Shortly before the end of World War II the great Austrian physicist, Erwin Schrödinger, then living as an anti-Nazi emigré in Ireland, wrote the little book "What is Life ?" that was to draw wide attention to the dawn of a new epoch in biological research. Just why this book should have made such an impact was never quite clear. After all, in it Schrödinger presented ideas that were even then neither particularly novel nor original. The book, furthermore, does not make for easy reading; though it seems to be quite clearly written, the clarity turns out to be deceptive, since most readers must have had the uneasy feeling from time to time that perhaps they had not really understood what Schrödinger was trying to get across. On professional biologists the book had probably little or no influence. In so far as they bothered at all to read "What is Life ?," they probably considered the title a piece of colossal nerve. At their most charitable, they must have viewed the book with amused tolerance. But its propagandist impact on physical scientists was very great. Their knowledge of biology was generally confined to stale botanical and zoological lore, and having one of the Founding Fathers of the new physics put the question "What is Life ?" provided for them an authoritative confrontation with a fundamental problem worthy of their mettle. Since many of these physical scientists were suffering from a general professional malaise in the immediate post-war period, they were eager to direct their efforts toward a new frontier which, according to Schrödinger, was now ready for some exciting developments. In thus stirring up the passions of this audience, Schrödinger's book became a kind of "Uncle Tom's Cabin" of the revolution in biology that, when the dust had cleared, left molecular biology as its legacy.

Schrödinger opens with the comforting statement that "the obvious inability of present-day physics and chemistry to account (for the events which take place in a living organism) is no reason at all for doubting that they can be accounted for by those sciences." Since, as Schrödinger points out next, organisms are large compared to atoms, there is no reason why they should not obey exact physical laws. And even the peculiar quality of living matter, namely that it "evades decay to equilibrium," does not put it beyond the pale of thermodynamics, since organisms evidently feed on "negative entropy," whose ultimate source is the sun. No, the real problem in want of explanation is the hereditary mechanism. For, while the genes are evidently responsible for the order that an organism manifests, their dimensions are not so very large compared to atoms. How then do the genes resist the fluctuations to which they should be subject? How, wonders Schrödinger, has the tiny gene of the Hapsburg lip managed to preserve its specific structure for centuries while being maintained at a temperature 310° above absolute zero? Schrödinger proposes that genes preserve their structure because the chromosome that carries them is an aperiodic crystal whose atoms stay put in energy wells. These large aperiodic crystals are composed of a succession of a small number of isomeric elements, the exact nature of the succession representing the hereditary code. Schrödinger illustrates the vast combinatorial possibilities of such a code by an example that uses the two symbols of the Morse code as its isomeric elements.

In considering gene mutation, Schrödinger discusses what he calls "Delbrück's Model," under which alternate isomeric states of the genes correspond to different quantum mechanical energy levels, the probability of transition between states being low because transition requires a high energy of activation. Schrödinger thinks that "we may safely assert that there is no alternative to (this) molecular explanation of the hereditary substance. The physical aspect leaves no other possibility to account for its permanence. If the Delbrück picture should fail, we would have to give up further attempts." But now Schrödinger states an important credo which, as can be inferred from the article "A Physicist Looks at Biology," had been embraced also by Max Delbrück. In fact, this credo probably was the most important psychological incentive for physicists to turn to biology in the first place: "From Delbrück's general picture of the hereditary substance it emerges that living matter, while not eluding the `laws of physics' as established up to date, is likely to involve `other laws of physics' hitherto unknown which, however, once they have been revealed will form just as integral part of this science as the former." Thus it was the romantic idea that "other laws of physics" might be discovered by studying the gene that really fascinated the physicists. This search for the physical paradox, this quixotic hope that genetics would prove incomprehensible within the framework of conventional physical knowledge, remained an important element of the psychological infrastructure of the creators of molecular biology.

