Of course, not all these questions had received detailed answers. We still did not know the base sequence of any gene. Our ideas about the biochemistry of gene replication were oversimplified. Only in bacteria did we know how a gene was controlled, and even in this case the molecular details were lacking. About the control of genes in higher organisms we knew hardly anything. And although we knew that messenger RNA directed protein synthesis, the site of protein synthesis—the ribosome—was little more than a black box to us. Nevertheless by 1966 we realized that the foundations of molecular biology were now sufficiently firmly outlined that they could be used as a fairly secure basis for the prolonged task of filling in the many details.
Sydney Brenner and I thought that it was time to move on to new fields. We selected embryology—now often called by the more general term developmental biology. Sydney, after much reading and thinking, chose the little nematode worm Caenorhabditus elegans as a suitable organism to study, since it bred fast, was easy to grow in the lab, and had unusual but attractive genetics. (It is a self-fertilizing hermaphrodite.) Almost all the work now being done on this little animal—it is even used for studies on aging—springs from these pioneer studies of Sydney.
I decided that a key feature of development was gradients, whatever they were. In some way a cell in an epithelium (a sheet of cells) seemed to know where it was in the sheet. This was ascribed to the existence of “gradients” of some form or another—possibly the regular change in concentration of a chemical from one part of the sheet to another. The nature of these postulated gradients was then quite unknown. At about this stage Peter Lawrence joined us, and I followed closely his work on gradients in the cuticle of insects, which had been pioneered by Michael Locke. My colleagues Michael Wilcox and Graeme Mitchison studied an even simpler system, the pattern of cells in the long chains of cells formed by one of the blue-green algae (now called a bacterium). In spite of all their efforts, it proved impossible to get a foothold in the biochemical basis of the problem—what molecules were used to form this gradient or that?—and eventually I moved on to other aspects of the subject. I became interested in the histones, the small proteins found associated with DNA in the chromosomes of higher organisms, and attended closely to the work of my colleagues Roger Kornberg, Aaron Klug, and others, which led to the structure of nucleosomes, the small particles on which chromosomal DNA is wound.
In 1976 I decided to go to The Salk Institute on a sabbatical. The Salk (the full title is The Salk Institute for Biological Studies) is situated a little back from the cliffs overlooking the Pacific Ocean in La Jolla, a suburb of San Diego in lower Southern California. For twelve years, from shortly after the official start of the institute on December 1, 1960, I had been a nonresident Fellow (effectively a member of a visiting committee), and indeed I had been involved with it even before it started. In the very early days “Bruno” Bronowski and I would fly from London to Paris to consult with Jonas Salk, Jacques Monod, Mel Cohn, and Ed Lennox on such fascinating topics as the by-laws for the proposed institute.
The president of the Salk Institute, Dr. Frederic de Hoffmann, went to great efforts to tempt me to stay on there. Eventually he persuaded the Kieckhefer Foundation to endow a chair for me. I resigned from the Medical Research Council. Odile and I took up residence in Southern California, where we have been ever since.
California is effectively bounded on the east by the desert, on the west by the Pacific, on the south by Mexico, and on the north by the state of Oregon, where it appears to rain much of the time. California is almost twice the size of Britain, has a little less than half the population of the U.K., and is appreciably more affluent. It has a large and impressive system of universities. Odile and I are resident aliens—immigrants, that is—though we remain British citizens. An immigrant doesn’t have a vote but otherwise has all the privileges and duties of a U.S. citizen, including paying taxes.
Personally I feel at home in Southern California. I like the prosperity and the relaxed way of life. The easy access to the ocean, the mountains, and the desert is also an attraction. There are miles of lovely beaches to walk on—out of season they are usually almost deserted. The mountains ate only an hour away, and are higher than any in the British Isles (which is not saying much) and often have snow on them in the winter. The highest ones look down on the desert. In spring, if there has been enough winter rain, the desert bursts into flower. Even at other times it has a strange fascination, partly because of the subtle colors and the wide expanse of sky.
In spite of the almost ideal climate, scientists here seem to work hard. In fact, some of them work so hard that there is no time left for serious thinking. They should heed the saying, “A busy life is a wasted life.” I feel much less at home in the rest of America. New York seems almost as remote to me, in both distance and atmosphere, as London now does. My feelings about New York and California are thus just the reverse of Woody Allen’s. Woody loves New York and hates California. According to him, “It’s only cultural advantage is that you can turn right on a red.” But then he seems to enjoy what we in the west call “East Coast tension.”
Molecular biology had not stood still in the ten years since 1966, but mostly it had been a period of consolidation. Perhaps the most striking discovery was the retroviruses—RNA viruses that were transcribed onto DNA and incorporated into chromosomal DNA. The key finding was made independently by Howard Temin and David Baltimore. For this they were awarded the Nobel Prize for Medicine in 1975, sharing it with Renato Dulbecco, who is now at the Salk Institute. (The virus that causes AIDS is a retrovirus. Without this pioneer work it would have been difficult to make any sense of AIDS.)
