December 1967 ADULT HYPERTHYROIDISM which results in stimulation of protein biosynthesis may also result in increased breakdown of protein; which direction pre- dominates may depend on the concentration of thyroxine or other factors. The answer to this question may have to await the identification of the specific chemical mechanisms by which thyroxine stimulates protein synthesis or exerts its other effects. DR. WERNER: I think it is only fair to say that about 15% of the patients with hyperthyroidism actually gain weight (23). DR. McKENZIE: I have neverseen a rat gain weight when it is given an excessive dose of thyroxine. DR. WERNER: We turn now to the etiology of toxic diffuse goiter, Graves’ disease. I should like to ask Dr. McKenzie to say a word about LATS, recognized to be in the immunoglobulin family, at least upon chemical separation, and about the view that this agent could act as a repres- sor of a repressor gene (24), DR. McKENZIE: The point that you raise—could the IgG, long-acting thyroid stimulator (LATS), be acting as an anti- body suppressing an inhibitor within the thyroid gland—-has been raised in different ways by both Dr. Kriss and myself recently (24). The idea arises, of course, from the work of Jacob and Monod (25), who theorized from their work on E. coli that there was a genetic repressor involved in the control of protein synthesis in that organism. This concept has been applied, perhaps rather uncritically, at times, to the human organism, as a basis for explanation of the mode of action of a num- ber of hormones. Certainly, if a genetic repressor of protein synthesis is present within the thyroid cell, then inhibition of this repressor by an antibody or by any other means might well result in unlimited or “unrepressed’” synthesis of proteins 1767 which would be the enzymes and various substrates necessary for the unrestrained activity of the thyroid gland that occurs in Graves’ disease. Wetested this theory by studying the effect of inhibitors of protein synthesis (puromycin and cyclohexamide) or of synthesis of RNA (actinomycin D) (24). Wefound that the action of both thyrotropin and the long-acting thyroid stimulator in vivo in the mouse was diminished when any of these antibiotics was given previously, but only if the antibiotic was given a minimum of eight to 12 hours before the thyroid stimulator. That is, there was a period of at least eight hours during which the in vivo thyroid synthesis of protein or RNA could beinhibited to a major degree, with no inhibition of the thyroid stimulation induced by either thyrotropin or LATS. It seemed, therefore, that the acute action of these thyroid stimulators, which is what we measure in the mouse bio-assay (26), was not dependent on the fresh synthesis of either protein or RNA, although a supply of preformed protein obviously was essential. Consequently, it seems highly unlikely that LATScould act, at least in the mouse bio-assay, by inhibition of the hypothetical genetic repressor of protein synthesis. DR. WERNER: Dr. Hsia, would you like to say something about the etiology of hyperthyroidism from the standpoint of a geneticist? DR. D. HSIA, Department of Pediatrics and Genetics, Northwestern University, Chicago: There appears to be little doubt that hyperthyroidism is familial, but it is not transmitted by a single gene. At least three large studies have been carried out to determinethe modeof inheritance in hyperthyroidism. In 1941, Bartels (27) followed up 207 propositi from twoclinics in Copenhagen. A family predisposition was found in 47% of the series as a whole, but was as high as 60% in the families where the