A Visit With Dr. Francis Crick
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What follows is a transcript of a visit with Dr. Francis Crick (1916-2004), co-discoverer of the structure of the DNA molecule. Dr. Crick offers a fascinating look at the world of science at the time of this important discovery, as well as an equally fascinating glimpse into the thought processes of a brilliant scientist and thinker. This transcript is provided courtesy of Carolina Biological Supply Company.
Narrator: The 1953 discovery by Dr. Francis Crick and James Watson of the structure of the huge DNA molecule, the molecule which we now know stores the genetic information for all life, has been cited by many scientists as the single most important development in biology of the 20th century. Watson and Dr. Francis Crick's breakthrough, and the ensuing investigations into the nature of the genetic code and its transmission of information from generation to generation, have redefined the study of genetics and virtually created the science of molecular biology. For their work James Watson and Dr. Francis Crick, along with physicist Maurice Wilkins, were awarded the 1962 Nobel Prize in Medicine. Dr. Francis Crick recalls the award with his characteristic good humor.
Dr. Francis Crick: Well, I certainly didn't think I would win the prize. It's unclear whether Jim was thinking about it. He says in his book he was, but he never in those years mentioned it to me or to any other of my colleagues that I know of. It never occurred to me that it was prizeworthy until about three years later when someone mentioned it to me. And it indeed struck me this is just the sort of thing people get prizes for.
Narrator: Perhaps no one individual epitomizes the scientific theorist as does Dr. Francis Crick. Throughout his career in molecular biology, and later in neurobiology, Dr. Francis Crick has frequently eschewed experimentation preferring instead to concentrate his considerable genius on reading, thinking and talking his way to a problem's solution. Dr. Francis Crick's verve for a project has often been interpreted as immodesty, but his candid questioning of his colleagues, of himself, and most importantly, of their scientific methods has been instrumental in radically changing our world. His inquisitive nature has been apparent since childhood.
Dr. Francis Crick: I think I was always interested in science as early as I can remember. I don't think it was due to my parents. My father was a businessman. He never went to the university. My mother had been a teacher but she really didn't know about science. Whereas I wanted to know what is the world made of. And because I asked so many questions they bought me something called Children's Encyclopedia. And that covered all subjects. It covered history and literatures and music as well as science. And it had articles about the nature of the galaxy and chemistry and how things were made of atoms and so on. And I absorbed this with great enthusiasm and I think I must have at that stage decided to be a scientist. But I did confide to my mother, I said, "You know by the time I grow up everything would have been discovered." She said, "Don't you worry! When you grow up there will be plenty left for you to discover." So I think that is really how it happened.
Narrator: The young Crick attended Northhampton Grammar School and busily inquired into the nature of the world around him. At the age of 14 he entered Mill Hill School in North London - - where he obtained a thorough basic education in chemistry, physics and mathematics. Crick's undergraduate studies were at University College London where he received a degree in physics in 1937.
Dr. Francis Crick: As for the teaching, I studied physics with some mathematics. I didn't do chemistry because I didn't find that a very appealing subject. And I didn't do biology because people with my sort of background didn't do it in those days. I think the teaching was a little old-fashioned.
Narrator: Crick continued on at University College doing graduate work in physics until his research was interrupted by Word War II. After the war, however, he found himself less interested in physics and at a loss for a career. Meanwhile as interest in biology was ignited by Erwin Schrodinger's book What is Life? The Physical Aspect of the Living Cell. Crick became convinced that many fundamental problems in biology could be examined using the precise concepts and methods of physics and chemistry. In particular, he was eager to attack the doctrine of "vitalism" the notion that life processes are due to a vital principle not explicable by the laws of science.
Dr. Francis Crick: Well, I think what led me into biological research was really because I felt there was a mystery which I thought to be explained scientifically. And one of these areas was the borderline between the living and the nonliving and the other one was the problem of how the brain works - - the problems of consciousness. Of course nowadays we call those areas molecular biology and neurobiology, but those terms weren't known at that time. So after the war when I decided I would like to go back and go into scientific research, I realized I could start again and choose whatever field I wanted. And I found I was talking to friends about these particular problems. Although I knew nothing about them I was gossiping about them. And I thought that showed I was really interested. And then, after thinking about it further, I narrowed it down to what we call molecular biology and I looked around to see how I could start in that.
