Scientific Side Trips: Six Excursions from the Beaten Path

Our40-year research partnership began on a sunny June day in 1966 at theMassachusetts General Hospital, where we met with twelve other nervous neophytes to begin our internships in internal medicine.Within a few days, we developed the friendship and mutual respect that were to sustain our collaborative effort over four decades. Our backgrounds were quite different. Joe grew up in small-town South Carolina and graduated from the youngUniversity of Texas SouthwesternMedical School in Dallas, where he came under the spell of Donald W. Seldin, chairman of medicine and intellectual father to generations of physician-scientists. In stark contrast, Mike grew up in big-city Philadelphia and graduated from the nation’s oldest medical school, the University of Pennsylvania School of Medicine. We were drawn together by a shared fascination with clinical medicine and medical science and a desire to one day make discoveries of significance to both. In 1968, after two years of residency, we were both accepted for scientific training at the National Institutes of Health (NIH), where Joe worked in the laboratory of Marshall Nirenberg, who was soon to receive a Nobel Prize for solving the genetic code. Mike worked with Earl Stadtman, the biochemist’s biochemist who later received the United States National Medal of Science.We also had clinical duties. Joewas assigned to care for a pair of siblings (ages 6 and 8)who were suffering repeated myocardial infarctions due to massively elevated levels of low-density lipoprotein (LDL) cholesterol in their blood. The diagnosis was homozygous familial hypercholesterolemia (FH), a rare form of a common genetic disease, the pathogenesis of which was unknown. The two of us discussed these children intensely, and we resolved some day to unlock the genetic secret behind this striking illness. In 1970, after two years at the NIH, Joe moved to Seattle to learn medical genetics under the skillful tutelage of ArnoMotulsky. There, Joe spearheaded a classic study of the commonMendelian causes of hyperlipidemia in survivors of myocardial infarction. Mike remained one more year at the NIH. In 1971, he moved to the University of Texas SouthwesternMedical Center, where he completed a fellowship in gastroenterology and began to study the properties of 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-controlling enzyme of cholesterol synthesis that was later shown by Akira Endo to be the target of the statin drugs (Ref. 1; see Ref. 2). Mike’s move to Dallas was strongly advocated by Joe, who enlisted the aid of Seldin. Mikewaswilling to try this youngmedical school. Amazingly, his wife, Alice, a born-again Yankee, agreed to themove, but only under the condition that theywould stay for one or two years atmost. That was four decades ago, and the couple is still happily in residence, having raised two Texan daughters. In 1972, Joe returned to Dallas, and we began our collaborative studies of FH. This work led to the discovery of the LDL receptor, the process of receptor-mediated endocytosis, and the mechTHE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 27, pp. 22418 –22435, June 29, 2012 © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.