Resolution and reconstitution of biological pathways from 1919 to 1984.

The central theme of this paper is the reconstitution of the Warburg effect, the high aerobic glycolysis of malignant tumors. The history of resolution-reconstitution started with the isolation of glycolytic enzymes. In 1945 Meyerhof prepared an extract from yeast that did not ferment unless an ATPase was added. An extract of Ehrlich ascites tumor cells that does not glycolyze in the presence of catalytic amounts of Pi and nucleotides without addition of an ATPase is presented as a model for future reconstitutions of the Warburg effect. Natural polypeptide preparations from placenta and hypothalamus 1) stimulate a protein kinase from tumor plasma membranes, 2) serve as substrates for another protein kinase from tumor plasma membranes, and 3) stimulate glycolysis of normal rat or chick embryo fibroblasts and may be related to the transforming tumor growth factors. We can hope that an exploration of the mechanism by which these polypeptides stimulate glycolysis could lead to the successful reconstitution of the Warburg effect in an in vitro system. It may also help us understand how tumor RNA or malignant DNA induces the various other biochemical changes that take place when normal cells are transformed to tumor cells.