Australian scientist (1924–2022)
Derek Ashworth Denton (27 May 1924 – 18 November 2022) was an Australian scientist who elucidated the regulation of electrolytes in extracellular fluid, the hormones controlling this regulation, particularly aldosterone, and the instinctive behaviours controlling intake of water and salts. He was cited in 1995 at election to the U.S. National Academy of Sciences as the world’s leading authority on the regulation of salt and water metabolism and relevant endocrine control mechanisms. He was one of Australia’s most eminent scientists.
Career.
Denton was the founding Director and Emeritus Director of the Howard Florey Institute, Honorary Professor at the University of Melbourne and a consultant at the Baker Research Institute. Denton's last book is "The Primordial Emotions: The Dawning of Consciousness".
Research.
Three months after medical graduation in 1947, he made a basic discovery on kidney function at the Royal Melbourne Hospital. In the face of profuse alkaline drainage (Na+ in excess of Cl- relative to extracellular proportions) from a pancreatic fistula (2-3 litres/day) the patient’s kidneys primarily regulated the ionic pattern of the extra cellular fluid – not plasma concentration or the load of ions to the kidney tubules. As the fistula drained, blood pressure declined, respiration increased, and Cl- excretion in urine increased despite decline in plasma Cl- level below the so called “renal threshold “. Adequate intravenous infusion of sodium lactate, or oral sodium bicarbonate reduced or stopped the urinary Cl- excretion. In this era, urinary Cl- was measured at the bedside (Fantus test) to assess whether salt content of the body was adequate or whether salt administration was needed urgently. This was recommended by Marriott in his Croonian Lecture and was the practice of the British Army in India. The proposal was physiologically unsound in specific circumstances of loss of Na in excess of Cl, and Marriott altered his recommendations. It was the wrong approach in diseases such as e.g. dysentery, cholera and paralytic ileus. No rapid estimation of urinary sodium by flame photometry had yet emerged.
Denton recognised also a crucial biological fact that no biologically relatively inactive cation had evolved in Metazoan organisms to play a role analogous to that which increase of bicarbonate plays on the anion side of the pattern during vomiting and excess Cl- loss. In this latter case no large urinary Na excretion was obligatory to keep acid-base balance compatible with life. The initial finding with pancreatic fistula was published by Nature (London, 1948). In 1949, he, and Dr Victor Wynn who had joined him in study of a second case, were supported by Professor R. D. Wright and Sir MacFarlane Burnet to set up the Ionic Research Unit of the NHMRC in the Physiology Department at Melbourne University. The Ionic Research Unit originated flame photometry in clinical medical practice internationally – a Wynn initiated step. Rapid measurement of sodium and potassium in blood and urine helped originate intensive care, and they published a monograph in Acta Medica Scandinavica. Denton and Wynn’s approach, particularly flame photometry with rapid assessment of biochemical disorder, eventually resulted in saving of tens of thousands of lives in Australia as well as in other countries by chemically accurate intervention. In 1952 Wynn went to London, where Professors Pickering and Robb at St Mary’s Hospital established a metabolic intensive care unit which Wynn directed. Some years later he was visited by Professor Francis Moore of Harvard who incorporated the Melbourne classification of distortion of body fluid status viz subtraction acidemia e.g. pancreatic fistula; addition acidemia e.g. diabetic coma; subtraction alkalemia e.g. vomiting gastric juice; and addition alkalemia (excess alkali ingestion) into his textbook ‘Metabolic Aspects of Surgery”
Denton, in Melbourne, directed his efforts to basic physiological processes involved in regulation of body fluids.
