Florian Schmaltz. Journal of the History of the Neurosciences. Volume 15, Issue, 3, 2006.
Research on chemical weapons (CW) is not limited to the domain of chemistry only. In fact, already during World War I a variety of disciplines was involved in finding practical solutions to the various scientific problems deriving from the employment of chemical weapons. Many new questions arose as a result of the CW arms race, which began to require more efficient offensive and defensive technologies for chemical warfare. Besides chemistry, physics, mathematics, aerodynamics, and meteorology, it was medicine that played an important role. Chemical warfare forged a new form of collaboration between the military, science, and the chemical industry, which was characterized by an intense reciprocal relationship, leading to the militarization of science and industry as well as to the development of a science-based industry and military. This structural change persisted in spite of Germany’s defeat in World War I. CW research continued despite its prohibition by the Allies and the monitoring efforts of the Inter-Allied Military Controll-Commission (Salewski, 1966, pp. 105-106; Szöllösi-Janze, 1998, pp. 457-459). During the Weimar Republic, Army (Reichswehr) authorities created a contract system with small, secret CW working groups at German universities and state institutions such as the Biologische Reichsanstalt in Berlin. From the mid-1920s onwards, German collaboration with the Soviet Union opened up new vistas for research and development (Zeidler, 1993, pp. 123-125, 198-200; Groehler, 1992). After Hitler seized power, CW research was reorganized, and already existent military research institutions received increased funds. Until 1945, more than 1000 employees worked at three major army-run CW installations, where they prepared and evaluated new CW agents, measured their physiological and toxicological impact and worked on gas detection and antigas protection gear. The largest installation was the proving grounds and laboratories at Raubkammer near Munster, with an average of 500 employees, peaking at 800 in 1944, followed in size by the Gas Protection Laboratory at Berlin-Spandau with 450 employees, and the Gas Protection Department (Wa Prüf 9) of the Army Ordnance Office in Berlin with an average of 143 employees, peaking at 200 in 1944 (, p. 9). While research on chemical warfare underwent rigorous centralization organization during WWI in Germany, and it was gathered at the Kaiser-Wilhelm Institute (KWI) for Physical Chemistry, the same may not be said for the Nazi era. Under the Nazi-rule, research was conducted within a decentrally organized network encompassing a variety of research institutions, which were coordinated by the Army Ordnance. This decentralized research organization had been set up within the context of reorganization of secret warfare research of the Reichswehr military forces, during the Weimar Republic, in order to circumvent the prohibition on chemical warfare research as stipulated in the Versailles Treaty (art. 171). Decentral organization was therefore no specific feature invented by the National Socialist scientific organizations, but it was already an existing fact. It allowed for a high degree of specialization, necessitated by the various problems raised by research on CW.
During WW II, chemical warfare was limited to the Asian-Pacific war theatre, where Japan applied CW against China since 1937 in large quantities (e.g. Wakabayashi, 1994). Contrary to World War I, no chemical warfare emerged on the European battlefields during World War II. However, research conducted in German laboratories led to a group of new nerve agents (Tabun, Sarin, and Soman), giving Germany the role of world leadership in the development of extremely toxic CW agents, which, soon after their discovery, were produced on a large scale and made available for deployment. The Allied Forces did not have any comparable nerve agents at their disposal. These substances were organic phosphoric acid esters, which as nerve agents were far superior to the already existing agents. The search for the mechanism of action of these novel nerve agents intensified research on anticholinesterase agents in the peripheral and the central nervous system. Neurosciences were now, unlike during WW I, involved in CW research and played a major role in the development of new Weapons of Mass Destruction (WMD). The inclusion of these nerve agents into the arsenal of CW by the Allied Forces after 1945 decisively influenced research in their respective countries (Gates and Renshaw, 1946).
The historical development of nerve agent research and its significance for the disciplines included in the neurosciences since 1940 has so far been neglected as a topic of research. Even though the significance of the organic phosphoric acid esters as nerve agents, and after WW II, also as insecticides (E 605) for the opening up of new fields of research in biochemistry, physiology, and in neurosciences had been discussed since the end of the 1950s, detailed historical studies had not been conducted (Metcalf, 1959). The canonical works on the history of this research on anticholinesterase agents tend to treat the question as to the importance of military research for the development of neurotoxicology and neurophysiology as a minor one (Holmstedt, 1959; Koelle and Augustinsson, 1963; Karczmar, 1970). Scientific-historical research is also confronted with major problems of accessing sources; most German documents on nerve agent research were systematically destroyed at the end of the war. In the United States and in Great Britain, relevant archival sources were only recently declassified and now support a first review for source-substantiated historical studies. In the United States, former experimentees, who had participated in human experiments during their active service in the U.S. military, attracted public attention in the beginning of the 1980s, when they claimed their damaged health to be due to their involvement in these experiments (). In Great Britain, the discussion on human experiments set in several years later, when the death of a former experimentee caused police investigation into the conditions surrounding his death (Evans, 2000). The following contribution does not claim to answer all of the numerous questions surrounding this issue, but it represents an attempt at shedding some light on some of the aspects of German nerve agent research during the Nazi-rule, in order to expose some of the mutual relationships between neuroscientific research, and political, military, and economic factors influencing its development (for details see: Schmaltz, 2005).
The following second part deals with the first synthesis of the new nerve agents in the context of industrial pesticide, research, the discovery of its enormous toxic properties, and the great interest the new agents evoked in the German military as possible “wonder weapons.” Part three of this article will describe the institutional background and the circumstances under which the physiological effects on the nervous system were identified, but not acknowledged right away. Part four analyzes the involvement of Nobel-laureate Richard Kuhn in CW research in the context of vitamin research. The epistemic models in vitamin and enzyme research were first used in defensive CW research for therapeutic treatment. However, the knowledge of certain correlations between neurophysiological behavior and chemical structure of vitamins were also important in offensive research for the clarification of the mechanisms of action of the nerve agents. As a result of these studies at the renowned Kaiser Wilhelm Institute for Medical Research in Heidelberg, headed by Kuhn, during WW II the highly potent nerve agent Soman was discovered. The fifth part will present concluding remarks and sum up the findings.
