Interview transcript

This is an interview with Professor Paul Boyer, who received the Nobel Prize in Chemistry in 1997 for his elucidation of the enzyme mechanism underlying the synthesis of ATP and we are in Lindau for the 50th anniversary of the “Nobelpreisträgertagung”, as it is called in German, in Lindau and it is 29th June in the year 2000.

Paul D. Boyer: And it’s a pleasant day, a beautiful day.

Yes it is a beautiful day and it has been very nice meeting you. So, let me begin to ask you a little about your family background and how you grew up and where you went to school and so on.

Paul D. Boyer: Well that’s a big question.

Yes.

Paul D. Boyer: Well, I grew up in Utah, in the mountain country in the United States. I was the third of six children in a very happy family. I was fortunate to have had parents and a mother that had such excellent ways of raising children, giving them the right amount of freedom and the right amount of discipline, but I was also fortunate in this, which was then a town of about 15,000 people, that it had excellent schools. They had a community and one of the things they first wanted to do was to make good schools and it was the quality of the first school that I had and my home environment that got me started in education. I’m just thoroughly indebted to it.

I had an excellent teacher in high school chemistry that got me interested in science …

I can remember my father was a small town physician but he had a series of books called The Book of Knowledge, a whole series of volumes and I can remember stretched out in front of the fire place looking through this, just the fascination of looking through that and then I went to on to finish the school there. I had an excellent teacher in high school chemistry that got me interested in science … and then also there was the university within walking distance of my home, so the idea that I would go to college was always there. So I grew up in a small town, small community in Utah, a very nice, well run, well oriented small town, the kind that America produced that were good communities.

Good to grow up in.

Paul D. Boyer: But you see I didn’t, it was such a short period before me the communities were already settled in 1848, here it is 1980, you see, that was just 70 years.

Oh yes. It was a very young community.

Paul D. Boyer: To me, 1848 was a long time ago and I’m more than 70 years old and I look back and look at the change in it, so I grew up in this, and this is how I got the urge in my family.

And this also then, you say, in high school when your interest in science began to …

Paul D. Boyer: It was the quality of the education. My high school science and chemistry and biology teachers, these were the classes that I liked.

So then you went to university, was that in Wisconsin or?

Paul D. Boyer: That was in Wisconsin. One of the professors at the University of Wisconsin had discovered that you can put vitamin D into milk by shining ultraviolet light so they patented it and the monies from that, they set up for scholarships and when I finished at the University of Utah, there was no course in biochemistry. I hardly knew that biochemistry existed but I was interested in, I knew enough to know that it was there but I didn’t know nearly the extent of the field, but there was a scholarship notice on the bulletin board that the University of Wisconsin, there was a scholarship that you could apply for to study biochemistry.

Yes, so you did.

Paul D. Boyer: And so I applied and was granted this scholarship and I was fortunate that the University of Wisconsin at that time had developed biochemistry far beyond what most universities had. They had an excellent department in biochemistry at that stage, so I had lucked into a good education, so again, like I was in Utah where I had a fine preparation, here at Wisconsin I immediately encountered a kind of education that I, in later years, would appreciate in the sense that, to make a great university, to make a place where you can really start to do basic research, takes a lot of administrative actions.

It takes people that do that and they come together, but I just assumed that, of course, there’d be a symposium on respiratory enzymes, bringing together and reading people that I could walk from my laboratory down the hall and sit in and listen to these people that were prominent in the biochemistry text.

But of course you hadn’t seen anything else. Yes, well, so that was of course a very good place to study.

Paul D. Boyer: Incidentally, I’ll interrupt to say here at Lindau, in terms of people that were important, at the exhibit they had of previous people there were some letters from two biochemists that were important in my early career in what they had done. One was Otto Warburg, a prominent Nobelist from Germany, and another one, Otto Meyerhof, who worked out what’s called how group culture’s broken down in their cell and there are letters from those over in this exhibit and I was fascinated to see those at this stage.

They had been here also, yes. That’s interesting. So then I read in your resume here that you did some work already during the war in California but that you then went on to University of Minneapolis and St Paul. That was where you did your first, you could say, beginning of the academic career.

