandl: You could even say that is was not merely the molecular clock, but molecular evolution in general.
Dr Emile Zuckerkandl: Specifically the clock. And it seems sort of odd that Simpson should have written that if the molecular clock says anything at all then it is a lie. I do not know where I met G. G. Simpson for the first time. Probably it was in Burg Wartenstein.
Jane Zuckerkandl: I am pretty sure that you met him for the first time in Burg Wartenstein.
Jane Zuckerkandl: In Roger Lewin's book [Patterns in Evolution] he makes as I recall, a case for the fact that at Burg Wartenstein in '62 which is before the clock became a current idea, Simpson and some of the anthropologists were those that were opposing the molecular approach. Roger Lewin is making the point that people like you who were present at that conference were battling against the current. And it took a long while before the battle --

Gregory J. Morgan: When was that conference?
Jane Zuckerkandl: Summer of 1962 in an Austrian castle, Burg Wartenstein. It was held by anthropologists.
Dr Emile Zuckerkandl: Actually Roger Lewin refers to it. ...

Gregory J. Morgan: Did you [Jane] attend this conference?
Jane Zuckerkandl: Yes I was present at this conference. ... The conference was organized by the Wennergren Foundation ... The meeting was organized around molecular evolution and anthropology. There were a number of outstanding anthropologists present, Dobzhansky was present, and Simpson was present. Was Mayr present?
Dr Emile Zuckerkandl: Of course.
Jane Zuckerkandl: It was quite a milestone meeting really.
Dr Emile Zuckerkandl: Ernst Mayr we already knew from Roscoff. He had been there and we got acquainted in the 1950s.
Gregory J. Morgan: The traditional biologists were quite strongly against what you were saying at this conference.
Dr Emile Zuckerkandl: Morris was there also. He was of course of the same mind as I except on the molecular clock.
Jane Zuckerkandl: Morris Goodman and you were the only two molecular people there, the rest were classical biologist or classical anthropologists.
Gregory J. Morgan: Did you present the clock at that conference?
Dr Emile Zuckerkandl: I do not even remember exactly what I presented. I subsequently wrote up a paper in which I set out to reflect the conference and what different people had said. It is not a wonderful paper. It is not one of the papers that I am pleased with at a distance.
Gregory J. Morgan: Did you publish it?
Dr Emile Zuckerkandl: Yes, it was entitled “Perspectives in molecular anthropology” and became part of a book published by the organizers of the conference, S. L. Washburn. Here is Roger Lewin's forthcoming book. The title is "Patterns in Evolution, the New Molecular View"

Gregory J. Morgan: Is this a historical book or is it rather a synthesis?
Dr Emile Zuckerkandl: It is a synthesis.
Jane Zuckerkandl: Here is the chapter on molecular anthropology
Dr Emile Zuckerkandl: Because whatever I exactly said in Burg Wartenstein, it was under the title "molecular anthropology" and it was the first time that phrase was used. Ten years later Morris Goodman organized another conference at Burg Wartenstein on Molecular Anthropology in part in commemoration of that earlier paper.

Gregory J. Morgan: So you knew Morris Goodman.
Dr Emile Zuckerkandl: I met him for the first time in '62.
Jane Zuckerkandl: Then he became a good friend.
Gregory J. Morgan: I was wondering whether or not Pauling's ethical principle of minimizing suffering motivated his work on molecular disease.

[end of tape 2 side A]

Jane Zuckerkandl: But Dr Pauling was such a pure mind. I don't see it. ... It was not a conscious motivation.
Dr Emile Zuckerkandl: Don't you think his medical preoccupation actually derived from--
Jane Zuckerkandl: I think it was more likely justified by it than derived from it.
Dr Emile Zuckerkandl: Because his mind as a physical chemist and as a structural chemist and a crystallographer was so far away in principle from his later medical preoccupations that it would seem to me that his concern with minimizing human suffering must have been a force in pushing him that way.
Jane Zuckerkandl: He had been led into a humanitarian dimension by Mrs Pauling with peace and nuclear testing ...

Gregory J. Morgan: My conjecture is that molecular evolution was an important gateway into his later vitamin c work.
Jane Zuckerkandl: That was very fundamental. Yes. Well certainly a major gateway. He always said that.
Dr Emile Zuckerkandl: The evolutionary argument was very important to him and to those around him.

