George F. Cahill Jr., who died July 30 at the age of 85, is remembered as one of the most imaginative scientists ever to have graced the field of metabolism. His obituary in The New York Times (1) and a more formal reflection (2) on his career by C. Ronald Kahn of the Joslin Diabetes Center, Cahill’s academic home for the best part of his career, capture the formal aspects of Cahill’s contributions to science. Perhaps the publication that most lovingly presents Cahill’s life and times, as well as his approach to science, was written by his former fellow and collaborator, the late Oliver E. Owen; it was published in Harvard Medicine (3) and was a favorite of Cahill’s.
This article is a more personal reflection on the impact of Cahill’s research on the field of metabolism and on the unique and unparalleled insights that it has provided. To understand his contributions to metabolism, it is important to recall a bit of the history of this field during the last half of the 20th century, the period when he worked.
Most of the major advances in metabolism in that era involved the discovery of the pathways of fuel utilization, the key enzymes in these pathways and the factors that control these processes. This was followed by the isolation and characterization of genes that code for major enzymes in metabolism and an understanding of their regulation. This field continues to provide insights into biological processes in general.
Cahill was not a biochemist but a physician–scientist: His approach to research was integrative and not reductionist in nature. One example of this is his early research on the effects of hormones on the metabolism of adipose tissue and liver. In the 1950s, research on the biology of adipose tissue was in its infancy. Before this period, adipose tissue was generally considered to be simply “fat,” as it was termed, just a storage site for triglycerides and of only marginal interest in the control of whole-body metabolism.
Cahill and Albert Renold, another physician–scientist, who had worked at Harvard Medical School with the famous Baird Hastings, collaborated on pioneering research on adipose tissue metabolism. In a series of papers in the early 1960s, many of them published in the Journal of Biological Chemistry (4, 5), Cahill and Renold provided a primer on how to study metabolic pathways in adipose tissue and liver. They also showed how to use this information to understand the effects of hormones, such as insulin and epinephrine, on the metabolism of these tissues.
I began my scientific life as a graduate student during this period and remember well the effect that these publications made on my own career: They taught me how to use isotopic tracers and to isolate the end products of metabolism, such as CO2, glycogen, fatty acids and glyceride-glycerol, from tissues. I would recommend these papers to the new generation scientists interested in metabolism for their clarity of approach and elegance of concept.
It was during this period that Cahill and Renold edited for the American Physiological Society the “Handbook of Physiology: Adipose Tissue,” which contained more than 4,000 references and was for many years the bible of adipose tissue metabolism. If he had done nothing more in his scientific career, Cahill would have been remembered as a pioneer for his studies of the metabolism of adipose tissue.
In 1962, Cahill was named director of what was to become the Joslin Research Laboratories, and he held the position until 1978. It was at the Joslin and in the Clinical Research Center at the associated Peter Bent Brigham Hospital that Cahill and his colleagues carried out the groundbreaking experiments in human metabolism for which he is justly famous. These experiments were described in some detail by his colleague Oliver E. Owen (6), and the reader is directed to that article for the insight that it provides on what it was like to do human experimentation in that era.
The major scientific question that interested Cahill during this period was the metabolic adaptation of humans to starvation. Techniques were available to determine the concentration of metabolic fuels in venous and arterial blood and in the urine in human subjects, and Cahill and colleagues used them to study metabolism during starvation. A major issue was fuel metabolism by the brain. In the early 1960s, it was known that the brain utilized glucose at a rate of 100 to 145 grams per day, but it was widely held that the brain did not oxidize ketone bodies for energy. Ketone bodies are unique as a metabolic fuel, because their concentration can vary from virtually undetectable levels after a meal containing carbohydrate to 7 mM after five weeks of starvation. As Oliver Owen pointed out (6), “Cahill was one of the few clinical investigators at the time to believe that during starvation there was not enough nitrogen in the urine to account for the alleged amount of glucose that the brain was thought to need for normal function.”
The link between the excretion of urinary nitrogen and glucose utilization by the brain was a critical insight, because the major source of glucose during starvation is gluconeogenesis from amino acids, a process that generates urea. The brain clearly had to use a fuel other than glucose during starvation to make the numbers add up. This point was experimentally established by directly measuring the utilization of ketone bodies by the brain in subjects starved for five to six weeks by determining the arterial-venous difference in the concentration of ketone bodies across the brain.
The results of these studies were published in the Journal of Clinical Investigation in 1967 (7) and quickly became a “Citation Classic.” In the metabolic field, these findings had a major impact, because they provided a basis for understanding the principle of fuel sparing, which occurs in all mammals. The fact that the brain, which normally uses glucose as its fuel of choice, would switch its fuel preference to ketone bodies, which are synthesized from fatty acids in the liver, provided a major insight into the control of energy metabolism. As Cahill pointed out on many occasions, a 70-kilogram human has 141,000 kilocalories of triglyceride and only 900 kilocalories of carbohydrate stored as glycogen, mainly in the liver and skeletal muscle; glycogen in the liver is depleted after about 12 hours of fasting, after which the major source of glucose is gluconeogenesis from amino acids. If tissues such as the brain and skeletal muscle continued to use glucose as a primary fuel, the depletion of muscle protein would be accelerated, greatly impeding our ability to survive a prolonged fast. Thus, the utilization of fatty acids, or fatty acid-derived ketone bodies, is at the heart of fuel sparing. As an example, fatty acids block both glucose uptake and oxidation via glycolysis and the citric acid cycle in skeletal muscle, a major adaptation to fasting.