During that little war period, I learned to work on and love what’s called protein molecules …

Paul D. Boyer: That’s when I had a start, yes. During that little war period, I learned to work on and love what’s called protein molecules and these are the big molecules made up of individual building blocks called amino acids and they’re also the ones that make passable enzymes but we worked on a protein there, very interesting one, that’s in the blood stream. When soldiers are injured and they go into what’s called shock, it’s because of the osmotic balance, as you know, of the blood and the serum albumin that you use for that is used to treat it, but they couldn’t pasteurise the serum albumin, that is kill the germs in it, because it got cloudy.

It would coagulate.

Paul D. Boyer: It started, like an egg yolk when it coagulates, so we worked on a method to make it so it’s possible and fortunately we were successful with that, but then I had this offer of an assistant professorship at the University of Minnesota and then I had this fine opportunity of having laboratory, equipment, students and the government at that time very ready to give me some money to do research so what more could I ask for? So not only that, I had by this time children and so …

So it was a full life.

Paul D. Boyer: It really was a full life.

Yes, that sounds good. I also have read that you went to visit Sweden and you got your … laboratory at the Karolinska Institute at some time during the 1950s.

Paul D. Boyer: Yes, in 1955, after now I’d been a professor, assistant professor there at Minnesota for about nine years, the Guggenheim Foundation makes available what they call Guggenheim fellowships and I had a Guggenheim fellowship award for studies in Sweden, so I took my three children, my charming wife and we found a place to live on Björngårdsgatan and I spent time actually both with the group at the Wenner-Gren Institute with Lars Ernster and Olov Lindberg  and then our time at the Nobel Medical Institute with Professor Theorell and as you mentioned, Professor Theorell was a very good host, nice environment, but he had the courtesy of winning the Nobel Prize that year.

Oh yes, that was in 1955, that’s right, yes.

Paul D. Boyer: And then from being with a laboratory, we had an invitation to go to the banquet in 1955, 43 years earlier.

You had a sort of preview.

Paul D. Boyer: I went to the Nobel banquet, yes, it was a fine occasion. But my family enjoyed Sweden very much then. That was their first exposure we had. They came away with a fine experience for the children, to be in a foreign country and one as hospitable and well organised as Sweden.

Sounds good, but this is also where you began with your work on the enzymes in energy metabolism in more serious ways?

Paul D. Boyer: Most of my career I spent working on these big molecules, they’re called enzymes, they do catalysis, they’re ones that make chemical reactions go and at that stage, I worked actually on an interesting enzyme in the Nobel Medical Institute and had a nice little publication with Professor Theorell from there. It was actually, well I won’t tell you what it was.

Actually I came about 15 years later to work at that same place. I remember that we talked about the old yellow enzyme, but I don’t know if that was the one. It must have been one of the flavour proteins that was called that.

Paul D. Boyer: On the alcohol dehydrogenase.

Oh yes, yes.

Paul D. Boyer: And at that time, it had not been recognised that there was a spectral shift with the binding of what was then DPNH and I discovered that spectral shift.

So that’s what you discovered, yes.

Paul D. Boyer: But at the Wenner-Gren Institute I started there, I worked with the mitochondria, as you know, the part, the little places where energy is captured in the cell, but for most of the next, from 1955 to most of the end of 1970s I worked on other enzymes, because I couldn’t get the experiments to go that would do the part we wanted.

No, no. But so then, when did you actually do the work on the ATP synthase? When did that begin?

… we were reaching for a gold but we got a brass …

Paul D. Boyer: That began in early 1970s. We had spent a considerable effort in the 1960s, in this process, as you know, of oxidated phosphorylation, the ATP, there’s lots of it made, it’s a very important compound. We thought from the paradigms in biochemistry, the way that we knew from other biochemical things that there should be an intermediate in the thing, so we spent lots of years looking for intermediate. Now I have a tendency to be lucky, because we did find a substance that we thought was an intermediate oxidated phosphorylation in making the ATP as we breathe oxygen. It turned out to be, though, an intermediate in a lower cycle, not the big problem, but the small problem, but it was a new chemical compound, never seen before in nature and it’s phosphohistidine, the first time it had been described and so then we’d at least, as I’ve sometimes said, we were reaching for a gold but we got a brass.

Ok. Yes. But it was a new finding.

Paul D. Boyer: But it was in 19 …

It was encouraging, I suppose, for your further work …

Paul D. Boyer: Oh yes, it was useful too. Not only that, that and other work got me membership on our National Academy of Sciences before I started the work that led to the Nobel Prize, the part that started the Nobel Prize.

