|T H E N I H C A T A L Y S T||N O V E M B E R D E C E M B E R 1999|
THE CHEMISTRY OF BERNHARD WITKOP
text and photos
"How are organic synthesis, X-ray analysis, photo-excitation, alkaloids, catecholamines, frog venoms, protein cleavage, DNA-breakdown, metabolic enzymes, receptors, ion channels, and the Black Forest near Freiburg related? The answer is through Dr. Bernhard Witkop . . . creative and insightful investigator and mentor who has greatly extended the scope of organic chemical approaches to the fascinating frontier of biological and medical sciences."
Yuichi Kanaoka*, October 1998
Socratic Sandals and Winning Ways: Witkop calls his election this year to the American Philosophical Society a "rare honor."
In a small back room at the end of a hallway on the second floor of Building 8, there sits a man with a typewriter. He is surrounded by floor-to-ceiling archives documenting his scientific journey over six decades of research and mentoring and his place in the evolution of his field. The art on the walls substitutes for windows.
A person might feel crowded in this room, but Bernhard Witkop feels at home. Scientist emeritus and NIH scholar since he stepped away from his post as chief of the NIDDK Laboratory of Chemistryhis niche here from 1957 to 1987Witkop continues chronicling the discoveries and characters of his role models, colleagues, and studentsthe chemistry, if you will, of twentieth-century science.
On the Shoulders of Giants: With meticulous reverence, Witkop has charted the names and dates that make up the long chain of his chemistry heritageand has covered the wall opposite his desk with this graphic reminder of his place in the scheme. Of the Laboratory of Chemistry, NIHs oldest lab, Witkop notes that every chieffrom his predecessors William Mansfield Clark, Claude Hudson, and Lyndon Small to himself and his successor John Dalyhas been elected to the National Academy of Sciences.
A homemade poster spans most of one wall in his office. Its a branching tree of the "Roots of Biochemistry in Chemistry," on which he occupies a line in a list of names he has connected to Heinrich Wieland (18771957). Wieland was his mentor at the University of Munich when Witkop was a student and the person he credits with having generated his interest in oxidative mechanisms, natural products, and highly active toxins. Wieland also shielded Witkop from the Nazis, an aspect of the unfolding of the field of chemistry not visible in the poster. That Wieland captured a Nobel Prize, however, is recordedhe is one of many winners of that prize with more than a passing connection to Bernhard Witkop.
Witkop has traveled in the rarefied circles of scientists whose works, like his own, define or redefine a discipline. As often as he has been the recipient of scientific honors, he has also been called upon to memorialize the lives of scientistsa task to which he is well suited by dint of his facility with language (he knows Latin, French, Italian, Japanese, German, English, and the Swiss-German Allemanic dialect), appreciation of the accomplishments and intellect of his peers, and sense of history. Only last spring, he was elected into the rather exclusive American Philosophical Society (APS), the Biological Sciences cohort of which contains perhaps 50 individuals, compared with the 3,000 on the prestigious National Academy of Sciences roster, to which he was elected in 1969. His writings regularly appear in APS Proceedings, and the December 1999 issue features his paeon to "Paul Ehrlich and His Magic BulletsRevisited."
A Wide Embrace: On the wall behind him are pieces of the cultures and honors that have become a part of Witkop over the years. The hanging to the left is a water color by Munio Kotake, a leading organic chemist in Japan, whose life and contributions Witkop has memorialized; in the center is a framed award from the American Chemical Society; and at right is a gift from a Taiwanese student, a hanging in which the yin-yang symbol is encircled by the 64 hexagrams of the I Ching, or Book of Changes, the ancient Chinese system of divination. Witkop finds it "amazing" not only that the 64 hexagrams exist at all but also that they are the same number as the 64 triplets of the genetic code. Among his many explorations these days, Witkop is comparing and correlating explanations of the hexagrams with the stop codons of the genetic code.
Witkop counts among his most worthy deeds his initiation of a program over 40 years ago that opened the doors of NIH to visiting scientists and paved the way for the ensuing thousands of visiting and Fogarty Scholars in Residencean achievement recognized October 10 at a 50th anniversary celebration of Israels Weizmann Institute of Science. The Weizmann Institute honored Witkop for having "urge(d) the authorities" at NIH in the late 1950s to launch a program that trained many of Israels outstanding scientists, including a former president of the Weizmann Institute. It was DeWitt Stetten (then scientific director of the arthritis institute) and himself, Witkop recalls, who "had to work very hard to convince the then-director of intramural research at NIH to introduce something that would go beyond the rigidity of the Civil Service System and allow us the freedom to hire foreign scientists. That was a tremendous advance," Witkop says, noting that the greatest number of visiting scientists he personally mentored came from Japan. Many of these individuals rose to the highest levels of scientific prominence in academic and industrial spheres in Japan. In 1975, the emperor conferred upon Witkop the Kun-Ni-To, or Order of the Sacred Treasure, honoring the exchange of science and scientists between Japan and NIH.
