Project K: "The Complete Solution of E. Coli "

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PROJECT K: "THE COMPLETE SOLUTION OF E. COLI"* F. H. C. CRICKt It is convenient to consider future developments in molecular biology (in the widest sense) under three headings: (a) studies on cell components, (b) studies on unicellular organisms, and (c) studies on multicellular organisms. The latter, although of great importance, will not be dealt with here. The division between cell components (which may come from any sort of cell) and organisms is admittedly arbitrary and is only introduced here to make the discussion easier. In practice, most work on complete organisms is supplemented by studies on the components of that organism. It is first necessary briefly to take stock of the present position. As far as classical biochemistry is concerned, many enzyme reactions are known, and for a minority of these the action of the pure enzyme is understood in outline. For no case have the details of the enzymatic action been firmly established in chemical terms. Within the field of molecular biology (in the narrow sense) we now understand in outline the synthesis of the nucleic acids and of proteins, their interrelation in the genetic code, and a little about their control mechanisms. It seems likely that future progress will take place in several broad areas: 1. The more detailed test-tube study of the structure and chemical action of biological molecules (especially proteins). Typical of such studies will be the detailed action of enzymes (already getting very close with the solution by X-ray crystallography of the structure of several enzymes), the way proteins fold themselves up (a backward field), the radiation damage to molecules, especially to DNA, and many other topics. It is characteristic of these studies that they involve the application of complicated and advanced methods of physical chemistry to biological molecules, and often * The idea arose in conversation with Dr. Sydney Brenner, who invented the title "Project K" and whom I have to thank for useful discussions on the topic. This short paper was originally circulated in a European Molecular Biology Organisation (EMBO) document [I] toward the end of 1967. It still seems to me to be an attractive scheme for people of the right temperament, and since EMBO is now unlikely to take it up I thought that it might be useful to give the idea wider publicity. t MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, England. Perspectives in Biology and Medicine · Autumn 1973 | 67 require rather large amounts of (pure) material. We may also expect the chemical synthesis of model compounds to play an important part. 2.The filling-in of the broad outlines already established, for example, the biochemical mechanism of protein synthesis, the unwinding of DNA, the mechanism of genetic recombination (which is probably related to DNA repair mechanisms), and, on the classical biochemical side, the exploration of more metabolic pathways and especially their interrelationships . 3.Work on subjects of fundamental importance which are little studied at the moment, for example, the structure and function of cell membranes ,1 the mechanism of cell division, and the biochemistry of spore formation. 4.The study of control mechanisms at all levels, in particular the interrelation of the known mechanisms, leading to an appreciation of the economy and "design" of the cell. 5.The behaviour of natural cell populations and their population genetics, leading to the consideration of the evolution of the cell. The above discussion is necessarily sketchy, but it clearly brings out three important points: (a) an enormous amount of work remains to be done without ever going to multicellular organisms; (b) important problems exist at all levels of complexity; and (c) there is likely to be an increasing demand for large amounts of pure cell components present in the cell in rather small amounts. For these reasons, it seems certain that in spite of the obvious opportunities awaiting the study of organisms having many cells, a major effort will almost certainly continue to be applied to single-cell organisms, in particular to bacteria. The point of this paper is to argue that such work should be concentrated on one organism (probably Escherichia coli, K12) and that a case exists for centralizing many aspects of such work in...

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