What Mad Pursuit

BOOKS IN THE ALFRED P. SLOAN FOUNDATION SERIES

Disturbing the Universe by Freeman Dyson
Advice to a Young Scientist by Peter Medawar
The Youngest Science by Lewis Thomas
Haphazard Reality by Hendrik B. G. Casimir
In Search of Mind by Jerome Bruner
A Slot Machine, a Broken Test Tube by S. E. Luria
Enigmas of Chance by Mark Kac
Rabi: Scientist and Citizen by John Rigden
Alvarez: Adventures of a Physicist by Luis W. Alvarez
Making Weapons, Talking Peace by Herbert F. York
The Statue Within by François Jacob
In Praise of Imperfection by Rita Levi-Montalcini
Memoirs of an Unregulated Economist by George J. Stigler
Astronomer by Chance by Bernard Lovell

THIS BOOK IS PUBLISHED AS PART OF AN ALFRED P. SLOAN FOUNDATION PROGRAM

Preface to the Series

THE ALFRED P. SLOAN FOUNDATION has for many years had an interest in encouraging public understanding of science. Science in this century has become a complex endeavor. Scientific statements may reflect many centuries of experimentation and theory, and are likely to be expressed in the language of advanced mathematics or in highly technical terms. As scientific knowledge expands, the goal of general public understanding of science becomes increasingly difficult to reach.

Yet an understanding of the scientific enterprise, as distinct from data, concepts, and theories, is certainly within the grasp of us all. It is an enterprise conducted by men and women who are stimulated by hopes and purposes that are universal, rewarded by occasional successes, and distressed by setbacks. Science is an enterprise with its own rules and customs, but an understanding of that enterprise is accessible, for it is quintessentially human. And an understanding of the enterprise inevitably brings with it insights into the nature of its products.

The Sloan Foundation expresses great appreciation to the advisory committee. Present members include the chairman, Simon Michael Bessie, Co-Publisher, Cornelia and Michael Bessie Books; Howard Hiatt, Professor, School of Medicine, Harvard University; Eric R. Kandel, University Professor, Columbia University College of Physicians and Surgeons, and Senior Investigator, Howard Hughes Medical Institute; Daniel Kevles, Professor of History, California Institute of Technology; Robert Merton, University Professor Emeritus, Columbia University; Paul Samuelson, Institute Professor of Economics, Massachusetts Institute of Technology; Robert Sinsheimer, Chancellor Emeritus, University of California, Santa Cruz; Steven Weinberg, Professor of Physics, University of Texas at Austin; and Stephen White, former Vice-President of the Alfred P. Sloan Foundation. Previous members of the committee were Daniel McFadden, Professor of Economics, and Philip Morrison, Professor of Physics, both of the Massachusetts Institute of Technology; George Miller, Professor Emeritus of Psychology, Princeton University; Mark Kac (deceased), formerly Professor of Mathematics, University of Southern California; and Frederick E. Terman (deceased), formerly Provost Emeritus, Stanford University. The Sloan Foundation has been represented by Arthur L. Singer, Jr., Stephen White, Eric Wanner, and Sandra Panem. The first publisher of the program, Harper & Row, was represented by Edward L. Burlingame and Sallie Coolidge. This volume is the seventh to be published by Basic Books, represented by Martin Kessler and Richard Liebmann-Smith.

The Alfred P. Sloan Foundation

Acknowledgments

THIS BOOK was started at the suggestion of the Sloan Foundation, for whose generous support I am most grateful. I was approached in 1978 by Stephen White, who persuaded me to sign the initial memorandum of agreement but I was very dilatory about beginning to write. I might have stayed in this state indefinitely but for Sandra Panem, who took over as book program director in 1986. She liked the idea of the book that was forming in my mind, and stimulated by her enthusiastic encouragement I produced a first draft. This was expanded and improved enormously as the result of her detailed comments, together with those of the Sloan Advisory Committee. I have also been helped by the comments of Martin Kessler, Richard Liebmann-Smith, and Paul Golob of Basic Books and by the copy editor, Debra Manette, who has improved my English in many places. I am also grateful to Ron Cape, Pat Church-land, Michael Crick, Odile Crick, V. S. (Rama) Ramachandran, Leslie Orgel, and Jim Watson, all of whom made helpful comments on one or another of the earlier drafts.

