FOLKERS, KARL AUGUST

(b. Decatur, Illinois, 1 September 1906; d. New London, Connecticut, 7 December 1997),

organic chemistry, biologically active compounds, vitamin B_12,, mevalonic acid, coenzyme Q.

The career of Karl Folkers sits astride one of the great transformations that took place in American economic and scientific history. During the early decades of the twentieth century, science in the United States began to make great progress, catching up in several fields with the more advanced European centers for research and professional training. This was the case with chemistry in general and organic chemistry in particular, where Germany had long been the dominant nation in conducting advanced research and training young scientists. America’s new prowess in science followed the years at the turn of the century when the nation had become the world’s largest industrial producer. Progress in the all-important chemical, electrical, and electro-chemical industries could only continue, however, if American businesses learned how to combine modern science with corporate entrepreneurship. Karl Folkers played an important role in both of the crucial transformations of that era—one in business and one in science.

Family, Education, and Vocation . Given his humble background, Folkers was an unlikely person to become a leader, an important contributor to either science or business. In most societies through most of human history, he would have been guided to a career like that of his father, August William Folkers, an immigrant from Germany in the 1880s. August worked in a candy store and then was a grocery clerk in a tiny community near Decatur, Illinois. Karl was the only child of August and his wife, Laura Susan (née Black), and like so many other children in the Midwest, he received a five-dollar chemistry set at Christmas one year. With help from his mother, he set up in a bedroom corner a tiny laboratory from which would spring a lifetime dedication to scientific research.

His interest in chemistry grew through high school in Decatur, which was only a few miles from the adjoining towns of Champaign-Urbana and the University of Illinois. Although his family had no money to spare, it scraped together enough to pay the low state tuition and send young Karl to the university in 1924, where he worked for his meals and spending money. He had, luckily, landed in an excellent school with a first-rate Chemistry Department, led by Roger Adams and Carl (“Speed”) Marvel. Folkers concentrated on organic chemistry, and Marvel directed his senior thesis.

In the academic world of the 1920s, relationships were highly personal and relatively informal. As Karl approached graduation in 1928, Marvel simply selected him to attend graduate school at the University of Wisconsin, where he could continue his career under the direction of Homer Adkins. It was understood that if Marvel recommended him, Adkins would admit him, so Folkers applied to only one graduate program and was accepted. As Folk-ers later observed, “It was just that simple.”

At Wisconsin, Folkers spent one unproductive year researching the impact of catalysts on ethyl alcohol and acetaldehyde, but then the work that Adkins was doing on high-pressure hydrogenation caught his imagination. His work quickly accelerated, and he made his first significant discovery, the effect under high pressure of a copper-barium catalyst on the conversion of esters to alcohols. More successful hydrogenation research followed, and by the time Folkers finished his PhD in 1931, he had published eight papers with Adkins.

As Adkins prepped his outstanding student to take a postdoctoral appointment at Harvard University (where he could work with James Conant), a glitch occurred in the old boy network. Although Folkers did not know it at the time, Conant was in line to become president of Harvard and was not accepting new postdoctoral fellows. Left adrift briefly, Folkers applied to Yale, where he could work with Treat B. Johnson. Unwilling to accept any coworker without knowing a great deal about his career and personality, Johnson first wanted a full autobiography from Folkers. Satisfied that Folkers was the sort of person who could make a strong contribution to his laboratory, Johnson accepted him for postdoctoral research. Driving an old, secondhand Model-A Ford, Folkers made the trip to New Haven, Connecticut, and approached what would become a decisive turning point in his scientific and personal life.

At Yale he met the attractive Selma Johnson, who was working in the Chemistry Department office, and after a round of dating and courtship, they were married in 1932. They would have two children, Cynthia Carol and Richard Karl, neither of whom would opt for a scientific career like their father's. At Yale, Johnson introduced Folkers to medicinal chemistry and pharmacology. Johnson was working on the chemistry of nucleic acids, synthesizing substances such as uracil. Folkers decided to follow his lead and to do so in an industrial rather than an academic setting. His choice may have been influenced by the devastating economic collapse that had hit the United States in the early 1930s. During the Great Depression, university appointments were hard to come by, even for talented, productive scientists such as Folkers.

At Merck and Co . Instead, he decided to join Randolph Major, who was turning Merck and Co. in a new direction, emphasizing innovations through research and development in medicinal chemistry. Majors had a new research facility at Merck, and he was determined to hire a cadre of top-flight scientists to work there and guide the company in new directions. Excited about the laboratory and the challenge of developing new therapies, Folkers returned to Yale to get his mentor’s evaluation of the two offers he was considering. General Electric had offered him a job paying what was in those days the magnificent sum of $350 per month. Merck matched that offer, and his mentor leaned heavily toward the opportunity to do medical research. “Oh,” he said, “that’s going to be marvelous. That’s like working on a very elegant watch.” Folkers agreed.