So you have worked in different areas of the bioenergetic …

Paul D. Boyer: All different areas of enzymes, I have publications with titles of over 20 different enzymes in the titles that I’ve studied along the way. At that time, you could be a little broader in your studies. I was interested in anything, any enzyme, I love them all.

They are beautiful creatures.

Paul D. Boyer: They’re beautiful things, so I can’t help but like them but it was in the early 1970s that I got a different insight into how the oxidated phosphorylation may occur and that’s when we started on what was called the binding change mechanism.

Yes, and that was indeed, you could say, a visionary view of how an enzyme might work that must have been completely, I mean, not out of the blue, I suppose, but didn’t have any precedents or …

Paul D. Boyer: But it developed over a period of 10 years, because at first we recognised in the … Well let me go back just a little bit. Are you familiar with the use of ¹⁸O to study the phosphate oxygen?

Yes, some.

Paul D. Boyer: So we had this technique that other people really haven’t used much, but we found it to be a very powerful technique and because looking at the fate of the oxygens, of the inorganic phosphate, when it made ATP those oxygen, one of them goes to make water. Now we found that by use of this stable isotope, ¹⁸O, we could measure this reaction of water going in and out of phosphates, part of the process, and by measuring that and other conditions we could probe down as to what’s happening at the heart of the enzyme that we couldn’t see by other ways so we had a way of seeing what …

So you had your special way of …

… it came to me at that stage, one of the few times I get a stroke of insight …

Paul D. Boyer: …seeing what’s happening down inside and really the start of the binding change mechanism was when I was sitting in a seminar talking about some aspects of theoretic chemistry that I did not understand, so I let my mind wander and then I suddenly … it came to me at that stage, one of the few times I get a stroke of insight, I can explain our ¹⁸O data if the energy is not used to make the ATP molecule, but if it can be made without the energy input, then the energy is used to release the ATP molecule. So that was the start of it, you see.

And that was a sudden inspiration that came to you.

Paul D. Boyer: That was the one time that I can count and say it was a starting point. Now at other times, you make progress and you can hardly recognise you started down a new path, you see, but this was a starting down a new path.

And then that gave rise to new ideas and maybe new experiments so that you could …

Paul D. Boyer: Yes, well that gave rise to the experiments that then led to these other two unusual aspects of the enzyme, even more dramatic aspect, that not only does it do this reaction by releasing the thing, but it does it with multiple catalytic sub-units and that one sub-unit can’t do it until another one has finished so at that time we thought the enzyme was a dimer, that we would have a tied ATP in one side and it couldn’t let loose of it until …

Something else had happened.

Paul D. Boyer: … added this side and then it would open up and do this, you see.

That would be a ping pong rather than …

Paul D. Boyer: … two catalytic sites changing confirmation and required to do it and that was the second aspect and then later on we came to the rotation … when there are three of them.

Which is beautiful.

Paul D. Boyer: Which is unusual, you see, so that’s why I say I have luck, because I could work just as hard on another enzyme and it not to be unusual, but then I wouldn’t be sitting here talking to you today.

Yes, ok. They say that luck is the reward of the prepared mind, so I’m sure that …

Paul D. Boyer: At least we were looking for something, yes, and that turned out to be unusual.

So then maybe if we now look at the work today in bioenergetics, what would you say is the most important questions that should be looked at today in this field?

Paul D. Boyer: The immediate questions, well the enzyme that I worked with is ATP synthase. Now, to tell you what I think the most important questions are, I need to tell you a bit more about the molecule itself. The mitochondrion, the inter-cellular organelle of which this is made, has a membrane in which the enzyme can, I know you’re well acquainted with this, and that’s through this membrane, you develop with the oxidations and electrochemical grating the charge across the membrane that wants to push positively charged protons through the membrane.

Now, we worked mostly on the part of the enzyme that was above the membrane. This is the membrane, we worked on the part that was above this. That’s where the adenosine and triphosphatase push is, as you know, and so we found that the protons, when they go through the membrane, cause the internal part of this to rotate like a motor and change, as you know, with the outer sub-units. I’d say one of the biggest problems in bioenergetics at the present time relates to this proton translocation. It’s not known how the proton translocation makes the bottom part turn. We know that it turns and does this, so one of the immediate important problems is try to get the structure of that bottom part and to deduce how it turns. Now that holds, then, not only for this one but for a whole host of bioenergetic processes that use membranes and translocation of ions across the membrane.