Narrator: For two years Francis Crick worked as a physicist, read and studied biology extensively, and bided his time until the opportunity presented itself to become involved in biological research. On his application for studentship to the prestigious Medical Research Council, Crick indicated his special interest in the division between the living and the nonliving. Thus, in 1949, one of the key performers in the search for the secrets of life found himself at the famed Cavendish physics laboratory in Cambridge, where many successful discoveries had occurred previously. Here scientists, working under the supervision of Sir Lawrence Bragg, were hoping to apply the working techniques of X-ray crystallography to better understand protein structure. At midcentury many scientists still believe that the family of macromoloecules called proteins contained the key to understanding the chemical basis of genetics. It was generally accepted that almost every cell has a complete set of instructions located in its genes and which determines how the cell grows, metabolizes and otherwise functions in relation to other cells. It was also thought that these genes reside on the cells chromosomes which were know to consist of both protein and deoxyribonucleic acid (DNA). Unlike most of his colleagues, however, Francis Crick remained unconvinced that proteins would hold the key to passing on genetic information.
Dr. Francis Crick: I think I first realized that the replication of genes was an important problem. And in that context one naturally wondered what genes were made of and one of the possibilities was DNA but it wasn't at all clear at that time that genes were partly made of DNA. There was some evidence which suggested that at least genes were partly made of DNA but no evidence to show they were entirely made of DNA. And so it was really in gene structure and gene replication I was interested in. And DNA was really only part of it.
Narrator: As Crick continued to learn about proteins and
X-ray diffraction for his Ph.D. thesis, the second of the key characters in the search for the secret of life appeared at the Cavendish. In 1951 James D. Watson, a brash young American on a postdoctoral fellowship, and with a background in genetics appeared. The synergic charge of energy between the two men was instantaneous. Two scientists with complementary backgrounds found they shared a conviction that DNA, not proteins, was the critical factor in passing on genetic information from generation to generation. They both believed that solving the structure of DNA would lead to an explanation of the self-replication of genes. And they both were eager to learn quickly whatever was necessary to find answers. However, their pursuit of the DNA structure would encounter several obstacles.
Dr. Francis Crick: The major obstacle we had to overcome I think was ignorance. We didn't know much about the various things which you had to know in order to solve such a structure. So we had to teach ourselves. Course I knew about crysytallography and Jim learned about it. And we had to learn about organic chemistry. And we had to learn a lot of biological things to see if DNA was likely to be important. And we had to try to put all those together and avoid mistakes; and of course if you read what happened it's really a saga of our getting over one mistake after another until finally we cleared all the mistakes out of the way and then it was easy.
Narrator: Crick and Watson's efforts to understand what role, if any, DNA played in the replication of the gene required their assimilation of considerable bits of information from many sources. For example, by the turn of the century it was know that nucleic acids were present in all cells. Also established by then were the three essential ingredients of nucleic acids: a sugar (ribose or deoxyribose), a phosphate and various bases (made for the most part from nitrogen and carbon atoms). By this time also the five important bases had been identified: two structurally similar purines, called guanine (G) and adenine (A) and three structurally similar pyrimidines, called thymine (T) cytosine (C) and uracil(U). By the early 1920s it had been proven that there were actually two nucleic acids, ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). The structures of these different molecules are similar except that (1) the sugar in DNA (deoxyribose) has one less oxygen atom that the sugar in RNA (ribose) and (2) the thymine base of DNA is replaced by uracil in RNA.
Then, in 1944, Oswald Avery and his colleagues made a critical discovery that became a landmark for the fledgling science of biochemistry. Avery showed that purified DNA, not proteins, was the primary carrier of genetic information. (See Access Excellence Classic Collection: The Structure of DNA) Although it took years before Avery's discovery would be accepted by many scientists, the stage was set for Crick and Watson to investigate the role of DNA in the gene.
To suspect that DNA played a role in heredity was one thing; to determine exactly what that specific role was meant solving the structure of the DNA molecule. How big was the molecule? What shape? How could the structure of the molecule determine its ability to replicate itself and thereby pass information on from generation to generation? Surprisingly, Crick and Watson's backgrounds did not necessarily parallel their insights.
Dr. Francis Crick: What you might guess were the roles was not the case. It was obvious that I knew more about X rays and structures that Jim did and he had more background in biological things which I'd only roughly taught myself. So you might have guessed that I did the structural part and he did the more biological aspect. That really wasn't true. For example, . . . Watson discovered exactly how the base pairs went together, which is structural, he made that discovery. And I was the one who realized that the Chargaff's rules meant that things paired up which you didn't have to know any structure for, just something about the history of science. The things ... in the same amount ... usually go together...
Narrator: But perhaps the crucial ingredient in Watson and Crick's success was their affinity of temperament; both were fun-loving and ambitious, impatient to the point of officiousness and often mercilessly candid.
Dr. Francis Crick: The other thing that was helpful was ... that you have to be on such candid terms that when the other produces an idea you can criticize it very freely without being offensive and so on. So that means that if one of you gets an idea which is cul-de-sac, which gets you in off on a false trail, the other one will pull you back and get you out of it. And I think that's really what helped. That every time one of us had a false idea the other would be very critical about it. And there are a number of cases of that we can actually document.