Getting settled in Merck’s Rahway, New Jersey, Laboratory of Pure Research—a name designed to distinguish the new lab from the firm’s routine testing and analysis operations—Folkers spent some time floundering as he tried to focus on a promising subject. He had the opportunity to flounder because Randolph Major gave his scientists a great deal of latitude to carry forward their own projects. Major might suggest a worthwhile area of medicinal chemistry to explore, but the path of exploration itself was left to the individual to chart. That is what happened when he threw a bag of red seeds on Folkers’s lab bench one day. “Here, Karl,” Majors said, “See what you can do with these.” Then he walked out of the room.

Folkers pushed ahead with the little red Erythrina seeds, isolating alkaloids that he could crystallize and analyze. Along the way, he was able to do some structural analysis, his forte, and to publish a series of papers on his work. The only thing that was missing was a medical discovery that would justify the time spent on the little red seeds. So too with his work on the arrow poison, curare. But in these early years in the development of what would become one of the world’s leading pharmaceutical research organizations, practical results were subordinated to “pure” research. Merck was on the steep part of its organizational learning curve, trying to master the research and development techniques that had long before been mastered by the German pharmaceutical powerhouses.

Steadily adding new scientists and new capabilities, Merck and Majors soon found a niche to explore that would turn out to be interesting as well as productive. Research on vitamins was just getting underway. Merck was collaborating with Robert Williams of Bell Telephone Laboratories, who was working on thiamine (B₁), and Folkers and Stan Harris, a synthetic chemist hired from the Rockefeller Institute, began to study pyridoxine (B₆). Folkers, who favored structural analysis, and Harris made a good pair. Using ultraviolet spectra, a new technique at the time, they worked out a structural determination of the promising substance. Following carbon, hydrogen, and nitrogen microanalyses, they had an empirical formula, but they still could not be certain about the molecular structure. Library research combined with color reactions led to a successful elucidation of the structure of B₆, which they were then able to synthesize. Concerned about more than the chemistry, Folkers followed his products through testing and into development. He was interested in useful pharmaceuticals, not just elegant research.

The vitamin line of research and development continued to be productive of both good science and good products. Folkers, who had been promoted to assistant director of research in 1938, next became interested in pantothenic acid, which he was able to produce with a total synthesis. That was followed by work on biotin. In both cases, Merck’s policy of being attentive to scientific progress outside the Rahway laboratory paid big dividends. Randolph Major kept in touch with pharmaceutical developments abroad as well as in the United States, and he wanted his scientists to be similarly well informed. At one point, Majors sent Folkers to Europe to go to as many universities and companies as possible and to stay as long as he felt he was being productive.

Antibiotics . By the time Folkers was drifting away from bench research and toward research administration, the global therapeutic revolution was well underway. The sulfa drugs coming out of Germany in the 1930s were an enormous breakthrough, enabling physicians to treat internal infections successfully for the first time in human history. Penicillin came next, in the early 1940s, followed by streptomycin, the first effective treatment against tuberculosis.

Folkers was on the front line in Merck’s exploration of both of these important antibiotics. The penicillin research—an effort to match the molecular formula with the right structural formula—was facilitated by the specialized capabilities Folkers had been systematically building up in the laboratory. He had, for instance, acquired another one of Homer Adkins’s students, Ralph Mozingo, who had set up a hydrogenation unit. Now he could also turn to a new unit in microchemistry for structural work at the micro-level. Rudimentary to later researchers, these capabilities placed the Merck laboratory on the front edge of pharmaceutical innovation in the United States. Along the way, Folkers hired the lab’s first woman scientist, Dorothea Heyl, a major development for that time. As Folkers later explained, “That was really something to convince those people that you were going to hire a woman.”

The research on penicillin began in the 1940s while the United States was at war— which precluded publication—but the streptomycin research took place under less restrictive conditions in peacetime. Merck’s contribution to the dramatic breakthrough led by Selman Waksman and Albert Schatz was to isolate the crystalline salts of both streptomycin and streptothricin, to work out the structures of these complicated molecules, and then to mass produce the antibiotic.

These accomplishments and Merck’s contribution to the development of cortisone placed Folkers and the laboratories under his direction at the front of American pharmaceutical innovation. In less than two decades, the American firm had become a leader in the world industry as well. No longer working in the shadow of the German firms, Folkers and his colleagues—including Boyd Woodruff in microbiology and Max Tishler, who led the developmental chemistry—had successfully transformed their firm from a second-tier to a top-tier position in new drug development.

