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Department of Nutritional Sciences, University of California, Berkeley, CA 94720-3104
SELECTED PUBLICATIONS
E. L. Robert Stokstad was born on March 6, 1913, in Fancheng, China, where his parents were Lutheran missionaries. They returned to Minneapolis when he was four, and in 1921 the family moved west to begin poultry farming at Petulama in California. Bob received his B.S. in Agriculture from the University of California at Berkeley in 1934 and conducted his postgraduate work there in poultry nutrition, under the direction of the late Professor Herman J. Almquist, receiving his Ph.D. in Animal Nutrition in 1937. They studied a hemorrhagic chick disease caused by a nutritional deficiency, and the missing factor was later shown to be vitamin K.
Bob then moved back to Petaluma, with a position on the staff of the Western Condensing Company, which manufactured casein and dairy by-products used as supplements in poultry diets. His main work was on the riboflavin needs of chickens. However, he also experimented with the hemorrhage-producing diet that Almquist and he had used, and he showed in 1938 that the yeast in this diet supplied a growth factor, which he named "factor U." The nutritional importance of yeast for humans had been demonstrated in 1932 by Lucy Wills, who showed its value in preventing megaloblastic anemia of pregnancy. In 1940, Stokstad went to the California Institute of Technology for a year as a postdoctoral fellow and learnt to use microbiological assays for growth factors, a technique pioneered by Esmond E. Snell. Snell had described a growth factor, which he called "folic acid" because of its presence in green leaves. Stokstad continued studies on this factor, which, by coincidence, proved to be the same as his own chick factor U, both at Caltech and then at Lederle Laboratories (American Cyanamid Co.) in Pearl River, New York, where he went in 1941.
He finally isolated folic acid in pure crystalline form in 1943 and worked with colleagues to study its chemical character. The amounts of folic acid obtainable from yeast were very small, but other workers at Lederle discovered a microorganism that made large quantities of "fermentation folic acid" (pteroyl triglutamic acid), and this discovery enabled him to carry out degradation studies that revealed the structure of the molecule and how its various components were joined together.
Bob Stokstad has given a lively account of some episodes in this work. The only quartz spectrograph at the Pearl River facility was in the control laboratory on the second floor. He could use this during the day, but it was locked up at the end of normal working hours. One evening, when he was working late and studying a timed reaction, the only way to make the needed measurement was to climb over a seven-foot partition, carrying a precious vial. Unfortunately, in using a door handle as a foothold he broke it off and had to confess to the director of the control laboratory next day how this had happened. At a later stage, when the Cornell Medical School had a new Beckman spectrophotometer, he had to sacrifice his war-time gas ration (three gallons per week) for the journey into New York City and back to make use of it.
The eventual finding was, of course, that the folic acid molecule contained a pteridine ring, para-aminobenzoic acid (PABA) and glutamic acid. Others at Lederle and Parke-Davis were then able to synthesize the new vitamin. Elucidation of the structure of folic acid helped explain the action of the antimicrobial sulfa drugs, which are analogues of PABA and block folic acid synthesis in microorganisms. Stokstad extended microbiological assays to the use of protozoa as test organisms and collaborated in the isolation of two additional growth factors. These compounds, which were then synthesized by the Lederle group and named "thioctic acid" (lipoic acid) and "biopterin," play important roles in metabolism.
In the post-war period at Lederle, while working with Thomas Jukes, Stokstad was involved in the discovery of the growth-promoting activity of the antibiotic aureomycin (chlortetracycline) for chickens, pigs and calves. This activity was found during a search for sources of vitamin B-12. Aureomycin is produced by microorganisms of the genus Streptomyces, which Lederle was using to produce antibiotics. The use of chlortetracycline as a feed supplement has been of great economic importance for farmers in the United States and elsewhere. It was also an important source of income for the Lederle company, and more than offset their having had no direct return from their investment in folic acid research.
In 1963, Stokstad returned to Berkeley to join the faculty of the then young Department of Nutritional Sciences. He built up a strong research group that studied the metabolic functions of folic acid, which had been the subject of controversy. When given to patients with pernicious anemia, folic acid was effective in the restoration of a normal blood profile, but the neurological damage associated with the condition continued to worsen, as in untreated patients. When vitamin B-12 was given by injection, both problems were corrected. The use of folic acid supplements was therefore questioned by the Food and Drug Administration. Stokstad's group investigated the biochemical linkages between the functioning of these two vitamins and demonstrated that vitamin B-12 deficiency induces a secondary folate deficiency. Folic acid could correct the anemia regardless of which vitamin was deficient but has no effect on other symptoms of vitamin B-12 deficiency.
