Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
SALK INSTITUTE FOR BIOLOGICAL STUDIES/MARC LIEBERMAN FRANCIS CRICK 8 june 1916 . 28 july 2004 PROCEEDINGS OF THE AMERICAN PHILOSOPHICAL SOCIETY VOL. 150, NO. 3, SEPTEMBER 2006 biographical memoirs F RANCIS CRICK, on whose behalf it would not be unreasonable to claim that he was the greatest and most influential theoretician of biology since Charles Darwin, died of colon cancer in La Jolla, California, on 28 July 2004, at the age of eighty-eight. My declaring that Crick was a “theoretician of biology” is not meant to imply that his main scientific interest concerned the working out of the quantitative relations that govern the behavior of complex biological systems. Rather, by calling him a “theoretician” I want to indicate that, like Darwin’s main scientific interests, Crick’s also lay in developing novel qualitative concepts that can account for previously unfathomed aspects of life. Crick was born in Northampton, England, on 8 June 1916. On completing his secondary education at Northampton Grammar School he went to University College, London, where he received a B.Sc. in 1937. He stayed on to do graduate work for a Ph.D. in physics. However, in 1939 his studies at University College were interrupted by the outbreak of war. During the war, Crick worked at the British Admiralty in London, devising detonators for magnetic and acoustic mines. Very likely, all that time a hapless German Anti-Crick sat at the Kriegsmarineamt in Wilhelmshaven, locked in a battle of wits with the future greatest theoretician of biology since Darwin in the design of ever more sophisticated mines able to discriminate between the approach of real enemy ships and dummy decoys. The DNA Double Helix Crick left London and the Admiralty in 1947 and went up to Cambridge for graduate studies in biology at the Strangeways Laboratory. He was not thrilled, however, by the research project assigned to him there—a study of the viscosity of the cytoplasm. So he moved to the Cavendish Laboratory, the renowned Cambridge center for the determination of molecular structures by X-ray crystallography. At the Cavendish, Crick joined the research group headed by Max Perutz and John Kendrew and began an X-ray crystallographic study of protein structure for his Ph.D. thesis. A crucial event in Crick’s career occurred in 1951, when James Watson, a young American postdoctoral student trained in the formal genetics of viruses and bacteria but hitherto a stranger to X-ray crystallography, turned up at the Cavendish. Watson was bent on determining the structure of the DNA molecule, in which the genetic information carried in the chromosomes of living creatures had recently been found to be encoded. Chemical analysis of DNA had shown it to consist of long chains of nucleotides, each nucleotide consisting of the five-carbon [468] francis crick 469 sugar deoxyribose, to which one of two kinds of purine bases—adenine and guanine—or one of two kinds of pyrimidine bases—thymine and cytosine—is attached. The nucleotides are linked via phosphate diester bonds, which join many consecutive deoxyribose moieties, thus forming a polynucleotide chain. Watson and Crick undertook a collaborative X-ray crystallographic study of DNA at the Cavendish, which, by the spring of 1953, had culminated in their discovery that the DNA molecule is a double helix, composed of two intertwined polynucleotide chains, held together by hydrogen bonds formed between an adenine and a thymine, or between a guanine and a cytosine, on opposite sides of the double helix. The Central Dogma At first sight, Watson and Crick’s discovery of the double helical structure of the DNA molecule resembled Linus Pauling’s—by then twoyear-old—discovery of the helical structure of protein molecules, in that the formation of intramolecular hydrogen bonds also has an important role in shaping Pauling’s protein helix. At second sight, however, the discovery of the DNA double helix emerged as an event with much greater heuristic consequences. It opened up enormous vistas for the imagination and led Watson and Crick to their formulation of what came to be known as the “central dogma of molecular biology.” The central dogma provided a coherent account of the mechanisms by which the parental DNA molecule achieves its two principal functions. One of them is its self-replication, that is to say, its provision of the genetic material for its offspring. The other is its expression, that is to say, its direction of the synthesis of protein molecules whose chemical structure (that is to say their amino acid sequence) is encoded in one of the two paired parental DNA polynucleotide chains. According to the central dogma, DNA self-replication is a one-stage process, in which, upon their unwinding, both of the pair of intertwined polynucleotide chains of the parental DNA molecule serve directly as templates for the assembly of a pair of replica DNA polynucleotide chains. DNA expression is a two-stage process, however. At its first stage, one of the two intertwined polynucleotide chains of the DNA molecule (the “coding strand”) serves as a template for the synthesis of a single chain of another type of nucleic acid, namely ribonucleic acid (RNA). The basic chemical structure of RNA is similar to that of DNA, in that RNA too is composed of long chains of nucleotides, with each nucleotide consisting of a five-carbon sugar (ribose rather than deoxyribose, as in DNA), to each of which one purine base (adenine or guanine) or one pyrimidine base (cytosine or the thymine-analog uracil) is 470 biographical memoirs attached. Just as in DNA, so also in RNA are the nucleotides linked via phosphate diester bonds, which join many consecutive ribose moieties, thus forming a DNA-like polynucleotide chain. At the second stage of the process of protein synthesis the nascent RNA transcript is translated into protein molecules with the DNAspecified sequence of amino acids. This feature of Watson and Crick’s central