Professor Daniel Edward Atkinson, the second biochemist appointed to what is now the Department of Chemistry & Biochemistry in 1952, was a seminal figure in 20th century biochemistry. He is known internationally for two major contributions to metabolic biochemistry – the concept of “energy charge” and the understanding of the physiological role of the urea cycle. He retired from UCLA in 1991 but kept active in the community until he and his wife Elsie relocated to Oregon in 2011. He passed away at the age of 102 on February 2, 2024.
Atkinson was born on April 8, 1921, in Pawnee City, Nebraska (the population in 1920 was 1,595). He was the eldest of four children of his father Max (a farmer, then a welder in town) and his mother Amy Neiswanger Atkinson. His undergraduate education was at the University of Nebraska at Lincoln, about 80 miles north of his home town. He received his B.Sc. degree there in agronomy and chemistry in 1942 and went immediately into the U.S. Navy as an officer and served on ships from 1943-1946. Upon his discharge, he enrolled in Ph.D. studies at Iowa State University with Professor Sidney Fox leading to his doctorate in 1949.
He was a research fellow in the Division of Biology at the California Institute of Technology from 1949-1950 and an Associate Scientist in Plant Biochemistry at Argonne National Laboratory from 1950-1952. In 1952, Atkinson joined the Department of Chemistry at UCLA (renamed the Department of Chemistry & Biochemistry in 1983) as an Assistant Professor. Francis Blacet wrote in his history of the department (“A Half Century in Chemistry at UCLA – 1932-1982”) that Atkinson inherited the mantle of Professor Max Dunn, who had been the only biochemist in the department during the previous thirty years. Atkinson was promoted to Associate Professor in 1956 and to a Full Professorship in 1962. His laboratory was active until his retirement in 1992, training over 30 Ph.D. students and over 20 postdoctoral fellows and visiting faculty.
In more than 90 publications with his students, Atkinson’s research pioneered the field of metabolic regulation. This work allowed for the development of the concept of “energy charge,” now a main topic of biochemistry textbooks and a fundamental bridgehead for researchers. He was also responsible for our present understanding of the biological role of the urea cycle in pH regulation. Students in our Chemistry and Biochemistry 153C course are still delighted to hear how his findings, initially challenged by the old guard, made their way into mainstream biochemistry.
His classic 1977 monograph published by Academic Press, “Cellular Energy Metabolism and its Regulation”, presented a global view of the logic of metabolism and is still widely read and acclaimed. In a 2005 review, John Duncan wrote, “… anyone wanting a readable introduction to the classic ideas of metabolic regulation could scarcely find a better place to start.” In a 2013 review of the book Ralph Osgood wrote, “Professor Atkinson, for those lucky enough to have encountered him or his research – was a pioneer in the field that was “Biochemistry” – not the odd hybrids dominated by structure studies we see nowadays, or watered down chemistry. And – there is a touch of delicious heresy. A great book still many years later from a great scientist.”
Atkinson’s global understanding of metabolism is prominently featured in the 2014 Biochemistry text of Garrett and Grisham where the authors comment that “Many of the ideas presented in this chapter (Chapter 27, Metabolic Integration and Organ Specialization) are derived from an insightful book by Daniel E. Atkinson of UCLA – ‘Cellular Energy Metabolism and Its Regulation)’. Atkinson’s book is also recommended at the end of the chapter, “A very readable book on the design and purpose of cellular energy metabolism. Its emphasis is the evolutionary design of metabolism within the constraints of chemical thermodynamics. The book is filled with novel insights regarding why metabolism is organized as it is and why ATP occupies a central position in biological energy transformations.”
Atkinson’s studies on enzymes of the central metabolic pathway led to our understanding of the control of anabolic and catabolic reactions by the ratios of cellular ATP, ADP, and AMP. ATP is the near universal chemical energy source that drives metabolism, transport, and movement. Atkinson developed the concept of “energy charge” where the fraction of the total adenylate pool as ATP equivalents (ATP plus ½ the amount of ADP/sum of ATP, ADP, and AMP) represents the energy storage balance of the cell – values near 0.9 indicate a high energy balance and values below 0.5 indicate that cells are lacking energy resources. Atkinson discovered that key regulatory enzymes possessed allosteric binding sites for AMP, ADP, and ATP that enabled them to respond appropriately to cellular energy charge. This concept was introduced in a classic 1963 paper in the Journal of Biological Chemistry co-authored with his student James Hathaway “The Effect of Adenylic Acid on Yeast Nicotinamide Adenine Dinucleotide Isocitrate Dehydrogenase, A Possible Metabolic Control Mechanism.” By 1965, evidence supporting the hypothesis led to a publication in Science “Biological Feedback Control at the Molecular Level”.
Dr. Graham Hardie, Professor of the Division of Molecular Physiology at Dundee University, discoverer of the AMP-activated protein kinase credits Atkinson’s energy charge hypothesis as a fundamental concept of the field. In a BioEssays review article he writes, “The AMP-activated protein kinase cascade is a sensor of cellular energy charge, and its existence provides strong support for the energy charge hypothesis first proposed by Daniel Atkinson in the 1960’s. The system is activated in an ultrasensitive manner by cellular stresses that deplete ATP (and consequently elevate AMP), either by inhibiting ATP production (e.g., hypoxia), or by accelerating ATP consumption (e.g., exercise in muscle).”