Fifty years had passed since Pavlov was using Pavlov-Glinski parotid fistulae in dogs with discovery of conditioned reflexes. Nine papers from Russia and Germany had reported in the interim that a permanent unilateral parotid fistula was not surgically feasible in ruminants. Denton succeeded surgically in sheep which opened a new era in the study of body fluid regulation. In effect, the parotid fistula (1-4l/day) represented a tap on the blood stream letting out sodium. Many animal preparations made also embodied his novel idea of adrenal autotransplant into arterio-venous skin loops constructed in the neck, as executed by Wright and Goding. This allowed revelation of direct action on the gland by adrenal arterial infusion of e.g. Na, K, ACTH in a conscious undisturbed animal. Following the discovery of the salt retaining hormone aldosterone by the Taits in 1953, with major medical implications, the hunt for the mode of control of it was internationally intense.
Following the Australian Group finding of a specific but limited role of Na, K and ACTH, cross circulation experiments by Denton, Goding and Wright discovered an unidentified humoral agent in aldosterone control, and contemporaneously Davis and Peterson at NIH made a similar finding in anaesthetized dogs. (subsequently angiotensin II was indicted – Ganong, Mulrow)). Denton and colleagues showed direct action of Angiotensin II on the adrenal by arterial infusion. The operative idea of the cervical autotransplant was later applied internationally to ovary and uterus, and the parathyroid, thyroid, pancreas, and in Melbourne to the kidney.
Evolutionary implications.
Continuous parotid fistula secretion (1-4 litres daily) contrived severe Na depletion rapidly in sheep. Salivary Na/K ratio of 170/10 changed dramatically over days to 10/160 as a result of adrenal secretion of aldosterone. Thus K, abundant in vegetation, could be used in the digestive life cycle for months.  This evolutionary advantageous process allowed use of the Na content of the rumen “reservoir” to support the circulation, and reproduction – foetal tissues and lactation. Thus, herbivores invaded and reproduced in the vast Na depleted interior of continents, alps, deserts and jungles. Their historic evidence of severe sodium depletion in native and introduced species of wild animals in the Alps in Australia was ratified by direct measurement of peripheral blood aldosterone with a double isotope dilution method set up by Dr John Coghlan of the Ionic Unit following his study with Professor Ralph Peterson in New York. The discovery of severe Na depletion of animals in the Alps of Australia was confirmed in camels in the desert in Africa by Knut Schmidit-Nielsen, and in moose in Canada by Jordan and Botkin. Hitherto salt depletion had been inferred by the attraction of animals to salt.  Meteorological data had shown that by 150-200 Km from the ocean coast rainwater is devoid of Na containing marine aerosols, and thus vast areas of the planet are Na depleted.
With regard to the HCO3 ion, Denton recognised early that data showing that alligators, with their swallowing of whole large prey and having plasma HCO3 rise from 40 to 100 mmol/litre, and Cl decrease from 100 to 40 mmol/litre with blood pH near 7.8 reflected a basic mechanism in the pathway of evolution of the constrictors and big reptiles. They passed a major portion of their extracellular CL- content into their stomach as HCl to digest prey over very many days.
Denton suggested also that the endocannibalism recognized by Alfred Russel Wallace in the vast Na depleted regions of the Amazon Basin reflected conservation by the tribes of very scarce minerals of critical importance.
With Hird and Reich, Denton showed the monotremes platypus and echidna were ureotelic which underlined biochemical changes crucial for mammalian evolution.
The months following graduation (1947), and the responsibility for the patient with a pancreatic fistula, led to study sojourns with Frank Fenner and Macfarlane Burnet in Melbourne, and Verney in Cambridge, UK in 1952.  On return from the UK, Denton’s discoveries starting from the two fistula patients, and several sheep in cages progressively revealed novel renal, endocrine and instinctive behavioural mechanisms of notable medical, integrative physiological, and evolutionary survival importance.
Australian and International Recognition of the Investigation.
