IN MEMORIAM
KARL AUGUST FOLKERS
Karl August Folkers, Ashbel Smith Professor
Emeritus of Chemistry, and director, Institute for Biomedical
Research, died on December 9, 1997, at Lake Sunapee, New Hampshire.
His beloved wife of 60 years, Selma Leona Johnson, preceded
him in death in 1992. His son, Richard Karl Folkers, daughter,
Cynthia Carol Jamieson, and two grandchildren survived him.
Karl Folkers will be remembered for his many
major contributions and assistance to many other investigators
over a period of more than six decades of chemical research,
especially on the structure, synthesis, and medical use of naturally-occurring,
biologically-active compounds, such as alkaloids, antibiotics,
B-vitamins, hormones, and coenzymes. His unique roles in structural
determination and synthesis of B-vitamins, and the isolation
and chemical nature of vitamin B 12 , provided major
advances toward making B-vitamins available for nutritional
supplementation. His extensive collaboration with others resulted
also in the structure and synthesis of the first hypothalamic
hormone, evidence for the last position assignment of substituent
groups in coenzyme Q 10 , the synthesis of coenzyme
Q 9 , and the structure and synthesis of the isoprenoid
precursor, mevalonic acid. His awards and honors covered almost
all of those in his field of research. However, he valued most
highly his long-term relationships with the many collaborators
and friends with whom he worked and consulted, and especially
the knowledge that somehow, with others, he contributed to the
health and lifespan of individuals benefitting from his work.
Karl August Folkers was born in Decatur, Illinois,
on September 1, 1906. His father, August William Folkers, born
June 5, 1878, in Eckwarden, State of Oldenburg, Germany, moved
to the United States with his parents in 1882. His mother, Laura
Susan Black, was born on March 4, 1878, in Reynolds County,
Missouri. As an only child, Karl had the benefit of a mother
who, as the oldest, assisted in rearing her many brothers and
sisters. Karl read books on chemistry, worked with chemistry
sets and apparatus before taking the subject in high school,
and read about chemistry as a profession early in his life.
While working in food service and in the chemistry library at
the University of Illinois, he completed his undergraduate degree
with a senior thesis directed by Carl (Speed) Marvel, who encouraged
him to go to the University of Wisconsin for graduate work.
At Wisconsin, on fellowship appointments, Karl worked with Homer
Atkins on high-pressure hydrogenation and discovered copper-barium
chromite as a catalyst for reduction of esters to alcohols.
Upon completing his PhD, his reading on biochemistry led him
to do postdoctoral work at Yale University on the synthesis
of pyrimidines with Treat B. Johnson, who introduced him to
pharmaceutical chemistry. While at Yale, Karl met Selma Leona
Johnson (born July 5, 1910, in Philadelphia). Their marriage
on July 30, 1932, began their lifelong, caring relationship
of mutual support and admiration for each other.
Karl's decision to initiate his professional
career at Merck in 1934 was influenced not only by his interest
in pharmaceuticals but also by the new "pure research"
building and activity being created there. His very successful
work on isolation and structures of Erythrina alkaloids began
when his director, Randolph Majors, handed him a bag of Erythrina
seed to see what he could do with it, leaving the problem entirely
to him. Karl gave Majors credit for his foresight in promoting
vitamin research, and for his advice to be aware of outside
research and to visit other laboratories doing good research.
Appointed assistant director of research in
1938, Karl was assigned the group that had just isolated vitamin
B 6 (pyridoxine) and had limited the structure to
two possible isomers, analogous to the work of the Richard Kuhn
group in Germany. Karl and his group completed the final structure
and provided the first synthesis of vitamin B 6 ,
for which they were corecipients of the 1940 Mead Johnson Company
Award of the American Institute of Nutrition.
The total synthesis of pantothenic acid, discovered
and partially synthesized by Roger Williams, was achieved in
1939 when Karl's group completed the structure of the lactone
moiety with which Williams was working and needed collaboration.
Karl received the American Chemical Society Award for meritorious
work in pure chemistry in 1941.
