KREBS, HANS ADOLF (1900-1981)
German biochemist
Few students complete an introductory biology course without learning about the Krebs cycle, an indispensable step in the process the body performs to convert food into energy. Also known as the citric acid cycle or tricarboxylic acid cycle, the Krebs cycle derives its name from one of the most influential biochemists of our time. Born in the same year as the twentieth century, Hans Adolf Krebs spent the greater part of his eighty-one years engaged in research on intermediary metabolism. First rising to scientific prominence for his work on the ornithine cycle of urea synthesis, Krebs shared the Nobel Prize for physiology and medicine in 1953 for his discovery of the citric acid cycle. Over the course of his career, the German-born scientist published, oversaw, or supervised a total of
more than 350 scientific publications. But the story of Krebs's life is more than a tally of scientific achievements; his biography can be seen as emblematic of biochemistry's path to recognition as its own discipline.
In 1900, Alma Davidson Krebs gave birth to her second child, a boy named Hans Adolf. The Krebs family—Hans, his parents, sister Elisabeth and brother Wolfgang—lived in Hildesheim, in Hanover, Germany. There his father Georg practiced medicine, specializing in surgery and diseases of the ear, nose, and throat. Hans developed a reputation as a loner at an early age. He enjoyed swimming, boating, and bicycling, but never excelled at athletic competitions. He also studied piano diligently, remaining close to his teacher throughout his university years. At the age of fifteen, the young Krebs decided he wanted to follow in his father's footsteps and become a physician. World War I had broken out, however, and before he could begin his medical studies, he was drafted into the army upon turning eighteen in August of 1918. The following month he reported for service in a signal corps regiment in Hanover. He expected to serve for at least a year, but shortly after he started basic training, the war ended. Krebs received a discharge from the army to commence his studies as soon as possible.
Krebs chose the University of Göttingen, located near his parents' home. There, he enrolled in the basic science curriculum necessary for a student planning a medical career and studied anatomy, histology, embryology and botanical science. After a year at Göttingen, Krebs transferred to the University of Freiburg. At Freiburg, Krebs encountered two faculty members who enticed him further into the world of academic research: Franz Knoop, who lectured on physiological chemistry, and Wilhelm von Möllendorff, who worked on histological staining. Möllendorff gave Krebs his first research project, a comparative study of the staining effects of different dyes on muscle tissues. Impressed with Krebs's insight that the efficacy of the different dyes stemmed from how dispersed and dense they were rather than from their chemical properties, Möllendorff helped Krebs write and publish his first scientific paper. In 1921, Krebs switched universities again, transferring to the University of Munich, where he started clinical work under the tutelage of two renowned surgeons. In 1923, he completed his medical examinations with an overall mark of "very good," the best score possible. Inspired by his university studies, Krebs decided against joining his father's practice as he had once planned; instead, he planned to balance a clinical career in medicine with experimental work. But before he could turn his attention to research, he had one more hurdle to complete, a required clinical year, which he served at the Third Medical Clinic of the University of Berlin.
Krebs spent his free time at the Third Medical Clinic engaged in scientific investigations connected to his clinical duties. At the hospital, Krebs met Annelise Wittgenstein, a more experienced clinician. The two began investigating physical and chemical factors that played substantial roles in the distribution of substances between blood, tissue, and cerebrospinal fluid, research that they hoped might shed some light on how pharmaceuticals such as those used in the treatment of syphilis penetrate the nervous system. Although Krebs published three articles on this work, later in life he belittled these early, independent efforts. His year in Berlin convinced Krebs that better knowledge of research chemistry was essential to medical practice.
Accordingly, the twenty-five-year-old Krebs enrolled in a course offered by Berlin's Charité Hospital for doctors who wanted additional training in laboratory chemistry. One year later, through a mutual acquaintance, he was offered a paid research assistantship by Otto Warburg, one of the leading biochemists of the time. Although many others who worked with Warburg called him autocratic, under his tutelage Krebs developed many habits that would stand him in good stead as his own research progressed. Six days a week work began at Warburg's laboratory at eight in the morning and concluded at six in the evening, with only a brief break for lunch. Warburg worked as hard as the students. Describing his mentor in his autobiography, Hans Krebs: Reminiscences and Reflections, Krebs noted that Warburg worked in his laboratory until eight days before he died from a pulmonary embolism. At the end of his career, Krebs wrote a biography of his teacher, the sub-title of which described his perception of Warburg: "cell physiologist, biochemist, and eccentric."
Krebs's first job in Warburg's laboratory entailed familiarizing himself with the tissue slice and manometric (pressure measurement) techniques the older scientist had developed. Until that time, biochemists had attempted to track chemical processes in whole organs, invariably experiencing difficulties controlling experimental conditions. Warburg's new technique, affording greater control, employed single layers of tissue suspended in solution and manometers (pressure gauges) to measure chemical reactions. In Warburg's lab, the tissue slice/manometric method was primarily used to measure rates of respiration and glycolysis, processes by which an organism delivers oxygen to tissue and converts carbohydrates to energy. Just as he did with all his assistants, Warburg assigned Krebs a problem related to his own research—the role of heavy metals in the oxidation of sugar. Once Krebs completed that project, he began researching the metabolism of human cancer tissue, again at Warburg's suggestion. While Warburg was jealous of his researchers' laboratory time, he was not stingy with bylines; during Krebs's four years in Warburg's lab, he amassed sixteen published papers. Warburg had no room in his lab for a scientist interested in pursuing his own research. When Krebs proposed undertaking studies of intermediary metabolism that had little relevance for Warburg's work, the supervisor suggested Krebs switch jobs.
