Phone talk with Jean-Marc Lalouel

    (Howard Cann et al., 20 sept. 2010 at Génopole d'Evry)


    DR

    Howard Cann : Jean-Marc, I think I told you already that there was an international program to document the history of the genome project.  It is divided up among countries that were involved in the genome project and of course Paris, France, as you know better than I do, was very important in that story. For which, sure we appreciate your help. May I ask an introductory question: you are an MD, is that correct?

    Jean-Marc Lalouel : Yes.  I am a MD and I have a Doctor of Science degree in quantitative genetics. My MD was from the Faculty of Medicine in Paris. At the time, there was a single faculty of medicine. I got my degree in 1970.

    HC : After your MD, what did you do ?  Did you take a residency or an internship?

    JML : No. During the last year of my MD, I actually did graduate studies. I did it twice or three times. I forget exactly what kind of stuff.  That was in quantitative genetics.  Gustave Malécot was teaching and he was really my mentor. Well, I am considered in the US as one of the few students of Malécot. I am actually the only one remaining active.

    HC : So you spent how many years with Gustave Malécot?

     JML : I spent that one year and I actually went to visit him in Lyon. A l’Ecole Normale Supérieure (qui n’est ni normale, ni supérieure…), il y avait Gustave Malécot qui venait de Lyon trois fois par semaine et qui enseignait la génétique quantitative « à sa façon », c’est-à-dire la théorie probabiliste de la génétique qu’il a inventée quand il a écrit sa thèse en 1948.
    It was to be close to him and I went back and visited him. I went away and when I came back in 1972-73, I went and visited him again. I have always stayed in touch with him, because I think I am one of the guys who really clicked with what he did. When we went into publishing with genetics, with Newton Morton in Hawaï, I was clearly considered a student of Malécot. It concerned the models he had done. I related by these tests. It involved migration, subdivided by population. He was the man who introduced heredity theory in genetics. He replaced the approach of civil rights which clicked with his theory, the theory of probability. He published that in his thesis of mathematics in Lyon. (But) il was in French and nobody cared about this stuff.

    HC : Apart Newton Morton, who rehabilitated him?

    JML : It was the demographer Jean Sutter.

    HC : What happened after that fourth year in medical school?

    JML : It was not like that at the time. It was one hundred years from what they used to call CPOM 1.You would have 3,000 kids starting out. Then after a year, they dropped out. Then we went for 5-6 years, I forget.  Then they changed the whole thing. …./  I did my clinics in the last year. During that year, I did the “troisième cycle”.  It was applied quantitative genetics. It was École Normale Supérieure. I think it was Lamotte, but I forget.  It may have been Guy Lamotte, an analyst guy.

    HC : And after medical school and the work with Malécot ?

    JML : I was on a waiting pattern, as a post-doc, with Newton Morton in Hawaï. Hawaï has nice weather; I come from Africa and I like this kind of weather. It is tropical. At the time, Newton Morton was the leader in my field, quantitative human genetics. He also had the personality. I do not know how much you know about Newton Morton, but he was a very arrogant and aggressive individual. I had the same attitude. Well, no, we had constant fights, but we got along, because we knew each other. We argued with him all the time, because he would always argue the opposite case to mine. Every day, he would change. He would argue A and I would go with B; he would argue B the next day and I would go with A. If you were in a bad state, you would change your opinion. I would just go surfing and say, ‘I am coming back when you are gone.’

    J.-F. Prudhomme : You have been trained in mathematics and in statistics?

    JML : I read mathematics for fun. I actually have quite a collection of mathematics books and I am taking some of them to my island. I like the numbers theory; which is useless.

    HC :  How long did you stay with Newton?

    JML : I went to Hawaï, came back to France for a period of time, of a year of two, to write my Doctor of Science degree.

    HC : When was that ?

    JML :  The date was 1975. I remember the thesis was printed on both sides and when the committee met, one guy opened the book and then he turned to the other guy and said, ‘You know what?’.  He opened my thesis and then he turned to the other guys of the committee and said, ‘It is printed on both pages.’ The guy never read it (!). It was basically about multi-dimensional scaling, methods to represent local differentiation of population (thesis title).

    HC : Who was it ?

    JML : It was the maths teacher, Elefort . He jumped on me because he hated the fact that I had so much mathematics.  He was also a teacher in the Diploma of further studies (DEA) that I did at the time. It was from the Marie Curie University.  At the time, it was Paris 6.

    HC : Was that in the department of anthropology ?

    JML : No. I have no idea. I have no idea where it was actually. It was at the École Normale Supérieure. I obtained it there, because of the professor, Lamotte, I forget his first name. I do not think it was rue  d’Ulm, or at Paris 6.  It was basically a bunch of guys. There was Didier; there were all kinds of guys who were from the École Normale.  They were from agriculture. Mostly engineers took that degree.

    HC : At that time, were you involved with Josué Feingold ?