Gregory J. Morgan: Was it a justificatory device, or rather was it through thinking about molecular evolution Pauling began thinking about vitamin c?
Jane Zuckerkandl: I think the second.
... He was attacked by Tom Jukes over the evolutionary argument.
Dr Emile Zuckerkandl: I do not remember the argument, wait, I think that Tom Jukes said well that is really not convincing because what the human organism achieved is precisely that it is free-ed to a large extent from that need of vitamin c that other species that produce vitamin c presumably have.
Dr Emile Zuckerkandl: I have a technical question. In '62 we left Caltech, went to France for several months and then returned to Caltech. Am I right in saying that we had to leave the United States for a visa question? We had to return to Europe.
Jane Zuckerkandl: Yes, I think that is right.
Gregory J. Morgan: Let us turn to January 1961. This is when you began to work in Schroeder's lab?
Dr Emile Zuckerkandl: I went into Schroeder's lab immediately and Schroeder was away. In January 1961, maybe Schroeder was back, yes he probably was back.

Gregory J. Morgan: Now the early work was using fingerprint analysis?
Dr Emile Zuckerkandl: But in the absence of Schroeder.

Gregory J. Morgan: When he returned you began to look at amino acid sequences.
Dr Emile Zuckerkandl: Amino acid sequences were worked upon in Schroeder's lab during his absence. I got the data I told you about earlier. [Reading the entry listed 20 January 1961] that may well have been the gorilla hemoglobin.

Gregory J. Morgan: If you look at the entry listed 12 May 1961, Morris Goodman writes to Pauling asking for gorilla and orangutan sera. Unfortunately you have finished working with it and have thrown it out.
Dr Emile Zuckerkandl: Yes. We went to the San Diego Zoo--
Jane Zuckerkandl: You had better not bring that up. There are so many anecdotes associated with these things.

Gregory J. Morgan: Really. You had fun at the zoo -- we will leave it at that. When I talked to Richard Jones he thought he had gone to the zoo to collect samples.
Dr Emile Zuckerkandl: We made several excursions. One of them was to Corona del Mar, the Marine lab of Caltech and Albert Tyler was there digging with us for the Echiurid worm.
Jane Zuckerkandl: There must have been numerous times whence you or Dick went --
Dr Emile Zuckerkandl: There was the question of getting the pig and cattle and no doubt Dick Jones did some part of this. I do not remember which.

Gregory J. Morgan: Can you briefly describe the procedure that you used to analyze the blood once you have collected it.
Dr Emile Zuckerkandl: You isolate the red blood cells by centrifugation--
Gregory J. Morgan: Were there any new techniques that were developed in order to analyze the samples?
Dr Emile Zuckerkandl: I do not believe any new techniques were developed. The decisive available technique was Ingram's fingerprinting. And Dick Jones was very good at that. We had the technique--
Jane Zuckerkandl: Edman degradation?
Dr Emile Zuckerkandl: Yes. Thank you. We used Edman degradation

Gregory J. Morgan: There was some lag between the technique being invented by Ingram and people using it to do comparative work. A couple of years, maybe.
Dr Emile Zuckerkandl: Maybe. And Ingram was very interested in that paper, the one with Dick Jones. He thought that was a very promising avenue.

Gregory J. Morgan: Then you began to look at sequences however.
Dr Emile Zuckerkandl: Yes. But, I have never realized the plans that I then made about sequencing hemoglobin. It was really left to others in the field to do that work.

Gregory J. Morgan: Even as a theoretician you did not analyze the finger print patterns further. It was the end--
Dr Emile Zuckerkandl: That was the end with the sole exception of the gorilla hemoglobin where we went one step further and actually supposed that if you found no compositional changes in the tryptic peptide then the chances were high that the sequence would be the same as in the corresponding human tryptic pattern. The whole tryptic peptide pattern was so similar that the assumption was that the sequence in general would be similar. Maybe a very few differences. We looked at gorilla and found one difference per chain, thinking that there were two in one chain, which was a mistake, but we left the question open. In chimpanzee the fingerprint showed no difference and others showed subsequently that there was no sequence difference.

Gregory J. Morgan: The technique was most effective when there was little difference between the respective samples.
Dr Emile Zuckerkandl: Yes.

Gregory J. Morgan: In June 1961 you begin working on the "Horizons in Biochemistry" article.
Dr Emile Zuckerkandl: Yes.

Gregory J. Morgan: In connection with this article you went to Seattle and Berkeley.
Dr Emile Zuckerkandl: ... I am sorry I do not remember the contents of what I learned. I do not think that I learned much from Fraenkel-Conrat.