Discovery, Toxicology and Production of Nerve Agents by the IG Farbenindustrie and the Army Ordnance Office (Heereswaffenamt)
During the middle of the 1930s, research on organic phosphorous compounds experienced a veritable boom. These compounds offered a wide range of practical possibilities of application in chemical industry. Organic phosphoric acid esters were well suited as plasticizers for plastics, as extracting agents, as oxidation inhibitors for lubricants and as flotation agents in mining (Schrader, 1963, p. 2). In 1934, at the I.G. Farbenindustrie in Leverkusen, the chemist Gerhard Schrader was given the task of systematically investigating organic fluorophosphorine compounds in reference to their qualities as pesticides. Schrader began his search for contact insecticides with phosphorus sulphuric acids, and by the end of 1936, turned his attention to nitrogen-phosphoric acid compounds. On December 23, 1936, he managed for the first time to synthesize the compound ethyl dimethylamidocyanophosphate, a nerve agent, which was later named Tabun (, p. 24; Harris and Paxman, 1983, pp. 73-74.; , p. 71). In January 1937, Schrader accidentally poisoned himself while synthesizing Tabun and became aware of the extremely toxic effects of this chemical substance. The symptoms of a minor poisoning were asthma and a protracted contraction of the pupils, a so-called miosis. Even though the dosage in question had been minimal, his eyesight under artificial lighting conditions was seriously constricted, forcing him to refrain from working for several days. A toxicological test conducted at the laboratory for commercial hygiene of the I.G. Farbenindustrie in Elberfeld confirmed that Tabun was indeed extremely toxic to endotherms, and therefore also to humans. This rendered it unsuitable for use as a plant protectant, but applicable as an agent of chemical warfare to be used by the military. The I.G Farben duly sent a report on its discovery to the Army Ordnance Office, which signalled great interest. In the secluded regions of the “Lüneburger Heide,” the military forces constructed the Third Reich’s largest research center for chemical warfare, the Army Proving Ground Munster-Nord, a pilot-facility for the production of Tabun, which already in the middle of June 1937 commenced small-scale production. At the second-largest military C-weapons facility, the so-called Army Gas Protection Laboratory (Heeresgasschutzlaboratorium) at the Spandau Citadel, research on Tabun was also set up immediately. Within the very short period of two years, the intensified cooperation between the military forces and the industry led to the development of a feasible industrial manufacturing procedure. In November 1937, Schrader was transferred from Leverkusen to Elberfeld, in order to systematically continue his studies on Tabun. There, in a well-insulated part of the laboratory, a 100 m3, large gas chamber was set up for nerve agent-experiments. On October 10, 1938 Schrader discovered the nerve agent Sarin (Isopropyl methanefluorophosphonate), which was even more toxic than Tabun.
When Hitler decreed “Preparations for the Gas War” after the German attack on Poland, the military and I.G. Farbenindustrie together designed an encompassing production program for chemical weapons. On September 7, 1939 the military forces and board members of the I.G. Farbenindustrie agreed on the construction of a Tabun-factory with a capacity of 1000 tons per month. The location selected was Dyhernfurth, a town near Breslau in Silesia; construction began in the middle of March 1940. In May 1942, nearly two years later, Tabun-production in Dyhernfurth was started.
Due to the already mentioned animal experiments in Elberfeld and in Spandau, relatively precise evaluations of the lethal dosages for various animals existed soon after the discovery of Tabun and Sarin. But comparable information on the effects on the human organism did not exist. Therefore the Institute of Pharmacology and Military Toxicology of the Military Medical Academy in Berlin, headed by Wolfgang Wirth, a leading expert on chemical warfare research, began testing low-level dosages of the nerve gasses on humans. Founded in October 1934, the Military Medical Academy was intended as an institution for teaching and researching for sanitary officers, in the tradition of the Kaiser Wilhelm Academy for Military Medicine, which had been forced to close its doors in 1920 according to the Versailles Treaty, which prohibited military research in Germany (Neumann, 2005, p. 78). Wirth conducted these low-dosage experiments on himself and on sanitary officers, who had supposedly volunteered in exchange for remuneration. It remains unclear whether the experimentees were sufficiently informed of the risks involved. In addition to the financial reward, many of these young soldiers hoped to evade combat by participating in the experiments. However, previously red-taped secret service documents of the Allied Forces prove that comparable experiments with humans were also conducted at the Elberfeld laboratories of the I.G. Farbenindustrie, testing much higher dosages. Based on the human and animal experiments with Tabun and Sarin, German experts for chemical warfare agents were able to determine the lethal dosages of these two new nerve agents for animals, and to estimate it for humans. Even though large-scale industrial production of Tabun was already underway, the decisive question as to which biochemical and physiological reactions actually caused the lethal effects were still unanswered.
Pharmacological Nerve Agent Research at the Institute of Pharmacology and the Military Toxicology of the Military Medical Academy (Berlin)
Today, the biochemical primary effects of the nerve agents are better known: they damage the enzymes, which are indispensable for the functions of the peripheral and the central nervous systems. In animals and in humans, regulated conduct of nervous stimulation proceeds along nervous pathways consisting of interconnected nerve cells. Impulse transmission occurs on a chemical level through neurotransmitters, between single nerve cells as well as—at the motor end plate—between nerve and muscle. As a vital neurotransmitter, acetylcholine is required at the chemical synapses of the motor end plate. The chemical transmission of the impulse is effected by an action potential at the neuromuscular end plate and causes a pouring out of acetylcholine. The transmitter acetylcholine diffuses in the synaptic cleft and is bound at the post-synaptic membrane by receptor molecules, thereby causing potential modifications (electrochemical coupling). Within the synaptic cleft, and partially bound to the post-synaptic membrane, there is a high concentration of the enzyme acetyl cholinesterase. Its function is to decompose the acetylcholine into choline and acetic acid, which causes an immediate dropping of the acetylcholine-concentration. This rapid degradation of acetylcholine is hydrolyzed by the enzyme acetyl cholinesterase. The products of the enzyme reaction undergo reuptake into the nerve ending and become available for the resynthesis of acetylcholine (Dudel, 1996, pp. 116-119). This is where the effect of the nerve agents sets in. It relies on a strong suppression of the enzyme acetyl cholinesterase in the central and the peripheral nervous systems (acetylcholine-hydrolase) and the butyrocholinesterase contained in the organs and in the blood plasma (Klimmek, Szinicz, and Weger, 1983, p. 73). This is made possible by the chemical structural resemblance between the nerve gas molecules and the acetylcholine molecules. The agent causes an irreversible inhibition of acetylcholinersterase by phosphorylating or phonphonylating the serine hydroxyl at the enzyme’s active site, thereby destroying its power to hydrolyze acetylcholine. The accumulation of acetylcholine in the peripheral and central nervous system leads to cholinergic manifestations (Somani, Solana, and Dube, 1992, p. 76; Sidell, 1997, pp. 132-135). This elongates or enlarges the end plate potentials, leading to disoriented conduct of impulses (Dudel, 1996, p. 119). As the chemical impulse transmission controls voluntary muscles (movement) as well as involuntary muscles (breathing, heart activity) the inhibition of cholinesterase leads to a collapse of the circulatory system; a sufficiently high dosage may therefore cause death within a few minutes.