Schrödinger's book offers no concrete suggestions as to how one might actually go about studying the nature of the gene, but it predicts presciently that "advances in understanding how the hereditary substance works will come from biochemistry, under the guidance of physiology and genetics." "What is Life ?" closes with an epilogue on Determinism and Free Will, the traditional philosophical paradox posed by the existence of conscious life. Schrödinger resolves this paradox according to more or less conventional empiricist thought, except that, following the philosophical Zeitgeist of the 1940's, he adds an existentialist twist: the conscious "I" is a canvas on which experiences have been collected, and these experiences lead "me" to the belief that "I" control the motion of atoms.

At the time of writing his book, Schrödinger's knowledge of the state of genetics was some years in arrears. He did not seem to have known of the rise of biochemical genetics in the late 1930's and thus did not mention the main doctrinal advance of that epoch, the "one gene-one enzyme" theory, that was to pave the way for molecular genetics. Another symptom of his somewhat outdated information was his emphasis of the fruit fly Drosophila as the main genetic object whose hegemony was, by that time, already giving way to micro-organisms, especially to the mold Neurospora. A rather ironic gap in Schrödinger's information was that he did not then know that for the past five years Delbrück, whose model of the gene seemed to have inspired Schrödinger's book in the first place, had been working with bacterial viruses, the very experimental material that was eventually to provide the answers to what Schrödinger wanted to know.

Bacterial viruses were discovered in 1915 by the English microbiologist F. W. Twort, and two years later - perhaps independently, perhaps notby the French-Canadian, F. d'Herelle. In any case, it was d'Herelle who named these viruses bacteriophages and it was through his efforts they came to play a glamorous role in the bacteriology of the 1920's. By the middle of the 1930's, however, this glamor had begun to tarnish, since the widely propagandized control of bacterial diseases by means of bacteriophages had failed to materialize. But as interest in the practical application of bacteriophages waned, interest in them as tools for fundamental biological studies waxed. In the early 1930's it was being shown by M. Schlesinger that bacteriophages can be studied by chemical and physico-chemical techniques, and by F. M. Burnet that they are suitable for genetic investigations. At the same time, W. M. Stanley had crystallized the tobacco mosaic virus, an event of great heuristic impact. For that a self reproducing object like a virus can be crystallized as if it were so much sodium chloride gave momentum to the notion that viruses, as "living molecules," ought to be a most favorable experimental material for unravelling the physical basis of biological self reproduction.

In the late 1930's three men took up the study of bacteriophages: Alfred D. Hershey, Salvador E. Luria, and Max Delbrück. Their meeting in 1940 marks the origin of the Phage Group whose work and personalities form, in large part, the subject of the retrospective essays of this volume. The members of this group were united by a common goal, namely the desire to understand how during the brief, half hour latent period the simple bacteriophage particle achieves its hundredfold self reproduction within the bacterial host cell. The initial growth of this group was so slow that during its first five years only a few recruits joined its ranks. Among these few was T. F. Anderson, one of the first American electron microscopists. But in 1945, Delbrück took a step that was to set off a rapid and autocatalytic growth of the Phage Group. He organized the annual summer phage course at Cold Spring Harbor. The purpose of this course was frankly missionary: to spread the new gospel among physicists and chemists, a purpose that was not exactly hindered by the appearance in that same year of "What is Life?"

The greater number of workers assimilated into the Phage Group through the Cold Spring Harbor course, as well as the easier access to new tools such as radioactive tracers and ultracentrifuges, engendered more rapid progress during the next seven years. In 1952 the fifty or so stalwarts, gathered at the Abbaye de Royaumont near Paris for the first International Phage Symposium, knew by then that the phage DNA is the sole carrier of the hereditary continuity of the virus and that the details uncovered hitherto concerning the physiology and genetics of phage reproduction were to be understood in terms of the structure and function of DNA. In the very next year, the discovery of the Watson-Crick structure of DNA and the proposed mechanism of its replication provided the fundament for that understanding. A period of explosive development now set in, made possible not only by this intellectual breakthrough but also by the sudden increase in government support for biological research. Within another nine years, by 1961, the goal was reached: the mechanism by which the phage DNA replicates and directs the synthesis of viral proteins was more or less understood, and what remained was merely to iron out the details. No paradox had been encountered, no "other laws of physics'' had turned up. Making and breaking of hydrogen bonds seems to be all there is to understanding the workings of the hereditary substance.

