On October 1, 1929, Richard Kuhn became first of the four KWImF research directors to move into the new laboratory on the banks of the Neckar River. At twenty-eight years of age, he was also by far the youngest. In addition to a growing reputation as an experimentalist in organic chemistry, he brought with him an encyclopedic knowledge of physical and analytical chemistry. Moreover, he had already begun to apply his research to studies of biological function, with an emphasis on enzymatic reactions.
Photo: Courtesy of Irmgard Weiland
Kuhn and his assistants immediately began a stretch of incredible productivity, publishing more than 250 scientific papers during the 1930s. The period was highlighted by structural and functional studies of molecules with characteristic double carbon bonds, called polyenes. These molecules form the basis of many natural pigments in plants and animals. Isolation, synthesis and structural work on polyenes, especially of the carotenoid family, dominated the early years of the Chemistry Institute. In the process, Kuhn and his assistants developed many new techniques, such as modern chromatography. The chemical analysis of polyenes led Kuhn to his path breaking biochemical studies of vitamins in the 1930s. His first major breakthrough came with carotene, a pigment which is found in carrots and other plant and closely associated with vitamin A. In 1933, he began a collaboration with the physician Paul György on the B family of vitamins. They were the first to isolate and purify vitamin B2 (riboflavin) and soon demonstrated how this compound works as a growth factor in biological processes. Kuhn's work with polyenes, flavins, vitamins, as well as cumulenes brought him broad recognition and opened the door to a surge of similar biochemical research throughout the world.
Despite his relatively young age, Kuhn soon became a powerful and respected scientific leader - both within his own institute and on the national scene. At the age of 37, he was chosen as head of the German Chemical Society and was highly sought after by leaders in the chemical and pharmaceutical industries for his expertise. He was greatly admired by his own assistants and, when Ludolf von Krehl died in 1937, it was Kuhn who took over as the overall director of the KWImF.
Richard Kuhn was born in Vienna on December 3, 1900. His father was a highly regarded hydraulics engineer, his mother a teacher, who educated her son at home. Kuhn flourished intellectually in this environment, entering the gymnasium at the age of nine. His subsequent years at school were blessed both with inspiring teachers and gifted fellow students. Among them was another precocious classmate - the congenial and eccentric Wolfgang Pauli. Pauli became a lifelong friend who would win the Nobel Prize for his contributions to quantum physics during the 1920s. The Kuhn family was also closely connected to the university community of Vienna. Ernst Ludwig, a family friend and Chairman of the Department of Medicinal Chemistry at the University, frequently invited the Kuhns' bright son to help prepare experiments for his courses, thus seeding the young man's future fascination for biochemistry.
At the end of the First World War, while still in school, Kuhn was drafted into the Austrian Army Signal Corps. Although he was soon released from duty and avoided significant action, the military experience had been emotionally difficult. Relieved at his release, Kuhn enrolled immediately at the University of Vienna. With the help of his family's connections, he managed to secure a laboratory position in Ludwig's former department, now directed by Hans Fischer. Rapidly mastering his lessons at the University of Vienna, however, Kuhn soon outgrew its intellectual boundaries.
Aware of the international reputation of the chemist Richard Willstätter, Kuhn transferred to the University of Munich in hopes of studying under the famous chemist. Willstätter was the direct intellectual descendent of two of the most famous figures in the history of German science, Justus von Liebig and Adolf von Baeyer. Winner of the 1915 Nobel Prize for his determination of the structure of chlorophyll and one of the original directors of the Kaiser Wilhelm Institutes in Berlin-Dahlem, Willstätter had returned to Munich in 1916 to replace von Baeyer as chair of the Department of Chemistry. At the time, this was the most prestigious post in all of German chemistry. In Munich, Willstätter turned attention from his classic work on alkaloids and plant pigments to explore enzyme chemistry - a time of major breakthroughs in a field that would be critical to the development of modern biochemistry.
It took little time for Kuhn to attract Willstätter's attention and great favor. Kuhn swiftly finished his undergraduate studies and Willstätter accepted him as a Ph.D. student in 1921. Kuhn earned his degree, summa cum laude, a year later with a thesis on "The Specificity of Enzymes in Carbohydrate Metabolism." Kuhn's originality and experimental skill so impressed his professor that Willstätter asked him to stay on in Munich. At 21 years of age, Kuhn began to demonstrate an uncanny knack for teaching, directing other students and introducing new concepts and techniques to the laboratory. Despite constant material shortages due to the economic crisis following WWI, Kuhn was remarkably productive, publishing frequently and leaping the important German academic hurdle of habilitation in only two years.
