Portal de Periódicos da CAPES

Homage to August Krogh celebrating the 90th anniversary of his Nobel prize in Physiology or Medicine

2011; Wiley; Volume: 202; Issue: 3 Linguagem: Inglês

10.1111/j.1748-1716.2011.02325.x

1748-1716

Erik Hviid Larsen, Ylva Hellsten, Jørgen F. P. Wojtaszewski,

Genetics and Physical Performance

As a student of zoology at the Natural Science Faculty of the University of Copenhagen, Krogh was advised to attend Christian Bohr’s lectures in medical physiology. After the very first lecture Krogh decided that physiological research should be his future occupation (Rehberg 1951). Christian Bohr taught his students the significance of quantitative work and the necessity of proving that a theory is accounting quantitatively for a physiological mechanism. The time spent in Bohr’s laboratory became of greatest significance for Krogh’s scientific training. Christian Bohr, professor of Medical Physiology and recognized as Europe’s leading physiologist in blood and respiratory physiology, received a student with a similar talent for physics and a unique capacity for designing instruments and working quantitatively with meticulous accuracy. This Krogh revealed already in his dissertation (Krogh 1904a) and in the cowork with Bohr and Karl Hasselbalch on the binding of oxygen to haemoglobin in mixtures of oxygen and carbon dioxide the tensions of which he could control and measure (Krogh 1904b). Between his first international publication in 1903, On shells floating on the surface of the sea and his last scientific paper in 1948 on Determination of temperature and heat production in insects, Krogh published fundamental discoveries on metabolism, respiration, circulation and osmoregulation in animals and humans (Hill 1950, Schmidt-Nielsen 1995). From the beginning of his career Krogh’s studies were divided between human physiology concerned with problems of significance for health and medical sciences, and comparative physiology dealing with problems of significance for zoology. Characteristically for his experimental studies, Krogh developed methods and equipment designed for the specific organism and physiological function whether the organism was the living human body or an animal, and no matter the level of technical sophistication required. It was a common joke in Copenhagen that the difference between the Zoophysiological Laboratory and the Institute of Medical Physiology was that in the former, experiments were carried out on humans and in the latter on animals (Rehberg 1951). Krogh’s incentive for comparative studies was a search for the mechanisms that organisms have evolved in the adaptation to their physical environment: The principle by which I have been guided in most of my physiological researches is frankly teleological. How do organisms solve their problem? or rather: How is the particular problem (which more or less accidentally) has caught my attention being solved? (Krogh 1938). He emphasized, ‘You will find in the lower animals mechanisms and adaptations of exquisite beauty and the most surprising character’ (Krogh 1929). Under the influence of Christian Bohr and John Scott Haldane in Oxford, Krogh became interested in the mechanism of gas exchange in the lung. For attacking the problem, he designed a microtonometer and improved the micro gas analysis apparatus, which enabled him to measure the gas tensions of a volume sufficiently small for obtaining rapid equilibration between the gas mixture of blood and that of an air bubble introduced into the circulation, which was analysed subsequently. Krogh’s studies proved that absorption of oxygen and elimination of carbon dioxide is due to diffusion. He published his results in 1910 in seven papers on The mechanism of gas-exchange with his wife Marie Krogh as coauthor on two of the papers. They have ever since formed the basis of our knowledge concerning the gas exchange in the lungs. In 1911, Krogh and Johannes Lindhard initiated several years of continued cowork on the physiology of exercise. The studies led Krogh to question the commonly accepted idea that the strongly increased demand for oxygen by the working muscles is fulfilled only by an increased blood flow. Krogh reasoned that the greater supply of blood would provide more oxygen to the cells, but this would be counterbalanced by the shorter time the blood remained in the capillaries. This contradiction would disappear if the amount of blood in the muscle increases during work. Krogh hypothesized that during rest only a small fraction of the capillaries are open at any given time and that the number of open capillaries increases during work in such a way that the distance between the capillaries and the oxygen-consuming cells decreases. He confirmed his hypothesis by quantitative microscopical examinations of in vivo and in vitro preparations. Because it was impossible to measure the oxygen tension in the muscle tissue, with his cylinder model of a single capillary surrounded by muscle tissue he attacked the problem by mathematical modelling. He determined the diffusion constant of oxygen in various tissues and measured the diffusion distance in muscles of a simple geometrical arrangement of capillaries. This enabled him to calculate that the oxygen tension of the muscle tissue, even during intense work, is only slightly lower than that of the venous blood. In the course of 1919–1920, the results were published and immediately they aroused the greatest attention and by 1920 he was awarded the Nobel prize in Medicine or Physiology for his discovery of the capillary motor-regulating mechanism. In Krogh’s monograph from 1922 on The Anatomy and Physiology of Capillaries he presented drawings by the young anatomist Bjowulf Vimtrup’s microscopical observations of individual capillaries equipped with contractile Rouget cells (pericytes), which was suggested to constitute the capillary motor mechanism. During a visit in 1922 to J. J. R. Macleod’s laboratory in Toronto, Krogh obtained exclusive rights in the three Scandinavian countries to produce and manufacture insulin to the medical community and public (Schmidt-Nielsen 1995). After his return to Denmark, Krogh contacted the physician Hans Christian Hagedorn, who was a specialist in carbohydrate metabolism and diabetes. Together, on a commercial basis they started the production of insulin for the Scandinavian countries, and for several years Krogh devoted himself to the insulin project. During these years, the Danish tradition developed for basic and clinical research in diabetes. Today, insulin production constitutes a highly successful industry in Denmark covering about 50% of the international insulin market consumption. In the 1930s, Krogh resumed the problem of the nature of mass transport across biological membranes. In his new investigations, Krogh provided the evidence for ion transport in a direction opposite to that governed by external physico-chemical forces. This he denoted ‘active’ transport as opposed to diffusion, which he called ‘passive’ transport. Soon after, he wrote his Croonian Lecture paper, which is a monumental scholarly review of the studies on the ion distribution between freshwater animals and their natural environment, and between cell water and the interstitial fluid (Krogh 1946). Krogh concluded that the different ion composition of the respective fluids has not to do with a true equilibrium, but with a steady state maintained against a passive diffusion and requiring the expenditure of energy. Thus, departing from the discovered mechanism of mass transport across biological membranes Krogh pointed out another fundamental discovery, namely, the dynamic state of the ion composition of the extracellular and intracellular fluids, which he suggested should be studied quantitatively by the radioactive isotope tracer technique. With the above review paper Krogh kicked off new questions on homeostatic mechanisms and membrane transport, which flourished after WWII and came to occupy a new generation of physiologists. With the Croonian Lecture published at an age of 72 years and shortly after he retired from his chair in Zoophysiology, Krogh maintained the highest standard of achievement throughout his life. Our celebration at The Royal Danish Academy of Sciences and Letters of the 90th anniversary for his Nobel prize is not merely a remembrance of his work in microcirculation, but a timely opportunity to present excellent scientific studies of today concerned with issues August Krogh initiated during his time in physiological research in Copenhagen.