However, according to postwar statements made by Wolfgang Wirth, the physiological effects of Tabun and Sarin were studied in various test series and on five different systems at the Institute of Pharmacology and Military Toxicology of the Military Medical Academy:
|1.||Oxygen consumption on chicken blood and rats’ livers.|
|2.||Glycolysis (enzymatic conversion of dextrose into lactic acid) on chicken blood and rats’ livers.|
|3.||Catalysis (makes up oxygen and water from hydrogen peroxide, through the haemin protein peroxidase) on rabbit blood.|
|4.||Phosphatase (catalyses aliphatic and aromatic phosphorus acid esters) on pigs’ kidneys.|
|5.||Cholinesterase on blood and cerebrospinal fluid of cats and monkeys.|
As Wirth admitted in 1945, during interrogations at “Dustbin,” an Interrogation Center set up in Kransberg near Frankfurt/Main, these experiments remained largely unsuccessful. Due to his lack of experience in the field of enzyme research, a lack of time and of trained scientific personnel, it had been difficult for him to overcome the methodical challenges presented by the experiments. In his Tabun experiments Wirth had used the strongly inhibiting effect of hydrogen cyanide on cellular respiration, causing an acute lack of oxygen on tissue, as a parameter. Similar to hydrogen cyanide, Tabun contains one cyanogen-molecule, so Wirth assumed an equally similar effect. But his experiments did not result as desired. Equally dissatisfactory were the experiments on the effects caused by Tabun and Sarin on the glycolysis on chicken blood and rats’ livers, as well as the catalysis on rabbit blood, and the phosphatase on pigs’ kidneys. According to Wirth, “catalysis and phosphatase were strongly damaged, glycolysis less damaged than oxygen breathing.” Of the enzyme systems observed, the inhibiting effect of Tabun on the cholinesterase “had impressively differed from the remaining ferment effects, by several orders of magnitude.” From these measuring results, Wirth concluded that the enzymatic effects on cholinesterase were to be seen as the main target. Nevertheless, he still maintained the opinion “that the inhibition of both catalase and phosphatase were not uninvolved in the poisoning effects,” even though to a much lesser degree than the inhibition of the cholinesterase. Only after several months of stagnation in his efforts of clarifying the effects of Tabun and Sarin on oxygen consumption of the cells and various enzyme reactions, did he attempt to solve experimentally difficult research problems in reference to the physiological effects of the nerve agents by eliciting expert advice from other scientists. It seemed obvious to include several of the pharmacologists, who since 1939 had been transferred to his institute from various universities and who were experienced in experimental enzyme research, in his project. For this reason, Wirth created a project team, which included the professors Hans Gremels (head of the Pharmacological Institute Marburg), Ludwig Lendle (head of the Pharmacological Institute Münster, after 1943 Leipzig university), Werner Koll (head of the Pharmacological Institute of the Danzig Medical Academy), and Otto Girndt (Medical Academy Düsseldorf). The members of this research team worked in Berlin as well as at their respective university institutes, which functioned as a decentralized network of subsidiaries of the Military Medical Academy.
Hans Gremels (University of Marburg)
For a long time, little was known of the experiments conducted by Hans Gremels. Their significance lay in the fact that Gremels was the first to correctly discern the main effect of the nerve agents in the blockade of the enzyme acetyl cholinesterase, as published recently by Angelika Ebbinghaus and Karl Heinz Roth in a historical study, citing a report by the British Intelligence Objectives Sub-Committee from 1946 (Ebbinghaus and Roth, 2002, p. 23). The significance of this discovery and its underestimation by his superior, the head of the Institute of Pharmacology and Military Toxicology, Wolfgang Wirth, is worth a short analysis.
Hans Gremels was born in 1896, in Großbreitenbach (District of Ilmenau, Thuringia). After having received his university entrance diploma (Abitur), he joined the military and served from 1915 until the defeat of the Central Powers. From 1919 until 1923 he studied medicine in Jena and in Hamburg. After his approbation as a physician he worked at the Pharmacological Institute at the Hamburg university. In December 1924 he earned his doctorate (MD) and subsequently worked at the I. Medical Department of the Hamburg St. Georg hospital. In May 1925 a Rockefeller scholarship enabled him to spend one year at the Physiological Institute University College in London. At the end of March 1927 he returned to the St. Georg hospital in Hamburg. In April 1928 he transferred to the Berlin Pharmacological Institute, and in July 1933 began working as an assistant professor for experimental pharmacology at the Munich university. During the 1937 summer term he took on a deputy position teaching pharmacology at the medical faculty of the University of Marburg. There were some reservations concerning his appointment, mainly due to the fact that he had been addicted to morphine until 1935, a condition that was corroborated by several authorities. After having applied for membership in the Nazi Party in September 1937 he was subjected to a second evaluation and was subsequently appointed full professor in February 1938. During the 1939 summer term, Gremels held a lecture on chemical warfare, which however did not meet with a lot of interest on the side of the students (Aumüller, 2001, pp. 315-316).
