- Krebs, Hans
- Nobel Prize Medal awarded to Hans Krebs for his discovery of the citric acid cycle
[with:] Nobel Prize Diploma, two vellum membranes with calligraphic inscription in Swedish giving Krebs's citation dated 22 October 1953 in blue and red ink, signed by 29 members of the Royal Swedish Academy of Science, the first membrane with a miniature (205 x 215mm.) signed by Bertha Svensson-Piehl depicting a figure in red picking fruit from a tree with birds above against a background of Scandinavian buildings, mostly in blues, greens, and liquid gold, the second membrane with a vignette (20 x 220mm.) in a similar style, mounted as linings in a blue morocco portfolio gilt, the upper cover with a central cartouche of laurel leaves and the initials "HAK", the lower cover with the rod of Asclepius, in a custom made box
Krebs was born in Hildesheimin northern Germany and, after brief military service at the end of World War I, he followed in his father's footsteps and studied medicine. By the time of his graduation, however, it was clear to Krebs that his future lay in research rather than medical practice. After early training under the eminent biochemist Professor Otto Warburg, Krebs established for himself an international scientific reputation with the publication in 1932 of a paper that explained how the liver produced urea, a highly important discovery that that confirmed his outlook as a biologist trying to elucidate chemical events in living cells. The following year, however, Hitler came to power in Germany and Krebs, who was Jewish, was dismissed from his position at the University of Freiburg. Krebs's scientific reputation made it much easier for him to leave Germany than it was for many others; he was almost immediately offered a position in Cambridge and in 1935 Krebs was offered a lectureship at the University of Sheffield, where he was to work for the next 19 years and conduct his most important research.
Working with William Johnson, a post-graduate, at his new laboratory in Sheffield, Krebs began thorough and systematic work on the chemical reaction in glucose metabolism. The publication of a series of reactions that produced oxaloacetate from citric acid provided Krebs with the final clue he needed for his crucial breakthrough, and late in 1937 Krebs published the sequence of reactions he called the citric acid cycle.
The Krebs cycle is a chain reaction that is the central metabolic pathway in all aerobic organisms. It is the second stage of the process of cellular respiration by which nutrients are converted into energy through the breakdown of glucose, fuelled by the consumption of oxygen, and about two-thirds of the energy derived from food is converted through the Krebs cycle. The first stage of the process, glycosis, breaks down glucose into a compound called pyruvate. Krebs revealed the fundamental importance of pyruvate which, when further broken down into Acetyl-coenzyme A (a two carbon compound), enters the cell's mitochondria. There it is condensed with oxaloacetate (an acid with four carbon atoms) to form citric acid (with six carbon atoms). The citric acid then passes through a complex series of reactions through which it is oxidised, generating ATP – the crucial molecule for intracellular energy transfer – and also NADH (which is transformed into more ATP in a later process, the electron transport chain). The other products of the reaction are Carbon Dioxide, which is expelled from the cell, and oxaloacetate, thus enabling the cycle to begin once again when more Acetyl-coenzyme A is introduced into the mitochondria. In unravelling this elegant sequence of reactions Krebs revealed the body to be highly efficient in its conversion of fuel to energy.
The full significance of Krebs's breakthrough was not immediately apparent; indeed his initial report on his discovery was rejected by Nature in 1937. Meanwhile, in the darkening years of the later 1930s, Krebs established himself more fully in his adopted home of England, marrying an Englishwoman in 1938 and becoming a naturalised citizen in 1939. When war came he was among the many refugees whose education and intellect allowed them to play an important and distinctive role in the Allied war effort. In Krebs's case this took the form of assisting with government research on nutrition, in which capacity he is credited with helping to develop the nutritious but unloved National Wheatmeal Loaf.
After peace was restored, research began to proliferate that consolidated Krebs's pre-war breakthrough. In 1945 he was made the director of the new Unit for Research in Cell Metabolism in Sheffield. The Unit moved to Oxford with Krebs when he became Whitley Professor of Biochemistry in 1954. New technologies and procedures rapidly became available that revealed the fundamental role of the citric acid cycle to the metabolism of all foodstuffs (fats and proteins as well as carbohydrates), whilst F.A. Lipmann's discovery of acetyl coenzyme A, the molecule through which carbon enters the Krebs cycle, added greatly to the scientific understanding of the metabolic process. The Nobel Prize followed these developments – indeed the importance of Lipmann's discovery was such that he shared the 1953 Nobel Prize with Krebs (although the two men had not been collaborators). It was followed by numerous other honours for Krebs including a Royal Society Copley Medal, a knighthood, and the German order of merit, but he remained a straightforward and unaffected man who was active in the laboratory almost until his death in 1981.
Krebs provided the key to understanding how the cell converts energy, knowledge which is of great importance to medical research on metabolic disorders, and it was primarily in this context that he was awarded the Nobel. Beyond this, however, the process of metabolism is so basic to all complex living organisms that understanding the chemistry of the citric acid cycle provides profound insights into the early development of life. This was a point made by Krebs himself at the conclusion of his Nobel lecture:
“Before I conclude I would like to make an excursion into general biology, prompted by the remarkable fact that the reactions of the cycle have been found to occur in representatives of all forms of life, from unicellular bacteria and protozoa to the highest mammals. We have long been familiar with the fact that the basic constituents of living matter, such as the amino acids and sugars, are essentially the same in all types of life. The study of intermediary metabolism shows that the basic metabolic processes, in particular those providing energy, and those leading to the synthesis of cell constituents are also shared by all forms of life.
"The existence of common features in different forms of life indicates some relationship between the different organisms, and according to the concept of evolution these relations stem from the circumstance that the higher organisms, in the course of millions of years, have gradually evolved from simpler ones. The concept of evolution postulates that living organisms have common roots, and in turn the existence of common features is powerful support for the concept of evolution. The presence of the same mechanism of energy production in all forms of life suggests two other inferences, firstly, that the mechanism of energy production has arisen very early in the evolutionary process, and secondly, that life, in its present forms, has arisen only once.”
Krebs's insight has been proved correct above all in our deepening understanding of the role and evolutionary history of the mitochondria, the organelles – known as the cell's powerhouse – wherein the Krebs cycle takes place. An explanation for Krebs's observation about the commonality of the citric acid cycle to so many forms of life has been found in endosymbiotic theory. It is now thought that mitochondria originated about two billion years ago as a bacterium (a form of a-protobactria) that could use oxygen to produce energy. They evolved at a time when the earth's atmosphere was becoming increasingly oxygen-rich, following the evolution of photosynthesising single-cell organisms. This bacterium was taken up by a larger host but was not absorbed; instead it provided a means for the host organism to use oxygen to produce energy (whilst in turn the smaller bacterium was protected by being within the cell walls of its host). This capacity for energy generation was a necessary precondition for the evolution of complex multi-cellular organisms. The bacteria evolved into mitochondria, which still retain a small amount of their own DNA whilst providing the energy that complex organisms require for everything from brain activity to locomotion.
Krebs's elucidation of the cell's primary metabolic process did not only constitute the discovery of the major source of energy for all living organisms, but has also shaped our understanding of the origins of life itself.
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