Gregory J. Morgan: It looks like the next month or so you were writing or finishing writing the article and it was sent to the publisher at the end of 1961. On the 12 September 1962 Pauling suggests you for a position at UCSD. He sends a paper "mainly written by him". I wonder what paper this is?
Dr Emile Zuckerkandl: It is not the Washburn paper which was published in 1963. It was probably the [1962 paper].

Gregory J. Morgan: Does this paper show the significance for anthropology.
Dr Emile Zuckerkandl: That is a good question. ... I wonder if Dr Pauling thought of the ending? It could only have been the experimental paper with Dick Jones or this one.

Gregory J. Morgan: Did you attend the Arden house conference?
Dr Emile Zuckerkandl: That is the one I refer to. That was the one that I refer to [earlier]where I gave a very uninteresting talk. When was that?

Gregory J. Morgan: It was the 6 November 1962.
Dr Emile Zuckerkandl: That is the conference that I refer to.

Gregory J. Morgan: This is a meeting of Hemoglobin researchers?
Dr Emile Zuckerkandl: Right.

Gregory J. Morgan: Do you remember anything else about the conference?
Dr Emile Zuckerkandl: Besides the fact that Dr Pauling told me about his suggestion.

Gregory J. Morgan: Were there many people there?
Dr Emile Zuckerkandl: Perhaps between 50 and 100.

Gregory J. Morgan: Was it out of New York City?
Dr Emile Zuckerkandl: Yes, Arden House belongs to

Gregory J. Morgan: Columbia University?
Dr Emile Zuckerkandl: Yes, Columbia University. And actually I have a colleague at our Institute here who is an emeritus professor of biochemistry and molecular biology at the College of Physicians and Surgeons at Columbia and he is the one who has been in charge of organizing the conferences at Arden House for many years. That was before his time. His name is Henry J Vogel. Vogel was the main editor of the volume on Evolving Genes and Proteins in which our 1965 article appeared.

Gregory J. Morgan: He was a hemoglobin researcher?
Dr Emile Zuckerkandl: No. He worked on a number of topics. Very much on lysine and arginine synthetic pathways. He is the originator of the notion of genic repression even though he has not been credited with it.
Gregory J. Morgan: Let's talk about the paper on paleogenetics mentioned in the letter of 16 December 1962.
Dr Emile Zuckerkandl: That is probably the paper that essentially carried out Dr Pauling's idea.

Gregory J. Morgan: That was the paper that was published in the Scandinavian journal?
Dr Emile Zuckerkandl: Yes. I included material on convergence?
Gregory J. Morgan: I think you added one of the final paragraphs to the paper.
Dr Emile Zuckerkandl: The discussion at the end I wrote. I thought there were a few interesting things one could add to this paper. I know that Dr Pauling found that good. I would say that the whole part of the paper that makes a first tentative deduction of an ancestral protein sequence of a hemoglobin chain was carrying out Dr Pauling's idea. And then there is some discussion, which I added. I also wrote the first part, but it was really Dr Pauling's idea. You know that this idea is being carried out and given a lot of credit. One of the things I introduced into the paper mentioned that in the future it should be possible to synthesize ancestral chains and examine their properties and some people are now doing this ...
Gregory J. Morgan: Look at the entry on 26 June 1963: It looks like you are going to collaborate on another paper.
Dr Emile Zuckerkandl: Oh yes, the Oparin volume. That is a paper that had some ideas that I am glad were put out, but it also has its weaknesses.
Gregory J. Morgan: What do you think the good ideas were?
Dr Emile Zuckerkandl: It was a general formulation of the [?] informational macromolecules [?]. It also had but not well enough expressed the idea that one likely method of the control of rate of gene expression might be though the choice of codons because of the likelihood that the different isoacceptors might not be present in equivalent amounts. One could either maximize or diminish the rate of synthesis through that means. But somehow this was expressed in another paper, a very short one in French I think, but the people who then worked on this topic, it was never referred to really as the predecessor of the work done by Ikemura.

Gregory J. Morgan: The letters of 21 July and 29 July 1963 ...
Dr Emile Zuckerkandl: Joshua Lederberg invited me for two consecutive summers to spend a couple of months at Stanford. Jane, was it the first or the second time around that Josh organized a meeting on what forms life might take in the universe in relation to the planned search for life on Mars?
Jane Zuckerkandl: I think that was probably the initial visit and initially the reason that he invited you up.
Dr Emile Zuckerkandl: And the second time he offered me a position.

