Roger D. Kornberg during the interview.

Transcript from an interview with Roger D. Kornberg, 2006 Nobel Laureate in Chemistry, on 6 December 2006. Interviewer is Adam Smith, Editor-in-Chief of Nobelprize.org.

Roger Kornberg, welcome back to Stockholm.

Roger Kornberg: Thank you.

I gather you know the town quite well having been here first in -59?

Roger Kornberg: First in -59 and then on several subsequent occasions every one of which I’ve enjoyed.

This I assume is the best yet?

Roger Kornberg: This has to be the pinnacle of all the visits, yes.

You know what pinnacle’s like here. I’d like to turn first to the relationship between biology and chemistry. You work on a system which many would think of as a very fundamental biological mechanism, and yet you’ve been awarded the Nobel Prize for chemistry. Why is that?

Roger Kornberg: In the very first place the work we’ve done is purely chemical. The discovery for which the prize was given is the arrangement of atoms in a large molecule, that is as much the definition of chemistry I think one could hope to define. Beyond that, and I think it’s important to bear in mind that what we study is not so much biology as life chemistry, so the answers to the questions that we have about biology all lie at the level of chemistry, and the thrust of modern biologic science and modern biomedicine is to discover of a chemical basis for all that goes on.

Now, it’s also worth mentioning my background is from chemistry, and the work that lead up to the structure for which the prize was given began in what I did, which even the most traditional chemist would today regard as the proper domain of chemistry, so this sprang from chemistry, what eventually emerged is indisputably chemistry, the connection to biology is in explaining a life process. One last point on those lines, what is traditionally the preserve of chemistry always involved the study of molecules derived from nature, one of the most classical undertakings in traditional organic chemistry has been the structure determination of the total synthesis of molecules derived from nature, some of the famous molecules that you know of, vitamin B12, chlorophyll, what have you, these are all molecules derived from nature, many organic chemists over the years pursued the structures and synthesis of alkaloids derived from nature, protein molecules nucleic acids are no less or more chemical molecules than vitamins or alkaloids.

We hear constantly though that chemistry as a discipline is rather under fire, and that people are not going into chemistry in the way they used to, so do you think it matters how one labels the research? For instance you work in a department of structural biology, is it important the label which one gives to the research one does?

Roger Kornberg: You’ve come absolutely to the heart of the matter, so labels were once applied as a way of identifying the distinct nature of the various disciplines, of course the boundaries have become blurred, the disciplines have to some extent merged, I think labels are always useful for administrative purposes of dividing up research groups into manageable units and the traditional labels from the past are just as useful for that purpose today as they ever were before.

… in my personal view chemistry is really the queen of the sciences …

The fact remains that as I said the boundaries have blurred, but what is more, the work that we do in the structural biology department is it’s in some places done in the departments of chemistry and in other places done in departments of biology, beyond that I might add that in my personal view chemistry is really the queen of the sciences, chemistry is the common ground for all scientific investigation. So our best hope of applying physical principles for the world around us is at the level of chemistry, our best hope of understanding the biological organism and ultimately the form and function of the human body is at the level of chemistry. I have said before and I would repeat that if there is any one subject that an educated person should know in the world that is chemistry.

Nice message. So would you describe the work you do as interdisciplinary? Or do you think that’s a very overused term these days?

Roger Kornberg: In the sense that what were traditionally regarded as distinct disciplines have come together in our work then it would be regarded as interdisciplinary, people have remarked that the culmination that we make of functional studies commonly referred to as biochemistry with structural studies, which more commonly lie in the province of physical chemistry is distinctive. For myself I see really no alternative, I think the problems that we study and that others will do of a similar nature in the future can only be approached in this way.

When you chose students, young people, to come into the lab do you look for any particular background in them or … I think there’s an increasing tendency for people to want to use lots of different techniques in their research, they tend to quickly want to quickly want to jump to the point of using lots of things, is that something that you would go against?

Roger Kornberg: I have a very straight forward answer to your question, the one thing I look for is chemistry.

Okay.

Roger Kornberg: People come to my lab from a background in biology, they come from a background in physics, and the question I always ask is about their training in chemistry, if they have studied chemistry then what chemistry did they study and how well did they do it. If someone comes along who has studied physical and organic chemistry and then obviously been good at it, then I know that they will fit in well, that they will succeed in what we do.

And if they …

Roger Kornberg: And absent that I’m doubtful.