    JML : Not very much. I think he was teaching clinical genetics a little bit. I have never been too close to him, but I knew him well, of course. I think he was teaching us as part of this DEA. He probably had a few classes in clinical genetics. That is part two, after Albert Jacquard. That one was teaching us some kind of population genetics that he had written this book on.  I took a counter in my MD degree. I write my own version of population genetics. After the MD, it was published as a book. I did not find that the theme that he was selling, of folding diagonal matrices into triangles, was helpful at all, because you could not do linear algebra.

    J F Prudhomme : You published a book in l’extension monographie des Annales de génetique.

    JML : Exactly. They published it for free, because my grandpa used to own it, my grandpa was a famous gynaecologist.  (So) it is my own digestion of population genetics, if you wish. However, it is obviously more influenced by Malécot than by Jacquard.

    HC : Now, after you got your degree, did you go back to Hawaï ?

    JML : Yes, I went back to Hawaï to work with Newton Morton and at that time I got really serious about numerical analysis. I got into complex digital analysis big time and then I got into molecular thinking.  I just started thinking about it. I was with him until 1980 and I was doing complex aggregation analysis, complex model analysis. That was a fun model, but the power resolution of those models in practise was questionable and that got us into all kinds of fights with people who were active in the field. Newton Morten enjoyed fighting people. That was a political stage; the science was great but I think the politics were not very helpful. That was a good training ground for what we did later on. At the end of this, 1980 or 1981, I decided to go back to France. I wanted to try. I am not sure that I like France. I grew up in Africa. It is fine to go to medical school. I just wanted to try working in France. I arrived for a Chair at Paris 7, in what was then Human Biology and they wanted to change it to molecular genetics. I had repeatedly given Marc Fellous my opinion about that. 

    HC :  You beat out  Marc Fellous…

    JML :  First, my application was thrown out. I was supposed to drop it in past the deadline for applications, but André Langaney, who was the head of Musée de l’Homme, was acting on my behalf. He knew that I was not wrong, so the whole thing was broken up at a high level. I ran again.  I got that job and the first meeting we had was among professors at Paris 7, who actually created a position for Marc Fellous.  It was human biology in Paris 7 circa 1980 or 1981. The idea was to change that. They were looking at a bunch of candidates. They are all physical and pathology. There was Olivier and Gianno. They were good gentlemen. What they were representing in large part were different fields. The idea was to get molecular. I remember that I transformed the bathroom, I made the bathroom unisex in the department, because I made the other one for radioactive substances. All right, we are up to 1981 and 1982 now. Basically, at that point, Mark Lathrop was the post-doc with André Langaney at the Musée de l’Homme, with a scholarship from Canada. I do not know where he came from. He had gotten his PhD in Seattle with Rick Ward. Ward worked mostly with Joe Felsenstein, because this one was a more mathematically-person. (Lathrop) had done his thesis on the impact of errors on pedigree reconstruction on genetic inferences.  What we did was practical, because we did some good stuff. It was very abstract, but we hit on one thing and said ‘Okay.’  There was all this marketing coming up, with the Mark Skolnick paper and Skolnick, Ray White, as well as David Botstein.  After that famous paper, I was totally obsessed with this idea. Would we be able to map the human genome, at least to generate a linkage map? Instead of doing it using a pairwise linkage, we could just mark it at the time. We even could get more power using mini-markers.

    HC : There were multiple markers. That was about what year ?

    JML : It was 1983. In 1982, we talked about it, but we were doing other stuff.

    HC : When you say, ‘We talked about it,’ was that with Mark Lathrop?

    JML : Yes. That was with Lathrop. He came over and was interested in the stuff I was into. He was writing in Pascal when I was writing in [Fortran ?] , so he was of the younger generation. He had a better language. We said, ‘Let us do this thing for multi-locus mapping.’ The advantage of Pascal is you could do recursive programming with it. We could have sub-routing, calling each other. It is critical to do general pedigrees. At the time, people were signing down pedigrees, like Bob Nelson and so on.  Or there were even people in Utah. They were signing down pedigrees.  In Fortran, you did not do port cubing, going up in the genealogies of going down at any point. Okay ? By adding sub-routing, we could call each other. You were able to recursively apply an average essentially to what we call an arbitrary pedigree, as opposed to signing down and trying the other pedigrees, one ancestral copy.  The Pascal language was very helpful, but C was not really known at the time. Pascal was a very good teaching language, very clear. I had learned it in two days. I remember that Mark Lathrop and I sat together.  We always sat together. This is really something we did well when we apportioned it. When I talked with him, he found it evident that we would have more information with multi-locus mapping at which two genes. Later on we did prove that, from a formal statistical standpoint. First, we implemented the stats. We spent five days sitting in front of a computer and using a blackboard and we just about had it done.  This was the multi-point.

    HC : Was Mark Lathrop a post-doc through all that time, with Langaney, or did he come to work with you formally?

    JML : He was a post-doc with Langaney during that time, but I do not know what job he had. I think Langaney saw well that he would work with me, because he found that I was in a better position to engage his talent.  I have a very good relationship with Langaney. I went in with him in mind and he is still alive.

    HC : What is fair to say about Mark Lathrop ?  It is not clear to me. Do you consider you and Mark to be equal on the development of multi-point, or were you the master and he the worker. What is fair here?