Mastering the Japanese language sufficiently to talk highly technical shop with his Japanese students and colleagues and to deliver lectures in Japan in the native tongue of his audience is another achievement of which Witkop is most proud. It was the arrival of his first Japanese postdoctoral fellow in 1957 that prompted him "at an age over 40 when, I thought, your gray matter is no longer able to handle a new difficult language" to learn Japanese. And it was 1961 when he delivered his first lecture in classical Japanese at meetings in Tokyo and other cities in Japan. The lecture was entitled "Protein Accountants and Protein Auditors" and elucidated the method by which Witkop and his collaborator Erhard Gross corrected a mistake in the sequence of ribonuclease that had just been established by a triumvirate of scientists who later received the Nobel Prize for that work. One of the three, Christian Anfinsen, Witkop recalls, "was at NIH when he did (the ribonuclease-sequencing work), and he got the Nobel Prize for it, together with Stanford Moore and William Stein."
The findings of Anfinsen and the correction of the sequence by Witkop and Gross ("Nonenzymatic Cleavage of Peptide Bonds: The Methionine Residues in Bovine Pancreatic Ribonuclease") were published simultaneously and "amicably" in the June 1962 issue of the Journal of Biological Chemistry, Witkop recounts. Witkop considers a review paper on this subject"Chemical Cleavage of Proteins" (Science 162: 318326, 1968)as his "star paper," for which he has received well over 1,000 requests.
Around the time Anfinsen received the Nobel, Witkop received the Paul Karrer Medal (named for the 1937 chemistry laureate) in 1971 for the discovery and development of the cyanogen bromide method to cleave large proteins that had enabled him to "audit" the ribonuclease sequencing and that has been applied to the genetic synthesis of hormones, allowing, for instance, the synthesis of the genes for the A and B chains of human insulin.
Marking a Life: Created in 1989, this German 200-mark bill shows Paul Ehrlich and the basic skeleton of Salvarsan (arsphenamine), the first effective antisyphilis agent, on its face (and a picture of mast cells and Ehrlichs microscope on the back). Witkop, together with Ehrlichs grandson, helped design the banknote, which, Witkop observes, will be phased out with the ascendancy of the Euro. Witkop is a member of the Paul Ehrlich Foundation and Committee and has written and lectured extensively on Ehrlichs life and scienceincluding an invited lecture at the Nobel Foundation symposium in 1981. When he left his NIDDK lab in 1987 and became an NIH scholar, Witkop inaugurated the Paul Ehrlich lecture series, which hosted some of the worlds most outstanding chemists, including, in 1993, this years Nobel laureate in chemistry and another of Witkops friends, Günter Blobel.
Bernhard Witkop was born in 1917 in Freiburg, Germany, near the foothills of the Black Forest. His father was a professor of German literature, who counted Thomas Mann, a Nobelist in literature, among his friends. He died in 1942 of natural causes, Witkop says. Witkops mother, however, who was Jewish, had to flee to Holland and his siblings to Switzerland and Venezuela. Witkop recounts his own experiences as a student during the Nazi era in a chapter devoted to "personal recollections" in the mammoth multi-volumed A History of Biochemistry (Volume 38, Chapter 3: "Stepping StonesBuilding Bridges," published in 1995 by Elsevier).
In the fall of 1935, Witkop wrote, he started his first semester at the University of Munich, where on September 30, 1938, he watched a motorcade including British Prime Minister Neville Chamberlain roll through the streets of the city that would become a "symbol of appeasement and betrayal."
In this chapter, too, are accounts of Witkops contact with chemistry Nobelist Richard Wilstätter, who was a friend of Witkops mothers family and who resigned his University of Munich post in protest over budding anti-Semitism, and of the flight of Paul Ehrlichs widow, Hedwig, the morning after Kristallnacht in November 1938.
Witkop remained at the University of Munich, working toward his degree in chemistry in the sheltered laboratory of Wieland, one of Europes outstanding chemists and a winner of the 1927 Nobel Prize for his work on the structure of bile acids. Wieland managed to ferry his ship through the rough waters of World War II.
Wieland, Witkop says of his mentor, "was one of the great pioneers in organic chemistry and a cofounder of modern biochemistry. And he was an upright man, fighting for his convictions, a true professorprofessing his repugnance of the Nazis. Under his tutelage, the quality of science, in spite of the tyranny of the Nazis, did not suffer too much."
