*The interview has been condensed in certain sections for clarity

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This past September, THURJ had the opportunity to sit down Professor Matthew Meselson, Thomas Dudley Cabot Professor of the Natural Sciences in the Department of Molecular and Cellular Biology. Kind, charismatic, and generous with his time, Prof. Meselson spoke with us about his early beginnings in science, such as the famous 1958 experiment that proved the semiconservative replication of DNA, as well as about his current research and public policy interests. In addition to being a professor at Harvard and serving on the council of several eminent scientific councils, such as the National Academy of Sciences, Prof. Meselson is also the Co-Director of the Harvard-Sussex Program on Chemical and Biological Weapons.

SM: Thank you so much for your time today, Professor Meselson. To start off, one question I’m curious about is had you also been interested in science when you were younger? Like—

MM: [almost immediately] Yes.

SM: [laughs] Always. Why I’m asking is because I know you went to the University of Chicago and studied history and the classics there. And so I’m wondering whether that had originally been your main interest and if science came along later or had always been there.

MM: [laughs]. Yes, that was a detour. No, what happened was during the war, most young people didn’t feel like just goofing off during summer vacation, so you either went and got a job or went to summer school. Each summer, I would do one or the other, and because I went to summer school, I got enough academic credits to get my high school diploma. So I went to the registrar at John Marshall High School in Los Angeles, and said “I’ve got all the credits I need, I’d like my high school diploma.” And she said that California state law requires you have three full years of physical education. Well, I was very surprised by that. I didn’t see what the relevance of that was, and I certainly didn’t just want to hang around for another year and a half, taking gym! So, I started asking around to figure out what I could do, and someone told me, “Well, there’s this place called the University of Chicago and they’ll take you without a high school diploma.” And I’d thought I’d go there and right away study chemistry, physics, and math.

And so that’s what I did. I went there – I was sixteen years old – and it turns out there’s no electives, except one course you could take, which was a philosophy course. Instead, we read the classics. And I wouldn’t have done that ordinarily had I gone on a regular path. I would have gone straight into some chemistry or physics concentration. But that was a wonderful thing; I’m very glad it happened.

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SM: After your time at the University of Chicago, what did you study next?

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MM: So I spent three years there. And then I spent a year doing noth- ing, just living in Europe. And then I went to Caltech and had to be a freshman all over again. But I did not like Caltech very much then, because except for Linus Pauling’s course in elementary chemistry, there was a lot of memory involved, even in physics. So I left and went back to the University of Chicago and got what would have been a bachelor’s degree in chemistry, except then they didn’t give B.A.’s in chemistry. They gave me a letter that said we do not give a bachelor’s degree in chemistry, but if we did, we would give one to Matthew Meselson. That letter enabled me to get into graduate school at Berkeley in physics. And I stayed there one year, and I didn’t like it. It was huge. In those days after the war, they took many more people in physics than they were going to graduate with PhD’s, and I knew I wasn’t cut out to be one of those top-flight physicists. And besides, I wasn’t interested in physics for physics; I was interested in applying it to biology.

So I was about to go back to the University of Chicago, because they had a program called mathematical biophysics. And those words sounded just right – math, bio, physics. But that one year I had been at Caltech, I’d done a research project for Linus Pauling in chemistry, and so I knew him and I knew his children. There was a party at his house one summer – that summer I had been planning on going back to the University of Chicago. And the party was at the swimming pool. I was in the water, and Linus Pauling, world’s greatest chemist, said, “Well, Matt, what are you going to do next year?” And I said, “I’m going to go to the University of Chicago” And he looked surprised, and he said, “Why don’t you come to Caltech and be my graduate student?” And I’m still in the water, so I just look up to him and say, “Well, ok!”

And that’s how I got to be a graduate student at Caltech. I loved it there – it was wonderful. I did x-ray crystallography because I thought understanding the structure of large molecules would be important for understanding biology. And at that time, my major interest was to know how it is that you can put together ordinary atoms and create something that’s alive.

SM: Do you find though that the studies you had done in history and the classics, even though you obviously have a career in science, that there were any lessons or experiences that still carry over in terms of scientific thinking or research?