In the midst of Kuhn's rapid rise, the
Department of Chemistry at the University of Munich was suddenly
thrown into controversy. A number of academic nominations that
Willstätter had put forward had been denied. Those nominees,
as well as Willstätter, were all Jews. Willstätter saw
this as no coincidence and took the refusal of the appointments
as a personal challenge. In 1924, Willstätter resigned his
chair in an emotional protest and, despite pleas from many
colleagues, stubbornly refused to reconsider.
Richard Willstätter was one of the most important figures in Kuhn's life. Kuhn maintained a warm personal and professional correspondence with the senior scientist on a monthly basis until the end of the 30s. The admiration was clearly mutual and Willstätter claimed Kuhn as his favorite student. As we will see, this close relationship would come into play at several critical junctures in Kuhn's life.
(seated) with Richard Willstätter.
Photo: Courtesy of Max-Planck-Institut für Medizinische Forschung
With his mentor's blessing and considerable help, Kuhn began to look elsewhere for an independent position. In 1926, following Willstätter's recommendation, Kuhn was offered the Chair of the Department of General and Analytical Chemistry at the Federal Institute of Technology in Zurich (the position had initially been offered to Willstätter). The full professorship in Zurich was quite a feather in the cap for a 25-year-old scientist. Once fully independent, Kuhn began to build a reputation for his own theoretical ideas and experimental creativity. He also met his future wife Daisy there, a Swiss student in one of his classes. Kuhn continued to work on enzyme chemistry in Zurich, publishing a textbook in 1927 on Chemistry, Physicochemistry and the Biology of Enzymes. Increasingly, however, his work began to reflect a deeply held interest in stereochemistry of plant pigments, especially polyenes.
When Krehl and Harnack began searching for candidates for the KWImF Chemistry Institute, Kuhn's name had been at the top of the list of several important advisors, including Otto Warburg. Although Warburg had declined Krehl's invitation to direct the Physiology Institute, he cared deeply about the development of the new KWImF and played an active role in recruiting scientists for Krehl.
In his own work, Warburg had established important connections between the color chemistry and enzymatic activity. For this reason, he had closely followed Kuhn's structural investigations of enzymes and pigments. In fact, Warburg had taken it upon himself to contact Kuhn and encourage the young scientists to consider broadening his approach to include investigation of the relationship of the chemical structure of these molecules to their biological functions in living cells.
During the period in which Warburg was still weighing his own options in regard to the KWImF physiology position, he suggested to Krehl that Kuhn would make an excellent director of chemistry research. In fact, it was Warburg, authorized by Krehl, who sent the initial letter asking Kuhn to join the progressive new institute.
If chemistry was a critical piece in the
puzzle of Krehl's grand scheme, Richard Kuhn seemed to be cut out
perfectly for the KWImF. Although Warburg would remain in Berlin,
Otto Meyerhof, who accepted directorship of the Physiology
Institute - was equally excited about having Kuhn as a
potential collaborator in Heidelberg, especially since Kuhn
had experience with carbohydrate chemistry and the involvement of
lactic acid in muscle - central themes in Meyerhof's own
research. Furthermore, Karl Hausser, the nominee to head the
Physics Institute, was interested in investigating the physics of
light and its interactions with pigments in both vegetable
material and in humans.
The real questions about Kuhn were whether he was mature enough for such a leading role and, secondly, whether he would be available. Willstätter and Warburg assured Krehl that Kuhn had already demonstrated enough administrative skills in Munich and Zurich to complement his obvious scientific genius. Unfortunately, the matter of his availability was more problematic, for he was being heavily recruited by several other institutions in Germany and Austria.
Kuhn weighed his options carefully. Privately, the benefits of joining Krehl were rather clear cut, as Willstätter, Heinrich Wieland and Warburg each impressed upon him. The KWImF post offered Kuhn the opportunity to control his own destiny, just as his career was beginning to take off. He knew that the KWG was extremely well funded and he was guaranteed a custom-made laboratory - important considerations given the fragility of the German economy. Moreover, the society had an established reputation for minimizing bureaucracy and there would be minimal teaching obligations. Still, Kuhn stalled for time, shrewdly using the various offers in his negotiations with the KWG. In fact, despite his young age, he was able to negotiate a budget forty percent higher than those awarded to his senior colleagues, Meyerhof and Hausser.