In writing the rest of the book, I have not made a deliberate attempt to acknowledge those who have been very close associates and have also influenced me strongly. While I shall not try to list here all my many friends and colleagues, there are three whom I must single out for special mention. The text does make clear how much I owe to Jim Watson. It does less than justice to my long and very fruitful association with Sydney Brenner. He was my closest associate for almost twenty years, and during much of that time we had long scientific discussions on almost every working day. His clarity, incisiveness, and fertile enthusiasm made him an ideal colleague. My third debt is to Georg Kreisel, the mathematical logician, whom I always address by his last name in spite of our having known each other for about forty-five years. When I met Kreisel I was a very sloppy thinker. His powerful, rigorous mind gently but steadily made my thinking more incisive and occasionally more precise. Quite a number of my mental mannerisms spring from him. Without these three friends my scientific career would have been very different.

My other major debt is to my family. Not only did they encourage me to become a scientist but they helped me financially. My parents made considerable sacrifices to enable me to go away to boarding school, especially during the Depression. My uncle Arthur Crick and his wife not only assisted me financially while I was a graduate student at University College but also gave me the money to buy our first house. My aunt Ethel, in addition to teaching me to read, helped financially when I first went to Cambridge after the war, as did my mother. They both helped also with the education of my son Michael. While I had very little money when I was young, I was secure in the knowledge that, thanks to my relatives, I would have enough to live on.

During most of the period covered by the main sections of this book I was employed in Cambridge by the British Medical Research Council. I am especially grateful to them, and in particular to Sir Harold Himsworth (then Secretary of the MRC) for providing such perfect working conditions there for me and my colleagues.

I should also record my gratitude to my present employer, The Salk Institute for Biological Studies, and in particular its president, Dr. Frederic de Hoffmann, for allowing me to work in such a delightful and stimulating atmosphere.

While writing this book I was mainly occupied in studying the brain. I thank the Kieckhefer Foundation, the System Development Foundation, and the Noble Foundation for their financial support of my efforts.

I thank the Editor of Nature for allowing me to quote at length from my article entitled, “The Double Helix: A Personal View,” published on April 26, 1974; the New York Academy of Sciences for permission to quote extensively from an article of mine, “How to Live with a Golden Helix,” which appeared in The Sciences in September 1979; Richard Dawkins and W. W. Norton and Company for permission to use several passages from his book, The Blind Watchmaker, published in 1986; V. S. (Rama) Ramachandran and Cambridge University Press for allowing me to quote a paragraph from his chapter “Interactions Between Motion, Depth, Color, Form and Texture: The Utilitarian Theory of Perception,” soon to appear in Vision, Coding and Efficacy, edited by Colin Blakemore; and Jamie Simon for doing the drawings.

Finally, my warmest thanks to my secretary, Betty (“Maria”) Lang, who has coped splendidly with the many successive versions and all the tedious chores associated with producing a manuscript.

What Mad Pursuit

Introduction

THE MAIN PURPOSE of this book is to set out some of my experiences before and during the classical period of molecular biology, which stretched from the discovery of the DNA double helix in 1953 till about 1966 when the genetic code—the dictionary relating the nucleic acid language to the protein language—was finally elucidated. As a preliminary I have put a short prologue that outlines a few details of my upbringing and education, including my early religious education, followed by an account of how I decided (after the Second World War) what branch of science to study, using the “gossip test” to help me. I have also included an epilogue, describing in outline what I have been doing since 1966.

There is an important difference between the scientific work described in the main body of the book and that touched on in the epilogue. In the former case we know with reasonable certainty what the correct answers are (the protein-folding problem is an exception). In the epilogue we do not yet know how things will turn out (the exception here is the double helix). For this reason many of my remarks in the epilogue are a matter of opinion. My comments in the main body of the book have somewhat more authority. One of the striking characteristics of modern science is that it often moves so fast that a research worker can see rather clearly whether his earlier ideas, or those of his contemporaries, were correct or incorrect. In the past, this opportunity did not arise so often. Nor does it today in slowly moving fields.

I have not tried to give an exhaustive account of what I did scientifically during those exciting years, let alone the large amount of work done by others. For example, I have said little or nothing about the ideas Jim Watson and I had about virus structure, nor about my collaboration with Alex Rich on a number of molecular structures. Instead I have included only those episodes that seem to me to have some general interest or to teach some general lesson about how research is done and what mistakes to avoid, especially those mistakes most relevant to biology. To do this I have to dwell somewhat more on errors than on successes.