MM: Yes, especially now. I remember reading the book, Chance and Necessity by Jacques Monod, a very famous Nobel Prize winning biologist. He and Professor Francois Jacob discovered how genes are regulated. And somewhere in this book, he says that it will never be possible to modify the human germline and that what we know about molecular biology already tells us of the impossibility of doing this. [finds the excerpt].
Yes, he writes, “Modern molecular genetics offers us no means whatsoever for acting upon the ancestral heritage so as to improve it with new features...on the contrary, it reveals the vanity of any such hope.”

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Well, when I read that it was obvious that he was wrong. Because already by then, somebody named Beatrice Mintz had shown that if you take the embryo of a mouse and mix the cells with the embryo of a different mouse, you can get a mosaic mouse. And you can also get offspring from the mosaic mouse. And you can take a nucleus from one cell and put it into another cell. It was also known then that you can transform bacteria by changing the DNA. And so putting all these things together that were known at the time, it seemed that already then you could outline how you might be able to change the human germline by changing the DNA in a single human egg, re-implanting it into a uterus, and getting a baby that is genetically different in the germline. And I said in a talk I gave called “Biological Riddles to which the answer is man,” this wouldn’t happen for a while, but once it starts it will certainly become commonplace. For example, if you could tell people, “If you allow us to modify the germline of your offspring, they will never get cancer,” and that turns out to be true, even people very much opposed to this kind of modification to the human germline will say “Well, wait it’s very hard to say no to that.”

Once it starts, it’s very hard to stop. And it also raises the question, “What is it about being human that we really value?”

In fact, in that talk I previously mentioned to you, I specifically said, “Nevertheless, the prospect of human intervention into human nature, even if only theoretical for the time being, will cause us to be increasingly drawn to the study of human origins and the sources of civilization, in order to know what humanity is, in order to keep faith with it. Certainly the study of the humanities is an indispensable component of this endeavor.”

So I think going to University of Chicago made me realize that there was this absolutely marvelous literature, particularly the Greek Classics and Homer, that put me into that frame of mind to understand these issues.
Recently as you probably know, the National Academy of Sciences has released a report on genetic engineering of the human genome. In Chapter 5, they discuss changing the human genome in order to remove or change genes that cause bad diseases. That chapter recommends, that subject to certain guidelines and controls, that we go ahead with that. But the next chapter is called “Enhancing the Human Genome,” and that’s not to get rid of something bad. That’s to, I don’t know, do whatever you think will make people “better,” and that the Academy says is too soon to start that. They don’t say, though, don’t ever do that. So this already shows an enormous shift in the way that people are thinking.

 

We are a very transient form of Homo sapiens. You could say there will be worlds beyond worlds and men beyond men, big changes coming. H.G. Wells once wrote, humans could have organized society so that everyone would have enough to eat, shelter, a decent education, but our species hasn’t chosen to do that. So, it’s very hard to predict, but I suppose what it means to be human will change.

 

SM: Going back to the early beginnings of your career, you’re very much one of the founding fathers of molecular biology in so many ways.

 

MM: [laughs] More like a cousin.

 

SM: You have many famous experiments for which you are known, such as showing the replication of DNA is semi-conservative, the existence of messenger RNA, restriction enzymes, etc. I just wonder, is there one experiment or topic in particular that has been the most exciting for you?

MM: Well of course it was the semi-conservative replication of DNA, for a number of reasons. First of all, because we had to do a lot of work to get there. We had to invent a new method for measuring densities of macromolecules. Second, when we finally got the result, it was all in a sudden flash in a dark room. You see one piece of film with a hybrid DNA band. Third, because we had such a pleasant working relationship, Frank and me. It was just marvelous. I was a graduate student living a wonderful graduate student life.
You mention mRNA. That was actually not my idea. That was the idea of Sydney Brenner. He came with Francois Jacob to my lab in Pasadena to do that particular experiment, partly because he was coming anyways to do a completely different experiment with me, which we therefore didn’t do. And also because it was only in my lab that this experiment could be done. We had the necessary carbon and nitrogen isotopes and the necessary experience with cesium chloride density centrifugation experiments. So I worked on the centrifuge experiments, although not as much as Sydney did. It really wasn’t my experiment; I was a collaborator.

