The second period, the "folic acid" period, resulted from Dr. Butterworth's ("Ted" to his many friends) keen interest in this vitamin. He had completed in 1950 a fellowship in hematology, the medical specialty that more than any other was to feel the full impact of the momentous discoveries of folic acid and of its synthetic antagonists aminopterin and methotrexate. He participated in early studies on the treatment of acute leukemia with aminopterin, one of the first drugs in the history of medicine to bring about remissions of a malignant disease. He also witnessed the extraordinary benefits, described by Spies, that followed the administration of a few milligrams of folic acid to patients with anemia of pregnancy and tropical sprue. These dramatic experiences drew Dr. Butterworth to the study of folic acid, which remained the focus of his research for the rest of his life. While still in the military, he was assigned to the U.S. Army Tropical Research Medical Laboratory in San Juan, Puerto Rico, to study tropical sprue, a disease responsible for one-sixth of all casualties sustained by the Allied forces in India and Southeast Asia during World War II. There is no doubt that Dr. Butterworth's involvement in the research efforts to understand the pathogenesis of sprue had a crucial influence in his future commitment to nutrition. Sprue patients died from severe malnutrition resulting from a gamut of deficiencies and were saved by tiny amounts of the then poorly understood essential nutrient folic acid.
In 1958, Dr. Butterworth committed himself to academic medicine, resigning from the Army. Once in charge of the newly formed Division of Nutrition, Dr. Butterworth, always focused on folic acid, proceeded to recruit two biochemists with expertise on the pathway of microbial biosynthesis of this vitamin. Charles M. Baugh, Ph.D., who in later years would become dean of the Medical School of the University of South Alabama at Mobile, joined him in 1966, and Carlos L. Krumdieck, M.D., Ph.D., in 1967. Dr. Butterworth was interested in the naturally occurring forms of folic acid, the so-called folyl-polyglutamates. Precious little was known about the biological role of these peculiar derivatives of the vitamin, but Dr. Butterworth, with remarkable scientific intuition, foresaw that in this obscure area of nutritional biochemistry lay important nuggets of knowledge. He encouraged Drs. Krumdieck and Baugh to pursue the chemical synthesis of these molecules, which, once achieved, allowed the Birmingham group to conduct pioneering studies on the digestion and absorption of dietary folates. It was also discovered that the anticancer folate antagonist methotrexate was itself converted to polyglutamyl derivatives, a finding that significantly helped in understanding the pharmacology of the antifolates. Basic studies on the biochemical role of the polyglutamyl derivatives of folic acid were greatly facilitated by the recruitment a few years later of an outstanding biochemist with expertise in pteridine biosynthesis, Isao Eto, Ph.D., a graduate of UAB's Department of Microbiology. With his participation, procedures for the analysis of reduced-one-carbon-substituted forms of the folate coenzymes with various polyglutamyl chain lengths were developed. Joseph E. Baggott, Ph.D., and Tsunenobu Tamura, M.D., continue to this day to do reseach on folic acid metabolism. The former, while still a doctoral student, provided strong support for the hypothesis that changes in the length of the polyglutamyl chain served to regulate the metabolism of one-carbon fragments in nature.
The emphasis on folic acid provided years later a fertile ground for projects by Sarah L. Morgan, M.D., M.S., R.D., who developed a new line of research concerning the control of toxicity of antifolates used for the treatment of non-malignant diseases, primarily rheumatoid arthritis. Her studies led to the worldwide use of supplemental folic acid during long-term low-dose treatment of autoimmune disorders with methotrexate. More recently, Charles W. Prince, Ph.D., who joined the department in 1987, and Carlos Krumdieck have initiated studies on the role of homocysteine, an amino acid that requires folic acid for its metabolism, on the pathogenesis of presbyopia and osteoporosis.