Narrator: And indeed, like most scientists, Watson and Crick followed their share of false trails. The crucial problem centered around how the four bases could fit together within the core of the molecule. Readily available data from scientist Erwin Chargaff showed that a one-to-one ratio existed between adenine and thymine on the one hand and between guanine and cytosine on the other. However, working out the exact configuration of the base pairs required considerable time. At first using cardboard cutouts and later using metal plates, brass rods and screws provided by the Cadendish machine shop Watson built various trial models to illustrate possible molecular structures.
Dr. Francis Crick: Well, I think we first realized it came in several stages. I realized that we were probably going to see it when Donohue told us that we should have the correct tautomeric forms of the bases. We hadn't got them correct before. I think really we could see it when Jim got the base pairs and I spotted that they got the right symmetry. But of course until we'd actually built the first tentative model which was quite small, incidentally, it was only just half a base pair - until we'd done that we weren't sure. So there was a gap of about two or three days where we did the model building and checked that everything was all right. Then essentially we knew that... we had it. Of course, we were never totally confident it was right. And we actually had that built before we had seen the experimental data, except Jim had just seen this one picture, but we hadn't got any measurements. So the next stage of confidence was when we saw the experimental data and realized it fit very well with our ideas.
Narrator: Of course there were other important participants in the establishing of the double-helical structure of DNA. Maurice Wilkins and his colleague Rosalind Franklin, even though their inability to fully cooperate slowed the process, nevertheless provided the X-ray diffraction data that confirmed the basic model of the DNA molecule. Linus Pauling's remarkable innovation of building three-dimensional models showed the way to determine a molecule's structure with only a minimum of experimental evidence. And there were other contributors, but essentially it was the perseverance of Crick and Watson that led eventually to a moment of epiphany in the spring of 1953.
Dr. Francis Crick: My most vivid memory is the moment when Donohue told us that the bases existed in one tautomeric form. Because I can remember where I was standing which is always what happens in vivid memories. You remember all the irrelevant details. I was at my desk, the two of them were by the board. And I realized then if that was the case then it should be possible for the bases to go together. But I didn't do that. Jim did that the next day. But that was really quite a vivid moment. Of course once we got the idea we were rather euphoric about it because we saw it had the potential for solving so many problems. And we did build a slightly higher model - - not the great big one you see in the photographs - - that was built later. And naturally we told our colleagues and various people came along. Bragg was actually in bed with the flu at the time - - our professor. So he came in about a week later.
Narrator: Watson and Crick's three-dimensional model of DNA molecule exhibits the two sides of a flexible ladder coiled around a common center to form a double helix. Each outside of the ladder, often called the backbone, is invariant throughout the molecule and merely repeats the phosphate-sugar bond over and over again. Attached to the inside of the backbone at the sugar is part of the ladder's rung. This variable part of the DNA molecule consists of one of the four bases: adenine, guanine, thymine or cytosine. It is the exact sequence of these bases along the inside of the ladder that determines the genetic message. The key to Watson and Crick's discovery was the realization that because of its size, shape and chemical makeup, each base on one side of the ladder could pair by hydrogen bonds with only one other base on the other complementary side of ladder. Specifically, the large adenine molecule could pair with only the smaller thymine and the large guanine molecule could pair with only the smaller cytosine. Once this structural simplicity was grasped the mechanism for molecular replication became apparent: Each of the two strands of the double helix could, upon separation at the hydrogen bonds between the base pairs, serve as a template for the synthesis of a new complementary strand. Thus, two new strands - - each a replica of an original to create two double helices. While Dr. Francis Crick feels that he and Dr. Watson deserve credit for their discovery, he also recognizes that an eventual breakthrough was inevitable.
Dr. Francis Crick: Well, I think as far as we deserve credit in the case of DNA there are perhaps two things. One is for choosing the problem and realizing there was a problem about gene replication and what genes were made of, which most people thought was too difficult and ought to be left on one side. So we chose a difficult problem, course we weren't to know it was going to have such as easy and dramatic answer, but at least we chose the problem. The other thing I think we deserve credit for was persistence and trying and also for learning about a lot of different subjects so we could put it all together. And not many people were prepared to do that. They were prepared to learn about their own part of the subject but they weren't prepared to learn about X-ray diffraction, for example, if they were biochemists. And if they were people doing X-ray diffraction then the details of the biochemistry is often left to somebody else. So I think those were the two things - - choosing an important problem on the one hand and really sticking to it and going at if from many points of view. Well, if Jim and I hadn't discovered DNA, which easily could have happened, I think somebody else was bound to. The structure was there waiting to be discovered. And once you've seen the structure, I think the implications are fairly obvious although possibly if other people had discovered it, it might not have been pushed as much as Jim and I pushed it. The question then is who might have discovered it.