    JML : There was not a sub-division of labour in this way. It was more the American way. I can certainly see fewer groups engaging with multiple loci now that Mark has mapped chromosomes more intensely. They would not be able to use the information for multiple markers. We had a low degree of accuracy at the time, so we knew that it would be far more informative to combine multiple markers. We came up with several of those locations for that added block at the time. This was instead of using multiple loci. When I talked with Lathrop regarding that, I think it did not take very much, he just saw it in his own mind that it made absolute sense.

    HC : You took him on in other words...

    JML : I had conceptually initialised and taken it. I think that we should have apportioned initially what we did next, because although I was the older guy, I was the boss, we wrote this together. I would not really consider myself as an old man, but that that was my last paper and I had to do my last paper.  When we wrote a Proceedings of the National Academy of Sciences (PNAS) paper on that in 1984, we signed it Lathrop, Lalouel, Julier, Ott.  [Inaudible] - he signed with us. He did not do much, but he was the guy who went on to look at linkage with and we liked him. Everyday thought that he was a senior author and we had worked for him. The lab was at Paris 7 in Jussieu, a dreadful place in a tower. 

    HC : For me, that is very enlightening, about the story of how you guys got multi-point started.

    JML : By the way, Newton Morton said, ‘I will prove that two looking out is and you do not need multiple linkage.’ He eventually published a paper with Torrance McLean. He hired a mathematician to prove a paper that was obviously wrong.  All the information for linkage was contained in pairwise. That is the bottom line. Actually, I am doing a presentation here when I leave, about how great it is to be Number Two. I have always been Number Two in my life.

    HC :  Let me ask you a question. There is another author on that PNAS paper and that is Cécile Julier. 

    JML : Cécile Julier was a DEA student. The other thing I did was, I started a graduate programme, which was the DEA. This was facilitated by the Government. It was in molecular genetics and mostly covered physicians, people coming from medical school. This was taken over by Marc Fellous and Alain (?). It became very popular and it covered everybody doing genetics in Paris, all the way to Strasbourg.  We had, what is his name, the guy up there ?

    HC : It was Jean-Louis Mandel.

    JML : Yes, we had everybody involved in that thing. I think that was very good. I enjoyed it. We wrote the form; we wrote the rules of the game. Part of this involved updating this and that and the politics of all that stuff. I had all the socialists and the right-wing guys, because at the time, the environment was incredibly political. I am political like that. There were so many people; there were socialists and there was the extreme right. They did not like each other. I was nothing; they did not know what I was, so everybody signed up with me. That was really cool. I loved it.

    HC : We heard about a group that you organised; maybe that is it. You talked a lot about a group for polymorphism markers.  Does that say anything to you ?

    JML: I was involved  with that. I do not remember exactly where it went, but that was one of the turning points in getting this DEA place. To get it approved by the Government, you had to go through all kinds of forms and all kinds of things. That was an enormous amount of work.

    HC : Cécile Julier  was one of the students.

    JML : She basically did the computations for that, but she was very smart.  She went from École Normale Supérieure. She was very clever. I really loved her. We got her to work on handling the data and she was smart enough to understand what we were doing. Then we invited J Ott as a courtesy, because we did not want to wipe him out of the field. He got plenty out of it, because most people said, ‘You were working for Jean-Marc?’ At the time, I was not ready to sign labs. Later on, when I came here, to Howard Hughes, I became a senior author, at the ripe old age of 41.

    HC :  Now the question is when did you appear at CEPH ?

    JML : Here is how it goes. We started doing this linkage mapping and doing these genetic studies with complex genotype, right? It started with Jean Dausset. We were studying several human diseases with him and stuff like that. At that time, the way it happened was, we knew about this lady (Hélène Anavi) that had bought paintings from him when he was running this art gallery when he was in medical school, way back. She made a phone call and said she was dying and would leave money to him when she died.  She was an American lady; that is all I know. Daniel Cohen was a resident. He was fairly young; he was skipping a generation. Daniel was a very clever, smart guy. One time, we met with Dausset. We had talked a little bit about linkage and he knew what I was interested in. Dausset said ‘Let her on,’ so two weeks later, it went pretty fast, Dausset got a call saying she died  and there was a substantial amount of money coming his way. What Dausset decided immediately was that he would like to dedicate each family. These are the families.

    HC : With these Dausset did Human Leukocyte Antigen (HLA).

    JML : He worked on these families and basically, he talked about activities. It was by doing heterografts, from one person to another. He was grafting the skin.  It was somebody from the US [i.e. Felix Rappaport].  It was obvious there was no IRV; that was way back. These families were extremely loyal to him. He realised the significance of large families for genetic studies. He had this vision. However, what he wanted to do was to donate to the international community. With this resource, he wanted to make a foundation and donate these families for association studies. On the one hand, he was far ahead of his time, because you could not do association studies with the mini-markers we had then. You had to do linkage; you could do linkage because you could come within centiMorgans but you could not come within the systems where you had linkage material. It was not the time of association studies. He was interested in HLA and disease.

