Dr. Rodnan* led us safely through the wilderness of misconceptions held in the past regarding the nature of gout to the remarkably simple and lucid concepts proposed by Garrod a century ago1 in which crystals of sodium urate were regarded as the cause of the acute attack of gout. Garrods demonstration of hyperuricemia in gout held even more significance for the future development of medicine since it was the first use of a test for a chemical component of serum in the diagnosis of a human disease.
It seems ironic that the further refinements of the chemical determination of uric acid in serum which led to its more widespread use provided one of the strong arguments that was eventually used to discredit Garrod's origina: concept. Hyperuricemia without clinically evident gout was discovered in a number of other diseases, as well as in asymptomatic individuals, many of whom were relatives of gouty patients.
There seemed, furthermore, to be no relationship between the acute attack of gout and tlie changes in the serum urate concentration.2 Furthermore, colchicine, with its specific effect in terminating the acute attack of gout, failed to alter either the serum urate or the urinary excretion of uric acid, while probenecid, which lowered the serum urate by increasing uric acid excretion, was ineffective in the therapy of the acute attack of gout; in fact its use often provoked acute attacks or made the attack more eve re.^
The most direct argument against Garrods hypothesis was the purported failure of injected urate crystals to produce an inflammation. In addition, the endogenous deposition of urate crystals in the development of tophi was usually painless. These observations led the majority of the investigators in the past two decades to deny a role for sodium urate in the genesis of the acute attack of gout to support them. This left us then with a concept that violated the rule of the parsimony of Nature, in which the deposition of tophi was related to the hyperuricemia but the acute attack of gout was not. A wide variety of hypotheses were proposed to account for the acute attack but none with any appreciable experimental evidence.
Over the past three years our concepts of the mechanism for the development of acute gouty arthritis have undergone a substantial reorientation which has taken us back to the propositions put forth by Garrod almost a century ago. The investigations leading to this change in view were performed in the laboratories of Drs. McCarty and Hollander in Philadelphia4s5 and our own laboratories in Bethesda by Drs. Howell, Malawista, Klinenberg and Buchanan.6z7 *Introduction, this volume.