Physiological Adaptation at the Molecular Level: The Frontier Where Research on Differentiation and Malignancy Meet

PHYSIOLOGICAL ADAPTATION AT THE MOLECULAR LEVEL: THE FRONTIER WHERE RESEARCH ON DIFFERENTIATION AND MAUGNANCY MEET VAN RENSSELAER POTTER* When Walter Cannon wrote The Wisdom ofthe Body in 1932 [1], almost nothing was known about the detailed pathways of intermediary metabolism or about intracellular enzymes and their control. Cannon's holistic point ofview emphasizing homeostasis was a brilliant synthesis of the contributions of Claude Bernard, as well as Richet, Pflüger, Fredericq , and others, but it has been waiting too long for a new synthesis at the molecular level. This view reiterates a point well stated by Eugene Knox, who coined the phrase "enzyme physiology." Recently, Knox editorialized on "Antizymes, Adaptation and Homeostasis" [2] and commented diat the concept of homeostasis has often functioned "more as a heuristic device for relating regulatory factors that were already known. It focussed on stability and constancy of the organism. . . . The new regulatory science has not ignored constancy, but its emphasis has been on the change that must accompany constancy. The larger theme is continuity of life through purposive change. Such a thought is contained in the world, adaptation, a concept much used by Darwin and the evolutionists and an older concept than homeostasis." Knox continued, "There is needagainforagrand conceptualscheme that will integrate whatsome knowas homeostasis with the related but newer molecufar discoveries ofgene expression, This lecture was given at the meeting of the Southwest Section of the American Association for Cancer Research, Albuquerque, New Mexico, November 15-16, 1979, at which time the author was presented the Fourth Annual Noble Foundation Research Recognition Award. Work in the author's laboratory has been supported in part by grants CA07175 , CA-22484, and CA-17334 from the National Cancer Institute. Since this manuscript was prepared, new advances have indicated that the processing of premessenger RNA is still another component of physiological regulation at the molecular level. Some of the new developments have been covered in a more recent lecture, "The Present Status of the Blocked Ontogeny Hypothesis of Neoplasia: The Thalassemia Connection" (to appear in OncodevekpmentalBiology and Medicine). ?Hilldale Professor of Oncology, McArdle Memorial Laboratory, University of Wisconsin Medical School, Madison, Wisconsin 53706.© 1981 by The University of Chicago. 0031-5982/81/2404-0244$01.00 Perspectives inBiology andMedicine · Summer 1981 \ 525 tissue differentiation, hormone actions, metabolic and neural controls, and pathogenesis" (italics added). It would be incorrect, however, to imply that the men credited with the concept of homeostasis were unaware of physiological adaptation even if they did not use the word. We have only to examine the introduction to Cannon's masterful 1929 review, "Organization for Physiological Homeostasis," to appreciate his awareness of change [3]. I believe his words deserve preservation. He began: Biologists have long been impressed by the ability of living beings to maintain their own stability. The idea that disease is cured by natural powers, by a vis medicatrix naturae, an idea which was held by Hippocrates, implies the existence of agencies ready to operate correctively when the normal state of the organism is upset. . . . Pflüger (1877) . . . laid down the dictum 'The cause ofevery need of a living being is also the cause ofthe satisfaction ofthe need.' Similarly, Fredericq (1885) declared 'The living being is an agency of such sort that each disturbing influence induces by itselfthe calling forth ofcompensatory activity to neutralize or repair the disturbance. The higher in the scale of living beings, the more numerous, the more perfect and the more complicated do these regulatory agencies become. . . .' Further, Richet (1900) emphasized the general phenomenon , 'The living being is stable. It must be in order not to be destroyed, dissolved or disintegrated by the colossal forces, often adverse, which surround it. By an apparent contradiction it maintains its stability only if it is excitable and capable of modifying itself according to external stimuli and adjusting its responses to the stimulation. In a sense it is stable because it is modifiable—die slight instability is the necessary condition for die true stability of die organism. Cannon was aware that in 1878 Claude Bernard was not blind to these ideas when he emphasized the constancy of the milieu intérieur, for his quotation from Bernard includes the following: "AU the...