    HC : They would get controls; they would get patients.

    JML : We had meetings; we had discussions, Dausset, Cohen and I. We were talking about stuff. I think it came from me. I went into linkage. I said, ‘If everybody were to use what I see as linkage rather than association, if everybody tied their markers on the same family, then evidently we can combine the data from different laboratories to generate maps. We can do multi-locus amounts.’ The concept wa3 eviDenu, that if we were to tie the same families, the information could be used for multi-locus linkage mapping. We explained the recommendation to Jean Dausset, who got it. We explained the recommendation regarding linkage to him and within the realm of what could be done with [ it ?]

    HC : What year was that?

    JML : It was 1982-83. When we were writing this linkage program, we were targeting this. I would say that 1983 was probably the time it culminated.

    HC : This was when you talked with Dausset and Cohen?

    JML : Yes. This was at the time. Daniel made [inaudible]. Dausset was more focused on trying to get his subject matter, which identified minor details [inaudible] systems of association. These were associations across the genome. Essentially, we managed to convince him.

    HC : I do not want to put words in your mouth, but it sounds to me like you brought this idea over to Centre IM and you talked to Cohen about it. Then you guys presented it to Dausset together.

    JML : I think it is fair enough to say that. Daniel was very smart and he caught on right away. The good news was, was just driven by science and not glory. I had to write it with Daniel. I thought he was clever, smart. He had Dausset’s confidence. I was interested in getting stuff done. When I am done with Daniel, he immediately saw the stuff. He basically took over. This was with Dausset. They set up this thing this time, focused on recommendations. The families would be the French families. Now, in the meantime, I was on the phone, first for half an hour, then for an hour, two hours a day, with Ray White in Salt Lake City.

    HC : How did you get together with Ray White?

    JML : It was because he was developing restriction fragment length polymorphism (RFLP). He was the original guy in this and he was ahead of his time, of us. He had his own American panel of Utah families in mind. He had actually chosen pedigrees at first. He did not choose families; he chose pedigrees. Initially, they felt there was more information in pedigrees. I was not with Ray White. First, I convinced him by phone that only certain information was needed on the recommendation. You get straight information from the grandparents and recommendation formation from the siblings. You could break pedigrees into nuclear families. The trends at the time were helpful in getting fate. This was statistical information. All he had to do was a probability assessment. He did not have to infer it. Ray got the point and then he did not know how to do the mapping, so I said, ‘Well, we will develop a method. We will start doing maps.’ In the first map we did, I think we had five markers.

    HC : You know, you got to start somewhere. Tell me something, how exactly did you get in touch with Ray ? Did you contact  him or what ? 

    JML : Actually, what happened was, I knew Mark Skolnick, who had come to Hawaï in 1978. I had developed a method of minimising function without completing their images, any complexion. In the likelihood of anything like right through their pedigree, or any complexion thing, all you had to do was disperse their images. From these, you could infer information that was taken from their image, secondary insight information. This stuff was called Gemini.../ Mark Skolnick and I went surfing. When I went to interview for my French job, Mark Skolnick was generous and he invited me over on the way, so he paid for part of my trip. He invited me to stop over to Salt Lake City. That was 1980 or so. I stopped by; I met Ray White. They were friends, but in different departments. Mark Skolnick was still at the LDS Hospital. We are still good friends.
      
    HC :  Okay. You met Ray White in about 1980 on your way to Paris, so to speak.

    JML : That is where I met Ray for the first time. He was shy and a very big guy, as you know.  I think he was intimidated by guys like me; who never stop. I do not shut up at any time; you can see that. In any case, I think somehow he did know from Mark Skolnick. I clicked up there and I was good at conceptual stuff. I think we developed the linkage-mapping stuff, I had already got it done with Ray. I said, ‘Look, we have got the method of dealing with your problem.  We have got the markers; we have got the mapping tools.’ We have got the software. At the time, we were installed at the new College of France, which was close to the Pantheon. We have got a really nice computer. You work in my booth, because that resolves the need to buy a Hewlett Packard and a Mac. We eventually bought an HP. We were working there and I was no longer going to Paris 7 (UPMC), because the politics was so bad.

    HC : I am interested in your ideas about the connection, how Ray and CEPH got together. What happened there?

    JML : I was communicating on a very regular basis with Ray by phone. I was spending hours. He was calling me because he had an unlimited amount of money from Howard Hughes. I mean, it was unlimited at the time. He would call me and we would just talk. In the end, I was already ready to leave. I was ready to leave for the United State and they had already made me a job offer with Howard Hughes. I had taken a job at Washington University. I was actually a tenured professor at Washington University for two years and I never joined, which was kind of funny. Still, we were talking and so on. Then we realised; I turned to Daniel and said, ‘Look, I am talking with Ray and they have a panel of families, or pedigrees, which are a bit  different from ours and so on.’ When we started talking about the notion that these families could be on a panel used for genetic mapping, the idea was to share this panel with international communities.  Both Daniel and I had this opinion.  Certainly, that concurred with the view Dausset had.