Stokstad's extensive work on the interrelationships of folate, vitamin B-12 and methionine metabolism forms much of the basis of current knowledge in this area. He and his co-workers were the first to isolate, purify and characterize many of the mammalian enzymes involved in folate metabolism. In a series of elegant studies, they showed that flux through the methionine resynthesis pathway, in which homocysteine is remethylated to methionine, is regulated in the liver by methionine status. The first enzyme in this pathway, methylenetetrahydrofolate reductase, is allosterically regulated by adenosylmethionine. This area has received much recent attention because elevated circulating homocysteine has been implicated as a risk factor for vascular disease. Recent studies have shown that some patients with occlusive vascular disease have a "heat labile" reductase enzyme caused by a polymorphism in its gene. Stokstad's metabolic studies, primarily conducted in rats, demonstrated that the "methyl trap" that occurs in vitamin B-12 deficiency could be ameliorated via methionine-induced inhibition of the reductase.
Bob Stokstad was also the first to fully identify and quantify the various folates in mammalian tissues and in foods. In the early 1970s, it was known that folate coenzymes were polyglutamate derivatives, but the chemical methods needed for synthesis of these compounds had only recently been developed. The Stokstad group jumped into this new area of peptide synthesis and synthesized a wide range of folate derivatives and developed a variety of separation methods to allow the identification of individual folate forms in biological samples. Even with these new techniques in hand, identification of folates in a single food was still a very laborious process, involving a multitude of techniques and literally tens of thousands of microbiological assays. This allowed Bob to indulge in one of his favorite pursuits: tinkering. He built a Rube Goldberg-type device for automatic microbiological assays. This machine, which was constantly being "improved," was famous (or infamous) in the nutrition department at Berkeley. Constantly vibrating and emitting various grinding noises, it was a joy and somewhat scary to behold, but it got the job done. During this period, Bob and his colleague Tsenonobu Tamura also performed some of the first definitive studies on food folate bioavailability in humans, using volunteer subjects living in the metabolic suite in the departmental penthouse at Berkeley.
Bob was popular with his graduate students; he took a keen interest in the development of students and young investigators and was very generous with his time and advice. He loved scientific inquiry and was a marvelous example for students. He also enjoyed teaching undergraduates. He served as Chair of the Department of Nutritional Sciences before his retirement from active status in 1980. As an emeritus professor he continued his research program in the Department until he suffered a disabling stroke in his office in 1992. His death, from pneumonia, came three years later.
His work was well recognized in his lifetime. He received many awards for his contributions to poultry science and to folic acid research, including the Borden Award (1952) from the Poultry Science Association and the Mead Johnson (1947) and Osborne and Mendel (1979) Awards from the American Institute of Nutrition. The citation for the last award ended: "An important aspect of Dr. Stokstad's work is the breadth of his scientific interests which range from specific biochemical and molecular events to broader areas of nutritional interaction and nutrient utilization in humans." In 1992 he was to have been a special guest at an international symposium in Korea organized in his honor, but sadly his stroke kept him at home. He was also unable to attend a FASEB conference later that year where his work was similarly honored. Bob served on many national committees, including the Food and Nutrition Board of the National Research Council and was president of the American Institute of Nutrition from 1976 to 1977.
Bob Stokstad was very much a family man. He and his wife Edith were married for 60 years, and each year his friends enjoyed receiving a Christmas card picturing a Stokstad family group with their sons, daughter-in-law and grandchildren, and detailing events of the year. At home, as well as in the laboratory, he was an enthusiastic and innovative hands-on constructor A large group of his friends and former colleagues came together at a memorial meeting in Alumni House, Berkeley, in October 1995, first to recall Bob's own achievements and then to hear papers about the renewed interest in folic acid. The roles of folic acid in reducing the tragic incidence of spina bifida in babies and in reducing the risk of heart attacks through its effect on the metabolism of homocysteine represent important new research areas that are making use of Stokstad's earlier basic research. Another symposium in his honor was held at the Experimental Biology 96 meeting in Washington, DC. Because of Bob's interest in students, an endowed memorial fund has been established in his name and will be used for student awards in experimental nutrition on the Berkeley campus. The American Society for Nutritional Sciences will also be giving an E.L.R. Stokstad Award annually for outstanding work in experimental nutrition.
designing and building furniture and many kinds of laboratory apparatus. He was personally gentle and modest, but persistent and never willing to accept that there could not be a better way of doing something.
FOOTNOTES
Manuscript received 13 August 1996. Initial reviews completed 22 August 1996. Revision accepted 7 October 1996.
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