Although I did not appreciate it, molecular biology was on the verge of a massive step forward, caused by three new techniques: recombinant DNA, rapid DNA sequencing, and monoclonal antibodies. Critics who previously had argued that few practical benefits had come from molecular biology were silenced by the realization that, with these new techniques, one could make money out of it. I shall not attempt to describe these very important advances in detail, nor the remarkable results that are now appearing almost every day, mainly because I have not been directly involved in them myself.
I decided that the move to the Salk Institute was an ideal opportunity to become closely interested in the workings of the brain. For many years I had followed parts of the field at a distance. (I first heard of David Hubel and Torsten Wiesel’s work on the visual system from a footnote in an article in the literary magazine Encounter.) I realized that if I were ever to study the brain more closely it was now or never, since I had just passed sixty.
It took me several years to detach myself from my old interests, especially as in molecular biology surprising things were happening all the time. One of these surprises was the discovery that, in many cases, a stretch of DNA coding for a single polypeptide chain was not continuous, as we had assumed, but was interrupted by long stretches of what appeared to be “nonsense” sequences. These sequences, now called introns, were eliminated from the pre-messenger RNA by a process called splicing. The resulting messenger RNA, with all the sense bits (called exons) now joined together, was then exported to the cytoplasm so that it could direct the synthesis, on the ribosome, of the protein it coded.
Such introns were found mainly in higher organisms. In our own genes the nonsense sequences (the introns) were often longer than the meaningful ones (the exons). Introns were much sparser in those “higher” organisms, such as the fruit fly Drosophila, that had rather little DNA. And in primitive organisms, such as bacteria, introns hardly occurred at all, and then only in special places [small introns in transfer RNA genes].
It was also discovered that not all of the stretches of DNA between genes was necessarily very meaningful. Much of our DNA, perhaps as much as 90 percent, appeared at first sight to be unnecessary junk. Even if it had some use, its function probably did not depend on the exact details of its sequence. Leslie Orgel and I wrote an article
suggesting that much of it was “Selfish DNA"—a better term might be “Parasitic DNA"—that was there not for the sake of the organism, but for its own sake. Richard Dawkins had already made this suggestion very briefly in a book of his called The Selfish Gene.
Leslie and I suggested that this selfish DNA had originated, on many separate occasions, as DNA parasites, which hopped from place to place on the chromosome, leaving replicas of themselves embedded in the host DNA. After a time many of these sequences would be made meaningless by random mutation and then, gradually, over a long period, would be eliminated by the host cell. Meanwhile new parasitic sequences might start to invade the host DNA until eventually a rough balance would be reached between host DNA and parasitic DNA. Whether all this is really true remains to be seen.
The possible existence of such selfish DNA is exactly what might be expected from the theory of natural selection. You are no doubt familiar with the idea of a parasite, such as a tapeworm, but you may not at first accept the idea that a molecule too could be a parasite living in your own chromosomes. But why not?
Notice that the existence of introns came as almost a complete surprise. Nobody had clearly postulated their existence before experimenters stumbled on them by accident. Introns would probably have been discovered earlier if they had existed to any appreciable extent in E. coli or in the coli phages. There was no hint of them from classical genetics, even in an organism such as yeast on which relatively high resolution genetic mapping had been carried out. Introns are just the type of thing that is often missed by a pure black-box approach: that is, when only the behavior of the organism is looked at rather than looking inside the organism itself.
During this period I also wrote a scientific book, for lay readers, on the origin of life. Leslie Orgel and I, while attending a scientific meeting on communicating with extraterrestrial intelligence (CETI) held near Yerevan in Soviet Armenia in September 1971, had hit on the idea that perhaps life on Earth originated from microorganisms sent here, on an unmanned spaceship, by a higher civilization elsewhere. Two facts led us to this theory. One was the uniformity of the genetic code, suggesting that at some stage life had evolved through a small population bottleneck. The other was the fact that the age of the universe appears to be rather more than twice the age of the Earth, thus allowing time for life to have evolved twice over from simple beginnings to highly complex intelligence.
We called our theory directed panspermia. Panspermia, a term first used by the Swedish physicist Svante Arrhenius, in 1907, is the idea that microorganisms drifted to the Earth through space and seeded all life on Earth. We used “directed” to imply that someone had deliberately sent the microorganisms here in some way.
The chief difficulty in writing a popular book about the origin of life is that it is mainly a problem in chemistry—mostly organic chemistry. And almost all laymen dislike chemistry. “I understood it all,” my mother once said to me about a review I had given her to read, “except for those hieroglyphics.” However, the object of my book was not to solve the problem of life’s origins but to convey some idea of the many kinds of science involved in the problem, ranging from cosmology and astronomy to biology and chemistry.
I myself had a rather detached view of directed panspermia—I still have—and there was even a passage in the book saying what a good theory should be like and why our theory, though not un-provable, was obviously very speculative. The book, published by Simon & Schuster in 1981, was entitled Life Itself. While I considered this title rather too broad for the contents, the publisher insisted on it.