    HC : Okay, so the idea came from you ?

    JML : No, the idea came from both sides.

    HC : It was from the French side.

    JML : It was Dausset’s desire to share that with everybody. If you do it, if everybody that is running markers runs them in those families, you could do multi-locus linkage, based on data, across all areas. However, you had to find a scenario to negotiate all this stuff. We started talking about it and we sent it. At that time, when this idea was pretty well-gelled in France and we agreed to do this, we sent letters to everybody, including Ray White. We have looked at seven panels of families that I wanted to share with the community. We would prepare DNA from those reference families. They would be families with large sizes, appropriate for mapping. We would generate a database; we would provide software to handle the database, for central return of the database and redistribution to the participating laboratory.

    HC : That is the story of CEPH.

    JML : Right. We would also give them linkage tools and all that stuff. This was with Mark Lathrop. The one guy that was certain, among the people we contacted, there were all kinds of guys and they got their bits. There was Ken Kidd; there was Gareth Forsyth. I had met Gusella before in Paris. I was known a little bit in the field at that stage. I was somewhat connected, just because of my student status with Newton Morton. All those guys entered and were excited. They saw the point of mapping the same families. They saw the economy of scale. They saw the economy of having all the tools, the same database and getting the DNA, that would be shipped by mail to them for free. There were multiple sites, but Ray White entered and said, ‘All right, it is a great idea, but we are doing this here.’ This is how much he had; at the time he had about 80 mothers and sons. In retrospect, this was not much, but at the beginning, compared to the 30-plus [inaudible] we already had, it was very impressive.  We were kind of intimidated by him. He was switching pedigrees. He would define the typical American position. We took the French position initially. It would be fine to have a panel in the US on one hand and then a panel in Europe. There would be regulations [inaudible] in this way. He did not want to participate initially, because of guilt. His view was he did not want to share families. Daniel and I were not happy. I felt, never mind politics, it did not make any sense to have two different panels and two different bands. Daniel would say, ‘All right. We have got to go out there and meet Ray White and we have got to convince him.’ I do not know how much you are going to write about this, because there is some good stuff. I will leave it to your good judgment to determine what should be public versus not public. It was somewhat [inaudible]. It came out well for Ray. What happened was, we contacted Ray by phone, right.  Daniel and I set out in the fall and winter of 1983. We decided we would have to meet Ray first hand. We decided we had got to talk to him and tell him that it did not make sense not to share families and all that stuff. We got to talk to him. I was on the phone with him and eventually I brought in Daniel. We said, ‘Come on, let us meet and talk about this project. We would really like to find a way to put this together.’ We decided to meet at the Miami Winter Symposium.

    HC : You and Daniel went to Miami and put pressure on Ray.

    JML : Daniel had a cousin. You know Daniel’s background, right? He is Jewish and from Tunisia.  Everybody is a cousin or an uncle to him somewhere. He had an uncle running a big hotel that was being renovated in Miami Beach. I think Daniel and I were the only guys in this hotel; that was really cool. We waited for Ray White to show up for three days during this Miami Winter Symposium. We did not want to attend any lectures. I myself have Attention Deficit Hyperactivity Disorder (ADHD); I cannot listen to anything. We did not want to attend. Then Ray showed up and then he was walking around and avoiding us.  He was very shy. It was very interesting; he was shy. I think he knew what was coming up, that we would have to have a meeting and make a decision and he was avoiding it. At some point, we cornered him and said, ‘Let us go out to dinner.’ We had dinner at some Japanese place; maybe it was Benny Hanna or something. I think there was a substantial amount of drinking going on at that time, which helped loosen things up. It is the tight scientific mind. Ray got a little bit soft and we basically bluffed him. He was with Howard Hughes. He was to get  Muscular Dystrophy Association (MDA) money to do his mapping. So I designate [inaudible] all we had to say, we had it. The painting collection had gone to Sotheby’s. There were a few messages in there and so on. We thought there was tones of money. We bluffed him and we said, ‘We have unlimited resources and we are going to throw them all into this stuff.’ I think Daniel has a lot to do with this. I am more political, which is, ‘All right, look, we are going to take the French flag half way down and the French flag halfway down. We are going to find a compromise and define a panel that will include some of Dausset’s families and some Utah families. We will convince Dausset’; that was my plan, ‘we would convince Dausset of the advantages of Utah families, who have grandparents that have great information.’ It was very important at the time, in completing linkage in multi-locus mapping. Ray’s information was important.

    HC : The grandparents were a big discovery for Dausset, I will tell you.