At the beginning of the war, Gremels was transferred to the Institute of Pharmacology and Military Toxicology of the Military Medical Academy in Berlin, where he was given the position of a “Sonderführer” (a civilian with special military rank, due to academic qualifications) in the middle of September 1939 (Krähwinkel, 2001, p. 569). There he initially investigated the pathological physiology of the traumatic wound shock and investigated therapeutic measures supported by so-called energizing cocktails (mixtures of sugar and alcohol) in combination with the stimulating drug Pervitin® (Methamphetamine). In July 1940 Gremels applied to the German Research Association (Deutsche Forschungsgemeinschaft) for additional equipment, in order to continue his research in Marburg, too. His application was approved in the middle of August 1940. He also applied for support to the Rochefonds, on the board of which sat his former teacher, the pharmacologist Walter Straub. Together with his assistants Fritz Heim and Wilhelm Schröder he conducted several studies in Marburg on the neurotransmitter acetylcholine on cats. Part of these studies, which allowed him to improve his research methods for the study of nerve agents, were pharmacological blood pressure experiments on cats, in which “test injections of acetylcholine and adrenaline were used to examine the tonus of the vagus and the sympathetic nerves.” Within the context of these experiments, the Marburg research team gathered experience with a “biological method for the determination of the speed of esterification of acetylcholine,” which was also applicable for nerve agent research. As Wirth corroborated during the Dustbin interrogations, Gremels’ blood pressure experiments on cats led to a first explanation model for the effects of nerve agents:
At the Pharmacological Institute of the Military Medical Academy, in 1941, the conclusion was drawn from Professor Gremels’ blood pressure experiments on cats that Tabun inhibits the cholinesterase in blood. Gremels considered this to be the main effect of Tabun, and paralleled it by comparing it to the effect of physostigmine.
This hypothesis seemed obvious in as far as the toxic effects observed in humans strongly resembled the symptoms of poisoning by the alcaloid extracted from the calabar bean of the West African vine Physostigma venenosum, which had become a popular research subject in the field of physiology towards the end of the ninteenth century.
Research on physostigmine (eserine) turned into an epistemic thing treated in many pharmacological studies, which significantly contributed to the discovery of the cholinergic system (Karczmar, 1970, pp. 2-3 and Holmstedt, 1972). In 1864, L. Kleinwächter discovered atropine to be the antidote to physostigmine (Kleinwächter, 1864). Proof of the chemical basis of the conduct of nervous stimulation was nearly discovered by Hermann Fühner in der 1918, when he showed that physostigmine exponentiates an acetylcholine-induced contraction of a frog’s stomach and the back muscle of a leach (Fühner, 1918b and Fühner, 1918a). At this time, it was still not known that the effect of physostigmine depended on an enzyme (cholinesterase) and a neurotransmitter (acetylcholine), which is split by the enzyme (Karczmar, 1970, p. 8). The experimental discovery of a chemical (vagus) function was finally achieved by Otto Loewi in 1921, in an experiment on isolated frog hearts, by proving experimentally that a deceleration of the heartbeat is controlled by the inhibiting effect of a substance he had termed “vagusstoff.” This substance was later identified as acetylcholine (Loewi, 1921; Finger, 2000, pp. 269-270; Muralt, 1946, pp. 49-50). Together with Henry H. Dale, Otto Loewi received the Nobel Prize in 1936. In 1938, after the annexation of Austria, Loewi was arrested by the Gestapo and, after his release from prison, immigrated to Great Britain. Also of great importance to neurophysiological research was the 1926 proof of the fact that the vagusstoff is decomposed by an enzyme, after having reached the synapsis; this discovery was also made by Otto Loewi and by E. Navratil, based on their experiments on frogs (Loewi and Navratil, 1926a). In their further experiments, Loewi and Navratil identified the vagusstoff as a choline ester, and termed it cholinesterase. Additionally, in 1926 they discovered that physostigmine and ergotamine sensitize the heart for the effect of the vagusstoff by inhibiting the decomposing effect of cholinesterase (Loewi and Navratil, 1926b; Finger, 2000, pp. 271). As the mechanism of action of the nerve agents Tabun and Sarin, discovered in Germany in 1936 and in 1938, depended on their strong inhibitory effects on acetylcholinesterase, in-depth knowledge on the cholinergic system was suddenly of prime importance to military research on nerve agents as WMD. But Gremels’ interpretation, according to which the results measured during his animal experiments provided a reliable indication that the primary effect of the nerve gas Tabun lay in the inhibition of cholinesterase, actually analogue with the effect of physostigmine but in a merely quantitative exponentiated way, were seriously doubted by the pharmacologists from the research team of the Military Medical Academy. As Wirth admitted in a report written for the Allied Forces in November 1945, Ludwig Lendle and Werner Koll in 1941 “did not accord Gremels’ results the decisive significance they actually had.” Due to this misjudgement, the “the discovery made by Gremels was initially not followed up on.”
But in addition to this internal rejection, external political factors were also responsible for the fact that Gremels’ explanation was not acknowledged. In the summer of 1941 Gremels, who had meanwhile taken on the position of dean of the medical faculty, was involved in a heated political conflict. As this conflict demanded his presence in Marburg he was not able to spend much time with further nerve agent studies at the Military Medical Academy. The argument was triggered by his having supported the habilitation procedure of the chief staff surgeon and sanitary officer of the reserve, Felix Mondry, whose political reliability was being doubted by the National Socialist Lecturers’ Association (Nationalsozialistischer Deutscher Dozentenbund) (Nagel, 1994, pp. 356-359; Nagel and Sieg, 2000, pp. 448-450). In spite of the support Gremels received from the medical faculty and from military authorities, he was without further ado suspended from his position as a dean by the vice chancellor of the Marburg university, Theodor Mayer, at the end of October 1941. Even though the efforts to remove him from his post, mainly instigated by his successor as a dean, the party activist Ernst Bach, failed, several months of relentless pressure caused Gremels to suffer a nervous breakdown in the summer of 1942, and to undergo psychiatric treatment. It took until the end of 1943 until he was able to resume his work (Grundmann, 2001b, pp. 527-530). Due to his psychiatric treatment Gremels left the military. Officially, he was transferred from the Military Academy to the Army Echelon Marburg on March 1, 1943; however, his assignment was still controlled by the Military Medical Academy. On a scientific level, too, Gremels’s theories were met with more and more criticism. They strongly referred to the “potential theory” as taught by his teacher Walter Straub, which were not all that popular in the scientific community. After his return to the university in 1943, Gremels continued his research on the effects of nerve agents, supported by a grant by the medical department of the Reich Research Council (Reichsforschungsrat).