Gregory J. Morgan: At Stanford?
Dr Emile Zuckerkandl: Right. And I went to Montpellier. [laughter]
Jane Zuckerkandl: He was actually very unhappy when you ...
Dr Emile Zuckerkandl: There were two reasons that he was unhappy. The first was my crazy preference for Montpellier and the second was that Lederberg did not see eye to eye with Pauling. Jane and I felt that they [Pauling and Lederberg] should discover one another. We persuaded Josh and his wife Esther to come with us to the Pauling's ranch and we spent a day there together. And it did not get any response. You cannot make marriages of minds. It is always a bad idea to be a matchmaker.

Gregory J. Morgan: You mention Lederberg in one of your papers in connection with a computer program to simulate an early version of the genetic code.
Dr Emile Zuckerkandl: Yes, Lederberg was one of the early computer fiends. He just loved this new means of doing research and we did some things together on it. ... Jukes and I were really competitors then and Jukes beat me. ... Eck had this incredible flash of insight, he understood the genetic code before any one else did and then he disappeared from the scene. I do not know what became of him. He collaborated with Dayhoff on something and then he just disappeared. The only thing that Eck was wrong about was the detail. He was not sure whether the non-coding position was the third or the second [position]. He chose the second position, but it was really the third, but otherwise he had the right idea.
Gregory J. Morgan: So Pauling writes to you [29 July 1963] advising you to continue the paper even though Jukes has already covered some of the same material.
Dr Emile Zuckerkandl: I think that never took place.

Gregory J. Morgan: You did not continue writing.
Dr Emile Zuckerkandl: I don' t think so, I probably judged that what I was doing there was really gone.

Gregory J. Morgan: Would you call the competition you had with Tom Jukes a friendly competition?
Dr Emile Zuckerkandl: I don't think that Tom Jukes is conscious of it in the way that I am. I remember going to a meeting in Berkeley and having with me a slide that was practically identical to the one King and Jukes published and showing that slide to Jukes.

Gregory J. Morgan: This was before they published?
Dr Emile Zuckerkandl: No, after.

Gregory J. Morgan: But you had made the slide before?
Dr Emile Zuckerkandl: Yes.
Jane Zuckerkandl: He did not feel very threatened.
[end of tape #2 side B]
[tape #3 side A]
Dr Emile Zuckerkandl: I am jumping back, this paper was first published in Russian for a volume for Oparin and then quite a bit later in '65 the original English text was published. ["Documents of Evolutionary History"] This is the only paper to which Dr Pauling has not contributed at all. And I don't think that I wrote it so well.

Gregory J. Morgan: Let us look at the letter of 13 October 1963 ...
Jane Zuckerkandl: It might have been two months [that we stayed in Portland]
Dr Emile Zuckerkandl: I speak of many experimental projects that were never carried out. ...
Jane Zuckerkandl: Montpellier ate up all your time again. And that was on what year?
Dr Emile Zuckerkandl: 1963.
Jane Zuckerkandl: You where not setting up Montpellier in '63, you are talking about projects that you might have done in the following years.
Dr Emile Zuckerkandl: Yes.
Gregory J. Morgan: At the end of October Pauling announces that he is leaving Caltech. That must have bee quite a shock or did you see it coming?
Jane Zuckerkandl: I think we saw it coming. ... we just knew what was going on.

Gregory J. Morgan: One of the contributing reasons for his departure was that there was no big party or any major celebration of his Nobel Peace Prize.
Dr Emile Zuckerkandl: It was absolutely offensive.
Jane Zuckerkandl: He was very offended ...
Dr Emile Zuckerkandl: ... When chemistry did nothing biology stepped in.
Jane Zuckerkandl: When they were told that chemistry was not going to do anything they gave the celebration. Again it was the same sort of thing, the chemists tended to be more conservative both politically and socially and the biologists were always the liberals. Pauling had more of a following in biology, more appreciation in this respect. ...
Dr Emile Zuckerkandl: Here is another paper. I presented this in Bruges. The one thing that is meaningful here is a one-sentence statement of the method of minimal changes for the construction of phylogenetic trees.

Gregory J. Morgan: The parsimony principle?
Dr Emile Zuckerkandl: Since then I found that the parsimony principle had been formulated earlier than this by Edwards and Corvalli-Sforza.

Gregory J. Morgan: Could you tell me more of this conference [April 1964].
Dr Emile Zuckerkandl: Bruges is one of the famous old cities of Europe. It is called the Venice of the North. Margoliash was at the meeting.