Kuhn brought several assistants with him from Zurich, the most important being Theodor Wagner-Jauregg and Alfred Winterstein. Both would play leading roles in Heidelberg during the 1930s. A number of other impressive students and assistants joined Kuhn over the course of the first two years to help build the foundation of his Chemistry Institute. These included Alexander Wassermann, Hans Brockmann, Edgar Lederer, Marcel Florkin, Max Hoffer, H. Roth, Christoph Grundmann, E.F. Möller, and Adam Deutsch. They were followed in the mid and late thirties by Hermann Rudy, Friedrich Weygand, Gehard Wendt, Francisco Giral, Pierre Desnuelle, Otto Westphal and Theodor Wieland (the son of Heinrich Wieland).
Kuhn was fascinated by the unusual structural symmetry of the carbon bonds that form the molecular backbone of polyene pigments. These conjugated bonds are characterized by a chain of carbon molecules with alternating single and double bonds. The discovery in the late twenties that crocetin, which falls within the sub-group of polyenes called carotenoids, contains such bonds had piqued Kuhn's interest in this family of polyenes. At the time, however, very little was known about the chemical nature of such pigments.
The carotenoids were to provide a vehicle for some of the most important successes of Kuhn's career. He and his colleagues isolated and purified a large number of them, including carotene, lycopene, flavoxanthin and violaxanthin. They also synthesized a large number of artificial carotenoids, which they later exploited in their functional research. This structural work required a number of creative new techniques that were developed at the KWImF, including purification methods and spectral analysis for quantitative determination of the finer differences in the chemical composition of the various carotenoids.
Kuhn and his colleagues clarified a large number of the general relationships between the chemical structure of these substances and their optical, dialectric and magnetic properties. For example, while investigating how the chemical structure of the carotenoid pigments affects the determination of color, Kuhn showed how the backbone sequence of single and double-bound carbon atoms give the polyenes their light absorbing properties and how slight variations create important differences in frequencies of light that could be absorbed - i.e. the variant colors we observe.
Kuhn also knew from the example of chlorophyll that such pigments do not simply provide color to organisms. He was soon drawn deeply into studies of how the small variations in carotenoid structures are involved in biological functions. Discovering those functions and determining how the chemical bonds affect the biological working mechanisms was the territory of only a few elite chemists and biologists. Kuhn was among them.
Richard Kuhn - A Born Teacher and Shrewd Administrator
Kuhn was regarded as a born teacher, and an entertaining and clear speaker, exploiting his resonant voice and a keen sense of drama in the lecture hall and seminars. In fact, before settling on science, Kuhn had seriously considered pursuing a career in acting. With an almost legendary command of scientific literature, he guided many gifted assistants, providing insightful suggestions during discussions, which others rarely considered. Although he was closely involved with his assistants' laboratory work and himself a tireless worker, he granted many of them unusual leeway in designing their own projects and determining working hours.
Richard Kuhn's intelligence and professional ambition propelled him rapidly through the professional ranks during the early years of his career. He accepted this role as a scientific leader with great pride. Despite his dramatic teaching style, Kuhn was very diplomatic and cautious as an administrator. He carefully avoided direct confrontation, preferring subtle criticism and a behind-the-scenes approach to his administration - both at KWImF in Heidelberg and in regard to external scientific politics. This style would lead to controversy later in his career, but in his early years he wielded it with great effect.
Privately, Kuhn was extremely shy and rarely revealed aspects of his personal life to others. Despite this, he was considered warm and unassuming by his assistants. He had a reputation in the laboratory for an almost childlike appreciation of the beauty of molecular crystals and colors of the pigments he investigated. He also took great pleasure in playing chess or volleyball with his assistants. Moreover, he was extremely protective of those under his charge. In return, he earned their deep and lasting loyalty.
Scientists had known of the existence of the pigment carotene for more than a century, but it wasn't until 1928 that the well-known Swedish chemist von Euler detected its association with vitamin A activity. Indications showed that vitamin A played a role in growth in higher animals (indeed, it is critical, especially for the maintenance of mucous membranes and for night vision). Kuhn was curious as to whether such activity was caused directly by carotene itself or whether it might be an intermediary product of vitamin A metabolism.