If they’re a biologist can they …

Roger Kornberg: If they’re a biologist they must have done chemistry, if they’re a physicist they must at least show an aptitude for chemistry. It’s interesting that there is a distinction to be made at that level, I’ve had brilliant young students with a background in physics come wishing to do research in our area or in my laboratory and sometimes they adapt very well, but other times it’s clear that their inclination is really more towards physics, and it’s where they belong.

You yourself became interested in science at a very young age, do you think that that’s an essential attribute of a scientist to have become a scientist when they were still a child?

Roger Kornberg: I would say that my own serious interest in chemistry dates from high school, and I think that’s not uncommon, that young people’s interests become defined at that age as they grow to maturity and they think seriously or can begin to comprehend what lies within them concerning the logical or natural directions they’ll pursue. I was exposed to science at a younger age but I don’t think that mattered so much as the inspiration I drew from a particular chemistry teacher in high school.

was very fortunate that I studied chemistry in high school during a narrow window of time when the particular textbook that was used was of an exceptional nature, I’ve … it was from a programme in the state of California put together by a large number of practicing chemists who wanted to convey the principles of chemistry, and they did so superbly well, I learned the principles and they have served me all my life, and I think I’ve had an advantage over many others because I was taught so effectively at that time, these principles became deeply engrained and they stuck in mind, the course consisted of a series of very simply but well chosen chemical experiments each of which illustrated a principle in a way, which as I say I myself found unforgettable.

Having explored a little what you look for in your students, what do you think your students look for in you? What makes a good mentor?

Roger Kornberg: My opinion about that is quite straight forward, I think that the relationship between student and mentor in my lab, and doubtless in many others, is one of equals pursuing the solution of a problem. And I think what I know my students look to me for guidance but I don’t seek to guide so much as to share, at the end of what is often quite some years of mutual struggle with a problem, and more often than not a period of frustration and in the case of the student significant self doubt, there comes a resolution, a discovery or an answer to the question or a way of surmounting whatever obstacle it was that confronted us. And that has the affect of binding us together as lifelong friends because we shared that struggle, and then has the effect on the student of giving the most important thing which is not so much specific information or even knowledge of how to attack a scientific problem as the self confidence, the belief, the knowledge that one can struggle with something which seems to be at some stage impossible and then ultimately succeed. I think if there’s anything I can convey to the people who work with me it’s ultimately that belief in one’s capacity to succeed and eventually a satisfactory outcome.

I’d like to ask you a bit more about that self doubt thing, that the work that you’ve been awarded the Nobel Prize for has lasted some 30 years, and there must have been times during that period when you yourself had considerable doubts that you were going in the right direction, but you stayed with it and …

… it was doubtful what we found would be relevant to human cells …

Roger Kornberg: There were doubts about many aspects of the work along the way, doubts about the choice of organism, we studied the problem in a lowly creature in the single cell, baker’s yeast, and it was thought by many people at the time when we began that it was doubtful what we found would be relevant to human cells, of course at the end of the day we know that down to the very finest detail what we’d discovered is identical, virtually identical in human cells. There were doubts about the wisdom of the undertaking in regard to the molecule or molecular machine that we investigated, certainly it was impossible at the time that we began to solve the structure, there is no question about it, and I knew that full well. And so it was, I think, properly viewed as foolhardy to undertake it.

The particular approach that I employed was referred to by a friend and a supporter as a harebrained scheme, and you know, I can see in retrospect that was also the case. And yet I can tell you that I never had any serious doubts, certainly not … I didn’t feel the sort of self doubt I sensed in some of the students who finally overcome it, for some reason I was either cursed or blessed with a degree of self confidence from an early age that I was glad to do these things and particularly relish the pursuit of something that seemed so difficult or unattainable, I didn’t want to try something that seemed soluble at the time because then what would be the challenge and what would be the thrill of success?

It might not be a sensible question but what is that you think drives you? Is it trying to find the solution to individual problems? Or is it just a fascination in the area you study in general?

Roger Kornberg: It’s the conventional wisdom about scientists is they’re driven by curiosity. The other common reason that is supposed why people do it is some form of altruism, wanting to do something that is good for people if be enviromedicine or for the world in some other area. I think almost all scientists do it for the reason I do which is the challenge of solving problems, and naturally we grapple with specific problems, if one can’t … and the key to solving them is actually to keep narrowing the focus until finally one has redefined the problem in a way that it can be solved, so the answer to your question is very much what motivates us and our source of satisfaction is in grappling with specific issues, and then as I say having the pleasure of finally discovering the way to either overcome a technical limitation or find an answer to a paradox about the material or whatever it may be.