Cahill and colleagues made another major discovery through research carried out between 1967 and 1971. They reported that alanine and glutamine are the major amino acids released by skeletal muscle of humans during prolonged fasting (8). Alanine is a substrate for hepatic gluconeogenesis, and glutamine is converted to glucose by the kidney cortex; the ammonia generated by this process is used to maintain the neutrality of the tubular urine. The discovery of the unique metabolic role of two amino acids during fasting out of the 20 that make up the protein of skeletal muscle provided another critical contribution to our understanding of the metabolic adaptations that occur during starvation.
Cahill’s research is monumental in its scope, as it establishes a framework upon which to understand human metabolism. Like the discovery of the urea and citric acid cycles by Hans Krebs, Cahill’s work provides us with a new way of thinking about energy metabolism. Over many years of teaching biochemistry to medical and premed students, I have found that nothing introduces the complexity of metabolism better than to begin with the work of Cahill and colleagues, as it forms a base upon which the interaction of specific metabolic pathways can be structured.
It is of interest that many textbooks of biochemistry include a figure showing the five phases of glucose homeostasis (figure 1) drawn directly from Cahill’s work (9). Understanding the metabolic imperatives that form the basis of fuel sparing makes it easier, for example, to understand why elevated levels of free fatty acids in the blood inhibit glucose utilization by skeletal muscle as observed in insulin resistance in humans.
Cahill lived a productive and very fulfilling life. He was married to Sarah Townsend du Pont, and they had six children and 15 grandchildren. He served in the U.S. Navy from 1945 to 1947, graduated from Yale University in 1949 and received his M.D. from Columbia University in 1953. His long relationship with Harvard University began with his internship and residency at Brigham and Women’s Hospital in 1953. He was appointed an assistant professor of medicine at Harvard University School of Medicine in 1962 and remained at Harvard until 1978, when he became director of research at the Howard Hughes Medical Institute. In 1990, he was named professor of biological sciences at Dartmouth College, a position he held until 1998.
Cahill was a very charming and charismatic man, loved and respected by his fellows and colleagues and a delight for his students. I remember being with him at meetings when he would inevitably ask the same question of a speaker who had presented what seemed a rather arcane lecture: “Your lecture was very interesting, but what message can I take back for my medical students?” It was only later in my life that I understood the importance of that question for all of us who teach metabolism. When he retired from Harvard and the Howard Hughes Medical Institute, he moved to his home in New Hampshire and was appointed to the faculty at Dartmouth College. After a year or so of lecturing, his classes were so popular with the students that the college had to move the class to a larger room.
As Carl Sandburg wrote of Abraham Lincoln, “a tree is best measured when it is down.” So it is with Cahill. He published more than 350 papers during his career in science, four of which were “Citation Classics,” with more than 500 citations each. He was sought after for his contributions to scientific societies and as a consultant to industry and governmental agencies and served on numerous editorial boards for scientific journals; the list of his service is too long to reproduce here. He won many honors over his lifetime, all related to his groundbreaking work in human metabolism, but oddly he was not elected to either the National Academy of Sciences or the Institute of Medicine. I think that this oversight was due in part to the years in which he did his research — during the transition from an emphasis on metabolism to the revolution in molecular biology and genetics. Also, his research was integrative rather than reductionist: It did not provide information on a new metabolic pathway or the structure of a gene; what it did was change the way we understand human metabolism, and in that way his contributions to science are unique.
As anyone who has worked in science can attest, generating great ideas seems simple in retrospect, but oh so difficult in practice! Few people have contributed more to medicine than George Cahill, and for that he has earned a rightful place among the greats of his discipline.
- 1. http://www.nytimes.com/2012/08/17/health/george-f-cahill-jr-diabetes-expert-dies-at-85.html
- 2. http://www.joslin.org/tribute-to-george-f-cahill-jr.html
- 3. Owen, Oliver E. Harvard Medicine. January 2009.
- 4. Cahill, G. F. Jr. et al. J. Biol Chem. 234, 2540 – 2543 (1959).
- 5. Bally, P. et al. J. Biol. Chem. 235, 333 – 336 (1960).
- 6. Owen, O. E. Bioch. Mol. Biol. Edu. 43, 246 – 251 (2005).
- 7. Owen, O. E., et al. J. Clin. Investig. 46, 1589 – 1595 (1967).
- 8. Felig, P. et al. J. Clin. Investig. 48, 584 – 594 (1969).
- 9. Ruderman, N. B. et al. “Gluconeogenesis and its disorders in man,” Gluconeogenesis: its regulation in mammalian species. 515 – 530 (1976).
Richard W. Hanson (firstname.lastname@example.org) is a professor at Case Western Reserve University and a member of the ASBMB Today editorial advisory board.