In 1940, Witkop completed his Ph.D. thesis on Amanita phalloides, the most poisonous mushroom in Europe. It was his dream, then, to go to Harvard, a dream that had to be deferred until 1947. "You could not leave the country during the war, but I did a lot of science. I worked on alkaloids and a very important reactiona one-step synthesis of a degradation product, a metabolite of tryptophan called kynurenine," he recalls. (Tryptophan was to be a continuing research theme; see "Forty Years of Trypto-fun," Heterocycles 20:2059-2075, 1983). After securing his Harvard fellowship, he struck up what was to become a lasting collegial friendship with future Nobelist Robert Burns Woodward. After three years at Harvard, Witkop received an invitation to work at the newly established National Heart Institute from its newly installed research directorJames Shannon. He weighed his offers from industry against the NIH offer and chose the "basic research institute." Shannon recruited Witkop along with Julius Axelrod, Anfinsen, Earl Stadtman, and other luminaries.
"Shannon was marvelous," Witkop recalls. "He didnt go by mission; he went by talents. He wanted people with curiosity to look behind the secrets of nature. For instance, when we discovered cyanogen bromide degradation, we didnt know that later the approach would be extended to the chemical synthesis of human insulin at the Eli Lilly plant. How can you plan such a thing? We were looking at chemical methods to cleave large proteins; we werent looking to advance an NIH mission in insulin research."
Whats in a Name?
The insertion of politics into NIH research is something for which Witkop has little sympathy, and it is with droll solemnity that he traces the evolution of the names of institutes and buildings on the NIH campus. When Witkop arrived at the NIH campus in 1950, the institute at which he would later become chief of the Laboratory of Chemistry was still known by its original namethe Institute of Experimental Biology. But it was soon to become the National Institute of Arthritis and Metabolic Diseases. Why the name change? Witkop asksand answers: "Because no one in Congress suffered from experimental biology. " By the time Witkop left his post in 1987, the institute had gone through three additional name changes to settle upon the current NIDDK, the last in a series of permutations that left arthritis and diabetes in separate domains.
As with the names of institutes, so the names of buildings. Witkop notes that the man who hired himShannonis the only NIH scientist to have a building named after him. "And Im one of the godfathers of Building 1 who insisted that it honor the name of James Augustine Shannon," he says. All the other named buildings, he observes, are named for politicians.
Chemistry at NIH
No Electronics, No Fluorescence: "The computer is a mixed blessing. I use a typewriter, and I write my manuscripts in longhand, striking out and replacing. I lose touch with my words on a computer," Witkop says, sitting at his scholars desk at NIH.
Witkop wrote the chapter on "Organic Chemistry in a Biomedical Research Organization" in the internally written NIH retrospective, NIH: An Account of Research in Its Laboratories and Clinics (edited by DeWitt Stetten and W. T. Carrigan, Academic Press, 1984). In both this chapter and his conversation, Witkop rejoices in the strong and enduring friendships and the decades of significant scientific collaborations formed at NIH.
With Kenner Rice, Axelrod, Sidney Udenfriend, Gordon Guroff, John Daly, Paul Torrence, and many others, Witkop "shared many research problems." These, variously, revolved around 5-hydroxytryptophan metabolism and serotonin biosynthesis; synthetic opium alkaloids, including the metabolic inactivation of lysergic acid diethylamide; catecholamine methylation (cited in Axelrods Nobel award); hydroxylation-induced intramolecular migrations, or the "NIH Shift," "accidentally discovered," Witkop notes in his historic recap, in the course of developing a phenylketonuria assay; amphibian venoms, such as batrachotoxins and other congeners and their neurologic targets; and interferon mechanisms of action.
Witkop sees his own history intertwined with the history of NIH and the field of chemistry, reflected quite tangibly in the bestowal of Nobel prizes upon so many individuals with whom he "shared research problems." Asked if he wishes he had one of those prizes for himself, he smiles and replies, "No. I think the Nobel Prize can be a nuisance. I recall what Mrs. Axelrod said: What a nuisance. Now I have to get a new dress. "
Nuisance or not, he greeted the news of his friend Günter Blobels capture of the 1999 prize with glee. He and his wife had been guests of the Blobels at their family restaurant in New York in October the night before Witkop attended the Weizmann Institute celebration. Two days later, Blobel learned of his award.
Awards are one thing, organic chemistry another. To Bernhard Witkop, organic chemistry, like beauty, is its own excuse for being. In fact, it is being. While other disciplines now introduce themselves as "molecular," as in "molecular genetics," organic chemistry has no such need. "That would be a pleonasm," Witkop observes. "The closer we come to the mystery of life," he says, "the more we can explain it in one language only, and that is the language of organic chemistry."
|*Yuichi Kanaoka was one of Bernhard Witkops first students from Japan under an NIH visiting scientist program Witkop was instrumental in launching. Kanaoka went on to become president of the Japanese Pharmaceutical Society and in 1998 wrote these words in the "Preface" to the 1998 volume of Heterocycles, an international journal for reviews and communications in heterocyclic chemistry, published by the Japan Institute of Heterocyclic Chemistry. With contributions from nearly 300 scientists the world over, the volume was dedicated to Witkop on the occasion of his 80th birthday. John Daly, his "long-time colleague" and successor to his lab chiefdom, wrote the introductory chapter.|
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