You also focused on this area that, it may be a meaningless question, but how do you avoid getting excited by problems that lie outside of the mainstream of what you’re studying? Because there must be lots of distracting nuggets that you could find?

Roger Kornberg: So on the one hand I would say that one of the things that I most enjoy about science, especially 20 years ago, was the possibility at that time of being interested in everything going on in science and following it and attempting to think in a creative way about almost every area of science, this was the style of Linus Pauling, and of other people of that stature who I admired and may have wished to emulate, but above all it was just the general fascination with science, there isn’t one area that’s more interesting than another and it was fun to learn about, as an undergraduate student I learned about and tried to study in the greatest depth that I could all areas of science, mathematics, science extending from physics to biology.

Up until about 20 years ago as I say it was possible to be aware of what were the outstanding issues in all of the areas, to read the literature, to follow the developments and occasionally to have ideas about them which may have been worthwhile. That ended with the explosion of information and with the exponential growth of science, and today it is simply no longer possible for anyone to be a generalist in the same sense. Even so, the distractions abound because the amount of information in the immediate vicinity of one’s own specific area really exceeds anybody’s possibility for comprehension, and so what I would say, despite the pleasure of the general interest in science before or the need to try and assimilate as much as possible of the relevant information that surrounds one’s own work today, the key to success is ultimately focus, it is in a way what I was saying before, it’s to narrow the description of the problem in a way quite contradictory to the notion of an interdisciplinary approach, on the contrary, one needs to be as narrow as possible to succeed, and the solution of any one problem as particular, and to find it you need to eventually hone in on something that is with pinpoint precision.

Given the explosion of science do you think that the finding environment for the sort of long term approach that you’re taking is getting better? Or worse?

… the only constraint is at the end of the day one must demonstrate success …

Roger Kornberg: I think that funding for a venture of the sort in which we’ve been engaged which extended over a period of many years was never really possible and never really will be, so it isn’t in general possible in the United States or anywhere else that I know of to seek funding for something that is open ended, that has no certain or even very likely prospect of success and it will obviously take a very long time, and the only way such work can be done is to define interim objectives and in the case of the work we do in the United States, and here I don’t know whether the same situation would apply elsewhere, to do related work that can be funded, but to draw upon the funds that are given for that also to pursue these longer term objectives which is very much encouraged in the American system, it’s understood that one may use the funds to do other science and the only constraint is at the end of the day one must demonstrate success.

What about the relationship between basic science and applied science? There’s a tendency for people to say okay, how can we use this, as soon as one reports any result and clearly in this case that question … one can come up with an answer to it, but the question doesn’t really mean that much, this is basic stuff, do you feel that it’s a worrying trend that people always want to apply what one is producing?

Roger Kornberg: On the one hand yes, it is a worrying trend in so far as it diminishes the support available for the pursuit of basic knowledge. On the other hand like all worrying trends in the world they have always been there and they always will be. And what the countervailing force is the drive on the part of individuals to seek the most basic truths and people will find a way, we do in our work, that’s the purpose, we delve as deeply as we can. There is no doubt that the future lies in all regards in the acquisition of increasingly fundamental, so the most basic knowledge, and useful applications always spring from that, and they are limited by the extent of our basic knowledge. That tends to be sometimes forgotten and there’s an understandable tendency on the part of people to want solutions to pressing problems now, nonetheless the drive to discover the most fundamental basis is something which is also strong, it can’t be prevented, it will go on, it will succeed.

Shifting track a little bit, one of the things that you’ve described as giving you greatest pleasure is to imagine the molecular machine that you study, and when we spoke in October just after you’d heard the news that you’d been awarded the prize you began to describe how you see it, could I get you to elaborate a little on how you picture this machine working when you see it in your mind’s eye?

Roger Kornberg: What is most fascinating about the very large molecular structure that we discovered from our work over the years is the extent to which it resembles a piece of machinery such as we know from daily life, so molecules have been … a good deal smaller molecules have been studied in the past and they are capable of executing specific transactions. What is astonishing about the piece of machinery that we have investigated, so much larger than those studied previously as I have mentioned, is that it executes many transactions, it contains multiple moving parts, these function in sequence and in ways that we still don’t fully understand, to execute an extraordinarily complex molecular transaction. Now the individual pieces can be viewed as the counterparts of tools or the components of machinery as we know it, and we name them accordingly, so the device that we study has a jaw, it has a rudder, it has parts that we call trigger and lid, and so on.