Just after Kuhn's arrival in Heidelberg, Paul Karrer, one of Kuhn's major competitors in the field, had put forward a proposal for the composition of carotene. One of Kuhn's new assistants, Edgar Lederer, had just obtained results that contradicted Karrer's structure. Kuhn suggested two possibilities: either Karrer's structure was wrong or, more likely, Lederer's compound was a mixture of substances. Indeed, Lederer's preliminary results indicated that to be the case. This was not definitive proof, however, because purification of carotene was incomplete. In fact, Karrer's own calculations were based on a forty percent purification of the carotenoid. Conclusive proof required the development of much more effective purification techniques. Kuhn suggested that Lederer adapt an old technique that had been abandoned by chemists, called chromatography. Lederer refined the methods, varying absorption materials with markedly improved results. Not only was he able to purify highly concentrated carotene, but in early 1931 he succeeded in separating two similar but distinct forms (isomers). Kuhn and Lederer called these isomers beta- and alpha-carotene. Two years later, Lederer discovered a third form of carotene, which he and Kuhn called gamma-carotene.
|Photos: Courtesy of Max-Planck-Institut für Medizinische Forschung|
Kuhn, Lederer and Winterstein turned to detailing the compositional differences between the different isomers. They soon confirmed that the basic chemical composition of carotene proposed by Kerrer was for beta-carotene only. Brockman and later Grundmann joined with them to examine carotenes from other plants for comparative studies and found that most of these plants contained primarily beta-carotene, while some, like carrots, had high levels alpha carotene in ratio to the beta- and gamma-carotenes. Physics director Karl Hausser was an important collaborator in these studies. His advanced spectroscopy techniques using single wavelengths of light allowed them to determine the light absorption spectra of the different molecules of carotene. This made it much easier to determine chemical composition of the molecules and provided proof of significant difference in their optical properties (beta-carotene, for example, significantly rotates the plane of polarized light, while alpha- and gamma-carotene are optically inactive).
One of Kuhn's original goals was to determine if and how carotene was connected to vitamin A activity. By feeding rats different carotenes, Brockman and Kuhn showed that alpha-, beta- and gamma-carotene were all broken down and converted into vitamin A in the liver. They therefore proposed that carotene is a provitamin, an immediate precursor to a vitamin in living tissue. They then demonstrated that the different isomers of carotene have a qualitatively identical effect on the growth of the rats, their sexual cycle and a number of diseases. They found, however, that beta carotene, produces twice as much vitamin A per molecule used in the conversion process. They also contributed extensively to the unraveling of the chemical mechanism which drives the vitamin A activity, although this was fully clarified much later.
Carotene was only the most highly visible of Kuhn's polyene studies. He and his colleagues examined many others in plants and animals during the 1930s, discovering eight new types and analyzing their chemical composition. These included physalien, helenien, flavoxanthin, violaxanthin, unstable crocetin from saffron, taraxanthin, and cryptoxanthin. They also made important contributions to work on rodxanthin and astaxanthin, for which they discovered a close connection to chromoproteins of crustaceans.
Kuhn was particularly fascinated with pigments containing forty carbon atoms in their structural backbone, especially xanthophylls, because their carbon skeleton is related to one of the structural constituents of chlorophyll. At the time, the question was still open as to whether carotenoids might originally arise from chlorophyll. In a similar vein, they examined a number of natural carotenoids with fewer carbons, such as crocetin and bixin, and demonstrated that these molecules are breakdown products from plants with larger forty carbon carotenoids.
Kuhn's investigations of polyenes were exhaustive, including synthesis of over 300 new materials and the study of the natural formation of carotenoid carboxylic acids and related compounds. Interestingly enough, although close collaborations never materialized with fellow KWImF director Meyerhof in the field of carbohydrates metabolism, two other scientists in Meyerhof's group worked on the physiological effects of vitamin A. George Wald and André Lwoff would both eventually earn Nobel Prizes later in their careers. Lwoff became close friends with Edgar Lederer and was the original inspiration for Lederer's and Kuhn's studies of polyenes in invertebrates. He also helped Lederer following the latter's flight to France after the rise of the Nazis.