The work attracted large financial support from private benefactors in Australia (Kenneth and Baillieu Myer, and Sir Ian Potter) and overseas, the Australian Government and Reserve Bank, the Rockefeller Foundation, and the National Institutes of Health (US).  This founded and supported the Howard Florey Laboratories in 1962, and then in 1970, the Howard Florey Institute of Experimental Physiology and Medicine, which has eventually become the largest neuroscience institute in the Southern Hemisphere (The Florey Institute of Neuroscience and Mental Health – 600 personnel).  He was the Founding Director and was termed by the Chancellor of Melbourne University, Professor Sir Douglas Wright AK, as the “"fons et origo"”.  Election by the Royal Swedish Academy of Science (1974) as one of 18 Foreign Medical Members, joining, "inter alia", Lord Adrian, Hodgkin, A.V. Hill, Burnet, Monod, Best, Bronk, Page and Moruzzi.  One of 4 OECD Examiners of Scientific Policy of the Government of Sweden in 1986.  For twelve years (1978-1991) he was with Professor Sune Bergstrom, Chairman of the Nobel Foundation, one of two foreign members of the Lasker Jury in the U.S. He became a Council Member (1977-1989), and then First Vice President of the International Union of Physiological Sciences (1983-1989), working with President, Sir Andrew Huxley PRS. Australian representative on the International Human Rights Network of Academies and Learned Societies, 2000-2015.
Following election to the Royal Swedish Academy of Science in 1974, Denton received the Pavlovian Award of the Pavlovian Society of North America for achievement toward understanding of factors in normal and abnormal behaviour (1975), and together with colleagues at the Howard Florey, the Biennial Prize of the International Society of Cardiology in 1976.  In 1979 he was elected Fellow of the Australian Academy of Science, and also the Royal Australian College of Physicians.  In 1982 awarded the P K Anokhin Medal by the Rector of the Schenov First Moscow Medical Institute “for contribution to world physiology”.  In 1986 elected as Honorary Foreign Member of the American Academy of Arts and Sciences. In 1987 elected Honorary Member, American Physiological Society, one of 50 so elected in the Society’s century of function.  In 1988, elected Honorary Fellow, Royal College of Physicians (London).  In 1995, elected Foreign Associate National Academy of Sciences USA. In 1999 elected Fellow of the Royal Society (London), and in 2000 elected Foreign Associate, Academie des Sciences, Institut de France.  In 2001 he received the Life Time Achievement Award of the International Commission on Food and Fluid Intake of the International Union of Physiological Sciences.  In 2005 and 2006, he received a Companion of the Order of Australia, and Doctor of Law ("Honoris Causa") University of Melbourne, and in 2014 the World Hypertension League Award for Excellence in Dietary Salt Reduction.
At election to the Academy of Science of the Institute of France, the same attribution of world leadership, that the Academy of Science of the US made was reiterated and the Danish group, Paul Astrup, Peter Bie and Hans Enzell in their book “Salt and Water in Culture and Medicine” (1993) stated “Australian Derek Ashworth Denton has contributed more than anyone in explaining the adrenal production of hormones and their importance in the regulation of salt metabolism”.
Denton synthesised a sweep of this work in his book “The Hunger for Salt: An Anthropological, Physiological and Medical Analysis” (Springer Verlag 1982) which was reviewed by Lewis Thomas, President of the Sloan Kettering Institute, nominated by Time to be ….…..”the best essayist on science now working anywhere in the world.”  Thomas wrote ……..”few researchers have the intellectual flexibility or the sheer courage to take on a really big subject and cover the whole.  Derek Denton has done this in “Hunger for Salt”, and the result is something astonishing among contemporary scientific letters – a single author book that covers everything – This grand book”, and by Harold Schmeck, lead Science Writer of the New York Times, as …………….”may be the most comprehensive treatment of the subject ever completed”, Dr. John Pappenheimer, the Emeritus Professor of Physiology at Harvard, characterized it as …….”the best example of integrative physiology to come of the second half of the 20th century”.
Fierce controversies on the role of excess salt intake as a major cause of hypertension in humans were rampant in the second half of the twentieth century. The issue was clouded by citation of multiple factors possible and the role of the Salt Institute in Washington, an industry funded body. At the primate research centre of the Texas Biomedical Institute in San Antonio, Eichberg and Shade showed humans closest relatives, chimpanzees, fed a diet with Na content equivalent to urban