On the regulation of cell division. (1966)

Most of our knowledge of the chemical mechanism of growth is derived from study of molds or bacteria.'-3This mechanism is composed of three parts, one of which carries the genetic information, mostly in DNA, while another transmits this in- formation by means of RNA's to the third, the ribosomes on which the proteins are synthetized.The outlines of the internal regulation of this system begin to emerge.In monocellular organisms this system, as a whole, demands no regulation.Life tends to grow and multiply, and so growth is limited, mainly, by the availability of food.This situation is different in multicellular organisms.When cells associated to form more complex multicellular systems, they had to submit their unlimited proliferation to strict limitations.Thus, a new regulatory system had to be created, capable of suppressing cell division.But this was not the only change.Motility had to be given up by most cells and a new kind of surface had to be developed which could join the cells to their neighbors and mediate their subtle intercellular rela- tions.4The whole nature of the cell had to be transformed.All this had to be done in a reversible way, for, under certain conditions, as is the case in wound healing, the cells have to revert at short notice to their earlier monocellular way of living,.detach themselves from their neighbors, creep into the wound, and multiply, to return to their initial state as soon as the process is completed.This demands a subtle and complex regulatory mechanism.Where it is located and by what chemi- cal signals it transmits its messages, we do not know.A priori we can make two assumptions: we could suppose that the great number of changes taking place are induced by an equal number of simultaneously working single regulatory mecha- nisms, or else we could suppose that the various changes are induced by one regu'atory center and transmitted by one and the same chemical signal to the various processes.This, being the simpler case, may also be the more probable one.It in- volves the assumption that all the systems concerned have identical receptors for the common chemical signal.Since growth belongs to the basic characters of life, the main function of this regulatory system had to be the suppression of growth, and, accordingly, the promotion of growth could be due to the suppression of this sup- pressor, being an example of Monod's "double bluff."2This regulatory system represents an almost virgin field of inquiry.Its more detailed knowledge is desirable also because the road to a better understanding of cancer leads through it.Our laboratory came in touch with this problem when one of us, working with J. McLaughlin,5 observed that various vegetable and animal tissues contained a sub- stance which could retard growth and another which could promote it.The two seemed to be closely related and the resulting action seemed to depend on their balance.We termed the promotor "promine," the retarder "retine."We were neither the first nor the last to observe such reactions.6The final clarification waits for the isolation and identification of these substances.In spite of the great amount of time and labor invested, our efforts on this line 203