Narrator: After receiving his Ph.D. from Cambridge University in 1953 Dr. Francis Crick continued work to decipher the genetic code. Working with Watson, molecular biologist Sidney Brenner, physicist George Gamov and others, Crick showed how the sequence of four bases in DNA and RNA (ribonucleic acid) instructed the creation of the sequence of 20 basic amino acids which, it turn, coded for the thousands of proteins that direct the processes of life. Of course, the implications of their initial discovery are still being explored.
Dr. Francis Crick: Well, I think the effect has been dramatic because first of all it's laid a very sure foundation for all the molecular events that happened. Although, of course many of them we don't understand yet in detail but we think we understand in principle the sort of thing that proteins do, a nucleic acid does, even if we are finding new variants and so on as we go along. And then problems like those in developmental biology - - how you make a hand. Whole problems of embryology are now being transformed by these new methods and to say nothing of the applied problems, the medical ones. I mean we wouldn't even understand what a virus like AIDS was about if we didn't understand molecular biology. And the discoveries which were made about that type of virus - - the retoviruses - - built on the earlier discoveries.
Narrator: By 1966, feeling that the foundations of the molecular biology were adequately outlined and that it was time for him to pursue other interest, Dr. Francis Clark turned his attention to embryology. Then, in 1976, he went to the Salk Institute in La Jolla, California, for a sabbatical year from the Medical Research Council. The following year, after 30 years and 87 scientific papers, he decided to make a career change from the MRC and moved to the Salk Institute where he pursed his interest in the workings of the brain.
Dr. Francis Crick: When I started to think about the brain I had to decide what sort of things to do. I decided it was probably better not to do experiments.
Although even now there might be some things I might do experiments on, I decided I better do theoretical work. I also decided that I would mainly be interested in our brains and the brains of related animals--the higher mammals shall we say,--because there are many experiments you can't always do on human beings which you can do on rats or monkeys or whatever. And the other thing I decided was that I would try and not merely look at the molecular aspects which is what I knew about, but look at it from all levels from the psychological aspects and neuroanatomy and neurophysiology. Even some of the philosophical things and see if one could build bridges between the different approaches. And that is essentially what I have been trying to do.
Narrator: As part of Dr. Francis Crick's continued interest in the nature of the consciousness he also investigated the complex phenomenon of human dreams.
Dr. Francis Crick: Graeme Mitchison and I got into the business of dreams not because we were thinking about dreams, it was because we were thinking about neural nets. It is a common thought in the subject that you won't understand that brain by just understanding how one single neuro works. You must understand how groups of neurons interact and work together. And people make very crude and simple models of these which they can test their performance in a computer. These are called neural nets. The trouble is that they don't behave terribly well. When you store memories in them the memories are not stored as they are in a computer or a filing cabinet.. They tend to be stored rather on top of each other and they get in each other's way if you put too many in. We were worrying about this and wondered how you could prove that. We invented a mechanism which would, as it were, while the net was off-line, separate out memories which got a bit confused because they were too alive. And then it struck us that this is maybe what happened in sleep and REM, sleep the active sleep when you have dreams. Because the sort of mixtures that you get in nets are the sort of things you have in dreams, And we therefore thought this was some evidence for that.
Narrator: The nature of consciousness especially in the areas of vision memory and dreams still fascinates Dr. Francis Crick and will probably capture most of his attention in the future.
Dr. Francis Crick: Well it is always really difficult to say what you want to do in the future. I certainly would like of course to understand certain aspects of the brain better. But at my time of life it isn't obvious that I will actually do that myself. I might make a contribution myself I might promote other people into doing problems. The problem which I would most dearly like to see understood but I am not sure that will happen so soon is the problem of consciousness what makes us aware and so on.
Narrator: Perhaps more than anything else Dr. Francis Crick was, and continues to be, a creative thinker and adept communicator of ideas. In his book, Life Itself: Its Origin and Nature, Crick propounds the theory of directed panspermia that he and colleague Leslie Orgel developed to explain the origin of life on earth. This notion that life on earth was seeded by microorganisms from a higher civilization and sent through space on unmanned rockets remains outside the mainstream of science; however, the mental exercises that Crick entertains both for and against his theory are stimulating and informative. Francis Crick's most recently published book entitled What Mad Pursuit: A Personal View of Scientific Discovery ostensibly tells a familiar story about the discovery of the DNA double helix. However, the author, with his relaxed and personal style, quickly conveys that his enthusiasm for science for knowledge indeed for life itself has not diminished. Although he may not lead the charge as he did in the early days of molecular biology, Crick is eager to promote research on the brain and the nature of consciousness. In his epilogue he sounds the clarion for young scientists everywhere. The brain sciences have a very long way to go but the fascination of the subject and the importance of the answers will inevitable carry it forward. It is essential to understand our brains in some detail is we are to assess correctly our place in this vast and complicated universe we see all around us.
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