In 1947, at the age of thirty-one, I went to Cambridge. After about two years working at the Strangeways Laboratory (a tissue-culture lab) I transferred to the Cavendish—the physics laboratory. There I became a graduate student again, trying to learn something about the three-dimensional structure of proteins by studying the X-ray diffraction patterns produced by protein crystals. It was then that I first learned how to go about doing research. It was during this period, while I was still a graduate student, that Jim Watson and I put forward the double-helical structure of DNA.

It has been difficult for me to write anything very new about the events leading up to the discovery of the double helix, since this has already been the subject of several books and movies. Rather than go over such familiar ground once again, I have found it better to comment on various aspects of the discovery and also on the recent BBC television movie Life Story, which deals with the discovery. In the same way I have not spelled out exactly how the genetic code was discovered—this is outlined in almost all modern textbooks. Instead I have dwelt mainly on the ups and downs of the theoretical approach, because I think few people realize exactly what a failure all this theoretical work on the genetic code turned out to be.

Since I am concerned more with ideas than with people, I have not included detailed character sketches of my friends and colleagues, mainly because I am reluctant to write candidly about close personal relationships with people still alive. In spite of this I have scattered through the text a number of small anecdotes, to give at least a few glimpses of what scientists are like, and to make for easier reading. Few people will willingly slog through an uninterrupted intellectual argument that lasts a whole book, unless they are acutely interested in the topic. In short, my main aim has been to put over a few ideas and insights in what I hope is an entertaining manner.

I have written both for my fellow scientists and for the general public, but I believe a layman can easily understand most of what I discuss. Occasionally the arguments become somewhat technical, but even in those cases I think that the general thrust of the idea is fairly easy to appreciate. I have sometimes placed short remarks from a more advanced standpoint in square brackets. To help those without a background in molecular biology, I have also included as a frontispiece a figure showing the approximate sizes of molecules, chromosomes, cells, and so forth, as well as two appendixes, the first sketching in the briefest outline the elements of molecular biology and the second setting out the details of the genetic code. Since most people (except chemists) hate chemical formulas, I have banished almost all of them to the first appendix.

In spite of all my efforts at clarification, a layperson may still find parts of chapters 4, 5, and 12 somewhat hard going at first reading. My advice to the reader, should he or she become stuck in such a passage, is either to persevere or to skip to the next chapter. Most of the book is fairly easy. Don’t give up hope just because a few paragraphs seem a little hard to follow.

The most important theme of the book is natural selection. As I explain, it is this basic mechanism that makes biology different from all the other sciences. Of course anyone can grasp the mechanism itself, though remarkably few people actually do so. Most surprising, however, are the results of such a process, acting over billions of generations. It is the general character of the resulting organisms that is unexpected. Natural selection almost always builds on what went before, so that a basically simple process becomes encumbered with many subsidiary gadgets. As François Jacob has so aptly put it, “Evolution is a tinkerer.” It is the resulting complexity that makes biological organisms so hard to unscramble. Biology is thus very different from physics. The basic laws of physics can usually be expressed in exact mathematical form, and they are probably the same throughout the universe. The “laws” of biology, by contrast, are often only broad generalizations, since they describe rather elaborate chemical mechanisms that natural selection has evolved over billions of years.

Biological replication, so central to the process of natural selection, produces many exact copies of an almost infinite variety of intricate chemical molecules. There is nothing like this in physics or its related disciplines. That is one reason why, to some people, biological organisms appear infinitely improbable.

All this can make it difficult for a physicist to contribute to biological research. Elegance and a deep simplicity, often expressed in a very abstract mathematical form, are useful guides in physics, but in biology such intellectual tools can be very misleading. For this reason a theorist in biology has to receive much more guidance from the experimental evidence (however cloudy and confused) than is usually necessary in physics. These arguments are set out in more detail in chapter 13, “Conclusions.”

I myself knew very little biology, except in a rather general way, till I was over thirty, since my first degree was in physics. It took me a little time to adjust to the rather different way of thinking necessary in biology. It was almost as if one had to be born again. Yet such a transition is not as difficult as all that and is certainly well worth the effort. To discuss how my career developed, I turn first to a brief account of my early years.