Nerve Agent Research at the KWI for Medical Research (Richard Kuhn)
In addition to the already mentioned branch offices of the Military Medical Academy, the so-called Gas Protection Department of the Army Ordnance Office (Wa Prüf 9) set up its own subsidiaries during the Second World War. These were often initiated by the awarding of research assignments, leading to closer cooperation between scientific institutes at several universities, which was finally institutionalized. This was also the case when the Heidelberg Kaiser Wilhelm Institute for Medical Research, founded in 1927, was included. The institute was part of a conglomerate of more than 40 institutes and research facilities of the Kaiser Wilhelm Society, the largest extra-university research organization in Germany. Among the altogether six Kaiser Wilhelm Institutes (KWI), which were involved in the defensive and offensive chemical warfare research of the Nazi-regime, the Heidelberg institute made the most important scientific contribution to the development of new chemical WMD.
The director of the KWI for Medical Research was the Austrian chemist, and later Nobel-laureate Richard Kuhn. Without ever becoming a member of the NSDAP (Nationalsozialistische Deutsche Arbeiterpartei), Kuhn became one of the most influential scientific managers of biochemical research during the Nazi-regime (Schmaltz, 2005, pp. 361-387). One of his most important functions was without doubt his being appointed as the president of the German Chemical Society (Deutsche Chemische Gesellschaft) in May 1938 and his previous efforts to effect their institutional consolidation to the regime (“Gleichschaltung”), after having joined its board in 1936 (Ruske, 1967, p. 164). One month after the beginning of the war, in October 1939, Kuhn was additionally appointed departmental head (Fachspartenleiter) for organic chemistry for the Reich Research Council.
The KWI for Medical Research began cooperation with the military experts for chemical warfare before the beginning of World War II. Since 1938, Kuhn’s assistant Christoph Grundmann had been working on a research project on behalf of the Army Ordnance Office, focusing on the question which therapeutic effects vitamin B6 might have in the treatment of skin injuries caused by mustard gas. The step from project-oriented research to institutionalized cooperation with the Army Ordnance Office was taken when a special facility for research on chemical warfare was set up in Heidelberg. One decisive condition for this to happen was the availability of space within the Institute of Physiology, which was then headed by Nobel-Prize-laureate Otto Meyerhof. As a Jew, Meyerhof was forced to leave Germany in September 1938 (Nachmansohn, 1979, p. 284; Macrakis, 1993, p. 65; Mussgnug, 1988, p. 157). After prolonged negotiations, the department for chemical warfare was finally set up in connection with the preparations for the attack on the USSR in January 1941, as a branch location of the Gas Protection Department of the Army Ordnance Office. One third of the academic staff of the Institute for Chemistry was taken on.
After the end of the war, Kuhn reported that towards the end of 1940, Professor Gustav Wagner, who was the Army Ordnance Office’s officer responsible for outposts of the Gas Protection Department (Wa Prüf 9), had approached him with the request that the KWI research derivates of pyrimidin (heterocyclic ring systems with two nitrogen atoms) as possible antagonists to vitamin B1, which was then known as aneurin (Edson, Evans, Edelstein, and Williams, 1946, p. 4). Before the beginning of the war, several publications by Alexander von Muralt on the function of vitamin B1 in the brain metabolism had appeared. The studies on vitamin B1 exemplify its relevance for the chemical transmission of stimulation in the central nervous system (Muralt, 1939, p. 191). It therefore seemed obvious to view the Heidelberg brain-physiological research on vitamin B1 as an important approach to the clarification of the pathological effects of nerve agents, particularly as the team led by Kuhn had previously, in 1939 and in 1940, made important contributions with their studies on vitamin B1 (Kuhn, Wieland, and Hübschmann, 1939 and Riechert and Hübschmann, 1940). Among the approximately 20 work teams conducting intensive biochemical research on vitamins during the 1930s and 1940s, the KWI for Medical Research was doubtlessly one of the internationally leading institutes (Werner, 1998, p. 29). The experience on the area of structural analysis of chemical substances and synthesis of vitamins, and the research on biochemical mechanisms of action in the body were now linked with the question of how nerve agents modified physiological metabolic processes and which vital processes were suppressed by their toxic effects. The working methods and the cognitive models from vitamin and enzyme research now received epistemic functions for the clarification of the mechanisms of action of the nerve agents Tabun and Sarin. A basic model for research on metabolic processes was the displacement theory formulated by Hans von Euler-Chelpin (von Euler, 1942). According to Euler-Chelpin “certain changes in the molecules of vitamins and bacterial growth promotants” could generate so-called antivitamins, capable “of cancelling the physiological effect of the respective vitamin.” According to this dichotomizing model, vitamins and specific active agents compete with each other according to the law of principle of mass action at the site of action (Deichmann, 2000. p. 250; Abderhalden, 1953, pp. 114-118). In 1944, antivitamin research at the KWI for Medical Research led to the consequential discovery of the nerve agent Soman. This discovery happened during experiments on the synthesis of a variety of sulphinic acid esters, during which the researchers of Kuhn’s team studied the connections between the chemical molecular structure and the biological effects on cholinesterase. Experiments on rats led to the observation that compounds, in which the terminal remainder of the chemical structure resembles the remainders of acetycholine, analogously caused a cholinesterase inhibition. Subsequently, the researchers conducted synthesizing experiments with the nearest analogue to acetylcholine compounds. The initial testing series with sulphuric ester compounds were ended unsuccessfully after a year, and it was decided to continue the tests with phosphoric acids. The search was for a substance with a molecular structure as “close as possible” to the natural vagusstoff (acetylcholine). Starting with the hypothesis of a connection between the spatial structure and the inhibitory effect on cholinesterase the experimental search concentrated on fluorophosphoric compounds. Practical implementation of the experiments was done by Kuhn’s scientific assistant, Konrad Henkel. In their structure, the synthesized phosphorous-fluorine compounds were meant to resemble an acetylcholine molecule at one end. After having synthesized a number of compounds, which were not appropriate for use as a chemical warfare agent, the esterification of neopentyl-carbinol (3,3 dimethyl butanol-1), the “skeleton” of which is very similar to the appearance of choline, led to a substance with a strong eserine-like inhibition of cholinesterase. According to statements made by Kuhn in 1946, it had been necessary to search for an alternative to neopentyl-carbinol, the alcohol required for esterification, as it was difficult to procure. This search produced pinacolonalcohol, an intermediate product accumulated in the production of neopentyl-carbinol. In its effect, the substance (code number 25075) synthesized with pinacolonalcohol, for the first time in the spring of 1944, by far surpassed all other previously synthesized compounds. It was later named Soman (Edson, Evans, Edelstein, and Williams, 1946, pp. 5 f). In 1944, within the already well-developed cooperation with the military, the Gas Protection Laboratory in Spandau received a sample of Soman from the KWI for Medical Research. As subsequent tests in Spandau showed, the new nerve agent was far more effective than Tabun and Sarin. As the technical conditions at the I.G. Farbenwerk in Ludwigshafen were perfect, a small pilot-production of Soman was already set up there in the summer of 1944, which supposedly produced about 70 kg of Soman until the end of the war.