dogma implied that there must exist a genetic code that relates the nucleotide sequences of the DNA’s “coding strand” to the amino acid sequence of the encoded species of protein molecules. A simple consideration quickly revealed that this code could be no simpler than one involving the specification of each amino acid by at least three successive nucleotides in the DNA’s coding strand. For the four kinds of nucleotides taken three at a time can provide 4 4 4 64 different kinds of code words, or codons. Thus each of the twenty kinds of protein amino acids of which natural protein molecules are composed can be represented in the genetic code by one such triplet codon. Moreover, because the number of available kinds of codons is greater than the number of kinds of protein amino acids to be specified, it seemed that some codons are synonyms, i.e., that they encode the same kind of amino acid. That the genetic code really does involve a language in which three successive nucleotides in the DNA polynucleotide chain are read threeby-three in the protein translation process was proved experimentally by Crick and Sydney Brenner in 1961. Another example of Crick’s brilliant formulation of a novel qualitative concept, which he cut from whole cloth, was his conjecture in 1958 that the “transfer RNA” molecules, then recently identified in the cytoplasm of all living cells, provide a set of nucleotide adaptors for protein synthesis. Crick proposed correctly that it is by means of these adaptors that messenger RNA recognizes the nucleotide triplet codon representing a particular one of the twenty different kinds of protein amino acids for its programmed, site-specific incorporation into a nascent polypeptide chain. In recognition of their seminal role in laying the foundations of molecular biology, Watson and Crick shared the 1960 Lasker Award and the 1962 Nobel Prize in Physiology or Medicine. The Origin of Life It so happens, however, that some other, less well known aspects of Crick’s work, namely, his failures, provide clues for the future of biological research. Inasmuch as I consider Crick the greatest theoretical biologist since Darwin, I suspect that the problems he addressed but failed to solve are probably insoluble: If Crick couldn’t solve them, nobody can. francis crick 471 One of these great, unsolved biological problems is the origin of life. Not only does it still remain unsolved, but it even lacks a credible, molecular-biologically coherent proposal for its solution. Furthermore, despite the obvious scientific importance of the origin of life problem (and the virtual certainty of the award of a Nobel Prize for its solution), few biologists seem to be working on it any longer these days. Some solutions for the origin of life enigma have been put forward from time to time, but none have the feeling of “Eureka!” that Watson and Crick’s discovery of the DNA double helix and their promulgation of the central dogma evoked in the mid-twentieth century. In 1981 Crick published a book-length essay entitled Life Itself: Its Origins and Nature, in which he presented a theory about the origin of terrestrial life. His main idea was what he called “directed panspermia,” namely, the possibility that terrestrial life might not have originated on Earth at all. Instead, extraterrestrial intelligences, or ETIs, living on a planet outside of our solar system about four billion years ago, might have known of our (as yet lifeless) planet Earth, with its mild climate, salubrious atmosphere, and oceans of nutritious primeval soup. So, they sent a rocket Earthward, loaded with living ET microbes. On impact with planet Earth, the rocket discharged its microbial cargo into our as yet sterile terrestrial oceans, and the rest is Darwinian history. On first sight, Crick’s directed panspermia theory seemed little more than science fiction, hardly worthy of the greatest theoretician of biology since Darwin. On second sight, however, it turned out to be a fiendish idea. For if it really had been the case that terrestrial life is descended from microbes deliberately sent here a few billion years ago by ETIs, then there is no reason to suppose that our kind of life actually had a natural origin. An ET Doctor Frankenstein might have fabricated our microbial ancestors from scratch in his lab, while his own ET kind of life involved neither our proteins, nor our nucleic acids, nor our genetic code. Hence, far from being science fiction (or a mere hocuspocus transfer of the real problem of the origin of life from one venue to another), Crick’s directed panspermia hypothesis implies that the problem of the actual origin of life may be insoluble in principle. For if the only kind of life known to us did not have a natural origin and if the ET life that did arise naturally is known to us only via the laboratory artifact it created (namely, our own ancestors), then the roots of life itself would be lost forever in cosmic space. Consciousness Suppose that—as improbable as it may seem at present—the origin of life did happen to be worked out one of these days. Then there would 472 biographical memoirs still remain another deep, unsolved biological problem, namely the consciousness provided to us TIs by our brain. Of all the remaining unsolved biological problems, consciousness is one of the most difficult, as well as one of the most fascinating. The search for a resolution of the enigma of consciousness became very popular lately among the romantic types of scientists who, in the mid-twentieth century, had laid the conceptual foundation for the latterday discipline of molecular biology. These romantics included Crick, who had left Cambridge in 1977 and moved to the Salk Institute for Biological Studies in La Jolla, California, where he remained until his death. His main working hypothesis about consciousness was that there exists a special neural ensemble, which he designated “neural correlates of consciousness,” or NCC. They convert the subliminal, or unaware, sensory