John Arthur Luetscher, Jr (1913–2005)
Dr John Luetscher was born in Baltimore, Md, the son of a practicing physician. After attending Princeton University, he entered Johns Hopkins Medical School to follow his father’s footsteps as a physician. He was attracted to the intellectual stimulation and challenge of academic medicine by the Hopkins environment and pursued a research fellowship in physical chemistry at Harvard University after completing his internship. During his fellowship, he was exposed to the rigorous and critical approach to science that was to characterize his entire scientific career. His fellowship work focused on plasma proteins and their participation in salt and water metabolism. He returned to Hopkins to complete his clinical training and in 1942 was offered a faculty position in the Department of Medicine there. In 1948, he left Hopkins to become Associate Professor of Medicine at the fledgling Stanford University Medical School, based at that time in San Francisco, where he joined Dr Thomas Addis, a well-known expert in renal disease. John’s interest in salt and water metabolism was enhanced by the discovery of an adrenal principle, “electrocortin,” which had been shown to influence sodium and potassium excretion. This steroid subsequently was named aldosterone, and John, in conjunction with his research associates, Quentin “Chip” Deming and Ben Johnson, was able to isolate aldosterone from the urine of humans with nephrotic syndrome and congestive heart failure.1,2 He is acknowledged to share the identification of aldosterone with the Taits, Jim and Sylvia Simpson, with whom he also shared the prestigious CIBA (now Novartis) Award of the American Heart Association Council for High Blood Pressure Research in 1977. Although aldosterone was initially identified only in the urine of patients with severe edematous states, the development of more sensitive assays led to the recognition of a role for this hormone in myriad clinical situations. John’s sensitive bioassay for aldosterone3 permitted Foye and Feichtmeier to identify the first human suffering from excessive aldosterone production resulting from an adrenal carcinoma4 even before Conn’s5 classical report of primary aldosteronism.
In 1959, John led the relocation of the Stanford University Medical center from a hospital-based institution in San Francisco to a full-fledged academic medical school based in Palo Alto. His seminal research had already attracted a large number of research fellows and associates, a pattern that was to continue for almost 3 more decades. At the risk of leaving out numerous such associates who benefited from his trademark critical scientific approach, I would mention the following who are well known in the hypertension, endocrine, and cardiovascular fields: “Chip” Deming, Ben Johnson, Pat Mulrow, Francis Ganong, Jerry Reaven, Richard Bailey, Carlos A. Camargo, Sr, Richard Cheville, Richard Day, Rainer Beckerhoff, R. Dennis Collins, Phil Zager, Gary Melada, Arunabha Ganguly, Willa Hsueh, Michael Bryer-Ash, Darrell Wilson, and myself. John’s scientific excellence was acknowledged when he was elected to serve as President of the American Society for Clinical Investigation in 1959 and when he received the Robert Tigerstedt Award of the American Society of Hypertension in 1988, as well as the previously mentioned CIBA Award for his contributions to aldosterone and renin research.
I was privileged to spend 3 years as a research fellow with John from 1966 to 1969. My first project was to develop and validate a bioassay for plasma renin activity, because the link between renin–angiotensin and aldosterone had been recently defined, and the observation that patients with primary aldosteronism had suppressed renin levels was potentially useful in the diagnosis of such patients. Increasing numbers of patients suspected to have this form of hypertension were being referred to the Stanford University Medical Center at that time. After a short period, the assay was established, and we began to validate it by drawing large amounts of blood on laboratory personnel, including myself, at the end of periods of high and low dietary sodium intake in order to establish normal values from which to compare the findings in patients. A by-product of these initial studies included the early recognition of the role of oral contraceptives in causing or exacerbating hypertension in women.6 These studies also permitted us to identify the syndrome of low-renin hypertension7 and inappropriate aldosterone production.8 My final project as a research fellow with John was the development of a radioimmunoassay for plasma renin activity.
While sometimes exasperating, the experience as a research fellow in his laboratory was a memorable and magical one in which a constant search for answers to questions was imbued. Every question was addressed with critical responses requiring justification and myriad additional questions about how one should go about achieving the answers. Defense of hypotheses and data was a very intimidating challenge but one that left the trainee with an immense sense of satisfaction when the barrage of questions finally ended. The most educational experience was observing how John applied that same intensity and rigor to his own ideas. I distinctly recall a period when John was consumed with developing an analog computer model of the circulation. After months of virtually solitary work, he emerged one day from his laboratory with a broad smile on his face and announced that his model could now duplicate the hemodynamic alterations associated with the Valsalva maneuver! Perhaps John’s most important contribution in his later years in terms of clinical relevance today was the observation of elevated levels of prorenin in diabetics9 and its relationship to diabetic microvascular disease.10 Amazingly, John continued his National Institutes of Health–funded research until the age of 76, concluding it then, not because of age, but rather because of irreparable damage to his laboratory and loss of experimental data as the result of the Loma Prieta earthquake!
As important as the scientific observations themselves were, no one could have foreseen the impact of his findings on the management of millions of patients. One example is the occasional “cure” of hypertension by withdrawal of oral contraceptives. Although contraceptive-induced hypertension became less frequent as the dose of estrogen was reduced in contraceptives during the 1980s, it has been replaced in importance by the increased use of high-dose hormone replacement therapy more recently. Thus, estrogen withdrawal has been associated today with the amelioration of hypertension in many women receiving estrogen in the form of contraceptives or postmenopausal therapy. More recently John’s seminal finding of aldosterone in the urine of patients with severe congestive heart failure has been reflected in the results of the Randomized Aldosterone Evaluation Study (RALES)11 and Eplerenone Post acute myocardial infarction HEart failure efficacy and SUrvival Study (EPHESUS)12 trials demonstrating the beneficial effects of mineralocorticoid antagonist therapy with spironolactone or eplerenone in reducing symptoms, as well as their life-extending effects in patients with that disorder, thus making such treatment routine. The findings of high levels of prorenin in diabetics, particularly those with nephropathy, and the association of this protein with microvascular disease that John initially reported has led to the routine administration of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in diabetics for the treatment or prevention of nephropathy.
After retiring from Stanford in 1989, John moved to Sacramento, Calif, to live near his son and granddaughter who helped him care for his ailing wife, Genevieve (“Jammy”), who died in 1999. He continued his interest in science, the world, and in classical music from his home until his death on January 30, 2005, at the age of 92. He is survived by his sons, John and Buck, a daughter-in-law, 2 granddaughters, and 3 great-grandchildren, as well as all of those whom he trained and mentored who continue his critical scientific legacy, the many students who were exposed to his educational skills, and a world of physicians and patients who unknowingly have benefited from his unique talents and discoveries. We all owe John Luetscher a great debt of gratitude for his myriad contributions.