Gregory J. Morgan: Was that the first time that you met Margoliash?
Dr Emile Zuckerkandl: No I met him at Rutgers University, but perhaps that was in 1964 also, in a meeting organized by Henry Vogel who was still at Rutgers. That meeting gave rise to the Evolving Genes and Proteins volume.

Gregory J. Morgan: You do not remember anything significant happening at this conference?
Dr Emile Zuckerkandl: I remember a round table meeting but the conference but I don't remember any specifics outside of an opposition to the molecular clock. ... The organizers of the conference were Scoffeniels and Florkin. Actually my own paper reminds me of Peter who denied Jesus three times before the cock crowed. I make a reference to this “self-denial” in the [1987] history of the molecular clock paper. I thought that after all the rate of evolutionary effective mutations in many proteins may well follow morphological change. There was no real proof either way. There was a short time during which my thinking fluctuated.
Gregory J. Morgan: You wrote a very nice letter to Pauling on the eve of your leaving Caltech on the 28 May 1964. Were you at the Sixth International Congress of Biochemistry held between 26 July and 1 August 1964?
Dr Emile Zuckerkandl: We were there. I presented this. When I got up to talk half the people left expecting me to give my talk in French, but I gave the talk in English as planned.
Jane Zuckerkandl: The Abstract was in French.

Gregory J. Morgan: Was the proceedings printed.
Dr Emile Zuckerkandl: No, but the abstracts were. ... The role of proline sites and the way proline sites are substituted
Gregory J. Morgan: Did Pauling attend the conference?
Dr Emile Zuckerkandl: I don't remember him being there.
Jane Zuckerkandl: I don't remember you being with a conference together with him.
Dr Emile Zuckerkandl: Oh yes, surely the one organized by Vernon Ingram. Was that the time I flew in from Mexico.
Jane Zuckerkandl: Yes you were in Mexico City and you flew up from there and then flew back to Mexico.
Dr Emile Zuckerkandl: It was Arden House or was it Endicott House? Because here it says Arden House.
Jane Zuckerkandl: Endicott House was in Boston and Arden House was in New York?
Dr Emile Zuckerkandl: Yes. I would have said the meeting was at Endicott House.

Gregory J. Morgan: You write to Dr Pauling The third of September 1964. You talk about the Rutgers meeting and the 1965 paper?
Dr Emile Zuckerkandl: Right. I gave a presentation at the Rutgers meeting and then wrote the paper.

Gregory J. Morgan: Did you add some things to the paper?
Dr Emile Zuckerkandl: I am sure things were added. It turned out to be quite long.

Gregory J. Morgan: Tell me more about he Rutgers Meeting.
Dr Emile Zuckerkandl: This was the one organized by Henry Vogel on Evolving Genes and Proteins.

Gregory J. Morgan: You write " The paper is going to be long ... and from people’s reaction to Paleogenetics I gathered at Rutgers that much needed to be said". Do you remember that "reaction"?
Dr Emile Zuckerkandl: I can remember one little thing. Does the name Ruth Sagan mean anything to you? Several people were sitting together. Margoliash said some things about molecular evolution and then left the group. When he was gone, Ruth Sagan said he will get over that, he is too intelligent to stay with such nonsense. Molecular evolution, what a stupid thing. That is not exactly what she said but that is the gist. And maybe that statement in the letter refers to something like this. People were just not ripe for molecular evolution. They did not see what there was to it.
Jane Zuckerkandl: It was a long time before it was accepted. Even today there is only one person [Walter Fitch] that has been made a member of the academy for work in molecular evolution.
Dr Emile Zuckerkandl: Let me tell you something that happened to me at this conference. It was another example of being scooped. In my presentation I intended to talk about the evolution of the genetic code. I was going to point out that the structure of the code was chosen in such a way as to minimize deleterious mutations. My talk was scheduled after a banquet evening. There was a banquet speaker, and the speaker was Tracey Soneborn. He made exactly the point I was going to make. Even so, I mentioned it in my and Pauling's 1965 page paper in passing without insisting on it.

Gregory J. Morgan: You obviously have to insist on getting an early presentation at these conferences!
Dr Emile Zuckerkandl: I am interested in having written the following, "I wonder whether you feel like giving further consideration to the question of back mutation ..." We discussed this together. I told him that surely one ought to take into account repetitive mutations at the same site as the number of mutations in a given polypeptide chain increases so does the number of double mutations in the same site. Dr Pauling wrote a formula taking this into account.