input received by our sensory organs into conscious (i.e., aware) experience of it in the parts of our cerebral cortex dedicated to sensory perception. Crick’s postulation of the NCC was particularly relevant for the pathological phenomenon neurologists call “performance without awareness,” which offers very promising experimental approaches to the enigma of consciousness. An opportunity for studying this phenomenon is provided by a rather rare category of persons who have sustained some slight damage to a restricted area of the brain dedicated to the processing of sensory input. They suffer from what appears to be a paradoxical impairment of their perception of one or another kind of sensory stimuli. A striking example of performance without awareness is provided by the condition that has been given the oxymoronic name of blindsight. It is manifest in some persons who have suffered a brain lesion— usually due to a cerebral stroke or a head injury. Blindsighted subjects report that they are unable to see anything at all, or at least are unable to see anything in some substantial part of their normal visual field. Yet carefully designed tests reveal that these subjects are, in fact, able to locate the spatial position of “unseen” visual stimuli. In other words, although the blindsighted subjects do see the stimuli after all, they are not consciously aware of having seen them. Thus the abnormal exclusion of a particular piece of sensory input from consciousness, i.e., of the existence of subliminal knowledge, holds out the promise of identifying the normal neural pathways that lead from subliminal sensation to conscious experience. Crick’s specific conjecture that the NCC consist of ensembles of cerebral nerve cells, which display a synchronous impulse rhythm at a frequency of 40Hz, did not work out. But Crick’s concept of the NCC has proved useful in the attempt to fathom the blindsight phenomenon. In his last years, Crick formulated a neurological explanation of blind- francis crick 473 sight in terms of two separate neural pathways along which the visual input is processed and passed on to the motor cortex for execution of appropriate body movements. One of these pathways passes through the parts of the brain dedicated to the production of conscious awareness, i.e., Crick’s postulated NCC on its way to the motor cortex. Hence if there is a lesion in that pathway the visual input may remain subliminal. The other pathway bypasses the cortical areas dedicated to the production of conscious awareness of the visual input and reaches the motor cortex via a more direct route. Thus blindsighted persons can respond to visual input with appropriate body movements in the absence of its awareness because their motor cortex does know of the visual scene subliminally. In his book-length essay, The Mysterious Flame, the philosopher Colin McGinn claimed that the problem of consciousness is insoluble in principle, not only from the biological but also from the philosophical point of view. Other philosophers interested in understanding the brain have branded McGinn as a “mysterian.” Yet despite having wrestled with the problem of consciousness for the last fifteen or so years of his life, even Francis Crick did not come up with any profound new insights into consciousness, other than his speculations about the NCC. Thus Crick’s failure to solve the problem of consciousness provides strong support for McGinn’s proposition that it is insoluble. Crick and God Crick’s attitude toward religion was uncompromisingly hostile. So at first sight it seemed surprising that he prefaced his anti-vitalist John Danz Lecture entitled On the Nature of Vitalism (Seattle and London: University of Washington Press, 1966) with this quotation from Salvador Dali: “And now the announcement of Watson and Crick about DNA. This is for me the real proof of the existence of God.” As readers of James Watson’s autobiography, The Double Helix, know, Watson wrote that he had never seen Francis in a modest mood. But not even Watson would have claimed that Crick really believed that they delivered the real proof of the existence of God. No, Crick considered Dali’s statement a tremendous joke, and although Dali’s intent was surely serious, Crick was making fun of Dali by according him a place of honor under the masthead of an anti-religious tract. In my opinion, however, Dali had sized up the situation quite correctly: The achievements of molecular biology did furnish proof for the existence of God (or for its atheistic synonym, “Nature”), the single principle that, according to Plato, makes science conceptually possible 474 biographical memoirs in the first place. Crick evidently subscribed to this Platonic doctrine as well, because in his Danz Lecture he pointed out that “though the three-dimensional conformation of proteins can, in principle, be worked out from the structure of their component amino acids, the necessary computations are almost prohibitively long. But proteins find their conformations all the same because Nature’s (read ‘God’s’) own computer— the system itself—works so fantastically fast. Also she (read ‘He’) knows the rules more precisely than we do. But we still hope that, if not to beat her (read ‘Him’) at her (read ‘His’) game, we can at least understand her (read ‘Him’).” Albert Einstein affirmed his unwillingness to accept the epistemological implications of Werner Heisenberg’s uncertainty principle by asserting that “God does not play at dice.” By their statements both Crick and Einstein reveal their allegiance to the Platonic doctrine, and Crick probably made the verbal substitution of a personified “Nature” for “God” only to avoid giving the impression that (God forbid!) he was a Christian. Crick may not have known that Niels Bohr suggested a theological solution to Heisenberg’s uncertainty principle, namely, that there IS no God but He DOES play at dice. Elected 1972 Gunther S. Stent Professor of Neurobiology, Emeritus University of California, Berkeley