However, I was doing another experiment at the time that really was my experiment, and that was looking into the basis of genetic recombination in lambda phage. There were two extreme ideas at the time. One was that recombination occurred by breakage and joining of 2 DNA molecules and you connect them up the other way around, and then you have recombinant molecules; so this requires breaking of 1 DNA molecule. The other idea was called copy-choice. That is you have two different DNA molecules, homologous, but not identical. And then you start copying off of one, and then you switch your copying machine (there is no such animal, but in those days we thought there could be), and then copy off the other DNA molecule. So now you have a molecule that has partly the sequence of 1 DNA and partly the sequence of the other.

And so at the time Sydney and Francois were doing their experiment, I had no family and obligations and I was doing this experiment on DNA recombination by myself, and I published the results together with John Weigle, a colleague in Switzerland. The excitement of seeing that result was not like seeing the DNA replication, but still great.

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And then there were some other things. I studied gene conversion in bacteria, and this made me wonder what good it is. I came to the view that maybe it is useful for repairing defects in DNA. How would that work? You would have to have some way in which the DNA-enzyme system would recognize a mismatch, a case in which the polymerase had made a mistake. And then it would go and remove this mismatch. But wait, if I remove either one base or the other with equal likelihood, this may perpetuate the mistake. For instance, let’s say you have a sequence that should be A-T, and instead the polymerase has made a mistake and it is A-A. You should put a T in, but how do you know which strand to put it in? Well, I realized you needed a way to know which strand is the new one, because that’s the strand where the mistake is. And I thought maybe that strand could be recognized by the methylation, since I knew that DNA does not get methylated right away after it is synthesized. It takes a little while and that would allow time for some kind of sensing enzyme to find a mismatch, a little bulge in the DNA, and then ask “Which of you two strands has methyl groups on it? Oh it’s you, then I will chew away the stuff on the other strand and try again.”

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And so, I published the results of that experiment on mismatch repair. And there were a few other things.

SM: What research interests are you currently pursuing?

MM: What I’m interested in right now is the question of why does sex exist? I got interested in that because I was visiting with a friend at Yale, a famous old naturalist named Ian Hutchinson, and I asked him, why does sex exist? There were already at that time several explanations with no clear proof of which one is right. And he asked, “Do you know about the Bdelloid rotifers – these are little invertebrate animals, and no one has documented the existence of sexual reproduction or males.” So we did a lot of work on these animals. At first we thought we were finding evidence that supported the pos- sibility that they had evolved for many millions of years without any outcrossing. But now, because of DNA sequencing that we’ve been doing recently it’s quite clear that they do engage in outcrossing. I’m quite interested in that now and I’m following it up. It turns out that our sequencing also indicates that they have a very unusual kind of meiosis, one that is only known in a certain kind of plants, which has implications for evolution that I won’t go into.

And the other part of my life is involved in what you could call politics. More or less by accident I took a job just for the summer in 1963 at the State Department in the arms control and disarmament agency. They essentially let me do anything I wanted. I ended up looking at the possibility of arms control of biological weapons. I was interested in that because DNA engineering was just beginning to come along. Paul Berg and other people were splicing DNA and putting other pieces together. And here’s my science, biology, used to wipe out all kinds of people. Not only that, but if you projected in the future, maybe you could even begin to affect the brain in warfare just opens up a lot of ominous things. So I decided to look into that, and I have spent half of my years at Harvard doing things about that.

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SM: Yes, I saw that you are involved with this program called the Harvard-Sussex program. Could you tell us a little bit more about your involvement with the program?

MM: Yes, I created that together along with a friend of mine called Julian Robinson. We’ve done a lot of things. We’ve published a jour- nal for many years. But I also got involved with doing things on the ground, with combining science with arms control. Three things: the first was the American association for the Advancement of Science (AAAS) asked me to design a study of the ecological and health side effects of the herbicide spraying during Vietnam. I conducted a small pilot study for six weeks during the war in Vietnam. Here was a case, where this was not biological warfare in the usual sense but a form of chemical warfare (although it is against plants not people). Naturally I had some concern that you just don’t want to get this kind of warfare started in any form, but I didn’t go into there with the objective of stopping it, just studying it.

But I learned a lot of things from that. And eventually we in fact did get the whole program stopped. In particular, the last day I was there, the commanding general asked me to come to his office and tell him what I thought about the military utility of the herbicides. I said I have no idea about that. And he said, “You what to know what I think?” And I said, “Yes sir.” He said, “I think they’re shit.” And I said something like, “But General Abrams, you’re the com- manding officer of all the American forces. Why are we using it?” And I distinctly remember what he said next. He said, “You don’t understand anything about this war young man.” This was in 1970. “He said, those decisions are made in Washington.”