Deeply involved in structural studies of penicillin
and aware of the status of Vincent du Vigneaud 's difficulty
in discerning between two possibilities for the structure of
biotin, Karl's group discovered that the hydrogen in Raney nickel
could be used to remove the sulfur in these compounds, which
was of great value in structural determination. This allowed
a joint publication of the structure of biotin, and Karl and
his group then provided an elegant first synthesis of biotin.
In 1943, Karl and his group confirmed, by
unequivocal synthesis, the structures of pyridoxal and pyridoxamine
initially obtained by Esmond Snell from pyridoxine (vitamin
B6). From 1945 to 1951 Karl was director of the organic
and biochemical research department at Merck and was involved
in the isolation and structure of antibiotics, particularly
the isolation and structure of streptomycin.
While visiting the University of Maryland,
Karl learned of Mary Shorb 's Lactobacillus lactis Dornier test
that responded to commercial anti-pernicious anemia extracts
from liver. He arranged for her to test a group of samples,
including a clinically-active liver extract preparation passed
through alumina, which appeared colorless in the shape of the
lyophilized water crystals. Fermentation residues from antibiotic
production were found to be potent sources of the factor, and
the observation of the pink coloration on the alumina chromatograph
rapidly led to the isolation of the red crystalline vitamin
B 12 . The work of the Merck group on the structure
was outstanding for the large molecule with its cobalt porphyrin-like
ring and side chain interacting with cobalt complexed with cyanide.
Although the final detailed structure was completed by x-ray
diffraction elsewhere, the work of Karl and his group made vitamin
B 12 available, and its identity with the animal
growth factor was quickly established. Karl and Mary Shorb were
corecipients of the 1949 Mead Johnson Award for their work on
vitamin B 12 .
Enlarged by a merger of Merck with Sharpe
and Dohme, including Lemuel Wright and Helen Skeggs, the Folkers
group discovered, isolated, and synthesized mevalonic acid as
an acetate-replacing factor for growth of certain lactobacilli.
The relationship of this factor to the biosynthesis of cholesterol
made possible direct approaches to the control of cholesterol
biosynthesis associated with heart disease.
In 1958, Karl and his Merck group confirmed
the structure of coenzyme Q 10 proposed by Fred Crane
and his colleagues at the University of Wisconsin, demonstrated
that CoQ10 from beef and human heart were identical,
and synthesized CoQ9. Coenzyme Q, which he felt should
be named vitamin Q, became one of Karl's major research interests
for the remainder of his life.
Karl, after moving through several changes
in his responsibilities from associate director of research
and development (1951), director of organic and biological research
(1953), executive director of fundamental research (1955), and
vice president for exploratory research (1962), resigned from
Merck in 1963 to accept the position of president and chief
executive officer at Stanford Research Institute. He held this
position until 1968.
During this period, the institute increased
its staff over 50 percent, doubled its revenues, and successfully
completed a land and new building program. Karl continued his
research, particularly on the biosynthesis of coenzyme Q and
its role in genetic dystrophy in mice.
In 1968, Karl accepted an appointment as professor
of chemistry and pharmacy at The University of Texas at Austin,
and as director of his newly-established Institute for Biomedical
Research. Andrew Shally and Cyril Bowers invited Karl to work
on the structure and synthesis of the hypothalamic hormone,
thyrotropin releasing hormone (TRH), which they had isolated.
Karl and his group provided the structural proof and synthesis
of this first hypothalamic hormone, TRH, in 1969.
For his role in the structure and synthesis
of the first hypothalamic hormone, Karl was corecipient with
Shally and Bowers of the 1969 Van Meter Prize of the American
Thyroid Association. Bowers and Folkers continued extensive
research on hypothalamic hormones and their analogs for over
two decades, with the leutinizing releasing hormone, LHRH, and
its analogs receiving major attention. Studies on the activities
of these analogs as antagonists and agonists of LHRH and their
toxicities provided the basis for design of several analogs
with potential medical use. The synthesis of inhibitory analogs
of substance P provided the means by which insight into the
role of this long-known peptide hormone could be effectively
studied, and extended to worldwide cooperative studies in this
general area of research on peptide hormones.