The range of the research topics investigated at the KWI for Medical Research included pharmacological-toxicological studies focusing on antidotes and therapeutic treatment measures, chemical analytical studies on organo-specific classification of cholinesterase and its inhibition by nerve agents. The interior structure of task distribution makes it possible to identify four different focal points of research:
|1.||Research on the mutual interaction of vitamin E and nerve agents.|
|2.||Research on various effects of nerve agents on the central and the peripheral nervous system.|
|3.||Comparative experiments for the classification of cholinesterase taken from different animals and organs.|
|4.||Experiments on the hydrolysis of nerve agents in the presence and in the absence of a variety of cholinesterase preparations and their effects on extracts of maggots of the black blow fly, Phormia regina, as well as on livers of endotherms.|
Vitamin E and Nerve Agents
Günther Quadbeck’s studies on the pharmacological effects of vitamin E and the effects of nerve agents were oriented along the results published by Hubert Bloch (Hygiene Institute of the Basel university) between 1941 and 1943 in Switzerland, on the cholinesterase-inhibiting effect of tricresylphosphate. Bloch investigated the toxic effects of this chemical substance, which was then used as a light-resistant plasticizer and an additive to motor fuels. In July 1940, this substance had accidentally been mixed up with edible oil and had caused mass poisoning in a hospital (Staehelin, 1941). The symptoms associated with this poisoning were determined by motor paralysis, which Bloch ascribed to a point of attack for the toxic substance within the muscle, and a possible coinvolvement of the nerve end plate, and which he investigated in reference to a possible influence on the “interplay acetylcholine-cholinesterase” (Bloch, 1941, p. 15). In the 1942 animal tests, Bloch and Adolf Hottinger discovered that as an immediate effect of a poisoning with o-tricresylphosphate a significantly increased excretion of the muscular metabolite creatine could be measured in the animals’ urine (creatinuria). As it was already known from vitamin research that creatinuria resulted from a lack of vitamin E, the Swiss scientists examined whether this symptom could be influenced by administering dosages of vitamin E. Experiments on rabbits showed that “creatinuria could be averted or significantly attenuated by prophylactic or early therapeutic administrations of vitamin E” (Bloch and Hottinger, 1943, p. 17). Quadbeck adopted the research-model developed in Switzerland. His hypothesis stating that nerve agents also caused creatinuria, which could be treated by vitamin E, was corroborated by experiments on rabbits. But contrary to poisoning caused by tricresylphosphate, this treatment had no therapeutic effect whatsoever on mortality after a higher dosage of the nerve agent.
Differences in Nerve Agent Effects on the Central and Peripheral Nervous System
Otto Dann compared the effects of the nerve agents on the central and peripheral nervous system with other cholinesterase-inhibiting substances, such as eserine/physostigmine and prostigmine as well as a host of other narcotics. Compared to nerve agents these substances had the decisive advantage of being less toxic to the various test models. In vivo, prostigmine lacked the extreme effects on the central nervous system, which are characteristic for physostigmine. Using preparations from rats’ brains, Dann determined the concentrations required for doubling the acetylcholine. For physostigmine, this amounted to 1 in 5.000, for prostigmine to 1 in 125.000, and for the nerve agent Soman the concentration determined was 1 in 1.000.000. Subsequently, he focused on the question whether these three substances also differ in their site of action. A crucial factor for the potency of the effect in the central nervous system was the respective substance’s capability of passing the blood-brain barrier. As this blood-brain barrier can only be overcome by lipophilic substances, it was possible to take the solubility coefficient of the substances in water (hydrophylicity) or in chlorophorm (lipophilicity) as an indicator for the ability to pass the blood-brain barrier. The higher the solubility in chlorophorm, the stronger the substance’s propensity to enter and to affect the central nervous system. Vice versa, a high solubility in water correlated with a high degree of efficiency in the peripheral nervous system. The measurements showed that prostigmine remained nearly totally in the water layer, whereas 95% of the eserine passed into the chlorophorm. Tests with Tabun showed that 30% remained in the water, and 70% entered the chlorophorm. Thereby Dann provided an explanation for Tabun’s capability of affecting the central as well as the peripheral nervous system. After subcutaneous injections of prostigmine Dann could not identify any increased acetylcholine level in the brain, but only a peripheral increase. Physostigmine also caused a peripheral increase. Extremely noticeable was the increase in the central nervous system. This relatively simple solubility test made it possible to predict the effect of various cholinesterase-inhibitors at their prospective site of action. Dann’s search for a medication with the ability to suppress the synthesis of acetylcholine was much less successful. The experiments were conducted with eserine-poisoned brain suspensions. Emetics and apomorphine, a morphine derivative without any anodyne or euphoristic effects showed only little activity in the desired direction. The substances tested encompassed the alkaloids arecoline, ephedrine, atropine, scopolamine, and the snake venom lobelin; further the hormone adrenaline, the opiate morphine, as well as the antihistamines Bridal® and Antergan®. None of the preparations showed sufficient antidotal effects.
Classification of Cholinesterases of Various Origins
During the beginning of the 1930s, the presence of cholinesterase in various organs was still debated (Ammon, 1935, pp. 103-107). Currently, several cholinesterases are distinguished. In addition to acetylcholine, butyrylcholinesterase existent in the serum, the intestinal mucosa and the pancreas (also called nonspecific or pseudocholinesterase) can decompose a variety of other cholinesters, whereas to so-called true cholinesterase can only split the vagusstoff acetylcholine. Towards the middle of the 1930s, it was generally accepted that cholinesterase can enzymatically split choline esters. The observation that “already minute changes in the structure of the choline molecule significantly altered the divisibility” (Ammon, 1935, p. 109) led to the question whether cholinesterase extracted from different organs differed from each other and whether they were classifiable.