I wanted to be sure my memory of this was exact. And I remembered his son, John, who was a captain in Vietnam agreed with him. So I found John, himself retired as a four-star general who now runs a consulting company down in Washington, and I asked him, “Is that right? Is that what your dad thought? Is that what you thought?” [laughs] He sent me back an email which is much stronger than what General Abrams said.
This experience showed me one of the really great difficulties of trying to understand what war is all about. On one hand the joint chiefs and a lot of people were saying you’re helping us to win the war (which we of course did not win), and on the other hand people like the commanding general were saying this type of warfare is useless; and the war, it still goes on.

SM: Do you have continued involvement in Washington? Are there any studies that are continuing with regards to current wars or biological warfare?

MM: Yes, lots. President Nixon renounced biological weapons categorically, and I had a lot to do with that. I wrote many papers for Henry Kissinger. Henry used to have his office in the building next door to the Semitic Museum. There was on the third floor a kitchen, and two Hungarian ladies made lunch every day. That’s how I got to meet him. He also participated in a Harvard-MIT arms control seminar that met in evenings, and I used to go to that. So when he was appointed as National Security Advisor by President Nixon he asked me to write him a paper (because by then he know I was interested in biological weapons). So I wrote him some papers. Basically I made the argument that biological weapons are really cheap. Which they are. And they can wipe out lots of people. Which they can. We have nuclear weapons. Do we really want to pioneer the introduction into the world of a weapon of very great mass destructive capability that everyone can have? Or is it best if it so expensive that no one can afford it? The next best is that only the US could afford it. And so on. And that was a winning argument.

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Before that, no one really put the argument that way except a few pals who I got to know in the Defense Department. Instead they argued, we better do this because someone else is doing it. Or maybe we better do it to find what the potential is out there. But no one was saying, wait that’s a door best left closed. If we develop it, how can we go on a campaign to get others to stop or not start? For example, when I was working at the state department, one of the things I did after deciding to work on the problem of biological weapons was to go to Fort Detrick, where we were then developing biological weapons. I was given a tour by a very nice young man named LeRoy Fothergill, a fairly eminent biologist. He had been on the faculty at Harvard Medical School before he had been joined the army. We came to a building, and it seemed like an ordinary building about seven stories high that looked like it had windows. But when you got up close, you saw that it had phony windows. I asked him what is this, and he said, “It’s a big fermenter, we make anthrax there.” And I said, “Why do we need to make anthrax?” to which he responded, “Well, it will save money. It’s a lot cheaper than nuclear weapons.”

That’s the point when I suddenly realized, “Wait, we don’t want a weapon that’s a lot cheaper.” I went back to my office. My office mate was Freeman Dyson, the physicist. I had taken quantum mechanics from freeman at Berkeley, so I knew him. And he was very encouraging. I remember him saying that my intuition about this is wiser than I knew. Freeman was always someone who thought developing biology for hostile purposes was really a dangerous thing to do. And so I spent years trying to persuade people to get out of this business, and eventually President Nixon did it.

SM: It must be so satisfying to not only conduct exciting basic science research in your lab, but to also be part of these bigger policy changes in Washington. Was it gratifying to give these reports to generals and higher-up officials in Washington and know the impact that these contributions would make?

MM: For me, it’s always been very much combining science with some arms control objective. In a sense there’s only really one science. We have a National Academy of Sciences, plural, but that’s not right. It should be a National Academy of Science, singular. Because I believe that people in the science field shouldn’t just be incredibly specialized. They should know something about all aspects of science. So it’s really very pleasant to be able to change.

The basic idea I have always had in my mind was to prevent our science, biology, for terrible purposes. People go blast each other and slice each other up. Every big technology that humans have ever devised – fire, gunpowder, nuclear fission, electronics – has been exploited for peaceful purposes as well as military purposes. The one exception is biology, molecular biology. That has the possibility not just to kill people but of changing them ultimately, not only by changing what it means to be human, but also by dissolving the difference between war time and peace time. And maybe because as any biologist would feel, this is my science. I don’t want my science to be used for hostile purposes.

SM: Thank you so much for your time.

 

MM: You’re welcome, thank you.

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