Milestones in the Development of Chromatography
After 1931, absorption chromatography
became one of the most common and indispensable tools used
in chemistry and biochemistry. Essentially, chromatography
is a filtering process that allows distinct compounds or
molecules to be separated by molecular size and weight. It
is used to purify chemical and biological samples to an
extremely high degree - an essential first step toward
accurate structural and functional analysis. Several of the
most important turning points in the technique's
development took place at Kuhn's institute in
In 1933, Kuhn began a new series of investigations on vitamins in the B family, during which his research group was the first to isolate and purify riboflavin, the essential vitamin B2. Riboflavin is important for the metabolism of proteins, lipids, carbohydrates and alcohol.
Vitamin B2 had been discovered in 1926 by Goldberg and some of the effects of B2 deficiencies were known, including a relation to the disease pellagra in man (a severe problem in Spain at the time) and skin diseases in animals. Possible connections between pigments called flavins and B vitamins had been proposed in the late 1920s, but when Kuhn started his research it was not known if flavins were a vitamin precursor, like carotene, or itself biologically active. The chemical composition and the mechanisms that enabled such activity were, of course, also a mystery.
At the University of Heidelberg, the pediatrician Paul György had been independently working with vitamin B2. Familiar with Kuhn's recent work on vitamin A and knowing his reputation as a chemist, György asked Kuhn to perform purification and chemical analysis for his investigations. Thus began a collaboration between these two scientists, which would stretch over three decades.
György initially asked Kuhn to isolate vitamin B2 from the livers of rats upon which he had been experimenting, but they quickly expanded their efforts, purifying flavin pigments from plants and animal materials. Extraction with traditional solvents proved ineffective and Lederer began to develop new chromatographic techniques to purify the materials. Even with special adaptations to the new methods, however, purification was a monumental undertaking. Although flavins are widespread pigments in nature, they are only present in extremely small concentrations. In fact, purification of one gram of the "beautiful yellow substance", as Kuhn called it, required over 5,000 liters of milk or the dried albumin from 34,000 eggs.
As a Jew with leftist political views, Lederer was forced to flee to France in March of 1933. Fortunately, the Gestapo was four days too late when they came to arrest him at the KWImF. At this juncture, Theodor Wagner-Jauregg took over as the key figure in the collaboration with György. He isolated flavins in yeast, heart muscle, and variety of other plant materials. KWImF Physics director Karl Hausser once again worked closely with the Kuhn group on the spectral analysis of the purified substances. And Weygand, Rudy and later Ströbele and Desneulle made significant contributions as Kuhn expanded the scope of the investigation to include clarification of the chemistry and functions of these molecules.
"The beautiful yellow pigments" turned out to be riboflavin, although Kuhn called it both lactoflavin and ovoflavin because they had first abstracted it from milk and egg whites. The chemical composition of both ovoflavin and lactoflavin proved to be virtually identical. Like polyenes, the flavins were characterized by a series of conjugate double bonds, but this time with an attachment of nitrogen.
From the beginning, Kuhn assumed a fixed relationship between vitamin B2 and the flavins his assistants had isolated, especially after correlating the sensitivity of B2 to specific wavelengths of light and the absorption patterns of the flavin pigments. Determining if the flavins were precursors or the vitamin itself was initially elusive due to difficulties crystallizing the lactoflavin, which hindered the structural analysis. Fortunately, they soon discovered a breakdown product of lactoflavin, called lumiflavin, which they were able to crystallize. And after determining the structure of lumiflavin, they were able to extrapolate enough information to synthesize lactoflavin and thereby determine its composition. Finally they had proof that lactoflavin was vitamin B2, not a precursor. Indeed, in experimental tests with rats, Kuhn's crystallized flavins proved to be the most active preparation of vitamin B2 yet discovered.
As with the vitamin A studies, the question remained as to how Vitamin B2 stimulates growth and other bioactivity. The key to finding this answer was once again the breakdown product lumiflavin. In 1932, Otto Warburg had discovered an important oxidation enzyme - his famous "yellow ferment." Warburg had shown that this yellow pigment is involved in catalysis of the oxidation of hexose-monophosphoric acid during yeast metabolism. Kuhn, who had remained in close contact with Warburg since coming to Heidelberg, quickly realized that his lumiflavin was probably the same substance as Warburg's oxidation enzyme and proposed that vitamin B2 is its precursor. Follow up tests showed that rats given lumiflavin and Warburg's enzyme produced similar increased growth rates.
organized a 1932 KWImF meeting on Problems and Fundamental
Processes of Biological Oxidation. Among those in attendance
were Richard Willstätter, Carl Neuberg, James Franck,
Fritz Haber, Otto Warburg, Hans Krebs, Hans Fischer.