At the KWI for Medical Research, it was primarily Dietrich Jerchel who sought for answers to these questions. His studies provided the raw data for assessing the effect of the nerve agents on the serum and the organs of various animals. Methodically, he oriented himself along a determination procedure developed in 1943, at the Canadian Bainting Institute at the University of Toronto (Mendel and Rudney, 1943; Mendel and Mundell, 1943; Mendel, Mundell, and Rudney, 1943; and Edson, Evans, Edelstein and Williams, 1946, p. 13). The reactants used were not only acetylcholine but also its derivatives methyl-cholinesterase and benzoylcholine, and 4-methyl-5-acetoxyethyl-thiazole. Among the most important results of nerve agent research at the KWI for Medical Research was the development of a precise measuring procedure for their toxicity. The procedure was based on the simple measurement of the acetic acid that may be detected during the decomposition of acetylcholine by cholinesterase in the plasma or the serum of dogs, rabbits, or mice. As an indicator of the amount of decomposed he used the manometrically determinable carbonic acid (CO2). The acetic acid released by the acetylcholine displaces an equivalent amount of carbonic acid from the bicarbonate-containing Ringer’s solution used as a solvent, which can then be measured as an indicator of the decomposition of the acetylcholine (Ammon, 1933, p. 488; Ammon, 1935, p. 104; and Ammon and Voß, 1935, p. 394). The varying degrees of cholinesterase-inhibiting activity, which depended on the origin of the organ preparations, provided the scientists with yet another search strategy. As Günter Quadbeck reported, they observed that cholinesterase from preparations of livers or of kidneys reacted significantly weaker to Soman than preparations originating from serum or brains. While the measured CO2 values in experiments with cholinesterase from serum or brains remained constant for a certain amount of time, CO2 generation in liver-preparations kept changing in a very noticeable way. Within the latter, cholinesterase-inhibition initially seemed extremely suppressed. After about 30 minutes, CO2 development rose markedly and after a short while approximated the development rate of an unpoisoned preparation. The observation led to the assumption that this phenomenon was due to a substance present in livers, which was possibly capable of decomposing Soman. The measuring results gave rise to the hope of identifying this substance and to find an appropriate antidote. Further experiments were undertaken in order to clarify to which degree liver extracts from rats exhibited this catalytic quality of speeding up the hydrolysis of Sarin. According to Quadbeck, already small amounts of the liver-pulp (0,3 ccm to 1 mg Sarin) led to a conspicuous acceleration of the reaction rate. Within ten minutes, 95% of the Sarin-hydrolysis had taken place. Checking tests in which the liver extract was replaced by a buffer with the same value however took several hours for the same course of reaction. According to Quadbeck, all efforts to find the substance causing the inhibitory effect remained unsuccessful.
Hydrolysis of Various Cholinesterase-Preparations and their Influence on Extracts of Blow Fly Maggots (Phormia Regina) as well as on the Liver of Endotherms
The hydrolysis-studies were conducted by a working group within the warfare-department; among their members were Günter Quadbeck, Konrad Henkel, and Helmut Beinert. They focussed on the question as to whether the hydrolysis-process was influenced by the presence of certain enzyme-systems. These experiments had an immediate relevance for the deployment and for detoxification, as nerve agents lose their potency through hydrolysis (Franke, 1977, pp. 394-395, 401-403, 424-425). The team discovered that hydrogen-ions catalized the hydrolysis, i.e. led to an accelerated reaction, rendering the nerve agents ineffective. The measured half-life of Soman in pure, 35˚C warm water was 4-5 hours. Under the experimental conditions, Sarin exhibited a validity of approximately 30 minutes. Therefore, Soman by far surpassed Sarin, in its period of action.
Another strain of experiments took its starting point in Quadbeck’s observation, that maggots of the black blow fly Phormia regina reacted much less sensitively to Sarin than did adult flies; at a proportion of nearly one million. It was therefore investigated to which degree the extract of these maggots, dissolved in potassion chloride, influenced the cholinesterase-inhibiting effect of Sarin. Even though the maggots store the nerve agent in their fatty tissue, the experiments proved an antagonistic reciprocity. According to Quadbeck, measurements showed that a Sarin-induced cholinesterase-inhibition in human serum could be reduced by the addition of maggot extract. This nonidentifiable inhibitory factor proved to be temperature-dependent, and was impossible to dialyze through cellophane. It was destroyed by high concentrations of ammonium sulphate. Quadbeck assumed that the factor in question was an extremely reactive and sensitive protein, which did not have the qualities of an enzyme, but reacted stoichiometrically with Sarin.
A New Method for the Detection of Tabun and Sarin, Developed at the Kaiser Wilhelm Institute for Medical Research
As a report by the British Intelligence Objectives Sub-Committee documents, comparative studies on the cholinesterase-inhibiting effect of Sarin in organ preparations from human livers were conducted at the KWI for Medical Research. Based on measuring results, the scientists produced a scale expressing increasing sensitivity for Sarin, in animals as well as in humans. According to this scale, susceptibility to Sarin grew in the following order: rat, rabbit, dog, cat, and horse (about equal), and human being. As Kuhn explained to his interrogators, the human organ was taken from a drowning-victim postmortem, approximately 24 hours after his death, and had shown to be nearly ten times as sensitive as the rat’s liver preparation. But there are also hints that the effects of cholinesterase were also investigated in experiments on preparations from human brains. This is documented by a note to the files dated April 8, 1943, posted by the Secretary General of the Kaiser Wilhelm Society, Ernst Telschow, after visiting Heidelberg. He wrote: “Prof. Kuhn is currently undertaking some very interesting experiments, for which he requires the brains of young and healthy individuals. I have assured him of presenting his interests to the appropriate authorities” On April 22, 1943, Telschow wrote in a letter addressed to Kuhn personally that he had already spoken to the Senior Legal Secretary Eichler and Superior Court Judge Dr. Westphal at the Ministry of Justice about “the relinquishment of certain human organs.” Supposedly, Westphal had explained that the anatomy in Heidelberg already received a sufficient number of such organs from Stuttgart, but that “recently several anatomy departments had failed to pick up their share of material (lack of fuel and so on).” The recommendation of the Reich Justice Ministry to Kuhn was to “directly contact the Heidelberg anatomy and to request a share.” In order to solve transport problems, Telschow advised Kuhn to use his connections to the military: “There is maybe also the possibility of requesting a vehicle from the military, if the anatomy is not able to effect the necessary transports.” So which sources were there for the brains Kuhn requested in 1943 for his “very interesting experiments”?