To return to the brain. When I first decided to study it in detail I thought I already knew about most of the problems, at least in broad outline. At Cambridge I had known Horace Barlow for many years—I was introduced to him by my friend Georg Kreisel, the mathematician—and in the fifties had heard Horace talk to the Hardy Club about the frog’s eye, with its postulated “insect detectors.” At the Hardy Club I had also listened to Alan Hodgkin and Andrew Huxley telling us about their famous model for the axon potential in the squid axon. Later on I met the neurophysiologist David Hubel at a little meeting organized in 1964 at the Salk Institute. The purpose of this meeting was to tell the Salk Fellows what was going on in neurobiology, in case we wanted to make some appointments at the Salk in these fields.
At the same meeting I met for the first time the neurophysiologist Roger Sperry and the neuroanatomist Walle Nauta. There were about a dozen speakers in all, but only a dozen or so listeners, as at that time the Salk was relatively new. However, the listeners were a formidable group, including, for example, Jacques Monod and the physicist Leo Szilard. The audience was so critical that the last speaker was visibly trembling when he took the stand. I only wish that the Salk had been able to start work on neurobiology at that time. While financial considerations made it impossible to do so then, now half its work touches on neurobiology.
I soon found out that what I had learned amounted to very little. Apart from the fact that a lot of work had been done in neuroanatomy and neurophysiology since I had first glanced at these subjects, there were whole areas, such as psychophysics, of which I knew absolutely nothing. (Psychophysics is not some new California religion. It is an old term for that branch of psychology that deals with measuring the response of a person or animal to physical inputs, such as light, sound, touch, etc.).
Moreover, I found there was a new subject that called itself cognitive science. (It has been said, somewhat unkindly, that any subject that has “science” in its name is unlikely to be one.) Cognitive science was part of the rebellion against behaviorism. Behaviorists thought that one should study only the behavior of an animal and should not try to take account of, or make models of, any postulated mental processes inside the animal. Behaviorism became the dominant school in psychology in the earlier part of this century, especially in America.
Cognitive scientists, in opposition to the narrow views of behaviorists, think it important to make explicit models of mental processes, especially those of humans. Modern linguistics is an important part of cognitive science, since it does just that. There is no great enthusiasm, however, for looking into the actual brain itself. Many cognitive scientists tend to regard the brain as a “black box,” better left unopened. In fact, some people define cognitive science as studies that take no account of such things as nerve cells. In cognitive science the usual procedure is to isolate some psychological phenomenon, make a theoretical model of the postulated mental processes, and then test the model, by computer simulation, to make sure it works as its author thought it would. If it fits at least some of the psychological facts it is then thought to be a useful model. The fact that it is rather unlikely to be the correct one seems to disturb nobody.
I found all this most peculiar and still do. Basically it is the philosophical attitude of a functionalist, a person who believes that study of the functioning of a person or animal is all important and that it can be studied, by itself, in an abstract way without bothering about what sort of bits and pieces actually implement the functions under study. Such an attitude, I found, is widespread among psychologists. Some even go so far as to deny that knowing exactly what goes on inside the head would ever tell us anything useful at all about psychology. They are apt to bang their fists on the table in support of such statements.
When pressed as to why they think in this way, they usually say that the whole bag of tricks is so fiendishly complicated that no good is likely to come from looking at it closely. The obvious answer to this is that if indeed it is so complicated, how do they ever hope to unscramble the way it operates by looking solely at its input and output, ignoring what goes on between? The only reply I have ever had to such a question is that it is essential to study organisms at higher levels and that the study of neurons, by itself (my italics), will never solve such problems. With this I entirely agree, but I cannot see that it justifies ignoring neurons altogether. It is not usually advantageous to have one hand tied beh
ind one’s back when tackling a very difficult job.
My own prejudices are exactly the opposite of the functionalists’: “If you want to understand function, study structure,” I was supposed to have said in my molecular biology days. (I believe I was sailing at the time.) I think one should approach these problems at all levels, as was done in molecular biology. Classical genetics is, after all, a black-box subject. The important thing was to combine it with biochemistry. In nature hybrid species are usually sterile, but in science the reverse is often true. Hybrid subjects are often astonishingly fertile, whereas if a scientific discipline remains too pure it usually wilts.
In studying a complicated system, it is true that one cannot even see what the problems are unless one studies the higher levels of the system, but the proof of any theory about higher levels usually needs detailed data from lower levels if it is to be established beyond reasonable doubt. Moreover, exploratory data from the study of lower levels often suggests important ways of constructing new higher-level theories. In addition, useful information about lower-level components can often be obtained from studying them in simpler animals, which may be easier to work on. An example would be recent work on the mechanism of memory in invertebrates.
My first problem was to decide what sort of animal to concentrate on. Some of my fellow molecular biologists had opted for small, rather primitive animals. As mentioned, Sydney Brenner had selected a nematode. Seymour Benzer had chosen to study the behavioral genetics of the little fruit fly, Drosophila, partly because so much basic genetics had already been done on it.
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