Granted that the mechanism of reproduction of an organism as simple as a bacteriophage does not seem to embody any hitherto unknown physical principles, what about that of higher forms of life ? How can one account for the processes responsible for the orderly morphogenesis of organisms from single germ cells into amazingly complex and highly differentiated multicellular forms ? It was with this more formidable question and with the next generation of problem solving already in mind that some phage workers turned to the study of animal cells soon after the discovery of the structure of DNA had made it clear that before long the nature of the gene would be fathomed in molecular terms. These studies on animal cells were to have important practical consequences, particularly in that they were to permit the flowering of quantitative animal virology; and though it still cannot be said that there has been any real breakthrough in understanding differentiation, the rise of molecular genetics brought a radical change to traditional embryology. One special case of differentiation, that of the antibody response of vertebrates, does seem near to its solution now, thanks largely to N. K. Jerne's recognition in 1955, of the selective nature of that response. Now that some reasonable molecular mechanisms for cellular differentiation can be at least imagined, the likelihood that the explanation of the development of the embryo will lead to the "other laws" seems to have greatly diminished, and with this denouement diminished also the appeal of embryology as an area for romantic strife.

Round about 1950, Delbrück began to think that bacteriophages were now, as he expressed it, "in good hands." This meant that he was beginning to lose interest in the hereditary mechanism before most of the real breakthroughs had even been made. He could evidently sense already at that time that the quest on which he, Luria, and Hershey had set out would presently lead to the understanding of biological self reproduction, without the encounter of any paradoxes on the way. Accordingly, he turned toward that remaining major frontier of biological inquiry for which reasonable molecular mechanisms still cannot be even imagined: the higher nervous system. Its fantastic attributes continue to pose as hopelessly difficult and intractably complex a problem as did the hereditary mechanism a generation ago.

Delbrück found sensory perception a suitable point of purchase upon neurobiology. Having in mind the successful precedent of virus as the simplest material exhibiting self reproduction, he looked about for an analogous simple model system of perception. His first choice was phototaxis of Rhodospirillum, a bacterium that translates light and dark stimuli into a motor response. After some initial studies had shown, however, that the nature of this response does not seem to be such a good model for perception after all, Delbrück addressed himself to the light-stimulated growth reaction of the fungus Phycomyces. Though they are phylogenetically most remote from the sensory organs of animals, the fungal light receptors do manifest two fundamental aspects of metazoan sense perceptors: accommodation and refractory period. About ten years ago, this work brought into being a Phycomyces Group dedicated to the solution of the fungal growth reaction. Nearly all of its recruits were physicists and, perhaps surprisingly, hardly any besides Delbrück himself were renegade phage workers. As was true for the Phage Group in its formative years, the Phycomyces Group has remained a small band, though Delbrück's recent institution of an annual summer course on Phycomyces at Cold Spring Harbor may presently swell its ranks with proselytes. One of the first to join the Phycomyces Group was W. Reichardt, a physicist who had been studying the optomotor response of a beetle and whom Delbrück persuaded that the behavior of a single fungal cell would be easier to analyze than that of a whole insect. Though Reichardt has remained a part-time phycomycologist, he resumed work on the insects after a few years and showed that, in regard to perception, the insect eye happens to be more tractable than the fungal light receptor.

Now that the success of molecular genetics has made it an academic discipline, one can expect that in the coming years students of the nervous system, rather than geneticists, will form the avant garde of biological research. Though it is still far from clear what kind of experimental material is to become the phage of neurobiology, it seems more than likely that it will be a metazoan with nerve cells rather than a unicellular organism. And what Delbrück sensed more than fifteen years ago is now becoming a commonplace: The inability of even imagining any reasonable molecular explanation for such manifestations of life as consciousness and memory still offers some hope that biology may yet turn up some "other laws of physics." But it is also possible that study of the higher nervous system is bringing us to the limits of human understanding, in that the brain, being a finite engine, may not be capable, in the last analysis, of providing an explanation for itself. In that case, the paradox will have been found at last: there exist processes which, though they clearly obey the laws of physics, can never be understood.