    JML : Yes, he did not realise it was important because it was not relevant for association. However, it was critical for linkage. You had a lot more power if you [inaudible]. We showed them that to get face, you had to use one child. You would get some information which is substantial because on the [inaudible], it is very substantial. We convinced Ray that it would be nice to put together a panel to get this association. We would be running the show together. We would have a board, whatever way you want to describe it. He would join us; it would be a joint effort.  He would be a member of CEPH, the Department, whatever it is. He said, ‘Leave it with me. We are going to talk to Dausset.’ Daniel and I were there. I was confident that I could argue the science with Dausset.  Ray said, ‘Look, we can find a compromise and we can use my families.’ We wanted his families like mad, because even though they had pedigrees, they would have to be split up, because that is more informative to do so, and as you know, some of the Utah families initially had 12, 29, whatever it was, or 13, 29, one, or 29, two. They were a subset of a larger group. They were kindred. We broke them up and we decided to do a panel.  I said, ‘Look, we will find a compromise.’  When we went back, we discussed it with Dausset. The panel size was not determined, but we discussed it with Dausset; we met with Ray. He was agreeable to participate so long as a substantial amount of Utah families were used. They had the advantage of having grandparents and a bunch of markers being run. Then he got resources and it would make no sense that there would be differences between the US and French families.  At the time, Dausset was very understanding. He immediately saw that it was the thing to do. We made a final compromise and the compromise basically was this. There were 10 French families.  We did it ourselves; we determined, we did about 40 families. We had all kinds of discussions; there was the sample size. Given the degree of heterozygocity of markers at the time, a typical sample size was needed to decide what could be done and what was affordable. You typed parents first, then you typed kids. We said there were 40 families; that is eight offspring.

    HC : Tell me, how did you happen  to choose 40 families ?

    JML : It was based on theoretical calculations. We did power calculations with Mark and we figured out what it would take. Ray had some input of his own. I do not want to put him out of that. I think it was more formal. We had real theoretical justification for the sample size. Other people had a shot at it and he needed to see whether it was necessary to do such large panels for what he needed. Then at the time, it was considered very large. We felt that it was very necessary to do close families, okay ? We decided on of 40 families; we added 10 French families to that. There were 27 from Utah.  Then you would wonder why the heck we got three other families. Jim Gusella wanted us to include the pedigree from this Lake Maracaibo. This was in Venezuela mapping Huntington’s chorea. He had the core issues in the middle, right ? There was Ken Kidd and his family of Amish pedigrees, in which he was mapping whatever. Who know what he was doing.  It was something like that, I forget. Most of those who participated insisted that we include their nuclear families. The core took shape, which it had apparently done in a lot of markers. We ended up doing this for political reasons. It was politics; sometimes you do things for political reasons. We declined. We included the pedigree from Venezuela. The core of the pedigree took shape. It included [inaudible] for Ken Kidd, otherwise he would not participate, you know ? This compromised on what you could say was the homogeneity of the panel, but at the time, we did not really care, because it would only affect g frequencies. However, the segregation advent would be informative in general; it did not quite matter. The political things really far outweighed the scientific notion at the time. I was not really positioned, so it was the right thing to do, to make those guys part of it. We could not do this without having those guys as part of it. I think Cavalli-Sforza was also using some of Ken Kidd’s families to do his family studies. We also made sure we had some of Cavalli’s involvement. Basically, ahead of the CEPH meeting, we were pretty much set up with CEPH.

    HC : Let me ask you about that. The CEPH meeting was on 20 October 1984.

    JML : Yes and you will see; I will send you a book with all my notes preparing the stuff, including the meeting we had with you. There was Jean Dausset, Daniel and Howard; I was the Chair.  I think this was nailed. I was smart enough not to make any decision on my own.  The idea was to defer it to a decision that was not imposed on our side, but something that would be set up at the meeting, even with good politicians to prepare the ground.  We prepared the ground. I talked to Jim Gusella. I know him, because I helped him get pedigrees in Sardinia; I forget what it was. It think it was Huntington’s chorea. I knew Ken Kidd; I talked with him and we said, ‘Look we are going to talk about this at this meeting.’ We had the decision that we would have that meeting and by that time, I think he had come over.

    HC : Tell me something, what else do you think we should know about?  We want to know how the CEPH project got started, the brains behind it, the science behind it. I think you have given us a pretty good insight into that. I knew a lot of it, but I did not know all of it, Jean-Marc. Let me ask another question : you went to Utah in what year, 1985 ?

    JML : Yes. I moved to Utah. I visited in June. I was recruited by Howard Hughes; I was the 13th scientist recruited in genetics at the time, I remember that. I was recruited by Howard Hughes, by George Cahill at the time. Don Fredrickson was the Head of the Institute and he was into hyperlipidaemia, so he understood common diseases. I came to Utah to make a speech on why we would be in a new building and dedicating the Utah effort to mapping complexity. It would be a genetic analysis of complexity. I actually made the presentation. Then I came back to France and I think I moved permanently in September or October. It was 1985. I was in France for the year we implemented CEPH.

    HC : After you went to Utah, you and Ray worked together on mapping.

    JML : Right.

    HC : Then Lathrop came over too.