Telschow’s mention of “brains of young and healthy individuals” renders the use of brains taken from victims of the National Socialist “euthanasia” programs highly unlikely, even though many of these brains were used for neuropathological studies at the KWI for Brain Research and the German Research Institute for Psychiatry/Kaiser Wilhelm Institute in Munich (e.g. Aly, 1985; Aly, 1987; Peiffer, 1997; Peiffer, 1999; Peiffer, 2000; and Schmuhl, 2002). Possible suppliers were the military field hospitals. Another possibility is the delivery of brains taken from executed prisoners of war, from concentration camps, jail inmates, as long as they were healthy. Due to missing documents, the sources of supply for both anatomical institutes are still not known. But Telschow’s contacting the head of the judicial department at the Reich Justice Ministry suggests that he intended delivery of brains taken from executed victims of the Nazi-justice, which had to be released for scientific experiments by the respective public prosecutor’s office. So far it has been impossible to find documents providing unequivocal information on the extent of Kuhn’s brain research experiments, and on the origins of these brains. However, it seems likely that Kuhn required these brains for the production of human cholinesterase preparations, intended for studying the cerebro-physiological effects of the nerve agents. This assumption is supported by the fact that Kuhn’s assistants had already conducted brain-physiological and toxicological animal experiments at the KWI for Medical Research. The experiments in question were Dietrich Jerchel’s experiments on the classification of cholinesterase on organ preparations stemming from different animals; secondly, the experiments conducted by Günter Quadbeck, who studied the differences in the cholinesterase-inhibition in organ preparations from the kidneys, the livers, and the brains of rabbits; and thirdly, Otto Dann’s experiments on rat-brain-suspensions investigating the question of cholinesterase-inhibition in the central nervous system and its susceptibility to pharmacological influence. For each one of these test series, research on human brains would have provided important reference data, which could have led to conclusions on the transferability onto humans of the results achieved in the animal experiments. Only the human-specific results could have provided relevant reference data to the results achieved on animal brain preparations. The reference data for a second organ would have experimentally further corroborated the measurements of the various degrees of nerve agent sensitivity of animals and humans, already taken on a human liver-preparation.
The new nerve agents were discovered by Gerhard Schrader within the context of industrial research on organic phosphoric acid esters as potential pesticides. Their primary effects were originally identified at a branch laboratory of the Military Medical Academy, by Gremels, the Director of the Pharmacological Institute of the University of Marburg. Proving method and refined neurotoxicological explanation models on the interconnections between the spatial chemical structure of the nerve agents and their biochemical effects on the peripheral and the central nervous system were developed at a department of the Kaiser Wilhelm Institute for Medical Research in Heidelberg, headed by Nobel-laureate Richard Kuhn. The methods and models applied at the KWI for Medical Research, originally developed for research on vitamins and enzymes, were an important condition for the 1944 discovery of the nerve agent Soman, the so-far most potent competitive cholinesterase-inhibitor. Even though Soman did not make it to large-scale production before the end of the war, its discovery may still be termed a consequential one, as up until today it is considered the most lethal chemical warfare agent, rivalled only by the VX-nerve agents discovered during the 1950s. The historical example shows how enmeshed basic research and applied military research, and defensive and offensive research are.
Politically motivated personnel decisions by the National Socialist Party in some cases obstructed scientific research, as is shown by the example of Hans Gremels. But these incidences should not lead to the conclusion that the Nazi-regime was generally negatively inclined towards science, as was often emphasized in previous science-historical studies. Nazi-science policy was signified by a strong emphasis on armament research, for which considerable amounts of money were made available. Science, military and industry were seen as mutually supportive resources (Ash, 2002). As exemplified by research on nerve agents, the Nazi-regime offered attractive working conditions to the scientific elite, creating excellent conditions for the development of chemical warfare agents, which were far superior to anything the Allied Forces had at their command. The case of the KWI for Medical Research proves that anti-Semitic persecution under the Nazi-regime resulted in an increase of resources available to the non-Jewish scientists who continued to work in Germany. German scientists made use of these enlarged opportunities, offered by the regime. This implied independent initiatives by the scientists; one of these was, for example, the request to use brains removed from victims of Nazi persecution for testing agents for mass extermination. As far as the remaining historical sources seem to prove, scientists working on nerve agent research during the Nazi-regime were not directly involved in human experiments in concentration camps. However, there are documents indicating that in April 1943 Richard Kuhn, the Director of the KWI, ordered a number of brains extracted from “young and healthy individuals”; these were most probably victims of Nazi state-terrorism and execution practice. Due to the present status of the records, it is still unclear whether, and how many, of these brains were ever delivered.
German research on the mechanisms of action of the new chemical warfare agents raises the question as to which role military research played in the development of neurosciences in the twentieth century. Military research objectives generated new questions and problems, aiming at the development of application-oriented military techniques. Neurophysiological and neurotoxicological basic research was inextricably tied to the development of new chemical WMD. As is known today, immediately after the war these German nerve agents were investigated by expert commissions of the Allied Forces and were included in the arsenals of modern WMD. The nerve agents affected power politics between the USA and USSR and their allies during the cold war era in the second half of the twentieth century. Until today, the nerve agents developed in Nazi Germany remain a threat in armed conflicts, asymmetric warfare, and terrorist attacks such as the deployment of nerve agents by the Iraqi Army in March 1987, against Kurdish civilians in Halabja (Human Rights Watch, 1993), or the terrorist Sarin attack on the Tokyo subway in 1993 by members of the Aum sect (Murakami, 2002). As their production is considerably simpler than that of nuclear WMD, their continued existence in the twenty-first century remains one of the burdensome legacies of the Nazi-regime.