Gregory J. Morgan: I found this about two days ago in the archive. You reprint this derivation in the 1965 paper. Is this something Linus derived?
Dr Emile Zuckerkandl: My recollection is this. I brought the problem to him. I have never been a mathematician. He worked this out and that formula was used and is still referred to today, but often people rightly say that formula does not take into account back mutations.

Gregory J. Morgan: This was the question I was about to ask you.
Dr Emile Zuckerkandl: Here I seem to suggest to Dr Pauling could you perhaps develop this formula so as take account to the back mutations.

Gregory J. Morgan: The derivation was dated 12 September and the letter was dated 3 September. Yet the letter refers to the derivation. There must be a mistake. This does not make sense does it.
Dr Emile Zuckerkandl: No.
Dr Emile Zuckerkandl: This must have been Dr Pauling's answer to me. Probably Dr Pauling said there is uncertainty with the probability [of back mutations] and so forth and so we do not have to present that to the readers.

Gregory J. Morgan: Wouldn't you think that a chance of a back mutation would be the same as a "forward" mutation.
Dr Emile Zuckerkandl: Yes and since then it has been integrated. There is one thing I noticed with Dr Pauling and mathematical treatments. He had a great drive towards simplicity and would not be interested in things that became complicated, at least in the field of molecular evolution. I can say that particularly because in Schroeder's laboratory there was another worker, Dick Holmquist, who was inspired by seeing Dr Pauling’s and my work in the field of molecular evolution. He went off on his own and developed formulas relating to processes in molecular evolution; substitutions and so forth. I went to Dr Pauling and told him about that work and tried to interest him in it. Dr Pauling looked at it and said that is too complicated. He seemed to imply that it is not worth doing this if it is too complicated. He did not like it aesthetically if you like. But Dick Holmquist got recognized for his contributions. He published.
Jane Zuckerkandl: He was one of the people at the time of Walter Fitch when they were working out algorithms. He did a lot of the mathematical work that was done early on.

Gregory J. Morgan: Here is the letter of 3 September 1964 from Woods Hole.
Dr Emile Zuckerkandl: Uhh, isn't that something. Well Henry Vogel recalls having a very long phone conversation with Dr Pauling in which Dr Pauling indicated to him various corrections to the manuscript which I sent him. The correction for multiple evolutionary effective hits was a major contribution of Dr Pauling’s to the paper published in Evolving Genes and Proteins.
Gregory J. Morgan: Was there any contact with James Crow in the early days.
Dr Emile Zuckerkandl: Nothing significant, I met him, but no I don't believe we really exchanged anything that he would remember or I remember.

Gregory J. Morgan: How did Walter Fitch fit into the picture?
Dr Emile Zuckerkandl: You will find something in that little write up I gave you. I was unhappy with Fitch when he began his brilliant career in molecular evolution because with Margoliash he made a very important contribution. He worked out a mathematically sound method for the construction of phylogenetic trees. I would never have claimed that what Pauling and I had done in any way replaced this important contribution, but I would have thought that the fact that a molecular phylogenetic tree had already been published should have been mentioned. It was not mentioned and later when I met Walter Fitch and talked with him about this, I found that he did not do this on purpose. But in the case of Margoliash the omission had to have been intentional. I had discussed with him molecular phylogeny in one-on-one conversations and of course he knew of our 1965 paper.

Gregory J. Morgan: Fitch was not aware of your work.
Dr Emile Zuckerkandl: That is right he had not been aware of it. So then we developed a long fine active relationship scientifically and personally. And then eventually Walter with Masatoshi Nei decided to found their own journal, Molecular Biology and Evolution. At that time Walter left JME as an associate editor.

Journal of Molecular Evolution  Return to top of page

Gregory J. Morgan: Did you have anything to do with the beginning of the Journal of Molecular Evolution?
Dr Emile Zuckerkandl: Konrad Springer and an associate of his came to Montpellier to ask me whether I would be the editor.

Gregory J. Morgan: When was that?
Dr Emile Zuckerkandl: 1970, because the journal began in 1971.
Jane Zuckerkandl: In my recollection, but it might be wrong, the first contact you had with Konrad Springer was in a meeting. ... It seems to me that it was in a meeting in Belgium. And Ponnamperuma was there. And it was connected with a tripartite conversation you had with Konrad Springer, Ponnamperuma and you. And Jukes had been somehow in this. Ponnamperuma had dissuaded Konrad Springer from turning to Jukes to organize the journal. You were there and he asked you. And then later after the first step was taken and you had given your O.K., he came to Montpellier to see you.
Dr Emile Zuckerkandl: Well I told you that Jane had a better memory than I.