    JML : I did not dare to invite him to come, because he did not want to go to the United States for political reasons.  However, given the scientific merit of what we were doing with Ray, he offered to come. He came with me as an associate and he stayed.  By the time he left, I did not want to do any mapping in equal running. I like to change now and then. I am full on in essential hypertension. I am done with this stuff.  I was tired of all the linkage stuff. I did not want to do mapping any more, anything of this kind. When Lathrop returned to France, he returned with a whole package. The picture was of a very large-scale thing that Ray White was doing.  I was interested in going small scale. It was all this mapping stuff.  There was linkage which worked out at something like USD 160,000 a year.  It went into 600 laboratories. Howard Hughes has become an enormous production. Then we had to develop it. We had to worry about the software that we would give you guys. In the end, I got tired of this stuff, you know. It was becoming more about management than scientific discovery for me. I wanted to focus on finding genes in essential hypertension. I said we would look at three and I found one interested. It was the end of the story of my involvement in mapping then. I was in a separate lab from Ray, because was he was head of the [inaudible] that year…/  I actually went back to France to have meetings with Pierre Corvol, because I really got into hypertension and Xavier Jeunemaitre came into my lab. He is now a big shot in hypertension. He is a real gentleman. He came over.  I trained Rick Lifton. I am very proud of one thing. I have trained people who have achieved more than I did. You take pride in this kind of stuff. There are not that many people out there who can say this kind of stuff. You look at people like Mark Lathrop and Rick Lifton. I have trained people in Japan that have done very well. I am proud of it. This was good stuff. I was very happy about this. I have moved on. Then I gave [inaudible]; obviously that did very well. I think I was some kind of mentor to him in some kind of ways. This was what I gained out of that. I was not interested in disease any more after that, not trialling anymore. I just dawdled; I was bored. I was away from all this [inaudible]. I knew I did not want to get involved in sequencing.

    J F Prudhomme : Why did you decide to stay in the US?

    JML : That is interesting. The little experience I had of working in France was that you would get minimum wage, because I had no seniority within the national education system. I became Chair of Human Biology. That is off the record; that is the reality of things. I had a minimum salary, because I had no seniority. Assistant professors were in their 40s; I was 35, 36. They hated me and they were paid twice as much as I was. This is why I went into psychiatry. I went to do my board certification for psychiatry with the intention that if I stayed in France, I would practise psychiatry on the side.  [Inaudible]. I would not make it sometimes. Then with Howard Hughes it is completely different. I got [inaudible], I got things, I am part of a company here. I have got things going on involving discovery. I did find that the dynamics for innovation are incredible in this country. This is why immigrants are here and that is why the country is strong. I did not find it possible in France, not having connections, not having grown up in France, not having been part of things. In surgery, I had one mentor, but as I moved away from vascular surgery, that mentor was not helpful any more. This was my interest; vascular surgery was my focus. Jean-Michel Cormier was the top guy in the field. I was doing private practise with him, in the clinic with the nuns. We were in surgery and all the nuns would cross themselves all the time. That was when I was in medical school. The reason I did not want to come back to France was, I personally felt that the opportunities for independent enterprise was not what I had experienced in the US. There is no question about it. Where did you arrive at these numbers based on your [inaudible], was there not ? There was no question. As a Howard Hughes investigator I got paid four times what I was paid in France.  Actually, now I can retire, even when the market is at its worst. Most people are staying and not retiring. Some guys are going to die on the job here, because they do not want to retire their lifestyle. They look at the stock market; it has gone down, their pension, whatever.

    HC : Jean Marc, is there anything else you want to tell us, about CEPH, about your career ?

    JML : There are just two things that are very important about the CEPH meeting. First, David Botstein was very instrumental in bringing people into line with his authority and the sharpness of his intelligence. David Botstein is one of the smartest guys I have ever met.   He realised the merit that there would be in typing all 40 families no matter what. The critical thing was to sell this down the road. People were doing small-scale studies and just wanted to type the families that served their purpose. In brief, he was very helpful in getting this collaboration going.  On the other hand, we did do one thing. There was a Trojan horse that we got in at the time, which was Collaborative Research, Helen Donis-Keller. The idea was, we should not exclude for-profit companies. In retrospect, I think that was a mistake, for the non-profit people. It turned out to be a competition in the end, between Donis-Keller and Collaborative Research.  They were full members of CEPH, but they had different lines of interest. They basically almost split up; they [inaudible] the publishing side was the first move. I hurried to the human-mapping meeting in Paris.  I rushed through some mimeographed copies of all the Utah maps. Somehow, there was a more substantial report or a greater deficiency. You have a deficiency when you have a Board of Directors, which wants cost effectiveness. It turned out to be a competition between Collaborative Research and Ray White.  There were some sad endings there. Maybe we made a mistake there. I do not know; I would say that is a question that one may ask. We have this sequencing effort; that was a National Institute of Health (NIH) effort. The next thing you know; what is his name?

    HC : It is Craig Venter.

    JML : Yes. Craig Venter went his own way the last three years. He found out that you could just do shots and sequencing. Then he beat the NIH. If we had Craig Venter and his company at the time, you would have blown them away. We lost a little bit of the credit that CEPH as a whole would have got as a global collaboration, publishing their concerted maps in a really nice way. We had to press to publication of maps before we were really ready. This was in terms of this international collaboration, because we had competition coming from within, with Collaborative research. This is a thought I would like to add.  It is always difficult to negotiate these things. We thought it was the right thing to do. I do not want to say it was wrong or right, but it did return to everyone that was within CEPH. It was not the best return for them, because all of a sudden, it became more of a competition between the Utah group and Boston. The bottom line is, through the initiative of individuals: Dausset, Daniel, you and me, Mark Lathrop, Ray White and so on, the first genome collaboration was set up internationally. This was free enterprise, without the intervention of Government. This was our own initiative.