And did the hormone denominate, to some extent, these processes?

Paul D. Boyer: Yes, to look for other things, for active transport of amino acids, you see, and it still is not known how the lactose transporter works in any detail, so there’s these problems in bioenergetics at the same level of explanation that we sought for the ATP synthase. Now those are the, what should I say? Those are the visible problems, those are the ones that are continuation of present aspects to get more explanations of them. Now, that doesn’t mean they aren’t important because our ATP synthase work was a continuation of trying to understand how oxidated phosphorylation occurred and then in terms of the bioenergetics and the mechanisms, the whole field of motion and contractility is opening up in a lovely way. We don’t yet, though, know how cells move across each other.

For example, in evolution, you produce, we think of the evolving of life on earth as working into a single cell organism and this is the way it was for billions of years. For billions of years, there were only bacteria, you see, and then we achieve a mollusc cellular organism. In order to do that, we had to have cells to start communicating with each other. Now, communication and control is in one sense bioenergetics, you see, and they had to learn how to move with respect to one another. How do cells move during development, you see? What is this type of thing? How do you use it to that? And the control of that movement, you see. The control of that movement makes it so that that movement produces an ear on this side some way.

That’s right.

Paul D. Boyer: And another one on this side, fortunately.

Yes, yes.

Paul D. Boyer: So this kind of control of the energy process is in development.

They are, of course, mostly not at all understood or hardly even described.

Paul D. Boyer: No. That’s right, they’re hardly even described and I suspect that beyond that, there are other types of organising principles for bioenergetics that we don’t recognise yet or don’t know that exist, so what I’m saying is that we tend to think of science as a continuation of what we already know. You’d do a better job with my ATP synthase and find out more about it but there are these other areas that are going to open up.

That may come for the future. Ok. Well, is there anything you would like to add that we haven’t talked about that we should discuss?

… the privilege of being a scientist at the present time in our society is a remarkably fine thing …

Paul D. Boyer: Oh yes. If you push a button on a professor, he’s always willing to talk. I would like to comment on two things. One, the Nobel Prizes. The responsibility of the Nobel committee is, as I’m sure you’re aware, they’re writing the history of science. They choose just one to the problem but the ones they choose become then much better known in nature so I think this is one of the prominent functions of the Nobel; but the other one relates to the public understanding of science. I think the fact that there is a Nobel Prize, that it gets in the newspapers, they’ve done a good job, up until my selection, of goods selections, you see, so that it’s been well received on it. This has helped the interaction of science and society because I feel that the privilege of being a scientist at the present time in our society is a remarkably fine thing, both for the scientist and humanity.

I think within a grouping of a university setting, where you can get a grouping of students and post-doctor of follows, that are sitting around a table here with 10 or 12 of you trying to understand the experiments you’ve just completed, trying to devise the experiments you want to do next, discussing them in an atmosphere where it’s bringing the best thoughts of these people. Out of this then comes the milieu and the things that makes it possible for me to think of a new approach at a different time, you see. I think that grouping of scholars in a university supporting now by society, they give us billion, they give us monies to buy instruments, is the finest thing that’s been developed to try to understand nature, to try to get the answers of science and then, so I appreciate that, I think that this is something that we need to tell humanity we appreciate.

Now, the other part of that is, is that what is produced out of basic research has done so much to change the world. Now, either you want to understand how the world operates and let it change and let it enrich the lives of the other people. To me, when I can listen to a fine piece of creative music, that’s an enrichment that somebody else gave me but I think for the general public, when they can learn about how the oxygen that they breathe, what it does or how the last aspect of astronomy, I think they appreciate it. I think there’s a beauty to it so I think we return to the …

That’s the enrichment of human life also, yes.

Paul D. Boyer: And that’s an enrichment and the best way to get that enrichment is to have the people and the places most capable of it doing the research so the Nobel helps do that, you see. I want to give an appreciation to what’s been possible for my life, to make it so that I can do what I’m interested in doing and to have it work out and be appreciated. It’s a wonderful thing.

That’s good to hear. Thank you very much.

Paul D. Boyer: Is there anything else you wanted me to talk about?

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