Karl's Institute for Biochemical Research
worked with Dr. John Ellis on extending his observation that
vitamin B6 alleviated the carpal tunnel syndrome
in his patients. Double-blind, cross-over placebo controlled
studies not only confirmed the effectiveness of vitamin B 6
, but also provided data that deficiencies of the coenzyme of
vitamin B 6 in erythrocyte transaminase required
twelve weeks of supplementation of vitamin B 6 to
become saturated in patients. Subsequently, a patient with deficiencies
of both vitamin B6 and riboflavin was found to respond
significantly to riboflavin and completely to both vitamins.
Karl attributed the need for riboflavin to its coenzyme role
in synthesis of the vitamin B 6 coenzyme. Such biochemical
evidence for the cause of disease was a driving force in his
research work.
Karl's search for medical uses for coenzyme
Q resulted in the observation that inadequate biosynthesis does
occur in tissues of patients with many different disorders and
can result from deficiencies of certain vitamins. With many
collaborators, it was demonstrated that benefits result from
coenzyme Q administered to patients with muscular dystrophy,
periodontal disease with deficiencies in gingival tissue, hypertension,
and cardiomyopathy with life-extending effects in advanced stages.
Potential benefits were also observed in cancer patients. His
laboratory developed the means of determining coenzyme Q in
one drop of blood, making the search for deficiencies easily
available.
Karl's Institute for Biomedical Research (IBR)
involved undergraduate and graduate students, postdoctoral fellows,
and many outstanding collaborators from throughout the world.
The Folkers' maintained close relationships with them all from
their Austin home or from their Lake Sunapee home in the summer.
After the death of his wife on August 12,
1992, Karl's health, but not his research activity, began to
decline. For the last two years of his life, he actively directed,
with the aid of his colleague Richard Willis, his Institute
for Biomedical Research from his Lake Sunapee summer home. He
remained actively involved in research through his final day.
Karl created the Folkers Foundation to support
biochemical research on causes of human disease. His lifelong
pursuit of discoveries that would identify such causes and improve
the life and health of those afflicted by various diseases would
be continued in the work pursued by the Foundation, which will
generate a fitting and permanent legacy of the life of Karl
Folkers.
Karl, with his collaborators, published more
than 700 papers in scientific journals and presented an equally
large list of invited lectures and papers at scientific meetings.
For his outstanding work, he received honorary doctoral degrees
in science from Philadelphia College of Pharmacy and Science
(1962), Uppsala University, Sweden (1969), University of Wisconsin
(1970), University of Illinois (1973), and an Honorary Degree
in Medicine and Surgery, University of Bologna, Italy ( 1989).
Other awards include: Presidential Certificate
of Merit (1948); Harrison Howe Award, Rochester Section (1949);
Scientific Award, Board of Directors, Merck and Co., Inc. (1951);
Spencer Award, Kansas City Section (1959); Perkin Medal, Society
of Chemical Industry (1960); Scroll Award, National Association
of Manufacturers (1965); Nichols Medal, New York Section (1967);
Robert A. Welch International Award and Medal (1972); Research
Award, J. D. and C. T. MacArthur Foundation (1981); American
Chemical Society-Priestly Medal (1986); President 's National
Medal of Science (1990); Karl Folkers Centennial Research Award
(first), Rutgers University (1992); Infinity Award, American
Academy of Anti-Aging Medicine (1996).
Karl helped organize, and chaired, many international
research conferences, including several for the Gordon Research
Conferences, for which he served on the board of trustees beginning
in 1971. He served on the National Defense Research Committee
(1943-46), on the Drug Development Committee of the National
Cancer Institute (1974-78), on the board of editors for several
scientific journals, in various positions in the American Chemical
Society (president in 1962), and on various advisory committees
for the National Academy of Science (elected a member in 1948)
and many American and foreign universities in scientific areas.
He was elected as an honorary member of Societa Italiana de
Scienze Pharmaceutiche (1969) and Phi Lambda Upsilon (1966),
as one of the Honorary Fellows of the American Institute of
Nutrition (1982), and as a Foreign Member, Royal Swedish Academy
of Engineering Sciences (1966).
Larry R. Faulkner, President
The University of Texas at Austin
<signed>
John R. Durbin, Secretary
The General Faculty
This memorial resolution was prepared by a special committee consisting
of Professors William Shive (chair), Bob G. Sanders, and Richard
A. Willis, and will be incorporated with additional material for
publication in Biographical Memoirs, National Academy of Sciences.
