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STUDIES ON CELLULAR REGULATIONS ALBERT SZENT-GYÖRGYI* When I embarked on the study of the proteins of muscle, I was a revolutionary in that field. Twenty years ofwork turned me into a reactionary . Also, after looking at the same problem for two decades, my vision became blurred, and I could not see the forest for the trees. So I felt it was time to move to a different subject. Supported by J. McLaughlin, I set out to elucidate the mysterious interrelation between thymus and muscle. Some queer associations made us try the action ofthymus extracts on the growth ofspontaneous mammary cancer in mice. So, willy-nilly, I found myself working on cell division, one of the most fundamental biological functions which involves most cellular activities. Some of our extracts retarded growth, others promoted it. We called the underlying retarding substance "retine," the promoting one "promine," and thought we had discovered thymus hormones. However, we soon found similar activities in the extracts of other tissues; retine and promine could thus not be hormones but were general tissue constituents. The evidence in hand was poor, but the idea that cell proliferation should be regulated by two antagonistic substances seemed attractive. To guide a horse, one needs reins and spurs. The isolation of these substances turned out to be a tough problem which could not be solved without some guessing. Such a guess was made when partially purified extracts showed a ketonic and aldehyde absorption in the infrared in the spectroscope of the Worcester Foundation for Experimental Biology. Could these substances, perhaps, be a-ketoaldehydes , derivatives ofglyoxal? This idea seemed exciting because living tissues contain an apparently ubiquitous and most active enzyme system, the glyoxalase, capable of transforming the reactive keto-aldehydes into * Institute for Muscle Research, Marine Biological Laboratory, Woods Hole, Massachusetts. Research was supported by the National Institutes ofHealth, grant GM10383. 350 Albert Szent-Györgyi · Cellular Regulations Perspectives in Biology and Medicine · Spring 1968 the corresponding chemically inert hydroxyacids (e.g., methylglyoxal into lactic acid). This enzymic system occupied, in the first half of this century, several of the most outstanding biochemists, such as Neuberg, Hopkins, Dakin, and Lohman. Later, the interest faded out because nobody could find a glyoxal derivative in tissues, and what is the use ofan enzyme without a substrate? Once they are there, keto-aldehydes are easily detected, giving a rich, red precipitate, a bis-hydrazone with dinitrophenylhydrazine. Tissue extracts prepared in the usual way showed no such reaction. Why, then, should there be a glyoxalase? In order to solve this puzzle, a second guess had to be made. This guess was based on the experience ofL. G. Egyiid, who synthetized a series of glyoxal derivatives and studied their action on bacteria [1-3]. They all inhibited cell proliferation in a more or less specific manner at a relatively low concentration by inhibiting protein synthesis [2] at the ribosome level [4]. This inhibitory action was abolished by isomolar concentrations ofsulfhydryl derivatives like cysteine [1-3]. Carcinoma and sarcoma cells behaved likewise [5]. Carbonyls, and especially keto-aldehydes, were known to react readily with cysteine [6]. What ifglyoxal derivatives were there in tissue extracts but could not be detected because they were covered up by SH? To test this possibility, I treated our tissue extracts with arsenic trioxide, As2O3, having been shown, long ago, by Voegdin, that arsenic exerts its strong biological activity by combining with SH. Ifthe As2O3 combined with the inhibitory SH, then the thus released keto-aldehydes had to declare themselves. So I treated our extracts with As2O3 and added dinitrophenylhydrazine. Down came a rich red semicrystalline precipitate , indicating the presence of a high concentration of free keto-aldehydes [7]. To our good luck, my former Ph.D. student, G. Fodor, now professor at Laval University, Quebec, and his associateJ.-P. Sachetto, had become interested in this research. They identified the crystalline precipitate as the bis-dinitrophenylhydrazone of a ketone aldehyde closely related to glucose [8]. It was the bis-hydrazone ofa "3-deoxyhexosulose," 2-keto3 -deoxyglucose, identical with the substance found earlier by Kato in soybeans [9]. We had no reason to doubt that this hexosulose was identical with retine, the growth...