Photo: Courtesy of Max-Planck-Institut für Medizinische Forschung
The research of Kuhn and Rudy from 1934 to 1936 helped to show that lumiflavin plays an enzymatic role for hydrogenation of lactic acid, pyruvic acid and succinic acid (major contributions were also made by Warburg and Christiansen). These are all important reactions involved in cell respiration. In addition, by combining a flavine mononucleotide with a protein moiety of Warburg's yellow enzyme, Kuhn and Rudy produced the very first partial synthesis of a fully functional enzyme. This was the first suggestion of a reversible relationship between vitamins and enzymes.
Other work continued in this vein. Wagner-Jauregg, for example, found biotin is identical to B2 and binds readily to a toxin in egg whites (B2 is one of the few vitamins with which overdoses result in harmful effects). This binding affinity was later exploited widely in experimental biochemistry. The now familiar name of Amadori rearrangement was also proposed by Kuhn and Weygand during this time.
Work on vitamin B2 evolved naturally into investigations of the larger vitamin B complex. Kuhn and his assistants first isolated vitamin B6 in yeast in early 1939. Within a few months, they established its chemical composition and structure, then synthesized the vitamin. Weygand and newcomers to the laboratory, Wendt and Westphal were deeply involved in this work. Kuhn called it adermin (pyridoxine) and this immediately became a new focal point of his research strategy. B6 turned out to be an extremely important co-enzyme involved in the metabolism of carbohydrates, fats, and proteins.
During the 1930s, Kuhn's research on vitamins as growth factors and enzymatic reactions in metabolism brought him work as an advisor and collaborator at I.G. Farben, the large German chemical company. It was in this role that he first came into contact with Gerhard Domagk. In 1934, Domagk had discovered the first effective agent against streptococcal and staphylococcal bacteria. The subsequent development of sulfa drugs was a milestone in biomedical sciences and a great deal of research followed as scientists throughout the world searched for more effective chemotherapies for bacterial infections. By the late 1930s, Kuhn's focus on vitamins also began to shift his research emphasis to how these and other compounds could be exploited for use as antibacterial agents.
Kuhn and his assistants found that B6 was extremely useful as an anti-dermatitis prophylactic and that it affected growth rates and hair loss in rats. As more evidence came to light, they realized that B6 was involved as a growth factor in many different kinds of cells and organisms. Work by others indicated that it was also essential for the growth of microorganisms. Kuhn surmised that the sulfa drugs must be competitors for the same biological receptors used by natural growth factors. He concluded that when the competing drugs bind with those receptors they inhibit the growth of bacteria.
From this point on, Kuhn moved enthusiastically in the direction of developing new bacterial chemotherapies. He knew that one of the problems with early sulfa drugs was that they required massive doses to be effective against bacteria, often with strong side-effects. He was convinced that a normal cell's chemical affinity for the natural growth factor was far higher than that of the sulfa drugs. His new strategy, therefore, was to unravel the natural mechanisms of the bacterial growth factors in hopes of synthesizing slightly different structures that would compete with them and disable the bacteria. Bactericides were an obvious goal, but Kuhn felt other similar compounds might be developed as prophylactics to inhibit initial growth of bacteria, thus avoiding unwanted side-effects associated with emergency therapy.
At the end of the decade, as the dark political storm was gathering outside of the KWImF, science became a kind of refuge for Kuhn. During these last months before the start of the Second World War, he and his students immersed themselves in a flood of successful experimental results, reaping international praise for the institute for the work on vitamins at the KWImF. It was during this time that Kuhn learned that he had been awarded the Nobel Prize in Chemistry (for more details on the award, see Chapter VI. Personal and National Tragedy Undermine Krehl's Dream).
Kuhn continued to investigate the chemical structures and biochemical functions of growth factors, inhibitors and antibacterial agents during the 1940s. Not surprisingly, isolation and political and economic crises during the war and post war periods took a toll on his research. With the German economic miracle of the 1950s, however, his research group returned to its former level of productivity, with notable successes involving studies of biological resistance factors and a return to important studies of cumulenes, radicals and other topics in pure organic chemistry. Kuhn died of cancer in 1967.