Since the announcement, approximately ten years ago in June of 2000, that a first draft of the (almost) complete nucleotide sequence of a human genome had been assembled, much interest has been directed to the ways in which genomic information can facilitate investigation into the evolutionary origins of humans and their diseases as well as to the ways in which this new knowledge can be put to practical use in medicine and other fields of endeavor. For example, just a few months ago, James Lupski and colleagues published an article (2010) in The New England Journal of Medicine that illustrated the potential of whole-genome sequence determination of a proband and more focused genotyping of family members to identify the genotype responsible for a disease phenotype (for the curious, Charcot-Marie-Tooth disease, a neuropathy) when many candidate genes had already been identified by other methods.
A review in Nature (Witkowski, 2010), of a new book reprising the history of the initial sequencing of the human genome, notes that key antecedents to the genome project included such developments as restriction enzymes, analysis of restriction fragment length polymorphisms, and polymerase chain reaction. What has not been much remarked upon is how the current range of genomic applications to both basic research (including those related to evolutionary medicine) and clinical medicine can be traced back to some lines of inquiry that were primarily initiated by the desire to find answers to abstract questions or clarify abstruse concepts, i.e. research directions motivated by curiosity. These questions or concepts were not originally regarded as having much whatever to do with such practical concerns as reducing the suffering associated with human diseases. Three individuals and their intellectual quests are especially pertinent and illustrative.
First consider Alan Turing, who was an English mathematician, logician, and pioneer of computer science (Hodges, 1983). Turing surely had a practical side. For example, his logical gifts played a notable role in contributing to the Allied victory over the Nazis during World War II. Turing was a major architect of the mathematically-based procedures used to break the encryption schemes used for long-distance communication by the Nazi military. He also worked directly on building actual computing devices in the years after World War II.
But Turing’s rise to professional prominence started with his efforts, in the 1930’s, to formulate a rigorous answer to a simple-sounding question lying at the foundations of mathematics: “What is the essence of a mechanical decision procedure?” How many admirers of the genome project and large-scale applied science would gladly have suffered an eccentric young man whose main interests revolved around grappling with a concept that would be meaningful for only the most abstract of thinkers? Even more to the point, what is the likelihood that a modern scientific granting agency would offer financial support to the author of a proposal to think about the problem of what precisely constitutes the physical realization of a computation?
Turing’s answer to this question led to his creation of a concept (now known as the Universal Turing Machine) that embodies the logical essence of modern computers. His work, in the 1930’s and 1940’s, on the logical and mathematical underpinnings of computing contributed fundamentally to the eventual development of modern hardware and software. It is clear that the vast quantities of human genome sequence fragments pouring out of various laboratories around the world could never have been placed in proper order without enormously powerful computers and the software that runs them. In this regard, all efforts to characterize the genomes of humans and other species owe a profound intellectual debt to Turing and the question, simple to ask but not to answer, that he posed.
Next, we turn to the German physicist-turned-molecular biologist, Max Delbrück. He left physics and decided to devote himself to biology for a combination of reasons, but the reason that is of paramount interest in the present context is his desire to follow up on a suggestion by the eminent physicist, Niels Bohr, that biology would prove to have a deep paradox at its core (Fischer and Lipson, 1988; Stent, 1992). More specifically, Bohr argued that biology might be, in some sense, complementary to physics. The exact meaning or significance of Bohr’s speculation may not be resolvable to the satisfaction of all, but the fact remains that Delbrück went into biology, by his own explicit declaration, on the basis of his fascination with Bohr’s philosophical speculations regarding the relevance of the concept of complementarity to the life sciences (Greenspan, 2007).
Having made the transformation to biologist, Delbrück proceeded to provide rigorous intellectual leadership to the fledgling field of molecular biology as well as a key experimental result pertaining to the origins of bacterial mutations (Luria and Delbrück, 1943). The key conclusion from this particular study was that the mutations that conferred on E. coli cells resistance to bacterial viruses appeared to occur spontaneously and with frequencies unrelated to their respective utilities. This latter experimental achievement was obtained with the active collaboration of another biologist enchanted with the newly developing molecular approach to biology, Salvador Luria.
Professor Luria brings us to our third individual, James D. Watson, because Watson began his professional scientific career as Luria’s graduate student (Luria, 1984). By the time Watson finished his Ph.D. with Professor Luria at Indiana University, he was absorbed with the question, “What is the molecular nature of the gene,” in part via the inspiration provided by the penetrating insights of Delbrück (Watson, 1968). At the time that Watson first began to ponder this question as a senior undergraduate at the University of Chicago, it may have struck some as of no special significance and others as hopelessly ambitious. Even those who thought it a question worth posing would have been hard pressed to imagine many of the possible applications that an answer to the question might, in the present era, provide. Ultimately, Watson’s quest, abetted through his collaboration with Francis Crick, and as has been recorded by Watson himself, by other scientific participants and by historians of science, contributed profoundly to the spectacular developments of molecular biology and genetics of the last fifty-plus years.
As the pressures to focus research wax and wane periodically, the individuals with the power to create and control scientific priorities, should remember just how fundamentally unpredictable major scientific advances can be in their provenance and in their evolution. Even within the enclaves demarcated by Ivy-covered walls, the individual devoted to seemingly esoteric questions unconnected to pragmatic concerns can be an object of derision. Today, academic researchers are frequently evaluated primarily on the basis of how many millions or tens of millions of grant dollars they attract to a university’s coffers. Therefore, it is fair to note that the milestone of human biology represented by the completion of the Human Genome Project, an enterprise ultimately both public and private and requiring more than ten years, dozens or hundreds of people, and tens of millions of dollars to achieve, was made possible in part by the undisciplined curiosity exemplified by the three individuals, Alan Turing, Max Delbrück, and James Watson, briefly profiled above.
The opinions expressed above do not reflect official views of the institutions with which I am affiliated.
Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L,
Bainbridge M, Dinh H, Jing C, Wheeler DA, McGuire AL, Zhang F, Stankiewicz P,
Halperin JJ, Yang C, Gehman C, Guo D, Irikat RK, Tom W, Fantin NJ, Muzny DM,
Gibbs RA. Whole-genome sequencing in a patient with Charcot-Marie-Tooth
neuropathy. N Engl J Med. 2010 Apr 1;362(13):1181-91. Epub 2010 Mar 10. PubMed
Witkowski, J. Long view of the human genome project. Nature 2010 Aug 19; 466:921-922. http://www.nature.com/nature/journal/v466/n7309/full/466921a.html.
Hodges, A. Alan Turing: The Enigma. A Touchstone Book, Simon & Schuster, Inc., New York, 1983.
Fischer, E. P., and Lipson, C. Thinking About Science: Max Delbrück and the Origins of Molecular Biology. W. W. Norton and Company, New York, 1988.
Stent, G. Max Delbrück, 1906-1981, In: Phage and the Origins of Molecular Biology, Expanded Edition, Cold Spring Harbor Laboratory Press, 1992, pp. 351-352.
Greenspan, N.S. Fascinating Bohr. The Scientist. September 28, 2007. http://www.the-scientist.com/news/home/53662/
Luria, S. E., and Delbrück M. Mutations of bacteria from virus sensitivity to virus resistance. Genetics 1943; 28: 491–511.
Luria, S. E. A Slot Machine, A Broken Test Tube: An Autobiography. Harper & Row, Publishers, New York, 1984.
Watson, J.D. The Double Helix: A Personal Account of the Discovery of the Structure of DNA . Signet, Atheneum Publishers, New York, 1968.