As Folkers pushed ahead in research, he took on a new problem involving pernicious anemia. Working with a liver residue provided by Henry Dakin, Folkers fractionated and lyophilized the sample. While the scientific literature of that day indicated that the anti-pernicious anemia factor was a protein, Folkers had a hunch that this was not the case. He had an active substance and used it to move ahead with a project that others had tried and abandoned. Additional work in conjunction with the University of Maryland (and Mary Shorb) suggested that the newly discovered factor might be produced through fermentation. Here Folkers could call upon the substantial resources Merck had developed in its work on penicillin and streptomycin.

Vitamins . Fractionating the fermentation residues, Folkers and his team discovered vitamin B₁₂. The discovery sent reverberations through the Merck organization that reached all the way to the president, George W. Merck, and then to the public after a press conference to announce the discovery. As it turned out, B₁₂ was far more important than anyone in the laboratory, including Folkers, had anticipated: it was the growth factor for all animals.

Elected to the National Academy of Sciences in 1948 and given broader research responsibilities at Merck, Folk-ers continued to conduct and direct research on antibiotics and vitamins. In the latter case, he reasoned (as did Randolph Major) that because vitamins were essential to life, they should be studied in the search for new therapies. Folkers was convinced that even if the search took twenty or thirty years, something important would eventually be found. Along the way, his laboratory made discoveries that were far more important to science than to the pharmaceutical industry. That was the case with mevalonic acid, a precursor in the biosynthesis of cholesterol discovered by Folkers and his colleagues in the search for vitamin B₁₃ (which would ultimately have important implications for the understanding of the “development” side of research and development), but his laboratory nevertheless helped improve processes from time to time, as it did with the production of B₁₂.

Relentless on the trail of a promising new vitamin, Folkers pursued research on coenzyme Q (Q₁₀) from his Merck days to the end of his career. Coenzyme Q came from the mitochondria isolated from the heart. “Knowing that it was functional in bio-energetics was basic,” Folkers said, “to the intellectual concept that it was probably vital to life itself.” More than four hundred scientific papers later, the clinical results that Folkers sought had still eluded him. When he retired at Merck in 1963, the company allowed him to take the coenzyme Q research with him.

Final Years . After more than twenty-eight years of active research and science administration at Merck, Folkers decided to try a new position and a better climate. He became president and CEO of the Stanford Research Institute, a position he would hold from 1963 to 1968. David Packard, who was chairman of the institute’s executive committee, and Folkers agreed that the latter could continue his own research on Q₁₀ while directing the two thousand people working at the organization. Under his tenure, the institute built a new Life Sciences Building and raised additional money in support of its activities. Some difficult discussions with board members who were multimillionaire business executives left Folkers bruised, however, and ready to accept a new position in Texas.

At the University of Texas, William Shive and the university’s president, Norman Hackerman, were eager to have Folkers move to Austin, and they created for him a new organization, the Institute for Biomedical Research, with which he was associated for the last three decades of his life. Here, as Ashbel Smith Professor of Chemistry and director of the institute, he was able to continue his research on Q₁₀ and also explore other avenues of medical science. One involved B₆ deficiency and the role that might play in carpal tunnel syndrome, a problem of increasing significance in modern society. Folkers also pushed ahead with an analysis of peptide hormones. Using samples provided by Andrew Schally of Tulane University, Folkers and his researchers were able to determine the structure of a tripeptide from the hypothalamus and then to synthesize the hormone. Schally received the Nobel Prize in Physiology or Medicine in 1977, shared with Roger Guillemin, for this breakthrough.

Folkers also collaborated for many years with Cy Bowers of the Tulane Medical School in a study of the inhibitors of the luteinizing hormone-releasing hormone (LHRH). The hard part in this work. Folkers said, was to obtain potent inhibitory activity. As the peptide structure is changed, specificity is lost. With no ready guidelines to follow, Bowers and Folkers and a number of postdoctoral fellows pursued experiments for fifteen years designed to produce an effective antagonist and perhaps eventually an anti-tumor agent. Looking always for the ideal research group, Folkers brought together in the institute chemists, biochemists, biologists, and clinicians receptive to the research problems he and his colleagues had identified.