Atkinson’s analogy of cellular energy charge with the charge on a battery came from his deep understanding of electricity and mechanics. His students also remember his analogy comparing an allosteric enzyme with the automatic transmission of a car that determines its output of the proper gear, corresponding to the enzymatic activity of a regulated protein. These outputs are both based on multiple inputs, with the input of speed, torque, and accelerator position in a car corresponding to the binding of modulating small molecules to the enzyme and its covalent posttranslational modifications. One of these students commented that Atkinson’s biochemical analogies made them understand for the first time how a battery or a transmission actually works!
By 1982, Atkinson embarked on a second major field of study – urea biosynthesis. Before Atkinson put his mind to the issue, the prevailing view was that the function of the urea cycle was to prevent the accumulation of ammonium ion. However, it was clear that there is little toxicity of ammonium ion to animals and Atkinson then looked at the process from the standpoint of balanced reactions. What became clear to him was that the catabolism of proteins to carbon dioxide, water, and ammonium ion was accompanied by the release of base in the form of bicarbonate anion. A careful balancing of the reaction in fact showed that the metabolism of neutral amino acids led to the production of equal amounts of ammonium ion and bicarbonate ion. (Acidic amino acids resulted in more bicarbonate; basic amino acids in more ammonium ion – but with the typical amino acid composition of proteins the end result is nearly an equal amount of bicarbonate and ammonium ion formed). While there was little to suggest significant toxicity from ammonium ion, the production of bicarbonate would be expected to raise the pH of the organism. In humans, blood pH is regulated to pH 7.40 +- 0.05; pH values about 7.45 are associated with pathology and eventual death! This understanding led Atkinson to realize that the urea production derives from the utilization of exactly equal amounts of ammonium ion and bicarbonate, producing a molecule that is readily excreted in the urine and that thus totally removes both of the products of protein catabolism. His 1982 review with Merrill Camien in Current Topics in Cellular Regulation “The Role of Urea Synthesis in the Removal of Metabolic Bicarbonate and the Regulation of Blood pH” expertly put forth the hypothesis which was expanded upon in 1986 and 1987 publications in the American Journal of Physiology. In fact, current treatments of urea cycle disorders employ dietary supplementation with phenylbutyrate and benzoate, that combine with the amino acids glutamine and glycine, respectively, which are then excreted in urine. Although this therapy is explained as treating the hyperammonemia that results from urea cycle disorders, it is noteworthy that the excreted products effectively dispose of both ammonia and bicarbonate!
A wonderful confirmation of Atkinson’s urea hypothesis came from a study of freshwater tilapia fish that live in lakes at pH 7.1 or related species that live in alkaline soda lakes where the pH is 9.6 – 10. While the species of fish in lakes at neutral pH lack enzymes of the urea cycle (like almost all fish that excrete ammonium ion and bicarbonate directly into the environment), the species of fish in the alkaline environment had a full complement of enzymes to make urea and keep their internal pH close to neutral. Other fish are able to turn on the synthesis of urea in response to alkaline environments.
In 2016, the UCLA Department of Chemistry & Biochemistry established the Daniel E. Atkinson & Charles A. West Prizes in Metabolic Biochemistry to be presented to undergraduate and graduate students to recognize their excellence in this area and to provide summer research fellowships for undergraduates and graduate students to conduct research in Chemistry and Biochemistry faculty labs. Professor Charles West arrived at UCLA shortly after Atkinson and were both crucial to building the biochemistry division to its 18 faculty members by the time they both retired in the early 1990s. Atkinson and West played major roles in recruiting most of these faculty. Both of them were exceptionally valued by their faculty colleagues, the students in their laboratories, by the national and international research communities, and by the multitude of undergraduates they taught. These awards and fellowships honor the significant contributions of both men to research, education, and the strength of the UCLA academic community. More than 116 of Atkinson’s and West’s students, colleagues, friends and family contributed to endow the fund that was matched by funds from the Department of Chemistry and Biochemistry originating from the patent income of Professor Michael Jung.
Atkinson was a Fellow of the John Simon Guggenheim Memorial Foundation in 1966-67 at the Department of Biology at the Massachusetts Institute of Technology and a Visiting Professor of Zoology at the University of British Columbia in 1975. In 1975, he was awarded an honorary D.Sc. degree from the University of Nebraska. He was a member of the American Society for Biochemistry and Molecular Biology (serving as a Council Member from 1979-1982), the American Chemical Society (where he served as chair-elect and then chair of the Division of Biological Chemistry from 1976-1978), the American Society of Microbiology, and the American Physiological Society. He served the Journal of Biological Chemistry as a member of the Editorial Board from 1966-1971 and as an Associate Editor from 1972-1977. Atkinson was one of six members of the campus committee appointed by Vice Chancellor Foster Sherwood in 1961 that recommended the establishment of the UCLA Molecular Biology Institute that led to Professor Paul Boyer accepting the directorship of the new institute in 1965.
Dan’s 1948 marriage to Elsie Ann Hemmingson (1922-2018) spanned seventy years and produced five children, Kristine Ruth, Owen Rolf, Joyce Elain, Ellen Lee, and David Eric. Atkinson is survived by 14 grandchildren, 11 great-grandchildren, and one great great grandchild!
Contributions to honor Atkinson can be made to the UCLA Atkinson-West fund that provides awards and opportunities for summer undergraduate research fellowships.
Written by Professors Catherine Clarke and Steven Clarke.