    HC : It is interesting that you say it was without the intervention of Government. The French Government really want not involved, was it ?

    JML : No, they were not.  All we wanted to do is included in my book. There was John Maddox, the editor. He was the editor of ‘Nature’. I was going after Maddox; he was right, we knew his views on CEPH. He was supposed to come to the 20 October meeting. He did all the other stuff, but then he did not show up. They only mentioned us when we tried to look at something that was getting the core state people out there. These were the people in positions involved; it was just for coverage of the effort. We wanted the exposure. I felt it was critical; he could write it nicely, I had good contact with him at the time. I had some reputation. If he had come and covered this stuff, I think we would have had better exposure. There would have been much greater reward to Dausset. Maybe some of the issue of profit versus non-profit would have been clarified; I do not know.

    HC : This is the last question. What was the role of Jean Dausset in the collaboration ?

    JML : First, Jean Dausset was the person who instigated the work. He was the gateway to the international community, the panels that were to be used for scientific discovery.  He gave the concept. I think that he, foremost among us, had the vision that he could contribute these resources, which he could have put into his own research in his lab. He decided he would do an international thing, giving his families, giving something up for other people’s return. I would say the greatest concept  that came first was that one.

    HC : Do you think that was Dausset or Cohen ?

    JML : That was Jean Dausset’s vision, no doubt about it. Jean Dausset’s vision was to make a non-profit organisation with his funds. He wanted to have people work together using resources. He already got a Nobel Prize in 1980. He wanted at least to have a legacy. I think he was almost philanthropic, in the sciences. The biggest vision came from there. That was the most significant thing. He got to the point of determination. Initially that was not his life and his field, but he got it.  I think that everywhere, he was very excited, but I think that he gave a lot of free rein to Daniel and in what we could do. We had regular meetings and when he came in, you were at those. He was dealing with all that stuff, but he was dedicating a lot. When it came to technical studies, he said, ‘Those young guys know what they are talking about.’ He did not bother about how we did our work. It was stuff like that. Neither did I. I would delegate to Dausset and stuff like that. Even in his 90s, he had a handle on how to lead large projects. He initiated a great concept. We discussed so much that was important, but he was focused in this direction that seemed to be most profitable at the time. We totally agreed with him, he showed a flexible mind which is rare in leaders. Then he knew that we were pursuing the right thing and he was determined and very enthusiastic. He certainly made an input everywhere thereafter, but I think the most significant one was what I describe. As a person who is fully confident in himself and who has had a successful career, he understood how to defer. We were two people that were not in his field of expertise; mine was recommendation. Daniel was a little more about [inaudible], DNA preparation and all that stuff, than I did. He knew how to delegate very well. At the same time, he would get involved and excited by the action. I miss him; I did not realise that he was dead.  I think he provided a wonderful opportunity. I am glad that his name is being preserved through this foundation. That is really cool. He was a gentleman. He visited me in Hawaï during the course of his trip. I have a picture of Dausset and I; it is a great photo, maybe I should send you a scan of it. I have a great picture of Dausset and I. He was about a foot taller than me.

    Fin de la communication téléphonique, commentaires hors ligne
    HC. : Ainsi, Lalouel  a fait la carte génétique avec Ray White.
    J F Prudhomme : Non, il s’agit de celle de Jean Weissenbach
    HC : Mais tu l’as entendu,  il est ravi d’être aux Etats-Unis.
    J F Prudhomme : Je n’ai pas dit qu’il n’était pas ravi. Je ne voulais pas l’embêter donc je ne lui ai pas demandé s’il avait des regrets, mais s’il était resté en France, il aurait fait la carte. En fait, je savais que Lalouel était important dans les débuts du programme, mais je ne savais pas qu’il avait autant d’importance.
    H C : C’est lui et Daniel Cohen qui ont convaincu Ray White. Il n’est pas évident que le CEPH aurait réussi la carte sans la formule de Ray et sa réputation.
    J F Prud : C’est vrai, mais il y a un point encore plus important dans ce qu’il nous a dit – et je n’avais pas compris cela – c’était la différence entre les études d’association  et les études de linkage. C’est lui qui a compris qu’il fallait faire du linkage et pas des associations. 
    J F Picard : De quels autres éléments biographiques  dispose t on à son sujet?
    H C : Lalouel  est né en 1945 au Tchad où son père était médecin. Lui même a fait un peu de chirurgie, mais en fait il n’a jamais pratiqué. Quand on demande ce qu’il est au fond, je dirais : généticien quantitatif. Il y a trois personnes qui sont les précurseurs de la génétique de population humaine, la’ trinité’ :  E  Fisher, S Wright et G  Malécot.. Newton Morton est venu après …et lui.