Asked by Leon Gortler in a 1990 interview what drove him to continue his relentless efforts to solve particular problems, Folkers replied that “one believes in something and maintains the faith until the project is solved.” Faith was at the center of his life. The problem of Q₁₀ was never solved but many others were. B₆ and B₁₂ were high points, mountain peaks in a long, distinguished range of research accomplishments in structural and synthetic chemistry. Folkers received many awards for his accomplishments in science, including honorary degrees in the United States and abroad, the (U.S.) President’s National Medal of Science (1990), and the Priestley Medal of the American Chemical Society (1986). Although Folkers’s health declined after his wife died in 1992, he continued to be deeply involved in research until his death in 1997. He left behind a great tradition of collegiality in research and life, service to the health of humankind, and above all, faith in the logic and goals of modern medicinal science.

BIBLIOGRAPHY

Leon Gortler conducted a long interview with Karl Folkers; the transcript is available in the Merck Archives, Whitehouse Station, New Jersey. All of the quotations used in this essay are from this interview, and the interview file in the Merck archives contains the only complete list located of the more than 700 scientific articles that Folkers published.

WORKS BY FOLKERS

With Homer Adkins. “The Catalytic Hydrogenation of Esters to Alcohols.” Journal of the American Chemical Society 53 (1931): 1095–1097.

With Treat B. Johnson. “Hydrogenation of Cyclic Ureides under Elevated Temperatures and Pressures I. 2-keto-1,2,3,4-tetrahydropyrimidines.” Journal of the American Chemical Society 56 (1934): 1180–1185.

With Stanton A. Harris. “Synthesis of Vitamin B₆.” Journal of the American Chemical Society 61 (1939): 1245–1247.

———. Synthesis of Vitamin B₆. II.” Journal of the American Chemical Society 61 (1939): 3307–2210.

With Stanton A. Harris and Eric T. Stiller. “Structure of Vitamin B₆. II.” Journal of the American Chemical Society 61 (1939): 1242–1244.

With Eric T. Stiller, Stanton A. Harris, Jacob Finkelstein, et al. “Pantothenic Acid. VIII. The Total Synthesis of Pure Pantothenic Acid.” Journal of the American Chemical Society 62 (1940): 1785–1790.

With Stanton A. Harris, Donald E. Wolf, and Ralph Mozingo. “Synthetic Biotin.” Science 97 (1943): 447–448.

With Frederick A. Kuehl Jr., Robert L. Peck, and Alphonse Walti. “Streptomyces Antibiotics. I. Crystalline Salts of Streptomycin and Streptothricin.” Science 102 (1945): 34–35.

With Donald E. Wolf, William H. Jones, and John Valiant. “Degradation of Vitamin B₁₂ to D_g-1-amino-2-propanol.” Journal of the American Chemical Society 72 (1950): 2820.

With Edward A. Kaczka. “Vitamin B₁₂. XXII. Relation of α-ribazole Phosphate to Vitamin B₁₂.” Journal of the American Chemical Society 75 (1953): 6317–6318.

With Donald E. Wolf, Carl H. Hoffman, Nelson R. Trenner, et al. “Coenzyme Q. I. Structure Studies on the Coenzyme Q Group.” Journal of the American Chemical Society80: (1958): 4752.

With Hans Sievertsson, Jaw-Kang Chang, Alexander Von Klaudy, et al. “Hypothalamic Hormones. 35. Two Syntheses of the Luteinizing Hormone Releasing hormone of the Hypothalamus.” Journal of Medicinal Chemistry 15 (1972): 222–226.

With Robert E. Olson and Harry M. Rudney. “Biosynthesis of Ubiquinone.” Vitamins and Hormones 40 (1983): 1–43.

With Anders Ljungqvist, Dong-Mei. Feng, William Hook, et al. “Antide and Related Antagonists of Luteinizing Hormone Release with Long Action and Oral Activity.” Proceedings of the National Academy of Science, U.S.A. 85 (1988): 8236–8240.

With Rodney Simonsen. “Two Successful Double-blind Trials with Coenzyme Q₁₀ (Vitamin Q₁₀) on Muscular Dystrophies and Neurogenic Atrophies.” Biochimica et Biophysica Acta 1271 (24 May 1995): 281–286.

OTHER SOURCES

Olson, Robert E. “Karl August Folkers (1906–1997).” Journal of Nutrition 131 (2001): 2227–2230. Also available from http://jn.nutrition.org/cgi/content/full/131/9/2227.

Shive, William. “Karl August Folkers, September 1, 1906—December 9, 1997.” Biographical Memoirs of the National Academy of Sciences, 81 (2002): 101–114. Also available from http://newton.nap.edu/html/biomems/kfolkers.html. Both Shrive and Olson provide additional references to Folkers’s more than 700 scientific publications.

Louis Galambos

Jeffrey L. Sturchio