Unfortunately for Krebs, the year was 1930. Times were hard in Germany, and research opportunities were few. He accepted a mainly clinical position at the Altona Municipal Hospital, which supported him while he searched for a more research-oriented post. Within the year, he moved back to Freiburg, where he worked as an assistant to an expert on metabolic diseases with both clinical and research duties. In the well-equipped Freiburg laboratory, Krebs began to test whether the tissue slice technique and manometry he had mastered in Warburg's lab could shed light on complex synthetic metabolic processes. Improving on the master's methods, he began using saline solutions in which the concentrations of
various ions matched their concentrations within the body, a technique which eventually was adopted in almost all biochemical, physiological, and pharmacological studies.
Working with a medical student named Kurt Henseleit, Krebs systematically investigated which substances most influenced the rate at which urea—the main solid component of mammalian urine—forms in liver slices. Krebs noticed that the rate of urea synthesis increased dramatically in the presence of ornithine, an amino acid present during urine production. Inverting the reaction, he speculated that the same ornithine produced in this synthesis underwent a cycle of conversion and synthesis, eventually to yield more ornithine and urea. Scientific recognition of his work followed almost immediately, and at the end of 1932—less than a year and a half after he began his research—Krebs found himself appointed as a Privatdozent at the University of Freiburg. He immediately embarked on the more ambitious project of identifying the intermediate steps in the metabolic breakdown of carbohydrates and fatty acids.
Krebs was not to enjoy his new position in Germany for long. In the spring of 1933, along with many other German scientists, he found himself dismissed from his job because of Nazi purging. Although Krebs had renounced the Jewish faith twelve years earlier at the urging of his patriotic father, who believed wholeheartedly in the assimilation of all German Jews, this legal declaration proved insufficiently strong for the Nazis. In June of 1933, he sailed for England to work in the biochemistry lab of Sir Frederick Gowland Hopkins of the Cambridge School of Biochemistry. Supported by a fellowship from the Rockefeller Foundation, Krebs resumed his research in the British laboratory. The following year, he augmented his research duties with the position of demonstrator in biochemistry. Laboratory space in Cambridge was cramped, however, and in 1935 Krebs was lured to the post of lecturer in the University of Sheffield's Department of Pharmacology by the prospect of more lab space, a semi-permanent appointment, and a salary almost double the one Cambridge was paying him.
His Sheffield laboratory established, Krebs returned to a problem that had long preoccupied him: how the body produced the essential amino acids that play such an important role in the metabolic process. By 1936, Krebs had begun to suspect that citric acid played an essential role in the oxidative metabolism by which the carbohydrate pyruvic acid is broken down so as to release energy. Together with his first Sheffield graduate student, William Arthur Johnson, Krebs observed a process akin to that in urea formation. The two researchers showed that even a small amount of citric acid could increase the oxygen absorption rate of living tissue. Because the amount of oxygen absorbed was greater than that needed to completely oxidize the citric acid, Krebs concluded that citric acid has a catalytic effect on the process of pyruvic acid conversion. He was also able to establish that the process is cyclical, citric acid being regenerated and replenished in a subsequent step. Although Krebs spent many more years refining the understanding of intermediary metabolism, these early results provided the key to the chemistry that sustains life processes. In June of 1937, he sent a letter to Nature reporting these preliminary findings. Within a week, the editor notified him that his paper could not be published without a delay. Undaunted, Krebs revised and expanded the paper and sent it to the new Dutch journal Enzymologia, which he knew would rapidly publicize this significant finding.
In 1938, Krebs married Margaret Fieldhouse, a teacher of domestic science in Sheffield. The couple eventually had three children. In the winter of 1939, the university named him lecturer in biochemistry and asked him to head their new department in the field. Married to an Englishwoman, Krebs became a naturalized English citizen in September, 1939, three days after World War II began.
The war affected Krebs's work minimally. He conducted experiments on vitamin deficiencies in conscientious objectors, while maintaining his own research on metabolic cycles. In 1944, the Medical Research Council asked him to head a new department of biological chemistry. Krebs refined his earlier discoveries throughout the war, particularly trying to determine how universal the Krebs cycle is among living organisms. He was ultimately able to establish that all organisms, even microorganisms, are sustained by the same chemical processes. These findings later prompted Krebs to speculate on the role of the metabolic cycle in evolution.
In 1953, Krebs received the Nobel Prize in physiology and medicine, which he shared with Fritz Lipmann, the discoverer of co-enzyme A. The following year, Oxford University offered him the Whitley professorship in biochemistry and the chair of its substantial department in that field. Once Krebs had ascertained that he could transfer his metabolic research unit to Oxford, he consented to the appointment. Throughout the next two decades, Krebs continued research into intermediary metabolism. He established how fatty acids are drawn into the metabolic cycle and studied the regulatory mechanism of intermediary metabolism. Research at the end of his life was focused on establishing that the metabolic cycle is the most efficient mechanism by which an organism can convert food to energy. When Krebs reached Oxford's mandatory retirement age of sixty-seven, he refused to end his research and made arrangements to move his research team to a laboratory established for him at the Radcliffe Hospital. Krebs died at the age of eighty-one.