Do you envisage them as solid or fluid?

Roger Kornberg: The components of such molecules must on the one hand be perfectly rigid in order to have a defined shape, much like the parts of a machine, to execute their function. At the same time at appropriate times they’re capable of bending, flexibility, they can adopt multiple states of organisation as appropriate for their function. But I think the underlying principle is one of rigidity and so precise definition in much the same manner as one would envisage a piece of /- – -/ combustion engine or what have you.

Right. And when people come to ask to work with you on this problem what do you think it is that draws them in first and foremost?

Roger Kornberg: I think that when young people are attracted to research on a particular problem, they likely begin either with an interest in the broad area, in the case of our work most broadly defined it is the area of biological regulation, it is the control of gene expression. In other cases they may also be drawn to the nature of the work, the kinds of technology and manipulations that are involved. I think both are important because after all one must have some degree of fascination with the broader questions, but at the same time the work itself involves many often repetitive activities on a daily basis, and if one can’t take pleasure in the actual manipulations then it will lose its appeal.

The Nobel Prize will bring yet more notoriety for you and your work, and you’re very, very focused on what you do, how will you, do you think, cope with the increased demands?

… there’s nothing I wish to change about my scientific life before this point …

Roger Kornberg: In the first place I can tell you that I’m determined I absolutely will go on with the work I do simply because I enjoy it so very much, also because as you mentioned the work has gone on for a very long time and it is a way of life, it would be difficult to adopt a different lifestyle or approach or define the same satisfaction in doing something else now. So I’m inclined to, I will almost certainly decline, most of the offers and temptations to do other sorts of things, and try to maintain the focus, for the reason as I say that it comes naturally and it’s what I enjoy. I wouldn’t, there’s nothing I wish to change about my scientific life before this point, so I have no reason to allow it to happen after.

Well, thank you for accepting our invitation.

Roger Kornberg: With pleasure.

To end we just, this year we, for the first time, solicited questions from the public via the internet, and a couple of interesting questions came in which I’d just like to pose to you. One I think is quite relevant because it relates in a way to the complexity of what you do. Chris Curry from Anchorage in Alaska wants to know whether regular people, by which he means I think people who not scientifically trained, can still contribute to scientific understanding in a way that I suppose he feels that they could in the past, before everything became so technical.

Roger Kornberg: I think it’s on the one hand not possible to think in a productive or an effective way about science without studying, without mastering a subject, I mean any … what we do, indeed most of the science that goes on is understandable by and could be pursued I think by an ordinary, by any ordinary person, there’s nothing so profound that it requires any very rare aptitude to grasp and to do. So the answer is on the one hand that what the questioner refers to as an ordinary person would have to be willing to invest, to learn and to understand, but at the same time any ordinary person would be capable of doing it. I would add to that that I think it’s terribly important for all ordinary people to learn about and understand chemistry and the particular types of thing we and others do, as I have said to you earlier on there’s really nothing more valuable to the life of any person than to have some conception of the chemical basis for all that goes on around us.

Thank you. And lastly, Louisetta Moody from the United Kingdom asks whether during the processes of transcription it is necessary to make perfect copies or whether there’s some allowance for error possible?

Roger Kornberg: The answer is at two levels, no process is perfect and mistakes are made. And there are mechanisms for correcting the mistakes, those mechanisms are not perfect either and sometimes the mistakes slip through. Now the mechanisms for correction are extraordinarily, are no less intricate and remarkable than the mechanism of transcription itself. It’s only in the last few months that we’ve actually understood how common errors are avoided and how accuracy is achieved in transcription, and that work from the last several months has only been published in the last week.

Where was that published?

Roger Kornberg: It was published in a journal called Cell and it represents really in some sense an important outcome or culmination of the structural study for which the prize is given. At the same time, as I say, it is impossible for the mechanism to be perfect and indeed that errors are made at a significant rate and we, and especially others, have studied over the years some of the mechanisms for correction, we continue to pursue them and I think there’s still a lot to be learned about how the machine that we investigate is capable of detecting errors, reversing course, and correcting them.

Roger Kornberg, thank you very much indeed for taking the time to talk to us, and once again congratulations.

Roger Kornberg: Adam Smith, thank you very much, it was a pleasure.

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